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LUGOL’S IODINE THE QUINTESSENTIAL SUPPLEMENT: against all diseases including cancer; & infections from fungi & protozoa to TB & HIV:

update 7 November 2015: comments & feedback please.
Orthoiodosupplementation in a Primary Care Practice Jorge D. Flechas, M.D. its undated but the latest ref is 2004..
but informative 2014 iodine update video by Dr Jorge Flechas:
some points: “why women have so many more thyroid problems eg estrogen blocks iodine; whereas ovary hot nodules may cause thyrotoxicosis from secreting T2.  Iodine alerts the brain, so dont take at night! give no more than ~12mg/d ie 2 drops 15% in pregnancy, it stimulates the baby!
“Iodine ie I2 diffuses into cells whereas iodide need to be transported in; babies lack the symporter Iodide transporter, so babies need iodine not iodide.
ie thyroid, ovary and WBCs can make thyroxine- but preferably  they mop up low iodine intake. Thyroid supplements doesnt provide enough iodine for needs elsewhere .
” Millions of women in Japan and Korea on their marine diet used to normally ingest ~13.5mg iodine a day, producing very low neonate problem rates in pregnancy and with IQ far higher than average.
“in the west, Iodine has been taken out of bread and milk, and salt intake cut – associated with increased rate of ADD in USA 500% and more cancer thyroid, breast, ovaries, endomet, cretinism, goitre .. – as iodine intake and output in USA has been halved by admin policy…
the kidneys excrete excess ingested iodine, so avoiding overdose from high iodine intake.

“ie if sufficiency, a 50mg iodine load will excrete >90% . so the spot test for low iodine excretion, and 24 hr high iodine excretion, reflect defective sodium symporter problem. This corrects with ongoing iodine supplement. 80% of vegans in USA are iodine deficient due to skipping seaweed for iodine! Asians eat seaweed in everything.. the body can hold 1.5gms iodine; 50mg in the thyroid, 20% in the skin, 30% in muscles…
– if depleted of iodine, we cant sweat or use our muscles (fibromyalgia), brains, or control the breasts or ovaries.. .. just add ATP cofactor ie incl vits B2 & B3 to iodine…
“Bread & esp cooldrink’ iodine (eg Mountain Dew) has been replaced by bromine, which causes schizoid behaviour… .. Iodine reverses the immortality of cancer cells.
” 3000mg/d ester C , and highdose iodine, and B2+B3 , reverse the iodine symporter block, & abolish the fibromyalgia in 80% of sufferers. .

This Flechas review is encouraging for repletion with Lugol’s 50 to 100mg iodine /day ie 6 to 12 drops 15%; after perhaps a precautionary skin test dose for allergy.
especially for protecting breasts, cancer, diabetics, obesity, heart disease, immune, memory and stroke problems.. .

It does seem that as with vits C and D3, iodine has a minimal RDA as far as basic prevention goes ie ~0.15mg – 1mg/d for avoiding cretinism (cf scurvy with >10mg/d vit C, or frank rickets with 400iu/d vit D3) ; and at the other end of the spectrum ie treating severe disease, grams a day of iodine and vit C, and vit D3 >50 000iu ie >1mg/day..

Then longterm maintenance with eg ~12 mg iodine a day ie 2drops/d 15% Lugols,  cf 1 to 3 gm a day vit C, vit D3 ~7000iu ~ 0.2mg/day… .

perhaps the corollary may be that , (as with vit D3 eg 2million ie ~ 50mg), a massive accidental load dose eg 2gms iodine- 20ml 15% Lugols- (which apparently bypasses the detox reaction at lower ie buildup dose, and incidentally provides 1gm potassium) may be both harmless and will reload for who knows how many years- presumably provided one takes a good magnesium and selenium ie realfood Banting diet .

To test tolerance, and try to reverse my familial irreversible atrial fibrillation, I have built up my Lugols’ dose  so far  to 15% 1 to 2 tsp a day ie 4 to 8ml, ~800mg combined (I + I2) iodine with 400mg potassium K  a day;
whereas a load dose vit D3 eg 0.6 to a million units (6-10gms of standard max strength 100 cwt powder – with a good magnesium and vit K2 diet as in realfood Banting) will replete safely and harmlessly for less than a year.
Its a pity the simple IODINE urine test is- unlike the skin patch test duration- so tediously long and costly (and both can occasionally mislead),
whereas the blood  vit D calcium-creat levels are quick to take but costly  tests.. .

But in those who can afford them , the tests are essential to validate the clinical results we get with iodine and vit D3 .

update 27 Sept 2015
IODINE THE QUINTESSENTIAL SUPPLEMENT

see prev Healthspanlife.wordpress.com ie May 2014 update.

quotes from authorities are in italics: please feed back on errors and experience

Massive iodine deficiency is  as universal worldwide (compared to 50 years ago) as are
*deficiencies of:                                                                                                ..vitamin C (except those who live on fresh fruit and veg);
..vitamin D (except those who work outdoors in sunny climes);
..magnesium; and
..natural saturated fats in all except keen carnivores;
..and increasing deficiency of other vitamins in the food chain, forced on the public by government-sponsored industries and “health authorities” for 50 years now;
*and unnecessary dangerous food-chain toxins ( refined carbohydrates; calcium/bromine/ fluorine/salt, aluminium, mercury supplements, synthetics eg transfats, pesticides eg glyphos Roundup, GMO foodstuffs, antibiotics ; and steroids). .

But with seafood almost wiped out by greed and pollution, and increasing global nuclear pollution, and failure by food producers to supplement   iodine never mind vit D and magnesium in the depleted food chain,

iodine repletion with vigorous Lugols iodine (with its consort selenium) is even more of a priority than concomitant vitamin D (with its consort vit K2) and magnesium supplementation, and vitamin C, plus a broad balanced other score A to Z multisupplement ..

So the dangerous scaremongering myths need to be debunked about the “dangers” of iodine at over a mg a day – when the safe general therapeutic dose is not just ~12mg/d but up to 100mg/d for longterm prevention, and over a gm/d for major diseases; ie >10 000 x the RDA. The US recommended adult dose of iodine for nuclear exposure is about 120mg, without any mention of remotest risk of toxicity.

This 1000 x order of magnitude with iodine is like
*the almost 10 000x margin between minimalistic vitamin C 10mg/d dose (RDA now 60mg/d) to avoid scurvy, up to >3v-7gm a day to treat infections, and >30 gm/day (intravenously, or buffered orally) to treat cancer;

*and vitamin D3 (RDA now up to ~800iu/d) up to 250 x more eg from 200iu /d to prevent rickets vs 50 000iu/d to treat some serious diseases, vs 2million iu single doses and 150 000iu/d for decades that have no documentable toxic effects in adults.
Infants obviously need proportionate dosing of all, not left to depend on mother’s milk when she has received no more than the usual prenatal supp folate and iron.. . .

The heaviest essential metal iodine is perhaps the most rare essential mineral – Wiki: “Iodine is rare in the Solar System and Earth’s crust (47th/60th in abundance):”- hence iodine deficiency is universal – especially now it has become fashionable in our lifetime to stop adding iodine to foodstuffs; and instead food manufacturers pump in toxic halides like bromine and fluoride (like dangerous mercury and aluminium in vaccines, aluminium in antacids) that (unlike chlorine,  iodine and refined sugars) have no essential biological need and benefit , only risks;

and recognition that commercial pure white runny salt NaCl – overdosing chlorine- is adverse because of worsening hypertension with aging and fast foods, instead of encouraging seasalt. .
The myths have been debunked that
*(unlike our essential blood chlorine in moderation), either fluorine or bromine are essential trace element halogens, any more than commercial cane sugar or fructose are biologically essential in our diet;

*and the Wolff-Chaikoff Effect myths (that iodine is toxic at much more than a mg a day) debunked by Abraham & Brownstein’s  review of scientific evidence the past century  including  Wartofsky, et al   1970  that we overdose with iodine at only 20 x the RDA (0.15mg/d) ie over a mg/ day,

*and the myth that only potass KI /sodium NaI iodides should be supplemented. The most proven iodine is in Lugols iodide providing the balance between  KI and free I2.

*Another commercially driven myth is that blood thyroid hormone levels are adequate to diagnose biologically significant iodine sufficiency, and commercial thyroxine to treat patients– the commercial hormones dont address, may worsen the serious iodine deficiency throughout the body that contributes hugely to acute and chronic, common and rare diseases

Studies of traditional Japanese after WW2 showed that their far better cancer-, cardiovascular,- thyroid health (before they emigrated to America, or took up Western diet) was attributable especially to the kelp ie iodine intake in their then-safe seafood diet, giving them an average iodine intake of about 12 mg/day- at least 100 times the current American imposed RDA of 0.15mg/d. But who can trust kelp, seafood from the poisoned oceans and rivers any more?

I recently took for a day each approx 20drops Lugols 2% pd in water ie iodine ~9mg a day; then 15% 4 drops ie 30mg/d …then up to , then 10drops ~70mg/d to test for detox reaction. I carry on with ~50mg/d,  as  many patients take it . I suppose my lack of detox reaction is not surprising since I have been detoxing for years on about 6 gm a day of a 50 -supp -multiblend( half vit C).- but no more than a mg/d of potass iodide. I  find physical and mental stamina better, no longer have  angina from stress or walking fast- which I could not do a fortnight before due to angina and fatigue. . .

One shudders to think of the billions of people – especially kids- who are dull, not achieving their full potential for lack of iodine, either because health professionals dont think we need more, or because patients are dismissed as euthyroid based on the usual thyroid lab hormone tests (which ignore iodine deficiency/excess in the majority who dont fall clearly in the over-or underactive blood hormone range).

Conventional western medicine apparently no longer considers or measures iodine deficiency, forgetting that iodine is the primary essential deficient mineral (along with magnesium, selenium, sulphur, phosphate; and iron in kids and reproductive women) for all systems in the body, not just for thyroid hormone levels- which dont reflect iodine security anywhere outside thyroid hormone production by the thyroid. .

IODINE OVERDOSE?
Iodine is needed in microgram mcg amounts for the thyroid, milligram mg amounts for breast and other tissues, and therapeutically as anticancer in gram amounts.[2]- Dr. David Miller
The theoretical iodine lethal LD50 for humans ie 1/10th of rodent dose is about 2 gm / kg, eg 6gm for a newborn baby, 140gm for an adult… a bottle of 20ml 2% Lugols in water contains 400mg, a 100ml bottle of 15% in water contains 15gm iodine(ie a 20ml bottle 3g) ie a harmless dose except corrosive if swallowed neat,.

Hence retailers if at all dispense Lugols 2%; we dont lightly prescribe/dispense 15% Lugols except for topical massage. And for cancer and we stick to 20ml dropper bottles.
not even Dischem and Clicks at Cavendish stock Lugols- only 2% iodine tinct IN ALCOHOL ie strictly for burning scratches… so no retailer should sell 100ml of any Lugols prep, only 20ml 2% Lugols, as is enforced in USA. It is indeed apparently regulated in the same way here., ‘tho’ the SA Medicines formulary doesnt mention that (recommends it only preop for eg thyroid storm), nor the multidisease benefits of Lugols including on the brain, wounds, infections, cardiac, vascular, cancer lungs etc;

nor the usual DETOXIFICATION REACTIONS as heavy metals are mobilized, for which (like eg metformin) the Lugol’s dose must be started low and titrated to tolerance with lots of fluids including magnesium, seasalt, selenium , vits B. eg Brief symptoms from heavy metal detox include “headaches, agitation, palpitations, nervousness, the jitters or irritated thyroid symptoms; pimples; skin rashes; fatigue, muscle aches, fever, diarrhea, worsen sinus/asthma, and brain fog. “. http://nourishingplot.com/2014/08/30/detoxing-fluoride-bromine-and-chlorine-naturally/ , http://www.iodine-resource.com/lugols-iodine.html ,   http://www.tiredthyroid.com/blog/2013/07/15/iodine-protocol-asthma-hives-sulfite-sensitivities/ and http://drsircus.com/medicine/iodine/iodine-and-detoxification. If these heavy metal detox reactions occur, stop the Lugols a few days, increase the detox remedies, then resume Lugols at a lower dose that you dont react to.
Threads   indicate that detox problems go away once iodine dose exceeds 50mg/d- especially if taken with a multisupp incl vit C, magnes , BCo, & selenium; and plenty of seasalt in water. (the only one of these not in a multisupplement AntiAging blend is salt).

In perspectivethe thyroid holds 50 milligrams of iodine, the breasts hold 200 milligrams, the skin holds 400 milligrams of iodine, and the whole body holds 2,000 milligrams, and possibly much more. Iodine is found and used in every hormonal receptor in the body. in 1911, 900 milligrams 0.9gm/day!) were considered usual and safe dosage. At 6 grams 6,000 milligrams/day!), iodine has been used to cure syphilis, skin lesions, and chronic lung disease. Iodine makes us smarter, helps with mental functioning. Low iodine is associated with low IQ’s with a difference of up to 13.5 points in children; but iodine deficiency is also associated with mental functioning in adults, because iodine not only chelates lead, but, according to Dr. Jorge Flechas, iodine prevents lead from lodging in the body in the first place. Low thyroid function decreases brain circulation, which slows intellectual function. low thyroid function is associated with cognitive impairment, memory loss, depression, slowness of mind, anxiety, suicidal tendencies, and a variety of psychiatric disorders. Bleichrod’s meta-analysis of 17 studies showed iodine sufficiency increases IQ by 13.5 points in children. Iodine prevents heart disease. Iodine is needed with the use of cordless phones, cell phones and now smart meters to prevent hypothyroidism. Iodine decreases insulin needs in diabetics.

IODINE ALLERGY? The risk of iodine allergy is quite low – Drs. Abraham and Brownstein were only able to identify 3 of 4,000 people who had a negative response to the iodine. People do not become allergic to iodine per se, but people react to the displacement of bound heavy metals; and can become allergic to protein-bound iodine as is found in shellfish or to the binding agents, excipients, fillers, preservatives and/or synthetics (rather than the bioavailable form of iodine itself) commonly found in tablets, capsules, and even liquids. Actually, iodine can help eliminate food allergies according to Dr. Derry.
But dont take Lugols at the same time as vit C, which neutralizes the antimicrobial effects of Lugols. so take them at opposite ends of the day.

and because iodine attacks only pathogens and abnormal cells, not our good probiotic biome or healthy cells, it has none of the risks of pesticides , antibiotics, antivirals, radiotherapy, chemotherapy etc.

RESEARCH ON LUGOL’S IODINE?
despite Dr Jean Lugol having published his landmark 1829 work on his iodine complex  ie ~185 years ago, there is predictably little research on it published on Pubmed, for the obvious reason that Big Pharma and the Disease Industry and governments wont fund research on such a cheap cure, which would greatly increase survival, but in the short term reduce illness and thus need for health industry workers, hospital beds, pharmacies and new drugs.
There are apparently only three clinically relevant LUGOL’s papers listed on Pubmed ie in the past 50 years:-

from India 2012 Consul ea – confirming that painting the cervix with Lugols (the Schiller test ) and vinegar is as effective as Pap smear for screening; thus combined, the two simple cancer diagnostic paints make up for Lugols iodine for cervix cancer being only about 85% sensitive and specific ie not as reliable alone as a costly lab Pap smear…
Greece 2007 Theodoropoulou ea  confirming that preoperative Lugol’s iodine 80mg/d for 15 days in euthyroid people was accompanied by increased intrathyroid total iodine but no changes in intrathyroid hormone HI or demonstrable increases of serum T4 and T3 were observed. It is hypothesized that the maintenance of normal intrathyroidal HI is the result of the combined inhibitory effect of iodine on thyroid hormone synthesis and on the release of T4 and T3 from the thyroid.
and
Italy 1986 Marani ea  –Iodine is therapeutic in various pathologies where immunity plays a dominant role, eg it facilitates cure in tuberculosis, lepromatous, syphilitic and mycotic incl sporotrichosis lesions . This effect does not depend on iodine’s action on the micro-organism responsible, but on host immune boosting. . Iodine may also be used in Panniculitis, in erythema nodosum, in nodular vasculitis, erythema multiforme etc. . To establish relationship between dietary iodine and immune response, 607 infants in an area of endemic goitre were studied: 215 were given Lugol solution (2 drops- presumably 20mg? a week for about 8 months ; and 392 not. Immune response was assessed by the skin test tetanus toxoid (in the U.S. 80% of paediatric cases aged 2-10 years old were positive). A significant difference was noted in the average diameter of the infiltrations after the tetanus toxoid skin test in the two groups considered (P less than 0.001). The results indicate that an adequate iodine intake is necessary for normal retarded immune response – a fact that the disease industry and Big Pharma blatantly ignore. . . (Iodine does not have the adverse effect of antibiotics on our gut biome, or causing antibiotic-resistant pathogens)

But there are dozens of scientific Lugol’s studies not referenced by Pubmed:

The End of Antibiotics and the Rise of Iodine as an Effective Alternative 2008 Mark Sircus

Iodine and viral infection?
David Derry, MD, PhD Thyroid Science 2009 Iodine: the Forgotten Weapon Against Influenza Viruses

Mamo & Naissides International Journal of Infectious Diseases (2005) from Australia show Iodine Could be effective in the treatment of human immunodeficiency virus and AIDS-associated opportunistic infections. as it is in rodents and cats .

Inactivation of human immunodeficiency virus by iodine-releasing products Harbison & Hammer Boston, Massachusetts 1989  showed that “povidine-iodine completely inactivated HIV at concentrations of greater than or equal to 0.5% ie is highly effective at killing HIV.
Betadine is simply “a stable complex of povidone and elemental iodine, contains 9.0% to 12.0% available iodine ie 90-120mg/ml .. Free iodine slowly liberated from the povidone-iodine PVPI solution kills microbe (but not healthy mammalian) cells through iodination of lipids and oxidation of cytoplasmic and membrane compounds, thus exhibits a broad range of microbicidal activity against bacteria fungi protozoa and viruses. Slow release of iodine from the PVPI complex in solution minimizes iodine toxicity towards mammal cells.” This compares exactly with a similar iodine complex  15% Lugols which contains about 10% ie 100mg iodine /ml water .. at far lower cost than but identical safety and efficacy to the patented Betadine – a modern designer marketable patented crib of Lugol’s .. …

see also
http://jeffreydachmd.com/wp-content/uploads/2014/03/The-Guide-to-Supplementing-with-Iodine-Stephanie-Burst-ND.pd

and

Lugols for animal thyrotoxicosis

and IODINE, A CRITICAL NUTRIENT 2014 http://drlwilson.com/Articles/IODINE.htm

and

Iodine: Its Role In Health and Disease: New Exciting Concepts Michael B. Schachter, M.D. 2007:   Guy Abraham MD, former professor of obsts gyne & endocrinology at UCLA School of Medicine, has written papers about iodine that drastically changed my thinking about its role in health and the prevention and treatment of disease. I had been impressed by Dr. Abraham’s previous work, which showed that vitamin B6 and magnesium could be very helpful to women with premenstrual syndrome (PMS) and was eager to learn what he had to say about iodine. Through a series of articles termed “The Iodine Project,” Dr. Abraham proposed that the optimal daily dose of iodine for a WELL person is approximately 12.5 mg, which is 100 times the RDA of 0.125 mg, ie that the current prevailing medical opinion that more than 2 mg a day of iodine is toxic is wrong. He traces the source of this major blunder to a scientific experiment on rats that was published in 1948 by Drs. Wolff and Chaikoff, which erroneously concluded that iodine inhibits the thyroid gland at doses of about 20 times the recommended daily allowance (RDA) for iodine. This conclusion was later generalized to humans and can be found in medical textbooks, including endocrinology and nutrition textbooks. Guy Abraham wrote in 2005: In hypertension, iodine sufficiency resulted in normalization of blood pressure without medications; as reported by other physicians using this program. Best results were achieved when orthoiodosupplementation was combined with a complete nutritional program emphasizing magnesium instead of calcium. Obesity increases the requirement for iodine and up to 100 mg elemental iodine/day may be required to achieve and maintain sufficiency. Increased demand for iodine occurs with excessive amounts of goitrogens from the diet and lifestyle. eg, smoking increases serum thiocyanate levels, interfering with the sodium/iodide supporter function. Low thyroid iodine is associated with thyroid hyperplasia and cancer. Could thyroid hormones cause the same iodine depletion in breast tissue? The prevalence of breast cancer is higher in women on thyroid hormones. Medical iodophobia resulted in removal of iodate from bread 20 years ago, replacing it with the goitrogen bromate- which associated with increased obesity, diabetes, and hypertension, thyroid and breast cancer. Recent reports show association between low iodine intake in women during pregnancy and attention deficit and hyperactivity disorder (ADHD) in their offspring. The most plausible explanation is a decreased sensitivity of the nuclear thyroid hormone receptor to thyroid hormones. We previously reported evidence for improved receptor response to thyroid hormones following iodosupplementation. Therefore, iodine is not only necessary for the synthesis of thyroid hormones but also for their effect on target cells. This effect is probably due to iodination of the thyroid hormone receptor. The essential element iodine, which is the inorganic, non-radioactive forms, deserves more attention from researchers and clinicians. It maybe the missing link in patients currently resistant to conventional hormonal therapy.
and see
http://www.earthclinic.com/remedies/lugols-iodine-supplements2.html
re adding enough selenium, chromium, vit C, Magnesium, Vitamin B2/3
and

Until 2007, in the United States, Lugol’s solution was unregulated and available over the counter as a general reagent, an antiseptic, a preservative,[11] or as a medicament for human or veterinary application .

However, effective August 1, 2007, the DEA now regulates Lugol’s solution (and, in fact, all iodine solutions containing greater than 2.2% iodine) as a List I precursor because it may potentially be used in the illicit production of methamphetamine.[12] However, transactions of up to one fluid ounce (30 ml) of Lugol’s solution are exempt from this regulation. When buying Lugol’s Solution on places like Amazon, most sellers fail to indicate the DEA tracking requirement. On the other hand Lugol’s Iodine solution is available over the counter in Canada and Mexico.
Toxicity Because it contains free iodine, Lugol’s solution at 2% or 5% concentration without dilution is irritating and destructive to mucosa, such as the lining of the esophagus and stomach.
Doses of 10 mL of 5% solution have been reported to cause gastric lesions when used in endoscopy.[13] The LD50 for Iodine is 14,000 mg/kg [Rat] and 22,000 mg/kg [Mouse].[14]
Most guidelines accept that anything with an LD50 >2 g/kg (-5 g/kg in some countries) can be classed as having a low acute toxicity[citation needed] which classifies Iodine as having low toxicity. Potassium Iodide is not considered hazardous.[15
http://jeffreydachmd.com/breast-cancer-prevention-with-iodine/

Iodine Dosages
Treatment of Influenza and other Diseases iodine-dosages 2009 “After testing over 500 patients, I found that 94.7% of my patients are deficient in inorganic iodine. Dr. David Brownstein In this chapter I will present different views and practices from present as well as from the long past when iodine was vastly more popular as a medicine than it is today. For whatever irrational reason, doctors and patients fear iodine thus en mass do not use to its fullest potential.
Humans tolerate large doses of iodine but the ultra high doses that were used many decades ago are not required to get the most out of iodine therapy. Just a little goes a long way, as the governmental iodized salt programs showed but this dosage level was only effective for Goiter and its avoidance. It actually takes very little iodine to prevent this disease but no one ever said that was the only purpose and need for iodine in the body. Today people are more deficient then ever before because our need for iodine has increased in direct proportion to our toxic burdens especially of other competing halogens. Read on at http://drsircus.com/medicine/iodine/iodine-dosages
Pps
see lugols_dosage_chart.  . But for obvious reasons stick to 2% till you know you tolerate and need much stronger drops.

23 MARCH 2015: THE CRUCIAL ROLE OF ANABOLIC PROHORMONES – MELATONIN, VITAMIN C AND steroids- PROGESTERONE, SUNSHINE and SOLTRIOL=D3 – AS HRT IN REDUCING ALL MAJOR DISEASE. Salute Dr Walter Stumpf.

 REVERSE THE POST-WW2  GLOBAL SHIFT FROM  HEALTHY ANABOLIC  OUTDOOR (VIT D AND ANDROGEN ie DIET CHOLESTEROL– FAT  DOMINANCE) EXERCISE ABUNDANCE TO THE RECENT LETHAL CARBOHYDRATE-SUGAR- ESTROGENICS- CORTISOL INDOOR TV DOMINANCE AND FAMINE.

update 22 MARCH 2015: VIGOROUS DOSE VITAMIN D UPDATE

NEW STUDIES:

More Canadian and USA studies confirm that vigorous vitamin D  need  applies especially to those living in far northern USA-Canada  and  EurAsia etc;    but also to all of us  globally who spend little time well exposed to the sun- especially the more driven  who both live/work indoors and cover even our limbs and heads outdoors as eg more ‘observant’ adults of many faiths do. As a new Creighton Univ study shows, we are at minimal risk of kidney stones on vigorous supplement vit D3 provided we balance it with enough water and magnesium supplement,

This is why in this age of increasing stress, longevity, epidemics, and pollution of both environment and the food and medicine chains, we have for a couple of years now   been advocating   and taking  vitamin D3  – on a  century of voluminous evidence (62500 papers on Pubmed alone) since 1914  from top nutritional scientists like Drs Jack Drummond, Linus Pauling, Walter Stumpf, Chris Nordin, Chris Gallagher, Rob Heaney, John Cannell, Bill Grant,  Mike Holick, Cedric Garland,  ea  – at least  vit D3  50 000iu a week (~7000iu/d)  ie a million units every 20 weeks;   retail costing  R30 ie R6pm  for us aging frailer types (half that dose ie 50 000iu twice a month @R3/month for the poor/ well or small kids).. at R12/US$, that costs all of $3 to $6 a year.

On about 9000iu vit D3 average supplement/day, my total 25OH vit D bloodlevel runs about 90-100 ng/ml ie 220-250 nmol/l.  so only 400- 1000iu vit D /day will boost the vit D  bloodlevel and benefits little if not  trivially.

But  vigorous D3 dose must be buffered by vit K2  about >100mcg/day , magnesium about 400mg/d, and the usual basket of other ~50 vits, minerals and other natural supplements, to protect us from kidney and arterial calcification etc. We have previously  highlighted trials eg from Pakistan showing that even 600 000iu vit D3 a month ie ~20 000iu/day safely and greatly improves recovery and healing from severe PTB+- AIDS in eg frail Pakistatin patients; whereas overdose of 90year old patients with a  2million iu  vit D3 dose (in Netherlands)  produced no toxicity. Hence we load sick patients with (an antibiotic-like )  200 000 to 400 000iu dose before continuing weekly or fortnightly maintenance- with the sickest fattest getting the highest dose, and infants scaled down accordingly (after a loading dose of eg 25 000iu)   to eg 1000-2000iu/d,  or 50000iu 1/2 scoop ie 25000iu every 2 weeks- the older extrapolation (as for adults)  of ~100iu/kg/day.

For the concerned vegan, vitamin D is vegetarian:  supplement of vit D2 is extracted from yeast or mushrooms;  vit D3 by UV irradiation of cholesterol from lanolin. Like all life, since vitamin D soltriol  is a sun-induced sterol oil product (in this case of cholesterol which in turn is built via  vitamin C ascorbic acid from plant glucose-sugar),   vitamin D does not contain or be made from animal flesh ie animal protein nitrogen  any more than does fish oil.

          Vitamin D may keep low-grade  cancer from becoming aggressive:
http://www.sciencedaily.com/releases/2015/03/150322080155.htm    Taking vitamin D supplements could slow or even reverse the progression of less aggressive, or low-grade, prostate tumors without the need for surgery or radiation, scientists say. Taking vigorous vits C & D does this for all cancers, all disease.

 

               VITAMIN D DEFICIENCY IS ASSOCIATED WITH INSULIN RESISTANCE INDEPENDENT OF INTRACELLULAR CALCIUM, DIETARY CALCIUM AND SERUM LEVELS OF PARATHORMONE, CALCITRIOL AND CALCIUM IN PREMENOPAUSAL WOMEN.   Da Silva Ferreira T,  Sanjuliani AF ea .   Nutr Hosp. 2015 Apr 1;31(n04):1491-1498.

25-Hydroxyvitamin D in the range of 20 to 100 ng/mL doesnt increase  kidney stones.    Am J Public Health. 2014 Sep;104(9):1783-7  Garland, Heaney ea Creighton Univ, USA   Increasing 25-hydroxyvitamin D serum levels can prevent a wide range of diseases. There is a concern about increasing kidney stone risk with vitamin D supplementation. The study included 2012 participants followed prospectively for a median of 19 months. Thirteen individuals self-reported kidney stones during the study period. Multivariate logistic regression was applied to assess the association between vitamin D status and kidney stones.We found no statistically significant association between serum 25-hydroxyvitamin D and kidney stones (P = .42). Body mass index was significantly associated with kidney stone risk (odds ratio = 3.5; 95% confidence interval = 1.1, 11.3).           We concluded that a serum 25-hydroxyvitamin D level of 20 to 100 nanograms per milliliter has no significant association with kidney stone incidence.       

A Statistical Error in the Estimation of the Recommended Dietary Allowance for Vitamin D. Letter to Veugelers, P.J. and Ekwaru, J.P.,           Nutrients. 2015 Mar 10;7(3):1688-90. doi: 10.3390/nu7031688.  Nutrients 2014, 6, 4472-4475; doi:10.3390/nu6104472.   Heaney , Garland ea.    1Creighton University & University of California, San Diego,   GrassrootsHealth, Encinitas, CA .   Recently Veugelers and Ekwaru published data indicating that, in its dietary reference intakes for calcium and vitamin D, the Institute of Medicine (IOM) had made a serious calculation underestimation  [2]. Using the same data set as had the IOM panel, these investigators showed that the Recommended Dietary Allowance (RDA) for vitamin D had been underestimated by an order of magnitude. Veugelers and Ekwaru, using the IOM’s data, calculated an RDA of 8895 IU per day. They noted that there was some uncertainty in that estimate, inasmuch as this value required an extrapolation from the available data, which did not include individuals receiving daily vitamin D inputs above 2400 IU/day.[…].

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210929/        Nutrients. 2014 Oct; 6(10): 4472–4475.Statistical Error in the Estimation of  Recommended Dietary Allowance for VitaminD     Paul J. Veugelers* and John Paul Ekwaru   University of Alberta, Canada

The Institute of Medicine (IOM) issues dietary recommendations on the request of the U.S. and Canadian governments. One of these recommendations is the Recommended Dietary Allowance (RDA). The RDA is the nutrient intake considered to be sufficient to meet the requirements of 97.5% of healthy individuals [1]. The RDA for vitamin D is 600 IU per day for individuals 1 to 70 years of age and is assumed to achieve serum 25-hydroxyvitamin D (25(OH)D) levels of 50 nmol/L or more in 97.5% of healthy individuals [1]. Serum 25(OH)D is the established proxy for vitamin D status and levels of 50 nmol/L or more have been shown to benefit bone health and to prevent disease and injury [1].

The IOM based their RDA for vitamin D on an aggregation of 10 supplementation studies that were carried out during winter months and at locations with latitudes above the 50th parallel north to minimize the influence of cutaneous vitamin D synthesis [2,3,4,5,6,7,8,9,10,11]. As several of these 10 studies examined more than one supplementation dose, collectively they provided 32 study averages of serum 25(OH)D levels. These are replicated as the green diamonds in Figure 1. The IOM regressed the 32 study averages against vitamin D intake to yield the dose response relationship of vitamin D intake and serum 25(OH)D (green solid line in Figure 1). The IOM further calculated the lower and upper 95% confidence prediction interval based on the 32 study averages and the standard deviation of these 32 study averages (green dashed lines in Figure 1). On the basis of this, the IOM estimated that 600 IU of vitamin D would achieve an average 25(OH)D level of 63 nmol/L and a lower 95% confidence prediction limit (2.5 percentile) of 56 nmol/L. The latter value was rounded downwards to 50 nmol/L to accommodate uncertainty in the estimation [1]. This data point (600 IU vitamin D, 50 nmol/L) is the basis for the current RDA and for the IOM’s conclusion that an intake of 600 IU of vitamin D per day will achieve serum 25(OH)D levels of 50 nmol/L or more in 97.5% of individuals.

The correct interpretation of the lower prediction limit is that 97.5% of study averages are predicted to have values exceeding this limit. This is essentially different from the IOM’s conclusion that 97.5% of individuals will have values exceeding the lower prediction limit. To illustrate the difference between the former and latter interpretation, we estimated how much vitamin D is needed to achieve that 97.5% of individuals achieve serum 25(OH)D values of 50 nmol/L or more. For this purpose we reviewed each of the 10 studies used by the IOM. Eight studies reported both the average and standard deviation [2,5,6,7,8,9,10,11]. These eight studies had examined a total of 23 supplementation doses [2,5,6,7,8,9,10,11]. For each of these 23 study averages we calculated the 2.5th percentile by subtracting 2 standard deviations from the average (depicted by yellow dots in Figure 2). Next, we regressed these 23 values against vitamin D intake to yield the lower prediction limit (red line in Figure 2). This regression line revealed that 600 IU of vitamin D per day achieves that 97.5% of individuals will have serum 25(OH)D values above 26.8 nmol/L rather than above 50 nmol/L which is currently assumed. It also estimated that 8895 IU of vitamin D per day may be needed to accomplish that 97.5% of individuals achieve serum 25(OH)D values of 50 nmol/L or more. As this dose is far beyond the range of studied doses, caution is warranted when interpreting this estimate. Regardless, the very high estimate illustrates that the dose is well in excess of the current RDA of 600 IU per day and the tolerable upper intake of 4000 IU per day [1].

The public health and clinical implications of the miscalculated RDA for vitamin D are serious. With the current recommendation of 600 IU, bone health objectives and disease and injury prevention targets will not be met. This became apparent in two studies conducted in Canada where, because of the Northern latitude, cutaneous vitamin D synthesis is limited and where diets contribute an estimated 232 IU of vitamin D per day [12]. One study estimated that despite Vitamin D supplementation with 400 IU or more (including dietary intake that is a total intake of 632 IU or more) 10% of participants had values of less than 50 nmol/L [13]. The second study reported serum 25(OH)D levels of less than 50 nmol/L for 15% of participants who reported supplementation with vitamin D [14]. If the RDA had been adequate, these percentages should not have exceeded 2.5%. Herewith these studies show that the current public health target is not being met.              We recommend that the RDA for vitamin D be reconsidered to allow for appropriate public health and clinical decision-making.

update 1 March 2015Screening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion? 

                   Since its founding, the  USPSTF has sought to provide a firm evidential base for early detection strategies, evaluating such screening methods as mammography and prostate-specific antigen testing. Although it has also evaluated a few interventions, its predominant focus has been testing for markers that identify persons at risk who are likely to benefit from preventive action. Only recently has the USPSTF ventured into the field—or perhaps the minefield—of nutrition, a territory distant from screening tests and risk assessment, with different and unfamiliar landmarks.

The USPSTF presents its conclusions on testing for vitamin D deficiency (1), reporting that it was unable to find evidence for or against such testing. It noted that one of the likely reasons was the absence of a scientific consensus on both the level of vitamin D status that should be judged “deficient” and what the measurable manifestations of deficiency might be. These are also issues for many other nutrients, such as folate, ascorbate, calcium, and protein. Vitamin D may have seemed to offer a way out of this confusion because serum 25-hydroxyvitamin D [25-(OH)D] concentration is generally recognized as one of the best indices of status for any of a broad array of nutrients. Also, it is now readily measurable and widely utilized.

One of the reasons its promise has not been realized is that most studies of vitamin D efficacy have used a disease-avoidance model, which is the standard approach used by the Institute of Medicine (IOM) for most nutrients (2). Furthermore, disease prevention is the explicit focus of the USPSTF. Nevertheless, the IOM and USPSTF approaches effectively equate health with the absence of disease, an equivalence that nutritionists have long rejected. Instead, nutritionists focus on full nutrient repletion when possible. The inevitable gap between disease prevention and nutrient repletion is still largely unexplored territory. For many nutrients, it can be surprisingly wide, as suggested in this case by studies of the intake required to provide vitamin D in human breast milk in quantities sufficient to meet the needs of infants (3). The IOM’s adult requirement for vitamin D is 600 IU/d (4), which is judged to be sufficient to protect against osteoporotic fracture. In contrast, quantitative and empirical evidence indicates that vitamin D intake from breastfeeding needs to be approximately 6000 IU/d (3, 5). Although high compared with the adult recommendation, such an intake almost exactly reproduces the measured vitamin D status of contemporary Africans leading ancestral lifestyles (6). Such populations provide perhaps our best window on vitamin D levels prevailing during the millennia over which human physiology was adapted to its environment by natural selection.

Whatever the actual requirement or 25-(OH)D cutoff may be, there is another likely reason that the evidence is unclear. The USPSTF drew from systematic reviews and meta-analyses of studies of vitamin D effects, such as the one accompanying the current report (7). In general, the criteria for including studies in such reviews are methodological rather than biological. Of the 6 published biological criteria (8) for including published reports in meta-analyses, the review published in this issue met only 2 (comparable basal status and same chemical form), and several of its component studies met none. Including studies that could never have been informative in the first place (especially when they are large) inevitably biases any review toward the null.

What seems not to have been widely appreciated is that vitamin D exhibits flat response regions at both low and high values of vitamin D status, with a sharp rise in the approximate center of the physiologic range of 25-(OH)D values (8). Studies like the WHI (Women’s Health Initiative), which enrolled women with low vitamin D status values and used a vitamin D dose insufficient to move them into the response range, provide little useful information about vitamin D efficacy. Yet, precisely such studies were included in the review by LeBlanc and colleagues (7). This is not to criticize the WHI, which was designed more than 20 years ago (before vitamin D pharmacology was well-understood), but it is to criticize contemporary reviews and meta-analyses that fail to take advantage of newer information or to use critical biological criteria (8) for selection of studies for analysis of biological effects.

In addition, a disease-avoidance approach becomes problematic for micronutrients in general (and vitamin D in particular) when one understands that micronutrients do not actually cause any of the effects simplistically attributed to them. Although necessary for cell response, such micronutrients by themselves do not initiate or cause the response concerned. For example, vitamin D is a component of the biochemical apparatus that opens the genome to allow access to DNA information needed for a particular cell or tissue response. In terms of cell function, this dependence means that when supplies of the micronutrient are inadequate, cellular response is blunted. This is dysfunction, but not clinically manifest disease. Such dysfunction may indeed lead ultimately to various diseases, but disease prevention remains a dull tool for discerning the defect, and a disease-prevention approach clearly does not measure whether the organism has enough of the nutrient to enable appropriate physiologic responses, such as lactation.

Finally, and aside from the USPSTF’s findings, one must ask whether treating without first testing is sound practice. Certainly, it would be rational to do so if the condition being treated is prevalent and the treatment is safe and inexpensive. That is the case with another micronutrient, iodine, and the iodination of salt. However, the current situation is different because consuming sufficient iodine generally does not require conscious adherence to a particular regimen, whereas taking vitamin D does. Usually, testing improves patient adherence because it provides patient-specific, personally applicable information. General assurances that one probably needs extra vitamin D are not as compelling a motivator as knowing one’s number. Thus, whether the practitioner adheres to the widely divergent guidelines of the IOM (4), the Endocrine Society (9), or the American Geriatrics Society (10), measuring vitamin D status seems to be warranted, not so much to diagnose deficiency but to determine patient status relative to the selected guideline.

update  20 Jan 2015 a new USA study Ng et al. Vitamin D status and survival of metastatic colorectal cancer patients  at the 2015 Gastrointestinal Cancers Symposium found that patients with metastatic colorectal cancer with higher vitamin D levels survived a third longer than those with lower levels – 32.6 months compared to 24.5.

update 12 Jan 2015        As the poet Juvenal (died 130AD) wrote: Mens sana in sano corporis– a healthy mind in a healthy body. Its great how the prime  antistress homeostatic hormones- a pinch of natural  melatonin at night, with ENOUGH  daytime  anabolic soltriol calciferol vitamin D3, restores good sleep, orchestrate homeostasis of all other hormones especially of  the crucial adrenals and gonadals and thus thyroid hormones. ..

Sleep. 2015 Jan 12. Massa ea, Harvard.  Low Vitamin D and Poor Sleep in Older Community – Dwelling Men   :  vitamin D3 is important for sleep duration and quality. 16% of this study population had very low levels of vitamin D (< 20ng/mL 25(OH)D). Lower serum vitamin D levels linked with short (< 5 h) sleep duration,doubled the odds ratio [OR] 2.15 for the highest (≥ 40ng/mL) versus lowest (< 20 ng/mL) quartile of 25(OH)D,; Ptrend = 0.004) and lowering  sleep efficiency. And low vitamin D is a major associate of  major depressionJózefowicz ea Univ Lodz, Poland 2014..

Thanks to global human (mostly male)  greed enslaving the masses the past 7 millennia ie since at least Sumerian times, we have moved rapidly in our lifetime post WW2  from  global homeostatic (food, commodities) plenty to a world of dyshomeostasis- cacostasis stress chaos – in most countries  from Afghanistan to Zimbabwe. Just a few years ago South Africa led Africa in productivity and skills, and still has the biggest reserves of riches- minerals-  in the world; with boundless natural power (sun, sea) and manpower to drive industry and food production. But in  20 years post apartheid, the ruling ANC under Mbeki and the Zumas  has with  selfserving treasonous greed  brought South Africa to its knees with cacostasis, destruction of continuous water, electricity ; school education,  organized and quality  food provision ie agriculture, social security, the post office, the national airline, health services, Home Affairs and pensions). Now there are  rapidly increasing functionally illiterate or  old  16 million on state grants supported by the 6 million capable of meaningfully working and paying taxes if they dont emigrate. And state grants have now been extended to age 23yrs because state school leavers are practically unskilled for  anything but being labourers. .

The national powergrid and oil reserves have been degraded so that total indefinite blackouts are now imminent, never mind weekly “outages” crippling work-  the economy – and destroying appliances. Never mind increasingly pandemic influenza and HIV, antibiotic resistance puts us in the post-antibiotic era in this age of deadly resistant TB and STDs, with  reckless immoral  leaders  like Zuma and Vavi leading the mob in extramarital sex and provoked violence. .

So as never before, everyone from conception to grave needs realistic regular vitamin D3 supplement at about R3 a month to bolster mental and physical health of children, mothers and the working , never mind the ailing aging, to reduce illhealth costs. . Stress- through raised thyroid, sympathetic and cortisol levels and depressed gastrointestinal, cardiovascular, musculoskeletal and immune control, grossly disrupts homeostasis and shifts victims into catabolic estrogen-dominance , insulin resistance mode- which only the hormone supplements  D3 and melatonin, and the essential vitamins and minerals  if not  risk-laden androgenics can try to balance,

George Chrousos ea.  University Athens, Greece since Nat Rev Endocrinol. 2009 and now   Neuroimmunomodulation. 2015 write: Stress – glucocorticoids – and disorders of the stress system- cacostasis vs homeostasis.      All organisms must maintain complex dynamic equilibrium-  homeostasis- which is constantly challenged by internal or external adverse forces – stressors. Stress occurs when homeostasis is threatened or perceived; homeostasis is re-established by various physiological and behavioral adaptive responses. Neuroendocrine hormones have major roles in the regulation of both basal homeostasis and responses to threats, and are involved in the pathogenesis of diseases characterized by cacostasis – dyshomeostasis. The stress response is mediated by the stress system, partly located in the central nervous system and partly in peripheral organs. The central, greatly interconnected effectors of this system include the hypothalamic -pituitary-adrenal (HPA) axis and hormones arginine vasopressin, corticotropin-releasing hormone  and autonomic norepinephrine centers in the brainstem.  Optimal basal activity and responsiveness of the stress system is essential for a sense of well-being, successful performance of tasks, and appropriate social interactions. By contrast, excessive or inadequate basal activity and responsiveness of this system might impair development, growth and body composition, and lead to a host of behavioral and somatic pathological conditions.. Glucocorticoids, the end-products of the HPA axis, play a fundamental role in the maintenance of both resting and stress-related homeostasis and, undoubtedly, influence the physiologic adaptive reaction of the organism against stressors. If the stress response is dysregulated in terms of magnitude and/or duration, homeostasis is turned into cacostasis with adverse effects on many vital physiologic functions, such as growth, development, metabolism, circulation, reproduction, immune response, cognition and behavior. A strong and/or long-lasting stressor may precipitate and/or cause many acute and chronic diseases. Moreover, stressors during pre-natal, post-natal or pubertal life may have a critical impact on our expressed genome.

VITAMIN D ECONOMY & GOAL OF SCREENING: Heaney and Armas, Creighton University  QUANTIFYING THE VITAMIN D ECONOMY: Nutrition Reviews  Dec 2014; and Screening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion? Ann Intern Med. Nov 2014   write:  sunlight and food  contribute only modestly  to the relevant optimal total serum vit D and 25OHvit D levels: unsupplemented individuals who average blood 25OHvit D of 20 ng/mL are receiving about 2,000 IU/day from nonsupplement sources (i.e food and sun) – whites double the amount  compared to dark blacks  from skin. . It has been established for 30 years that in fair-skinned individuals, a single exposure to UV-B at one whole-body minimum erythema dose can produce a rise in serum 25D that is equivalent to an oral dose of D3 in the range of 10,000 to 25,000 IU, ie by as little as 10–15 min of whole-body exposure at mid-day in mid-summer in a pale-skinned individual. Pale-skinned northern Europeans show a rise in serum 25D of 9 ng/mL (23 nmol/L) at the end of 4 weeks of exposure. By contrast, in dark-skinned individuals, the rise was  half  ie 4.5 ng/mL . Meat  eaters exhibit higher human 25D status . Input gaps left after estimating solar inputs (on the order of 1,300–1,600 IU/day, as noted above) could well be filled by hitherto unrecognized food sources. For example, Taylor et al.21 report a combined (D3 plus 25D) content of 112 IU vitamin D equivalents for 200 g of beef tenderloin or  an egg, associated with 2 ng/mL greater level of serum 25D.      The Grassroots Health project collects data on supplement type and has found no difference in the 25D concentration achieved with either 5,000 or 10,000 IU daily doses, irrespective of whether the D3 was delivered via a gel cap in oil or as dry powder in a tablet (unpublished data; S. McDonnell, personal communication). vitamin D could be absorbed from orange juice. On the other hand, fat malabsorption syndromes are known to lead to vitamin D deficiency, and the mechanism is generally considered to be a specific impairment in the absorption of fat-soluble vitamin D. However, poor absorption may reflect not so much mucosal dysfunction, as simple sweeping of any fat-soluble compound out of the gut, dissolved in the unabsorbed fat. Dawson-Hughes et al.,35 using pharmacokinetic methods in individuals with normal absorptive function, reported equal absorbability for D3 under fasting and high-fat meal conditions, with slightly better absorption from a low-fat meal. Mulligan and Licata,36 in an observational study of 17 poor responders to oral D preparations, reported greater absorption from a large meal containing fat than from intake on an empty stomach. However, the limited data, taken as a whole, suggest that the effects of dosage form or vehicle are probably small.

Finally, the issue of D2 versus D3 needs brief mention. Formerly considered controversial, there now seems to be a growing consensus37 that, for equimolar quantities, orally administered D3 raises serum 25D by about twice as much as D2.38–42 This has been shown for bolus doses, short-term continuous administration (12 weeks), and long-term continuous administration (12 months).

Intestinal absorption of D3 is mainly from the jejunum and ileum. Absorbed vitamin D can be found in both the portal venous blood and the lymph that drains the small intestine.  The lymphatic pathway may have particular physiological significance for orally acquired vitamin D, since it avoids a first pass of the absorbed vitamin D through the liver. This suggests that the quantitative relationship between vitamin D and 25D will be the same regardless of whether vitamin D enters from the skin or the gut.

Diffusion from the skin into the blood is slow, with a half-time of about 3 days.7 This half-time means that when regular sun exposure is the principal source of D3, serum D3 concentration will be essentially constant.

it is reasonably certain  that the concentration of vitamin D in fat tissue is substantially higher than the concentration in serum. – a given volume of fat tissue contains approximately 12 times as much vitamin D as the same volume of serum. However, a several-fold gradient is not surprising as D3 solubility in fat is effectively limitless, while DBP capacity, which is large, is finite.

Assuming a diffusional mechanism and a total body fat mass of 35% of body weight,  total body stores in an individual weighing 70 kg would range from 900 to 2,800 µg (37,000 to 113,700 IU). Using the calculations set forth in the prior section and applying them to an individual with a serum 25D level of 20 ng/mL, whose metabolic consumption would be ∼2,000 IU vitamin D/day, the total amount in the reservoir would provide enough of a reserve for 18–57 days at that same rate of utilization. At a serum 25D level of 40 ng/mL, that same reserve would support consumption for only 9–28 days. Neither estimate comes close to compensating for the “vitamin D winter” of most temperate latitudes. The smallness of this reserve explains why even outdoor summer workers who had high daytime skin exposure experienced reductions in 25D averaging approximately 20 ng/mL (50 nmol/L) by late winter. Of note, their 25D values had reached >50 ng/mL (125 nmol/L) by late summer, which is roughly the same as that reported for East Africans living ancestral lifestyles.48 This study indicates both that existing stores at the end of summer were not adequate to maintain the achieved summer level and that the late winter level (∼30 ng/mL) represented a utilization of approximately 3,000 IU/day.

Chemical partition
Extracellular 25(OH)D  The first step in the chemical conversion of D3 is 25-hydroxylation.Bikle et al.51 showed that skin cells contain all the requisite enzymatic apparatus to produce both 25D and 1,25D. However, it is doubtful that under ordinary circumstances, skin is a major source of the extracellular 25D measured in serum (D. Bikle, personal communication). Other sources remain to be identified.

The efficiency with which D3 is converted to 25D varies widely from individual to individual.  Various reasons can be put forth for these inter-individual differences that, though studied in somewhat less detail, have been reported by many investigators. One example is the variable methylation of the CYP2R1 gene and, hence, variable expression of the hepatic 25-hydroxylase.53 While there is currently no final answer, it is clear that differences in intestinal absorption of D3 could not explain the slow rise in participant B, relative to participant A. Moreover, the internal consistency in the shape of the respective curves virtually excludes methodological variability as a cause of the difference.

Extracellular 1,25(OH)2D  The second hydroxylation, which produces extracellular 1,25D, occurs predominantly in the proximal convoluted tubular cells of the kidney. While 25-hydroxylation is not highly regulated, the opposite is true for 1,25D, the synthesis of which is upregulated by parathyroid hormone and low serum inorganic phosphorus concentration and downregulated by fibroblast growth factor-23. Note that 1,25D is a principal regulator of intestinal absorption of calcium; during this process, it acts by upregulating expression of the calcium transport apparatus of the enterocyte. This is an endocrine effect as it is mediated through serum endocrine-like activity and exhibits a typical negative feedback control loop. Under usual conditions, 1,25D is necessary for regulation of calcium absorption. However, it is not the only factor involved in this process. It should also be noted that in the absence of other vitamin D metabolites, 1,25D by itself has been reported not to be sufficient to elevate intestinal calcium absorption.55,56

As would be expected for regulator molecules, the serum half-time of 1,25D is short (hours). Its concentration in serum is a reflection mainly of relative calcium need—being high in individuals on low-calcium diets or in those with calcium malabsorption and low in individuals with high calcium intakes. Also, 1,25D has long been recognized to be calcemic when used therapeutically. The mechanism is generally attributed to intestinal calcium absorption, but this cannot be a satisfactory explanation, as increased metabolic input alone (i.e., without considering output) is rarely sufficient to elevate the serum concentration of any metabolite. Moreover, 1,25D and its analogs do not elevate calcium absorption in patients with end-stage renal disease,57 a condition in which the calcemic effect of 1,25D is often readily apparent. While not adequately explored, there remains another possibility, i.e., an effect of 1,25D on bone-lining cells, where a fall in bone fluid pH to just below 7.0 is enough to solubilize bone mineral sufficiently to elevate serum calcium.58
Physical partition

The distinction between the endocrine and the autocrine pathways is one aspect of the physical partition between extracellular and intracellular processing of the vitamin. The prevailing assumption seems to be that most or all of the D3 entering the body is 25-hydroxylated and that the resulting 25D circulates in the blood, where it serves as the substrate for both renal and extrarenal 1 -α-hydroxylation, with the renal 1,25D product circulating in the blood like 25D and with the extrarenal 1,25D never being expressed in the only accessible body compartment, i.e., the blood.

As Hollis and Wagner59 have pointed out, D3 enters cells more readily than does 25D and, as noted above, there are several enzymes other than the hepatic CYP2R1 that are capable of 25-hydroxylation of D3.49,50 Hence, a physical partition of the vitamin D pathways prior to the 25-hydroxylation step has to be given serious consideration. That this is more than just a theoretical possibility is suggested by the fact, noted earlier, that oral 25D elevates serum 25D to a substantially greater extent than does oral D3.28–30 This was shown first by Barger-Lux et al.28 in a 10-week dosing study involving the two molecules. Figure 9 plots the 25D response to the two agents observed in a group of 54 healthy adults and shows a clear divergence of the dose response curves, with a greater than seven-fold difference in slopes. Cashman et al.,30 using a different design, found an approximate five-fold difference in response after 10 weeks of dosing, and Bischoff-Ferrari et al.,29 an approximate four-fold difference after 17 weeks of dosing.

Figure 9
Change in serum 25D plotted as a function of intake for varying oral doses of 25D and D3. Data from Barger-Lux et al.28
That there should be a greater rise in 25D when oral 25D is the source is, in a sense, trivial, as oral 25D is immediately reflected in the serum, while oral vitamin D must first be 25-hydroxylated, a process that, as described above, is necessarily slower, sometimes substantially so. Only a proper pharmacokinetic study that compares area-under-the-curve values for the two agents can fully quantify this difference. Such a study must either be long enough to allow the 25D plateau to be reached while on continuous dosing of D343 or, if using a bolus dose design, must follow the time course for the two agents for probably 4 months so as to allow full 25-hydroxylation of the administered D3 and full consumption of the administered 25D. No such data are currently available, and this aspect of the physical partition must remain speculative. Nevertheless, the issue is an important one, not just for the therapeutics of 25D but also for a full understanding of the vitamin D economy (see below).

The 25D half-time (as measured by Clements et al.60–62 using tracer-labeled 25D) presents certain puzzling features in its own right. A half-time of, say, 20 days (toward the lower end of the range found by Clements et al.) translates to a daily turnover of about 3.47% of the total mass of extracellular 25D. If the size of daily utilization is known, it is possible to calculate the size of the 25D mass from that fractional utilization rate. If all of the vitamin D input to the body is converted to extracellular 25D, then at a serum 25D concentration of 20 ng/mL (requiring, as shown above, a daily input of ∼50 µg), that 50-µg input is numerically equal to the daily turnover. So, total 25D mass would be 50/0.0347, or close to 1,500 µg. This figure is larger by an order of magnitude than that of the measurable total serum content of 25D, and the discrepancy becomes even larger at higher serum 25D concentrations or longer half-times. This seeming discrepancy has not been noted previously, with one potential reason being the computational difficulty of harmonizing biological units (IU), first with mass concentrations (µg/mL), then with SI units (nmol). However, if a substantial fraction of daily input of D3 is 25-hydroxylated intracellularly, after which it is immediately activated to 1,25D, then only the 25D in the extracellular compartment would be labeled by a tracer-based approach to kinetic analysis, and the calculated daily utilization of the circulating 25D would be lower and the corresponding 25D mass estimate would be closer to what is known from blood and soft tissue content. These calculations provide support for the suggestion of Hollis and Wagner59 that “parent compound D” has more functional significance than has usually been thought.

There is one quantitative aspect of the physical partition, whether occurring prior to or after the 25-hydroxylation step, which seems inescapable. Whether one takes as optimal a serum 25D concentration of 20 ng/mL or 40 ng/mL, the molar equivalent D3 inputs required to sustain either level are far higher than the moles of 1,25D required to support the calcium economy. As noted above, a serum 25D of 40 ng/mL requires approximately 4,000 IU/day, or 100 µg/day, and a serum 25D of 20 ng/mL requires approximately 2,000 IU/day, or 50 µg/day. By contrast, the calcium economy requires between 0.5 µg and 2.0 µg of 1,25D/day. (Higher doses, as noted above, produce hypercalcemia.) It follows that >90% of D3 utilization is occurring along the intracellular/autocrine pathway. If that is not the case, then most of the D3 input to the body is degraded metabolically and not used at all. The latter possibility seems quite improbable, particularly in view of the marginal or subadequate vitamin D status that seems nearly universal. Answering this question of the relative potency of oral D3 and 25D will illuminate the partition of D3 between the extracellular and intracellular pathways and will be an important step in unraveling the puzzle of the physical partition.

One instance in which the pre-25D intracellular pathway is operative is the transfer of vitamin D activity into human breast milk.59,63 25D does not transfer across the secretory mucosa of the mammary gland with sufficient efficiency to produce enough vitamin D activity in milk to nourish the infant, while D3 does. However, for this to occur, D3 must be present in the blood that bathes the mammary secretory apparatus. In earlier work, Hollis et al.63 showed that the concentration of vitamin D in human milk was about 28% of the concentration of D3 in maternal blood. In subsequent work (B. Hollis, personal communication), that figure was shown to be closer to 32%, and a recent study by Oberhelman et al.64 showed a transfer fraction that can be calculated to be about 44%. Based on recommendations of both the American Academy of Pediatrics and the Institute of Medicine for infant intake (400 IU vitamin D/day, which requires a milk concentration of about 520 IU/L, i.e., ∼34 nmol/L), these transfer fractions would require a maternal serum vitamin D concentration of about 30–40 ng/mL (78–120 nmol/L). (The corresponding 25D concentration would be >50 ng/mL [125 nmol/L]; see Figure 8.) Hollis and Wagner59 estimate that the total input of D3 needed to maintain a milk concentration sufficient to meet the infant’s needs for vitamin D was approximately 6,000 IU/day. The equivalence value derived above produces a needed input of approximately 6,000 IU/day, which is essentially identical to the empirical estimate of Hollis and Wagner.
Dosing schedules and serum D3 concentrations

Dosing frequency for oral vitamin D supplementation regimens will affect serum concentration of D3 in predictable and often very striking ways. This fact has been largely overlooked to date, as the serum concentration of D3 has been generally considered to be of no particular interest in its own right. The rationale for infrequent (or bolus) dosing is that it leads to better adherence and that an excess amount ingested today will be stored in fat for use tomorrow. However, this assumption overlooks the effect of infrequent dosing regimens on D3 blood concentrations.

Serum D3 has a half-time variously estimated to be in the range of 0.5–3.5 days, with most investigators favoring a value of about 1.0 days. In contrast, D3 produced in skin moves into the blood with a half-time of about 3 days. This means that when skin synthesis is the principal source of D3, serum D3 concentration will be essentially constant around the clock, as D3 input to the blood from the skin (though produced mainly at mid-day) is effectively constant. With oral ingestion, intestinal absorptive input of D3 occurs mainly during a 4-h period following ingestion. (In one study, a TMAX of as much as 12 h was reported.65 As this is well beyond the usual mouth-to-cecum transit time, the 12-h figure, if confirmed, would suggest appreciable colonic absorption, or small bowel mucosal retention, or a delay pool in the intestinal lymphatics.) In any case, assuming a 1.0-day half-time, serum D3 concentration will inevitably follow a sawtooth pattern, particularly if oral ingestion is the principal input. Figure 10 displays the patterns for purely cutaneous input and for daily, weekly, and biweekly oral administration. With a once-a-week schedule, as is evident from Figure 10, serum D3 concentrations are close to zero for several days each week and below the reference level for most of the interdose interval. Thus, in the practical order, a nursing woman who takes her total weekly dose of vitamin D once each week would produce milk with little or no D content for roughly 4 of the 7 days in each week. This irregular delivery will be even more pronounced with biweekly or less frequent dosing schedules.

Figure 10
Calculated time courses for serum D3 concentration for varying oral dosing intervals. The reference level is the serum concentration for continuous (as contrasted with intermittent) dosing. Each dosing scheme provides the same cumulative intake, according to one of the following regimens: once daily, or 7 times the daily intake once weekly, or 14 times the daily intake once every 2 weeks.
It should be stressed that Figure 10 illustrates the concept and is not a depiction of actually measured serum concentrations of D3. Under input conditions in excess of daily use, unused D3 will accumulate in fat, and its concentration there would be predicted to damp the oscillations of D3 concentration in serum to some extent.

An additional feature of interval dosing is the high D3 concentration peaks achieved in the days following each dose. The impact of such high D3 levels is unclear, although Vieth66 has pointed to the induction of the 24-hydroxylation pathway as a likely consequence, with a corresponding reduction in effective vitamin D activity. Further, as the binding capacity of DBP is approximately 4.7 µmol67 (or ∼78,000 IU/L), with true Stosstherapie, as in several recent studies,68,69 the DBP will be fully saturated by the ingested D3, resulting in displacement of both 1,25D and 25D off DBP and into circulation as free or unbound moieties for several days after dosing (i.e., until fat uptake lowers serum D3 sufficiently). This effect amounts to a transient vitamin D intoxication of uncertain physiological import. Unfortunately, there is essentially no published information about vitamin D concentrations in the immediate post-dosing period following large bolus doses. Whatever else may be said of Stosstherapie, it certainly is not physiological.
Factors influencing serum 25D concentration

Aside from the possible importance of D3 concentration as the substrate for autocrine activity of vitamin D, there is general agreement that serum 25D concentration is currently the principal indicator of vitamin D status.70 This is because extrarenal conversion of 25D to 1,25D operates at concentrations below the kM for the tissue 1 -α-hydroxylases; hence, serum 25D concentration limits the amount of 1,25D a tissue can synthesize when its cells are stimulated to produce a vitamin D-dependent response. While there is no consensus as to the optimal serum 25D concentration, there is also no disagreement about the importance of the substrate, regardless of which concentration may be deemed optimal.

Input of D3, a factor that manifestly affects 25D concentration, has been the subject of much of the previous discussion. Attention is now focused on the effect on serum concentration of 25D produced by variations in body size and in D3 output, i.e., utilization and/or degradation of the 25D in serum.
Obesity

One widely recognized influence on 25D concentration is obesity, with serum 25D being lower in obese individuals. This was originally attributed to a phenomenon termed “sequestration” (implying trapping of vitamin D in adipose tissue of obese individuals).71 However, Drincic et al.72 have shown that simple volumetric dilution is both a more logical explanation and one that fully explains the weight-based difference. Curiously, body mass index works in various regression models almost as well as body weight (and somewhat better in some datasets). This is surprising as body mass index is not a measure of mass but of fatness. The reason is presently unclear, and this observation suggests the possible existence of further mechanisms operating in obese individuals.
Parathyroid hormone-1,25D axis  Clements et al.60–62 showed that 25D half-time in serum ranged from 15 to >35 days, with 25D half-time being inversely related to parathyroid hormone concentration. The parathyroid hormone effect, noted both in patients with hyperparathyroidism and in animals subjected to calcium deprivation, was, in turn, mediated by serum 1,25D concentration. Why 25D utilization (or degradation) should rise in the face of calcium need is physiologically unclear, particularly as renal 1,25D synthesis is not as dependent on 25D concentration as the autocrine functions of vitamin D.

Inflammation.  The other major influence on serum 25D concentration is inflammation. It has been reported that vitamin D status is reduced in the face of systemic inflammatory processes.73–78 For example, Duncan et al.75 reported an inverse correlation of 25D with serum C-reactive protein, with 25D being 40% lower as serum C-reactive protein rose from <5 mg/L to >80 mg/L. Autier et al.,79 in a metaanalysis of the several reports on this relationship, confirmed the existence of the association but attributed the reduced vitamin D status to underlying illness rather than to the inflammation itself. That conclusion may be partly correct, at least for some chronic illnesses, but it cannot apply to the many documented cases in which vitamin D status drops acutely across an inflammatory episode, as with total knee arthroplasty.73,77 In one case study, Henriksen et al.73 reported a 12% drop in 25D by day 2 after total knee arthroplasty and a nearly 80% drop by post-surgery week 8. Reid et al.77 evaluated a series of 33 patients who underwent total knee arthroplasty and reported an approximate 40% drop in total 25D and a 33% drop in calculated free 25D by day 2 after surgery, which was associated with large increases in C-reactive protein.

Decreases in 25D of this magnitude and rapidity cannot be explained by decreased synthesis and must, therefore, reflect increased utilization, degradation, or loss. Depending on which values may be estimated for the total 25D mass (see above), reductions in 25D concentration of the size reported by Reid et al. translate to a loss of several hundred micrograms from the body, which is substantially greater than ordinary daily utilization of vitamin D. While increased utilization cannot be ruled out, it seems unlikely to be the sole explanation. Another possibility, which was suggested by Waldron et al.,76 is the loss of DBP (with its bound ligand) in the urine. In 30 patients undergoing elective orthopedic surgery, the ratio of DBP to creatinine in urine rose 2.5× by the second day post-surgery; this was associated with a >20-fold increase in C-reactive protein. Renal loss could certainly explain much or all of the change in 25D observed in these studies and could be the result of interference with the kidney’s megalin–cubilin system, possibly produced by the anesthesia or inflammatory cytokines associated with the surgery.

Although not directly related to the major focus of this review, the conclusion reached by several of the authors of the studies just reviewed, i.e., that, while inflammation clearly reduced D status, this reduction was without nutritional significance, is in no way supported by data in any of the papers concerned, nor is it consistent with the importance of serum 25D concentration as the principal limiting factor in the autocrine pathway.

METABOLISM AND UTILIZATION   the data assembled here make clear that, even with today’s widespread vitamin D inadequacy, total vitamin D inputs are far higher than previously thought, food sources are greater than previously recognized, and solar input, though theoretically capable of fully meeting any plausible vitamin D requirement, is actually only a minor present-day contributor to total vitamin D input at the population level. That does not mean that the human requirement is more easily met. Rather, it indicates that the requirement is higher than previously recognized, with populations still short of meeting that requirement by the amount needed to move prevailing serum 25D concentrations from current values to putatively healthier levels.

These analyses also make clear that at prevailing inputs (i.e., <4,000 IU/day), D3 is rapidly 25-hydroxylated and little D3 circulates in the blood or is shunted into adipose tissue for storage. Additionally, the recent recognition that oral 25D may raise serum 25D to a significantly greater extent than does oral vitamin D suggests the possibility of a hitherto little recognized or explored intracellular pathway in which the entire metabolic sequence is handled within certain target tissues and is not reflected in blood. A related finding in this respect is the importance of a maternal serum D3 concentration sufficient to support production of human milk capable of meeting infant needs for vitamin D.

Several of these insights have implications for the human requirement. For example, the vitamin D input needed to support an adequate amount of vitamin D in human milk has implications not just for lactation but also for human success as a species under presupplementation conditions. Inadequate vitamin D input in newborns would be expected to lead to skeletal abnormalities (for which the paleo-fossil record provides no evidence), in addition to possible consequences for immune system development.89 A total input of approximately 6,000 IU in modern humans equips them to feed their infants with a nearly full range of the nutrients needed for healthy growth.

CONCLUSION    Precise quantification of vitamin D inputs, transfers, conversions, and compartment sizes are essential for a full understanding of how the human body utilizes this essential micronutrient, why it is important, and what the consequences are of an inadequate vitamin D input.

Since its founding, the U.S. Preventive Services Task Force (USPSTF) has  provided  firm evidential base for early detection strategies, evaluating such screening methods as mammography and prostate-specific antigen testing. Although it has also evaluated a few interventions, its predominant focus has been testing for markers that identify persons at risk who are likely to benefit from preventive action. Only recently has  USPSTF entered  the (mine)field of nutrition, a territory distant from screening tests and risk assessment, with different and unfamiliar landmarks.

The USPSTF now reports it is unable to find evidence for or against vitamin D deficiency testing  (1),  the likely reasons being the absence of a scientific consensus on both the level of vitamin D status that should be judged “deficient” and what the measurable manifestations of deficiency might be. These are also issues for many other nutrients, such as folate, ascorbate, calcium, and protein. Vitamin D may have seemed to offer a way out of this confusion because serum 25-hydroxyvitamin D [25-(OH)D] concentration is generally recognized as one of the best indices of status for any of a broad array of nutrients. Also, it is now readily measurable and widely utilized.                 

One of the reasons its promise has not been realized is that most studies of vitamin D efficacy have used a disease-avoidance model, which is the standard approach used by the Institute of Medicine (IOM) for most nutrients (2). Furthermore, disease prevention is the explicit focus of the USPSTF. Nevertheless, the IOM and USPSTF approaches effectively equate health with the absence of disease, an equivalence that nutritionists have long rejected. Instead, nutritionists focus on full nutrient repletion when possible. The inevitable gap between disease prevention and nutrient repletion is still largely unexplored territory. For many nutrients, it can be surprisingly wide, as suggested in this case by studies of the intake required to provide vitamin D in human breast milk in quantities sufficient to meet the needs of infants (3). The IOM’s adult requirement for vitamin D is 600 IU/d (4), which is judged to be sufficient to protect against osteoporotic fracture. In contrast, quantitative and empirical evidence indicates that vitamin D intake from breastfeeding needs to be approximately 6000 IU/d (3, 5). Although high compared with the adult recommendation, such an intake almost exactly reproduces the measured vitamin D status of contemporary Africans leading ancestral lifestyles (6). Such populations provide perhaps our best window on vitamin D levels prevailing during the millennia over which human physiology was adapted to its environment by natural selection.

Whatever the actual requirement or 25-(OH)D cutoff may be, there is another likely reason that the evidence is unclear. The USPSTF drew from systematic reviews and meta-analyses of studies of vitamin D effects, such as the one accompanying the current report (7). In general, the criteria for including studies in such reviews are methodological rather than biological. Of the 6 published biological criteria (8) for including published reports in meta-analyses, the review published in this issue met only 2 (comparable basal status and same chemical form), and several of its component studies met none. Including studies that could never have been informative in the first place (especially when they are large) inevitably biases any review toward the null.

What seems not to have been widely appreciated is that vitamin D exhibits flat response regions at both low and high values of vitamin D status, with a sharp rise in the approximate center of the physiologic range of 25-(OH)D values (8). Studies like the WHI (Women’s Health Initiative), which enrolled women with low vitamin D status values and used a vitamin D dose insufficient to move them into the response range, provide little useful information about vitamin D efficacy. Yet, precisely such studies were included in the review by LeBlanc and colleagues (7). This is not to criticize the WHI, which was designed more than 20 years ago (before vitamin D pharmacology was well-understood), but it is to criticize contemporary reviews and meta-analyses that fail to take advantage of newer information or to use critical biological criteria (8) for selection of studies for analysis of biological effects.

In addition, a disease-avoidance approach becomes problematic for micronutrients in general (and vitamin D in particular) when one understands that micronutrients do not actually cause any of the effects simplistically attributed to them. Although necessary for cell response, such micronutrients by themselves do not initiate or cause the response concerned. For example, vitamin D is a component of the biochemical apparatus that opens the genome to allow access to DNA information needed for a particular cell or tissue response. In terms of cell function, this dependence means that when supplies of the micronutrient are inadequate, cellular response is blunted. This is dysfunction, but not clinically manifest disease. Such dysfunction may indeed lead ultimately to various diseases, but disease prevention remains a dull tool for discerning the defect, and a disease-prevention approach clearly does not measure whether the organism has enough of the nutrient to enable appropriate physiologic responses, such as lactation.

Finally, and aside from the USPSTF’s findings, one must ask whether treating without first testing is sound practice. Certainly, it would be rational to do so if the condition being treated is prevalent and the treatment is safe and inexpensive. That is the case with another micronutrient, iodine, and the iodination of salt. However, the current situation is different because getting sufficient iodine generally does not require conscious adherence to a particular regimen, whereas taking vitamin D does. Usually, testing improves patient adherence because it provides patient-specific, personally applicable information. General assurances that one probably needs extra vitamin D are not as compelling a motivator as knowing one’s number. Thus, whether the practitioner adheres to the widely divergent guidelines of the IOM (4), the Endocrine Society (9), or the American Geriatrics Society (10), measuring vitamin D status seems to be warranted, not so much to diagnose deficiency but to determine patient status relative to the selected guideline.

THE NEAR-IMPOSSIBILITY  OF OVERDOSING WITH VITAMIN D3 – except  by persistent repeated  injection  A Report  in Feb 2014 from Bansai & Arora ea New Delhi show how  extreme the overdose of vitamin D3 must be to cause hypercalcemic toxicity: an Asian  woman given 6million iu  imi over 10 days  after knee surgery presented 2 months later with 6 wks of persistent vomiting, fatigue, with moderate hypercalcemic renal failure  and 25OHvit D level of 150ng/ml; that normalized in 2 weeks.. So her peak level after the initial 2 weeks on an average ~50 000iu/day may have been around 500-600ng/ml..  Bansai and Arora quote two series from  endemically vit D deficient Kashmir (Pandita ea 2012 in Jammu and 2011  Koul ea Srinagar)   of a total 25 elderly  given chronic overdoses  D3 600 000iu monthly , who were found to have similar moderate hypercalcemia and renal failure with peak 25OHvit D of 100 – 300ng/ml: a mean vit D3 dose of between 20 000iu and >1million iu/day?, mean s. creat 2.5; mean 25OHvitD of 100 – 200ng/ml; mean calcium 13.1mg/dl. 20 000iu a day indefinitely in these frail small elderly averages at least 400iu/kg/day, at least 5 times the chronic recommended dose in the literature the past decades- and to boot, routinely given them with a highdose calcium supplement- when it is rather magnesium that should if any be boosted. .  Koul ea do note that about 100 000iu vit D a day ongoing  is required to cause hypercalcemia, the mean lethal dose being about 8million iu.

By contrast, previous reports below- eg from the Netherlands report of 2million iu single  overdose  in  90 year olds; and planned 600 000iu orally monthly dose in Pakistani men  wasted with TB (Salhuddin ea below)   showed no overdose signs.  So a single loading dose of 1 to 2  million units is unlikely to give overload. By these  precedents (eg 600 000iu p.o monthly- apparently official policy of the Pakistani Endocrine Society) one may  in acute infections  give up to 600 000iu as a loading dose (a million in an obese ill patient) in acute infection situations, then 50 000- 80 000iu weekly depending on weight, to maintain level around 90ng/ml.

Am J Clin Nutr March 2008  Pharmacokinetics of a single, large dose of cholecalciferol 100 000iu  IlahiArmas, and  Heaney   Creighton University Medical Center, Omaha,  Design: followed for 4 mo, 30 subjects were  supplemented with a single oral dose of 100 000 IU cholecalciferol. 10 subjects served as a control group to assess seasonal change of calcidiol.   The subjects were healthy with limited sun exposure (<10 h/wk) and milk consumption (<0.47 L daily);  excluded granulomatous conditions, liver disease, kidney disease, or diabetes or  taking anticonvulsants, barbiturates, or steroids.  Results: Serum calcidiol rose promptly after cholecalciferol dosing from a mean (±SD) baseline of 27.1 ± 7.7 ng/mL to a concentration maximum of 42.0 ± 9.1 ng/mL. Seven percent of the supplemented cohort failed to achieve 32.1 ng/mL at any time point. The highest achieved concentration in any subject was 64.2 ng/mL. The control group had a nonsignificant change from baseline of −0.72 ± 0.80 ng/mL during 4 mo.   Conclusions: Cholecalciferol (100 000 IU) is a safe, effective, and simple way to increase calcidiol concentrations. The dosing interval should be ≤2 mo to ensure continuous serum calcidiol concentrations above baseline.

THE IMPORTANCE OF IMMUNOSYNERGY BETWEEN ADEQUATE ANABOLIC HORMONES- VIT D3, MELATONIN (Berman 1926, Carrillo-Vico 2013), AND PROGESTERONE   in planned and current pregnancy, and aging?  Thangamani, Kim ea Purdue & Indiana Universities in   J Immunol. 2014 Dec 29:  Cutting Edge: Progesterone Directly Upregulates Vitamin D Receptor Gene Expression for Efficient Regulation of T Cells by CalcitriolThe two nuclear hormone receptor ligands progesterone and vit.D play important roles in regulating T cells.., we report that progesterone is a novel inducer of vit.D receptor (VDR) in T cells and makes T cells highly sensitive to calcitriol even when vit. D levels are suboptimal. This novel regulatory pathway allows enhanced induction of regulatory T cells but suppression of Th1 and Th17 cells by the two nuclear hormones. The results have significant ramifications in effective regulation of T cells to prevent adverse immune responses during pregnancy.

A recent review of vitamin D from Mike Holick (Boston Mass.) and a German team  again reminds us of two opposing forces limiting natural sunshine vitamin D supply: on the one hand the skin shuts down active vit D production if the sunlight burns, while on the other, there is simply not enough sunlight  beyond  35degrees latitude from the equator. Thus Germany and Canada-northern USA for example, at >45degrees north,  get far too little sunlight for vit D needs ; eg London is at 51degrees north; Cape Town-Florida-San Diego, Sydney-Buenos Aires, Hawai  and the Med. countries are at the 35degree south latitude. Even this close to the equator, many overdress- especially more observant religious  women-  and thus minimize  benefit from summer sunshine.

J Assist Reprod Genet. 2014 Dec 30.Vitamin D and assisted reproductionvitamin D should be routinely screened and repleted prior to ART? Pacis , Segars ea Dartmouth-Hitchcock Medical CenterLebanon NH  systematic review.  review  current literature regarding the role of vitamin D status & repletion  in pregnancy outcomes in women undergoing assisted reproductive technology (ART).  Thirty-four articles were retrieved, of which eight met inclusion criteria. One study demonstrated a negative relationship between vitamin D status and ART outcomes,  two studies showed no association. The remaining five studies concluded that ART outcomes improved after vitamin D repletion.The majority of reviewed studies reported a decrement in ART outcomes in patients with vitamin D deficiency. Cost-benefit analyses suggested that screening and supplementing vitamin D prior to ART might be cost effective.

25 Dec 2014 ANOTHER AVOIDABLE TRAGIC  TB DEATH:   Dr Nerissa Pather and countless other infectious disease sufferers – health workers and their patients :

 Sunshine Cures:  why did TB  sanatoria work (before there were  antibiotics)? was it indeed the boost of copious sunshine secosteroid antimicrobial soltriol in the skin destroying the M TB porphyrins? or was it belief, then-cleaner  air, high altitude,    rest, care and better nutrition?

Not for nothing was  skin ie CTB  Lupus Vulgaris a relentless scourge  in the clothed  in darker climes and times, except perhaps in ancient sunny Pharanoic medicine, until the Danish Faroe Islander   physician Niels  Finsen-  trying to treat his own Niemann–Pick disease–  used his  invention phototherapy generator on his patients  and found that it magically rolled back skin TB (for which in  1903 he  got the only Nobel prize  apparently ever awarded for dermatology!). This light therapy antimicrobial effect has recently 2005 been attributed by Danish researchers    Møller,  Wulf ea  to the lethal effect of light oxidation on Mycobact  TB porphyrins.    However, this Danish study abstract ignores the antimicrobial benefit of cholecaliferol activated by light on the skin from  the Karolinska Inst in Sweden. A Georgetown Univ paper 2005 details the complexities of   Sunlight, Vitamin D, and the Innate Immune Defenses of the Human Skin , further set out in Optimal Skin Protection with  Vitamin D.    Unfortunately the circle is not yet squared off, there is still no study showing that vitamin D (like bcarotene and likely  melatonin) improves the disease porphyria?

A recent 2009 Mt Sinai NY report of a case of CTB cutaneous TB stresses how rare this skin complication is despite the increasing spread of TB with AIDS- perhaps partly because of the higher prevalence of HIV in poorer peoples in sunnier warmer ie relatively better sunshine-cholecalciferol-endowed climates.

We easily make our optimal vit D3 ~100iu/ kg per day living playing and working outdoors in warm lands. But since we dress more in cooler climates, with aging and dress-conservative cover-up tribal eg Arabic and Hasidic and Mormon customs; and avoid sunburn, and from early middle age lose 3/4 of our skin vitamin D production by 70years, we  aging thus need the bulk of our vit D requirements as supplements ie ~7000iu/day or 50 000iu/week.

A century ago, TB, polio, measles, scarlatina, and syphilis were rampant, and infections rather than wars killed most – ending in the 1919 flu holocaust that devastated the family of Dr Sir  Arthur Conan Doyle (whereas the Flu pandemic took just  one of my   parents’ score of siblings- and polio just left my Mom with a limp..)..

2014  is the centenary  of  recent  recognition of the  cod liver oil  antirickets steroid factor – calciferol/soltriol -briefly misnamed “vitamin”  D – by McCollum, Davis (USA 1913)  and Mellanby(UK); so that in 30 years  by 1945, rickets had been all but abolished in USA. But the recognition of the antirachitic factor was facilitated by discovery in the preceding decade of vitamins A, B and C. The antiscurvy benefit of fresh uncooked coloured crops (and thus their juice)  had indeed been recognized for millennia – eg the Royal  Navy limejuice- , but a specific micronutrient vitamin deficiency  was first only recognized in 1907. Vitamin C ascorbic acid  identification also took another 25years . For 90 years, it has been recognized that a  lightly cooked exclusively fatty meat diet can provide enough vitamin C (let alone all micronutrients)  for  health in eg  atheroma- and scurvy-free Eskimos and anyone who cares to eat thus (Stefansson ) .

Sadly, the lifegiving vitamins have  been diluted,  all but eliminated from retail bottled codliver oil, a ml  of which now generally supplies perhaps only 125iu vit D, and vitamin A 1000iu … So even a tablespoon supplies only about 1200iu vit D.. The Weston Price Foundation discusses  why modern commercial codliver oil is good with its balance of vits A and D– but the vitamin D level is  still  far too low for cooler darker countries.  However we recommend, (apart from far cheaper vit D3 powder 50 000iu/1ml scoop) – a tsp cod liver oil at least 3 times a week because it is the cheapest natural- and with Scandinavian manufacturing controls, safe-  source of vital  EPA+DHA available as well as some vitamins A and E.

As real summer begins here between the southern oceans,  cold winter in the northern hemisphere, we must constantly remind that vitamin D3 cholecalciferol  is NOT an  exogenous vitamin ie a biological  nutrient essential (Funk’s ‘vitamine’, shortened by Jack Drummond  because they are not amines to the more appropriate ‘vitamin’) in the human diet ( like vits A, B, C, E & K) because humans cannot make them. . But since we make  vit D  with light exposure of our skin, since most humans dont get enough sunlight on our skin,  it is certainly  a conditioned essential anabolic steroid, which like other anabolic steroids (the balance especially of androgens) is vital at optimal blood levels through life for optimal health,  healthspan.

Unlike the real vitamins and essential minerals,  Calciferol is (like eg  CoQ10,  alphalipoic acid, nitric oxide, EPA and DHA)   made in limited quantities in humans with adequate organ function and sunshine; but none of them generally in anywhere near optimal quantities for healthspan against all diseases. So given humans’ capacity to live well to a century, we need such supplements from youth to ensure chronic health so as to die of old age in good health. .

How does this relate to the death this month of Dr Nerissa Pather? Multiresistant TB contracted on duty 12 years ago  eventually killed her,    whether or not such  high-risk people are  ever advised to take the best prevention- zinc, selenium, multivites but especially highdose vit C and D3.

D3  bio-insufficiency fragility and  dysimmunity  is further complicated  since to  correct  it requires both plenty of skin sunshine exposure, eaten vitamin C and it’s daughter cholesterol,   and optimal kidney and liver  function. Even then optimal vitamin D3 bloodlevel and effect may be blocked by foolhardy cholesterol blockade eg statins, and  by excess intake and thus bloodlevel of vitamin D2 ergocalciferol – which   authorities eg in South Africa and USA  still negligently promote/ dispense as the dangerously misnamed “strong calciferol”. It is indeed D3 cholecalciferol, not D2   that is the miracle sunshine strong calciferol steroid;  egocalciferol dominance, like insulin and estrogen  dominance,  is  harmful, and can and must  be avoided. .

So it is increasingly apparent that, just as intake/manufacture of  vitamin C the true sunshine vitamin (those colourful veg/ fruit orchards etc) , and  thence cholesterol, should each be at least a few gms a day, the human  (clothed indoor-dwelling) adult synthesis +  intake  of sunshine hormone  vitamin D3 soltriol  should be nearer to 10 000iu ie 250mg/day, or more practically 50 000iu  vit D3 a week  (at a trivial supplement  cost of eg R6/month or $5 a year) for a bigger adult- especially in longer darker winter (starting with perhaps  about 25000iu every fortnight  for babies) .. of course balanced  in most societies with the other supplements especially water, vitamin K2, zinc, selenium iodine  and magnesium (and iron for children and reproductive mothers) .

So, how many more millions must suffer and die from lack of the cheapest, best, safest conditioned essential antimicrobial antioxidant anabolic nutrients available?

An undated (post 2003) Pharmacology Bulletin from Canterbury NZ at least gives conservative  realistic vit D3 advice: a loading dose of D3  500 000iu , then 50 000iu/month. This compares with our routine loading dose of about 200 000 to 400 000iu to start, then 50 000iu every week or two (proportionate to body mass and illness). But Lennons here negligently still continues to  advertise their Strong Calciferol datasheet (updated 2004) as calciferol- last year they in fact confirmed it is D2 ergocalciferol, not cholecalciferol. Only their website http://www.ndrugs.com/?s=lennon-strong%20calciferol confirms that their strong Calciferol is D2;  whereas they also make low strength D3 tabs.

From today’s press “The South African Medical Association (SAMA) extends heartfelt condolences on  the passing of 38yr old Dr Nerissa Pather on  18th December 2014 . Whilst on community service at a  Kwazulu Natal clinic, Dr Pather contracted well-publicised multi-drug resistant spinal TB in 2002 , that rendered her paralyzed and in constant pain. The loss  to a communicable disease acquired in the course of duty is an incalculable tragedy. SAMA reiterates its call to all health departments and facilities to ensure that  basic TB prevention methods are available to all healthcare workers in our facilities. Sadly, this is not the case in many of our hospitals and clinics and continues to place health professionals at enormous risk. The potential consequences of infection and even acquiring drug resistant TB are tragically evident in the death of Dr Pather.  SAMA bows its head to a colleague who has paid the ultimate price in caring for her fellow human beings.”

A current report from Tehran  Calcium and vitamin D plasma concentration and nutritional intake status in patients with chronic spinal cord injury: stresses the  obvious, the  terribly low intake and levels of vitamin D in spinal cord injury patients. Why are we inflicting this further deprivation on the most vulnerable patients?

The tragedy is that with general authoritarian nihilism about universal vitamin supplements- some calling their promotion  quackery- unrecognized  deficiency eg  vit D3, rickets,  and vit C scurvy  are on the increase even in the more affluent eg USA and in sunnier climates- especially with increasing geriatrics and the frail surviving with eg HIV, TB, cancer, chronic bowel disease,   gross overuse of warfarin (vit K deficiency) and  statin (CoQ10 deficiency) etc. .

Vitamin D Deficiency in Critically Ill Patients  is rarely considered or treated .. N Engl J Med 2009 Lee, Eisman & Center   studied vitamin D status in ICU patients  referred to   St. Vincent’s Hospital, Sydney in  2007. Among approximately 1100 ICU patients per year, the mean  25-hydroxyvitamin D in 42 referred patients was ~17ng per milliliter, with a high prevalence of hypovitaminosis D . Moreover, three patients died (from metastatic thymic carcinoma, glioma, and lymphoma), and  had undetectable levels of 25-hydroxyvitamin D.   The current study of  ICU patients reveals high prevalence of hypovitaminosis D that was associated with adverse outcomes, independently of hypocalcemia and hypoalbuminemia. Supplementation with  vitamin D (at a mean dose of 820 IU per day) before admission was not protective.   Vitamin D deficiency is associated with increased mortality.However, vitamin D has pleiotropic effects in immunity, endothelial and mucosal functions, and glucose and calcium metabolism. The association between hypovitaminosis D and common conditions (e.g., the systemic inflammatory response syndrome, septicemia, and cardiac and metabolic dysfunctions) in critically ill patients may be important. Vitamin D–deficient and vitamin D–insufficient states may worsen existing immune and metabolic dysfunctions in critically ill patients, leading to worse outcomes.  A total of 17% of  ICU patients in our study had undetectable levels of vitamin D. hypocalcemia was identified as a reason for referral in only 5% of the patients. These findings highlight the need for consideration of vitamin D status and supplementation in patients in the ICU.

Arch Intern Med. 2008;168:1629-37 25-hydroxyvitamin D levels and risk of mortality in the general population.   Melamed , Astor ea. Albert Einstein College of Medicine, NY tested the association of low 25(OH)D levels with all-cause, cancer, and cardiovascular disease (CVD) mortality in 13 331 nationally representative adults 20 years or older from the NHANES III linked mortality files.  In patients on  dialysis, therapy with  vitamin D agents is associated with reduced mortality. Observational data suggests that low  (25[OH]D) are associated with diabetes mellitus, hypertension, and cancers. However, whether low serum 25(OH)D levels are associated with mortality in the general population is unknown.   Participant vitamin D levels were collected from 1988 through 1994, and individuals were passively followed for mortality through 2000.    RESULTS:  In cross-sectional multivariate analyses, increasing age, female sex, nonwhite race/ethnicity, diabetes, current smoking, and higher body mass index were all independently associated with higher odds of 25(OH)D deficiency (lowest quartile of 25(OH)D level, <17.8 ng/mL , while greater physical activity, vitamin D supplementation, and nonwinter season were inversely associated. During a median 8.7 years of follow-up, there were 1806 deaths, including 777 from CVD. In multivariate models , compared with the highest quartile, being in the lowest quartile (25[OH]D levels <17.8 ng/mL) was associated with a 26% increased rate of all-cause mortality (mortality rate ratio, 1.26; 95% CI, 1.08-1.46) and a population attributable risk of 3.1%.    The lowest quartile of 25(OH)D level (<17.8 ng/mL) is independently associated with all-cause mortality in the general population.

ANABOLIC STEROID SYNERGY?: the steroids cholecalciferol and androgen are both immune and anabolic -switch  protein/muscle/bone promoters, without apparent mutual antagonism or suppression; calciferol also lowers SHBG levels, freeing up more active unbound testosterone ie reducing estrogen dominance.

 Subst Abuse Rehabil. 2014 Dec 10;5:121-7. Effects of different doses of testosterone on gonadotropins, 25-hydroxyvitamin D3, and blood lipids in healthy men. Gårevik, Ekström ea. At the Karolinska Inst Sweden,   Twenty-five healthy male volunteers aged 27-43 years were given 500 mg, 250 mg, and 125 mg of testosterone enanthate as single intramuscular dosesAll doses investigated suppressed the LH and FSH concentrations in serum. LH remained suppressed 6 weeks after the 500 mg dose. These results indicate that testosterone has a more profound endocrine effect on the hypothalamic-pituitary-gonadal axis than was previously thought. There was no alteration in 25-hydroxyvitamin D3 levels after testosterone administration compared to baseline levels. The 250 and 500 mg doses induced decreased concentrations of ApoA1 and HDL, whereas the lowest dose (125 mg) did not have any effect on the lipid profile.

Pediatrics. 2014 Dec . Rapid Normalization of Vitamin D Levels: A Meta-Analysis.  McNally. Menon ea @Univs Ottowa, Thailand & Ireland  systematically reviewed pediatric clinical trials administering high-dose vitamin D to evaluate  (25[OH]D) response and characteristics of  final 25(OH)D levels . Uncontrolled and controlled trials reporting 25(OH)D levels after high-dose (≥1000 IU) ergocalciferol or cholecalciferol were selected. Two of 6 studies that administered daily doses approximating the Institute of Medicine’s Tolerable Upper Intake Level (1000-4000 IU) to vitamin D-deficient populations achieved group 25(OH)D levels >75 nmol/L within 1 month. Nine of 10 studies evaluating loading therapy (>50 000 IU) achieved group 25(OH)D levels >75 nmol/L. In meta-regression, baseline 25(OH)D, regimen type, dose, age, and time factors were associated with final 25(OH)D levels. Adverse event analysis identified increased hypercalcemia risk with doses >400 000 IU, but no increased hypercalcemia or hypercalciuria with loading doses <400 000 IU (or 10 000 IU/kg). Few studies in adolescents evaluated loading dose regimens >300 000 IU.
CONCLUSIONS:   Rapid normalization of vitamin D levels is best achieved by using loading therapy that considers disease status, baseline 25(OH)D, and age (or weight).

Diabetes Res Clin Pract. 2014 Dec A randomised controlled trial of ‘high” dose vitamin D in recent-onset type 2 diabetes .Elkassaby,  Fourlanos ea, Melbourne Australia.  Vitamin D insufficiency is associated with impaired pancreatic beta-cell function. Fifty adults with type 2 diabetes diagnosed less than 12 months, with normal baseline serum 25-OH D (25D), were randomised to 6000IU D (n=26) or placebo (n=24) daily for 6 months. In the D group, median serum 25D (ng/ml) increased from 24 to 60 (3 months). change in FPG (mmol/l) was significantly lower in D (-0.40) compared to placebo (+0.1) (P=0.007), as was the change in PPG in D (-0.30) compared to placebo (+0.8) (P=0.005). Change in HbA1c (%) between D (-0.20) and placebo (-0.10) was not different (P=0.459). At 6 months, changes from baseline in DCP, FPG, PPG and HbA1c were not different between groups.    ie modest Oral D3 supplementation   in type 2 diabetes was associated with transient improvement in glycaemia, but without a measurable change in beta-cell function.  this effect is unlikely to be biologically significant. This modest   dose D3  ie 42000iu/ week to eventual bloodlevel of only 50ng/ml therefore appears to offer little or no therapeutic benefit in type 2 diabetes.   THE DOSE THEY USED IN FACT PRODUCED STEADYSTATE VIT D3 LEVEL HALF THE POSTULATED TARGET LEVEL OF 90-100 ng/ml FOR SERIOUS ILLNESS.

J Asthma. 2014 Nov  Efficacy of high-dose vitamin D in pediatric asthma: a systematic review and meta-analysis.
Pojsupap , McNally ea Univ Ottowa :   studies  suggest a relationship between vitamin D status and asthma-related respiratory outcomes.  benefit of vitamin D supplementation for pulmonary function, symptoms and exacerbations is not well established.   Clinical trials reporting asthma-related respiratory outcomes following vitamin D administration at a dose equal or greater than 500 IU per day were included. Results:  five studies  met study eligibility and assessed final data synthesis. The median trial size was 48 participants (range 17-430) and the average daily dose of cholecalciferol ranged from 500 to 2000 IU/day. Meta-analysis suggested a statistically significant reduction (RR 0.41, CI 0.27-0.63) in asthma exacerbation with vitamin D therapy.

   J Infect Dis. 2013 Feb .  Vitamin D status and incidence of pulmonary tuberculosis, opportunistic infections, and wasting among HIVinfected Tanzanian adults initiating antiretroviral therapySudfeld,  Fawzi ea . Maintaining vitamin D sufficiency may decrease the incidence of pulmonary tuberculosis and other infectious diseases. We present the first prospective study of vitamin D among human immunodeficiency virus (HIV)-infected adults receiving antiretrovirals in sub-Saharan Africa.   Serum 25(OH)level was assessed at antiretroviral therapy (ART) initiation for 1103 HIVinfected adults enrolled in a trial of multivitamins (not including vitamin D) in Tanzania.After multivariate adjustment, vitamin D deficiency (defined as a concentration of <20 ng/mL) had a 3 fold significantly greater association with incident pulmonary tuberculosis, compared with vitamin D sufficiency (HR, 2.89;  [CI], 1.31-7.41; P = .027), but no association was found for vitamin D insufficiency (defined as a concentration of 20-30 ng/mL; P = .687). Deficiency was also significantly associated with incident oral thrush (HR, 1.96; 95% CI, 1.01-3.81; P = .046), wasting (HR, 3.10; 95% CI, 1.33-7.24; P = .009), and >10% weight loss (HR, 2.10; 95% CI, 1.13-3.91; P = .019). Wasting results were robust to exclusion of individuals experiencing pulmonary tuberculosis. Vitamin D status was not associated with incident malaria, pneumonia, or anemia.

update 22 Dec 2014:  as the solstice rolls by,  infections especially viral  flourish north and south,  from flu to gastro , HIV to ebola; HPV  to HZV to childhood exanthems;

so more reason to aim for optimal growth, mental and physical health with the peak anabolic antidepressant energizing anticancer antiinfective steroid –  cholecalciferol D3 – intake and levels.   About 65 000iu a week (with my multivit-multimineral combo)  puts my measured trough 25OHvit D  bloodlevel at 92ng/ml with normal blood calcium. Women can live long  without much androgen apart from frail bones, but not well without vigorous cholecalciferol D3 intake. Humans who live mostly bare  mostly outdoors- us  naked apes-  most of the year closer to the equator  make plenty of D3 from sunshine; but the darker our skins, the sooner vit D production shuts down; so  most of us need vigorous D3 supplement costing perhaps US$6 a year retail. .

update 19 Nov 2014  when this column on vit D started 5 years ago, there were 46000 vit D entries on Pubmed- this has mushroomed 40% to 61000 (compared now to 46000 on vit A; to 53000 on vitamin C; 37000 on vitamin E; 17000 on vit K; and 133000 on all  the 8 B vitamins ); whereas in 2009 there were 272500 entries on all vitamins– now up only 22% to 335 000. ie the papers on the secosteroid  vitamin D have risen at double the rate of the  vitamins.. (D3  C27H44O and D2 C28H44O, vs testosterone C19H28O2).

As the end-of-year solstice approaches, its time to review the crucial role of giving vigorous doses of vitamin D3, whether via   non-burn sunshine, or via the correct lowpressure tanning bed, or directly as vitamin D3  (not vit D2) supplement as appropriate TOGETHER WITH A MULTINUTRIENT PLUS EXTRA MAGNESIUM AND VIT K2. . Ironically, dermatologists would recommend vit D supplement not suntan for what many  consider the wrong reason- that suntanning does more harm than good, which it doesnt. :

at least THIRTEEN   VIT D  studies the past 16 years  SINCE 1998, from ~8 nations-  USA, Canada, Belgium, Spain , Germany, Denmark, UK  &  New Zealand,   – show  POORER   RESULTS  FROM TAKING TOO LITTLE VIT D; OR FROM USING VITAMIN D2 not D3, apparently by suppressing the crucial vit D3 level, and because vit D2 is metabolized faster. :

a new OBSERVATIONAL study in Am J Clin Nutr. Nov 2014  from the Cambridge EPIC-NORFOLK  group by  Kay-Tee Khaw,  Nicholas Wareham ea   Serum 25-hydroxyvitamin D, mortality, and incident cardiovascular disease, respiratory disease, cancers, and fractures: a 13-y prospective population study    examined prospective relation between serum  [25(OH)D] concentrations [which comprised 25(OH)D3 and 25(OH)D2] and subsequent mortality  in 14,641 men and women aged 42–82 y in 1997–2000  in Norfolk, UK followed up to 2012; categorized into 5 groups according to baseline serum concentrations of total vit D from below 30nmol/L to above 90nmol/L..  mean serum total 25(OH)D was 56.6 nmol/L 22ng/ml, which consisted predominantly of 25(OH)D3 (mean: 56.2 nmol/L; 99% of total). The age-, sex-, and month-adjusted HRs  for all-cause mortality (2776 deaths) for men and women by increasing vitamin D category were 1, 0.84 (0.74, 0.94), 0.72 (0.63, 0.81), 0.71 (0.62, 0.82), and 0.66 (0.55, 0.79) (P-trend < 0.0001). When analyzed as a continuous variable and with additional adjustment for body mass index, smoking, social class, education, physical activity, alcohol intake, plasma vitamin C, history of cardiovascular disease, diabetes, or cancer, HRs for a 20-nmol/L increase in 25(OH)D were 0.92 (0.88, 0.96) (P < 0.001) for total mortality, 0.96 (0.93, 0.99) (P = 0.014) (4469 events) for cardiovascular disease, 0.89 (0.85, 0.93) (P < 0.0001) (2132 events) for respiratory disease, 0.89 (0.81, 0.98) (P = 0.012) (563 events) for fractures, and 1.02 (0.99, 1.06) (P = 0.21) (3121 events) for incident total cancers.    Conclusions: Plasma 25(OH)D concentrations predict subsequent lower 13-y total mortality and incident cardiovascular disease, respiratory disease, and fractures but not total incident cancers. For mortality, lowest risks were in subjects with concentrations >90 nmol/L ie 36ng/ml, and there was no evidence of increased mortality at high concentrations, suggesting that a moderate increase in population mean concentrations may have potential health benefit, but <1% of the Norfolk population had concentrations >120 nmol/L 48ng/ml.

Chowdhury , Franco  ea  also University of Cambridge,  UK. BMJ. 2014 Apr .   Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies.    Study specific relative risks from 73 cohort studies (849,412 participants) and 22 randomised controlled trials (vitamin D given alone versus placebo or no treatment; 30,716 participants). In the primary prevention observational studies, comparing bottom versus top thirds of baseline circulating 25-hydroxyvitamin D distribution, pooled relative risks were 1.35 (95% confidence interval 1.13 to 1.61) for death from cardiovascular disease, 1.14 (1.01 to 1.29) for death from cancer, 1.30 (1.07 to 1.59) for non-vascular, non-cancer death, and 1.35 (1.22 to 1.49) for all cause mortality. Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements. In randomised controlled trials, relative risks for all cause mortality were 0.89 (0.80 to 0.99) for vitamin D3 supplementation and 1.04 (0.97 to 1.11) for vitamin D2 supplementation. The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics. However, for vitamin D2 supplementation, increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods.

in a systematic review and meta-analysisTripkovic ,, Lanham-New  ea . Univ Surrey  Am J Clin Nutr. 2012Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: In the collective 10 studies, 1016 participants aged 18–97 yrs, men to women  ∼1:3;  vitamin D3 had a significant and positive effect in the raising of serum 25(OH)D concentrations compared with  vitamin D2 (P = 0.001). When the frequency of dosage administration was compared, there was a significant response for vitamin D3 when given as a  BOLUS dose (P = 0.0002) compared with administration of vitamin D2, but the effect was lost with daily supplementation.. The studies were  in the United States, Canada, United Kingdom, Australia, Denmark, and Italy; all studies were single-center studies. Seven studies were conducted in healthy, free-living participants (4, 6, 7, 12, 13, 15, 17);

WE so far FIND AT LEAST 12 RELEVANT COMPARATIVE VIT D3/D2  TRIALS in humans and one in cows:

1.  Karen Hansen ea at Univ Wisconsin 2014  An evaluation of high-dose vitamin D for rheumatoid arthritis   show  that  giving vitamin D2  (not D3)  50 000iu fortnightly for a year is actually adverseIT DEPRESSES – perhaps halves – THE BIOLOGICALLY ACTIVE blood 25OHVIT D3 while boosting perhaps 5 fold the far less active blood 25OHvit D2 levels , and actually worsens  rheumatoid arthritis clinically and serologically .

     2. Vitamin D2 supplementation amplifies eccentric exercise-induced muscle damage in  athletes. Nutrients.  Nieman , Luo  EA. A, North Carolina  2013:6:63-75. Six weeks vit D2 (3800 IU/day) increased serum 25(OH)D2 fourfold  and decreased 25(OH)D3   by a fifth  versus placebo (p<0.001, p=0.036, respectively), with no influence on muscle function test scores, AND worsened  muscle damage .

    3. Swanson, Barrett-Connor, ea USA & Belgium May 2014 : In a cohort of older men,   Higher 25(OH)D2 is associated with lower 25(OH)D3 and 1,25(OH)2D3  , suggesting that vitamin D2 may decrease the availability of D3 and may not increase calcitriol.

4.Lehmann,  Dierkes ea  Germany 2013    in the same leading scientific journal  Bioavailability of vitamin D(2) and D(3) in healthy volunteers, a randomized placebo-controlled trial-  giving vit D2 2000iu/day for 8 wks in healthy volunteers actually halves the crucial 25hydroxy vit D3 level;  whereas giving vit D3 2000iu/d  doubles the vit D3 level. Earlier studies have suggested that vitamin D2 is less biologically active  than vit D3.

5. Biancuzzo, Holick ea Boston Mass. 2013 Serum concentrations of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in response to vitamin D2 and vitamin D3 supplementation  in healthy adults 18 to 79 years consuming 1000 IU vitamin D2 or vitamin D3 per day for 11 weeks at end of winter was analyzed.  Of the adults, 82% were vitamin D insufficient (serum 25-hydroxyvitamin D [25(OH)D <30 ng/mL]) at the start of the study. Administration of vitamin D2 and vitamin D3 induced similar increases (from baseline ~20ng/ml 25OH vit D)  in total 25(OH)D as well as in 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, respectively. Compared with placebo and adjusting for baseline levels, 1000 IU daily of vitamin D2 was associated with a mean increase of 7.4 pg/mL (95% confidence interval, 4.4-10.3) in 1,25(OH)2D2, and  decrease of 9.9 pg/mL (-15.8 to -4.0) in 1,25(OH)2D3. No such differences accompanied administration of 1000 IU daily of vitamin D3.

    6. Leventis P1, Kiely PD. London 2009 in  Scand J Rheumatol. Good Tolerability and biochemical effects of high-dose bolus vitamin D2 and D3 supplementation in patients with vitamin D insufficiency in 69 RHEUMATOLOGY patients with vitamin D insufficiency [25-hydroxyvitamin D (25(OH)D) <40 nmol/L]  50 patients study 1 received 300 000 IU i.m. vitamin D2 (ergocalciferol), 19 patients  in study 2 received 300 000 IU oral vitamin D3 (cholecalciferol) . Bolus i.m. vitamin D2 or oral vitamin D3 was well tolerated.  change from baseline in serum 25(OH)D was significantly greater at 6 and 12 weeks in study 2 (p<0.0001 ). In study 1, a modest increase in mean serum 25(OH)D at 6, 12, and 24 weeks was observed but no patients achieved a serum 25(OH)D concentration > or = 50 nmol/L. PTH remained elevated in 42% of patients with secondary hyperparathyroidism at 12 weeks. In study 2, 100% and 89% of patients had serum 25(OH)D>50 nmol/L at 6 and 12 weeks, respectively. All patients with elevated baseline PTH were fully suppressed at 12 weeks. No hypercalcaemia was observed in either group. The 300 000-IU bolus of vitamin D2 or D3 was practical, well tolerated, and safe. Vitamin D3 had greater potency than equimolar vitamin D2, with a higher, sustained serum 25(OH)D response and efficacious PTH suppression.


    7.  Sempos CT1, Picciano MF ea . USA  J Clin Endocrinol Metab. 2013 Jul;98(7):3001-9..  Is there a reverse J-shaped association between 25-hydroxyvitamin D and all-cause mortality? Results from the U.S. nationally representative NHANES.       A reverse J-shaped association between serum 25-hydroxyvitamin D (25[OH]D) concentration and all-cause mortality was suggested in a 9-year follow-up (1991-2000) analysis of the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). We repeated  the analyses with 6 years additional follow-up  in 15 099 participants aged ≥ 20 years with 3784 deaths, to evaluate whether the association persists through 15 years of follow-up. The reverse J-shaped association became stronger with longer follow-up and was not affected by excluding deaths within the first 3 years of follow-up. Similar results were found from both statistical approaches for levels <20 through 119 nmol/L. Adjusted RR (95% confidence interval [CI]) estimates for all levels <60 nmol/L were significantly >1 compared with the reference group. The nadir of risk was 81 nmol/L 32pg/mL (95% CI, 73-90 nmol/L 29-36pg/ml). The association appeared in men, women, adults ages 20 to 64 years, and non-Hispanic whites but was weaker in older adults.  A reverse J-shaped association between serum 25(OH)D and all-cause mortality appears to be real. It is uncertain whether the association is causal.

    8.  Logan  Houghton ea   Br J Nutr. New Zealand 2013;109:1082-8.   Long-term vitamin D3 supplementation is more effective than vitamin D2 in maintaining serum 25-hydroxyvitamin D status over the winter months.  Public health recommendations dont distinguish between vitamin D2 and vitamin D3, yet disagreement exists on whether these two forms should be considered equivalent.  over the winter in healthy adults living in Dunedin, New Zealand (latitude 46°S), Participants aged 18-50 years were randomized   to 1000 IU vitamin D3 (n 32), 1000 IUvitamin D2 (n 31) or placebo (n 32) daily for 25 weeks beginning at the end of summer. After 25 weeks, participants randomised to D2 and placebo had a significant reduction in serum 25(OH)D3 concentrations over the winter months compared with vitamin D3-supplemented participants (both P< 0.001). Supplementation with vitamin D2 increased serum 25(OH)D2 but produced a 9 (95 % CI 1, 17) nmol/l greater decline in the 25(OH)D3 metabolite compared with placebo (P< 0.036). Overall, total serum 25(OH)D concentrations were 21 (95 % CI 14, 30) nmol/l lower in participants receiving vitamin D2 compared with those receiving D3 (P< 0.001), among whom total serum 25(OH)D concentrations remained unchanged. No intervention-related changes in PTH were observed. Daily supplementation of vitamin D3 was more effective than D2;

    9  Seijo M1Oliveri B. ea  Spain  Medicina (B Aires). 2012;72:195-200.  [Is daily supplementation with vitamin D2 equivalent to daily supplementation with vitamin D3 in the elderly?].    equivalence of cholecalciferol (D3) and ergocalciferol (D2) as well as their corresponding doses and administration route remain controversial to date. Twenty-one ambulatory postmenopausal women from Buenos Aires with a mean  age of 77 ± 6.8 years  were randomly assigned to one of the following groups: GD2 (n = 13): 800 IU (drops) and GD3 (n = 8): 800 IU (pills).  Nineteen out of twenty one women showed deficient levels of 25OHD at baseline (< 20 ng/ml): GD2: 14.0 ± 4.8 ng/ml and GD3: 13.2 ± 4.9 ng/ml (NS). Whereas only GD3 exhibited an increase (≈ 25%) at 7 days, both groups showed a significant increase at the end of the study. However, neither attained adequate 25OHD levels (GD2: 17.4 ± 5.5 vs. GD3:22.9 ± 4.6 ng/ml; p < 0.001). Administration of 800 IU of vitamin D3 during 45 days was more effective than D2 in increasing 25OHD, but both failed to achieve adequate levels of 25OHD (= 30 ng/ml). but neither succeeded in achieving adequate levels of 25OHD (= 30 ng/ml).

    10 Holick  Tannenbaum ea usa   J Clin Endocrinol Metab. 2008;93:677-81. Epub 2007 Dec 18.IN LOW DOSE eg 1000iu/d,   Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin A 1000 IU dose of vitamin D2 daily was as effective as 1000 IU vitamin D3 in maintaining serum 25-hydroxyvitamin D levels and did not negatively influence serum 25-hydroxyvitamin D3 levels. Therefore, vitamin D2 is equally as effective as vitamin D3 in maintaining 25-hydroxyvitamin D status.
     11 Armas ,  Heaney ea.Creighton Univ Nebraska.  J Clin Endocrinol Metab. 2004 ;89:5387-91. Vitamin D2 is much less effective than vitamin D3 in humans.Vitamins D(2) and D(3) are generally considered equivalent in humans. Nevertheless, physicians commonly report equivocal responses to seemingly large doses of the only high-dose calciferol (vitamin D(2)) available in the U.S. market. Relative potencies of vitamins D(2) and D(3) were evaluated by administering single doses of 50,000 IU of the respective calciferols to 20 healthy male volunteers, following the  serum vitamin D over 28 d.. The two calciferols produced similar rises in serum concentration, indicating equivalent absorption. Both produced similar initial rises in serum 25OHD over the first 3 d, but 25OHD continued to rise in the D(3)-treated subjects, peaking at 14 d, whereas serum 25OHD fell rapidly in the D(2)-treated subjects and was not different from baseline at 14 d. Area under the curve (AUC) to d 28 was 60 ng.d/ml for vitamin D(2) and 204 for vitamin D(3) (P < 0.002). Calculated AUC(infinity) indicated an even greater differential, with the relative potencies for D(3):D(2) being 9.5:1. Vitamin D(2) potency is less than one third that of vitamin D(3). Physicians resorting to use of vitamin D(2) should beware of its markedly lower potency and shorter duration of action relative to vitamin D(3)

    12 Trang,  Vieth ea  University of Toronto, Am J Clin Nutr. 1998Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. In all species tested, except humans, biological differences between vitamins D2 and D3 are accepted as fact.  Subjects took 260 nmol (approximately 4000 IU) vitamin D2 (n=17) or vitamin D3 (n=55) daily for 14 d.  With vitamin D3, mean (+/-SD) serum 25(OH)D increased from 41+/-18 nmol/L before to 65+/-17 nmol/L after treatment. With vitamin D2, the 25(OH)D concentration went from 434+/-18 nmol/L before to 57+/-13 nmol/L after. The increase in 25(OH)D with vitamin D3 was 23+/-16 nmol/L, or 1.7 times the increase obtained with vitamin D2 (14+/-11 nmol/L; P=0.03). There was an inverse relation between the increase in 25(OH)D and the initial 25(OH)D concentration.  In the highest tertile [25(OH)D >49 nmol/L] the mean increase in 25(OH)D was 13.3 nmol/L (P < 0.03 for comparison with each lower tertile). Although the 1.7-times greater efficacy for vitamin D3 shown here may seem small, it is more than what others have shown for 25(OH)D increases when comparing 2-fold differences in vitamin D3 dose. The assumption that vitamins D2 and D3 have equal nutritional value is probably wrong and should be reconsidered.

13.  Hymøller L1, Jensen SK.Denmark   J Dairy Sci. 2011;94:3462-6.  Vitamin D₂ impairs utilization of vitamin D₃ in high-yielding dairy cows in a cross-over supplementation regimen.   D(3) given after D(2) is less efficient at increasing the plasma status of 25(OH)D(3) than D(3) given without previous D(2) administration.

A Vitamin D Expert’s Take on the Latest Warning to Stay Out of the Sun to Avoid Skin Cancer

By Dr. Mercola  16/11/2014  The US Surgeon General recently came out with a warning on skin cancer,1 claiming that the sun is dangerous and that you need to stay away out of it.

pioneer Dr. John Cannell, founder of the Vitamin D Council, has dedicated a large part of his professional career to the study of vitamin D and its health benefits, and he has a warning of his own to those who take this narrow-minded advice to heart.

It’s worth noting that the acting Surgeon General, Boris Lushniak, is a dermatologist. And of all the medical specialties out there, dermatologists are clearly the most biased against sun exposure, & as a result, against vitamin D.

This isn’t surprising, since they primarily see the ill effects of sun overexposure. But in taking an overly narrow view, the advice to avoid sun exposure as much as possible can have equally if not greater adverse health effects.                      The Connection Between Sun Exposure and Skin Cancer Unquestionably, UV   radiation can be dangerous; it can increase your risk for certain skin cancers such as squamous cell, basal cell, and melanoma. But there are significant differences even between these cancers, and appropriate sun exposure may actually be more beneficial than detrimental in some cases. Dr. Cannell explains:

“Squamous cell carcinoma is clearly associated with chronic sun exposure. It is more common on the face, the hands, and the scalp.

It is related to radiation burden over your lifetime, and together with basal cell carcinoma, which is sort of intermediate, it accounts for approximately 1,500 deaths a year in the United States…

Basal cell is sort of intermediate. There are studies showing that it is associated with chronic sun exposure, and there are studies showing that it’s not associated with chronic sun exposure.

And then there’s melanoma, which is responsible for almost 9,000 deaths a year and is the deadly skin cancer that is feared. The relationship that melanoma has with the sun is quite complicated.

It is clearly associated with sunburn, especially sunburns when you’re young (that’s incontrovertible) or sunburns in a sun tanning bed.”

However, there are at least two studies showing that melanoma is more common in indoor workers than outdoor workers. And the most likely places for melanoma to appear are actually NOT the face and the hands like squamous cell carcinoma, but rather the lower back and the upper leg—areas that are usually not chronically sun-exposed.

According to Dr. Cannell, there’s a vocal minority in the dermatological community that thinks the emphasis dermatologists have on avoiding sun exposure is wrong, because while sunburn is a risk factor, chronic sun exposure is not.

“A number of studies show that chronic sun exposure is related to melanoma, but they don’t separate out the sunburns, which is very hard to do because you have to do that by memory,” Dr. Cannell says.   Two Decades-Long Study Finds Sun Avoidance Doubles Risk of Death  Dr. Cannell notes a recent study2 done in Sweden, which followed nearly 30,000 middle-aged to older women for up to 20 years. The average follow-up was 15 years.

At the outset, they asked a number of questions about sun exposure, such as: Do you sunbathe? Do you take vacations in sunny areas in the winter? Do you garden with short sleeves and shorts? And, do you use sunbeds?

What they found, and this appears to be the only study of this kind, is that the women who avoided the sun were twice as likely to die over the course of the study. The researchers attributed this finding to a vitamin D mechanism.

What this study actually shows is that chronic sun exposure appears to be associated with less mortality. It’s also the first study to show that women who use tanning beds live longer than those who don’t.

This is in direct conflict to what almost every dermatologist will say, including the Surgeon General. It’s unfortunate, but the danger of almost any specialist is that they don’t take the broader perspective.

What the Surgeon General and almost every other dermatologist fail to take into account is the overall mortality, which is referenced in this recent study.  Risk-Benefit Analysis In addition to this study, dozens of others document the benefits of appropriate sun exposure. This includes a reduced risk of about 16 different cancers of Dr. Garland’s studies suggest this reduction is close to 50 percent.

So many hundreds of thousands of people are put at risk from other cancers as opposed to 10,000 people who are dying from skin cancer caused by sunburn. It’s really a matter of making an educated risk-benefit analysis.

“When you do a risk-benefit analysis and you look at all the data we have, the risk in my opinion appears to be in those who avoid the sun,” Dr. Cannell says.

“Now, if you avoid the sun, your risk for non-melanoma skin cancer goes down. That’s clear. But if you look at studies of either latitude or of 25-hydroxyvitamin D levels in relation to cancer, you find this inverse relationship: the higher the vitamin D level, the lower the internal cancer rate.”

Dr. William Grant of Sunlight, Nutrition, and Health Research Center (SUNARC) estimates that if everyone in the United States had a vitamin D level of 40 nanograms per milliliter (ng/ml), it would save approximately 150,000 lives a year.3

That’s 100 times the rate of squamous cell cancers, which are the only ones that are definitively linked to UV exposure. In Canada alone, it is estimated that 37,000 lives a year are lost due to vitamin D deficiency.4 Also, use of sunscreen has risen in the last 30 years, so if dermatologists were correct, there should be a decrease in stage 1 melanoma. But there’s not. As sunscreen use increased, stage 1 melanoma diagnosis increased…

“It’s thought that by blocking out UVB, patients are able to stay out in the sun longer than they would have otherwise and expose themselves to the more dangerous, or at least potentially dangerous, UVA radiation that’s in the sunshine,” Dr. Cannell says. “What we recommend is what’s called safe, sensible sun exposures. The Australian Cancer Council now recommends the same thing. I think in England there’s now a change in their recommendation from strict sun avoidance to some safe, sensible sun exposure. There are some movements in large organizations to realize that safe, sensible sun exposure is a healthy thing.”            

How Much Sun Exposure Is Sensible?    On its website, Cancer Research UK reports that “by enjoying the sun safely and avoiding sunburn, people can reduce their risk of skin cancer and enjoy the beneficial effects of the sun.” Cancer Research UK’s sun advice is endorsed by the British Association of Dermatologists, Cancer Research UK, Diabetes UK, the Multiple Sclerosis Society, the National Heart Forum, the National Osteoporosis Society, and the Primary Care Dermatology Society. The UK National Health Service5 also recommends sensible, individualized sun exposure to help optimize vitamin D.

It’s important to recognize is how quickly sunlight can make vitamin D in the skin. You don’t need to be outside for hours on end. But you do need more than just a few minutes of sun on your face and arms. According to Dr. Cannell, sunbathing at solar noon in the summer, at most latitudes in the United States you will make between 5,000-10,000 international units (IUs) of vitamin D within 30 minutes.

“You can ask yourself why nature would evolve a mechanism that made so much vitamin D so quickly,” Dr. Cannell says. “When I thought about that question, the only answer I could come up with is nature did it for a good reason. The organism needs vitamin D, so the system in the skin evolved to make it very quickly upon exposure to sunlight.

We recommend full-body sun exposure for up to anywhere from a few minutes to 30 minutes every day. On those days when you cannot get a full-body sun exposure, we recommend a vitamin D supplement or sensible exposure in a low-pressure UVB bed.”

If you’re getting regular sun exposure, I think the need for an oral supplement is really minimal to non-existent. When you swallow a pill, there’s no self-regulating ability. Your body doesn’t have an ability to selectively limit its absorption. But your skin has the ability to control how much vitamin D is being produced based on how much is in your blood.

I personally have not taken oral vitamin D for five years and my level runs from 50-70 g/ml. Lifeguards, roofers, and gardeners who work with their shirt off, all tend to have levels between 40 and 80 ng/ml in the summer. This also brings up an interesting question about the difference between normal and natural. Normal vitamin D levels are an average of what indoor workers have in both winter and summer. Natural are levels of a population with widespread sun exposure. The latter is going to be closer to ideal, or optimal.

vitamin d levels
References for establishment of optimal levelsThere are also other reasons to strive for sun exposure rather than swallowing a pill. As noted by Dr. Cannell, aside from producing vitamin D, sunlight also affects nitric acid levels and endorphins in the skin. Researchers at the University of Wisconsin recently discovered that there may be a system at 311 nanometers that is separate from the vitamin D system (which is at 298 nanometers), and that there may be an entirely new undiscovered biochemical system in the skin that makes yet another substance, besides vitamin D. Time will tell what comes out of that research, but there are indications that sunlight may be responsible for other biological processes that are unrelated to vitamin D production.

Dr. Cannell’s Recommendation on Tanning Beds There are basically two
types of tanning beds:

  1. 1. High-pressure UVA beds. They tan you the quickest because it’s UVA that tans the skin. They contain only a limited UVB spectrum, and will therefore give you color but not much vitamin D
  2. Low-pressure beds, which contain less UVB than sunlight at most latitudes, but still contain a significant amount of UVB. These are the beds Dr. Cannell recommends, provided you’re using a sensible approach that avoids sunburns. It’s important to realize that you can easily get burned after only a couple or a few minutes when using a tanning bed

Another important factor when selecting a tanning bed is the type of ballast it employs, to avoid excessive electromagnetic field (EMF) exposure. Most tanning units use magnetic ballasts to generate light. These magnetic ballasts are well known sources of EMF fields that can contribute to cancer. If you hear a loud buzzing noise while in a tanning bed, it has a magnetic ballast system. I strongly recommend you avoid magnetic ballast beds, and restrict your use of tanning beds to those that use electronic ballasts.

On days you cannot get either regular sun exposure or use of a tanning bed, Dr. Cannell suggests taking 5,000 IUs of vitamin D3. Other vitamin D experts recommend similar amounts. It’s worth noting that, according to the federal government’s Food and Nutrition Board (FNB), the no observed adverse effects level (NOAEL) of vitamin D is 10,000 IUs a day. This means there has never been a replicated reliable study showing that 10,000 units a day is in any way detrimental.

Many individuals who have reported side effects from taking high doses of oral vitamin D have noticed that when they supplemented with magnesium, they were able to tolerate the high oral doses of vitamin D. Dr. Carolyn Dean has written in her book, The Magnesium Miracle, that she has seen this so many times that she doesn’t advise taking more than 2,000 units of vitamin D without magnesium supplementation. Be sure to also have an adequate amount of vitamin K2 along with D to slow the progression of arterial calcification. Remember though that the best form of vitamin D is the one your body produces when it is exposed to sunlight that has sufficient amounts of UVB.

Five Tips to Get an Appropriate, Sensible Amount of Sun  Again, sunshine offers substantial health benefits, including vitamin D production, but you do need to exercise a few simple precautions to protect yourself from overexposure. Virtually all of the harm from sun exposure is related to sunburn. Here are my top five tanning tips:   *  Expose large amounts of your skin (at least 40 percent of your body) to sunlight for short periods daily. Optimizing your vitamin D levels may reduce your risk of as many as 16 different types of cancer, including pancreatic, lung, ovarian, breast, prostate, and skin cancers. If using a sunscreen, give your body a chance to produce vitamin D before you apply it. *When you’ll be in the sun for longer periods, cover up with clothing, a hat, or shade (either natural or shade you create using an umbrella).  *Consider the use of an “internal sunscreen” like astaxanthin to gain additional sun protection. Astaxanthin is a potent antioxidant (and pigment) produced by marine algae in response to their exposure to UV light. Typically, it takes several weeks of daily supplementation to saturate your body’s tissues enough to provide protection. *Consuming a healthy diet full of natural antioxidants is another useful strategy to help avoid sun damage. Fresh, raw, unprocessed vegetables and fruits deliver the nutrients that your body needs to maintain a healthy balance of omega-6 and omega-3 oils in your skin, which is your first line of defense against sunburn. Vegetables also provide your body with an abundance of powerful antioxidants that will help you fight the free radicals caused by sun damage that can lead to burns and cancer.

How Vitamin D Performance Testing Can Help Optimize Your Health  A robust and growing body of research clearly shows that vitamin D is absolutely critical for good health and disease prevention. Vitamin D affects your DNA through vitamin D receptors (VDRs), which bind to specific locations of the human genome. Scientists have identified nearly 3,000 genes that are influenced by vitamin D levels, and vitamin D receptors have been found throughout the human body.

  14  Oct 2014 update:  MORE ON OPTIMAL VITAMIN D3  DOSE, AND THE DIFFICULTY OF ACHIEVING CLINICAL  OVERDOSE:      Four  new reports highlight  how  difficult, and important  it is to achieve adequate optimal bloodlevels of vitamin D with vigorous vitamin D3 supplements, let alone overdose with any significant adversity: note three   used the  recommended vitamin D3,   not the long-condemned mislabeled Lennons/Aspen vitamin D2 (which is misleadingly labelled  “caciferol” without disclosing that it is D2 not D3). Even a single  2 million iu overdose of vit D3 in nonagenarians had no adverse effect-since the bloodlevel was back to zero by 3 weeks, thats above 100 000iu/day on average….

 with serum 25-hydroxy vitamin D (25(OH)D) < 30 ng/mL  on  placebo or vitD3 (n = 35)   60,000 units/week for 6 weeks.   mean baseline level of 25(OH)D was 9.6+-9.6 ng/mL, and after 6 weeks doubled to 19.5 ± 4.3 ng/mL,  (P < 0.0001). After discontinuing supplement at 6 weeks, serum 25(OH)D level dropped moderately  by  12 weeks (16.1 ± 8.3 ng/mL) as compared with the baseline.  The change in serum 25(OH)D level from baseline to 6 weeks in the intervention group was inversely related to baseline 25(OH)D levels and patient’s weight. In the control group, change in 25(OH)D was not significant.  Thus  vit D3 about
10 0000iu/day in these small and often malnourished people raises bloodlevel by only about 10ng/mL.
        Kearns ,Tangpricha ea, Emory University Georgia USA   in Eur J Clin Nutr. 2014 Oct 1 describe    The effect of  single  250 000iu bolus of vitamin D3  in healthy adults over the winter and following year: a randomized, double-blind, placebo-controlled trial.   At baseline, young healthy participants had a mean plasma 25(OH)D concentration of 17.5±6.1 ng/ml. Only two subjects exhibited plasma 25(OH)D concentrations >30 ng/ml. At 5 days, subjects on  vitamin D3 had  only doubled mean plasma 25(OH)D (39 vs 19 ng/ml, P<0.001). Plasma 25(OH)D concentrations returned to baseline by  90 and 365 days in the vitamin D3 group,  remained unchanged in the placebo group. PTH and calcium concentrations were unrelated to changes in 25(OH)D levels and similar between groups over time.

   van den Ouweland ,  Vollaard ea  Nijmegen, The Netherlands in    BMC Pharmacol Toxicol. 2014 Sep 30   describe  Pharmacokinetics and safety issues of an accidental oral overdose of 2,000,000 IU of vitamin D3 in two nonagenarian nursing home patients: a case report.    Oral overdose of 2,000,000 IU of vitamin D3 in two nonnagenarian  nursing home patients was monitored from 1 hr up to 3 months . Peak blood 25(OH)D3 concentrations were observed 8 days after intake (210  and 162ng/mL, respectively (ref: 20-80 ng/mL),   followed by a rapid decrease to undetectable levels after day 14.  Remarkably, plasma calcium levels increased only slightly up to 2.68 and 2.73 mmol/L, respectively (ref: 2.20-2.65 mmol/L) between 1 and 14 days after intake,; phosphate and creatinine levels remained within reference range. No adverse clinical symptoms were noted.   CONCLUSION:A single massive oral dose of 2,000,000 IU of vitamin D3 does not cause clinical toxicity requiring hospitalization. Toxicity in the long term cannot be excluded as annual doses of 500,000 IU of vitamin D3 for several years have shown an increase in the risk of fractures. This means that plasma calcium levels may not be a sensitive measure of vitamin D toxicity in the long term in the case of a single high overdose. 

            As previously reported, to avoid dehydration stones and vascular calcification – especially in hot dry climates – , the precautions with vigorous vit D3   are to add some vit K2 and magnesium to the supplement, and maintain good water intake .
           The fourth current paper, from Morocco, reports inexplicable use of dangerous massive dose of vit D2 in neonates- amounting to about 120 000iu/kg ie about 12 times the maximum adult dose reported :   Hmami , Bouharrou  ea Morocco University,  Arch Pediatr. 2014 Oct;21:1115-9.        [Overdose or hypersensitivity to vitamin D   Vitamin D intoxication with severe hypercalcemia is rare in the neonatal and infancy period. 9 babies between ages of 25 and 105 days were admitted  for treatment of severe dehydration  8 to 15% with  hypercalcemia, with preserved diuresis and loss weight between 100 and 1100 gm secondary to taking 600,000 units of vitamin D (Sterogyl(®). The pregnancies & deliveries  were normal. Clinical signs were dominated by weight loss, vomiting, and fever. The vitamin D values in nine patients were toxic (mean 220: 139 – 300 ng/mL, ; normal >20ng/mL; toxicity if >100ng/mL). Nephrocalcinosis was shown  in seven patients. DNA study  in eight patients, did not reveal a mutation of the vitamin D 24-hydroxylase gene (CYP24A1). Treatment consisted of intravenous rehydration with diuretics and corticosteroids. Serum calcium returned to  normal range within 4-50 days, with weight gain progressively over the following weeks. The follow-up (2 years for the oldest case) showed persistence of nephrocalcinosis. Genetic susceptibility and metabolic differences appear to modulate the threshold of vitamin D toxicity. However, respect for recommended doses, recognized as safe in a large study population, reduces the risk of toxicity.
and as in adults,    Yao ,  Huang  ea  Prediction of Allergies in Taiwanese Children (PATCH) Study Group in  J Pediatr. 2014 Oct 1 demonstrate a significant relationship between insufficient serum vitamin D levels and worse lung function in children in the community with a suggested dose-response effect.

VITAMIN D3 DOSE: We get excellent results in outpatient adults with loading oral dose of  vit D3 of about 200 000 to 400 000iu depending on illness severity and body mass; then pro rata about 50 000iu  per week till better, tapering to fortnightly when well; pro rata in kids. We monitor calcium and 25OH vitamin D3 levels occasionally  if affordable – but with the tapering regime, and published data, do not see or expect hypercalcemic problems from a mean conservative weekly maintenance dose of about 3500iu/d longterm, with predicted bloodlevel of 25OHvitD of about 35-40ng/ml.  As a senior with average chronic dis-ease load, I take ~63 000iu vit D3 weekly, but double it occasionally if I do get a bad cold; so I never miss a day’s work;   recent stress-related shingles (2nd attack in 30 years)  was just a nuisance, settled in 3 weeks with this regime plus multigrams of buffered vit C a day; oral lysine and alphalipoic acid each about 1/2 gm/day; and for a few days some weak steroid and humic acid cream topically for the neuritis and blistering, which has already healed to almost invisible.  This week at a family practice clinic I saw two successive women with shingles – now a frequent occurrence, even  without HIV…

Khan in Toronto in OHDM  this September  describes a ~60yr old man with tongue cancer who was treated inter alia with Vit D3 10 000iu a day; after a year his 25oH vitD level was ~106ng/ml,  when his dose was halved; his dose response  bore out the general experience that at average adult mass, vit D level rises by about 10ng/ml for every 1000iu vit D3 per day or pro rata dose weekly etc  eg 50 000iu/wk or 100 000iu fortnightly may give average vit D level of ~70ng/ml.  .

Singh & Bonham 2014 at Kansas University describe  A Predictive Equation to Guide Vitamin D Replacement Dose in Patients. The recommended daily allowance for vitamin D is grossly inadequate for correcting low serum concentrations of 25-hydroxyvitamin D in many adult patients.  In their population (average BMI 31.5) ,about 5000 IU vitamin D3/day is usually needed to correct deficiency, and the maintenance dose should be ≥2000 IU/day. The required dose may be calculated from the predictive equations specific for ambulatory and nursing home patients”   A BMI of 31.5kg at a mean height of about 1.7m gives a mean weight of 91kg, which at the consensus daily  vit D3 dose of 80iu/kg/d totals ~7100iu/d or 50 000iu/wk- perhaps a reasonable maintenance dose for winter, half  that in summer if reasonable weekly sun exposure. .

29 Sept 2014:       As detailed elsewhere in this column, there is at least 70 years of strong experience worldwide that  all microorganism infections are greatly diminished by natural  prevention (not synthetic vaccines loaded with toxic heavy metals and allergenics eg egg) , and  easily treated ie  thrown off, with vigorous immune-boosting supplements:  (mega)grams a day of vitamin C or as kgs/day of fresh produce;        vitamin D3 80+ iu/kg/d to  >10 000iu/d ie 300 000  to 600 000iu loading dose; then    +-50 000iu/wk,  plus  plenty of skin exposure to sunshine; iodine; zinc; selenium; silver; the other vitamins; Ecchinacea etc.  This applies both to acute and chronic infections and degenerative conditions.

To be used in highrisk cases eg MERS, AIDS, ebola etc: The  landmark trial  Effect of High-Dose Vitamin D3 on Hospital Length of Stay in Critically Ill Patients With Vitamin D Deficiency– The VITdAL-ICU Randomized Clinical Trial  by Amrein, Dobnig ea ,   published   today in JAMA  from Austrian hospitals  is most encouraging about the immense value of vigorous dose and bloodlevels of vitamin D3 against all types of severe disease.  The dose used in this trial (loading dose 540 000iu  =~18000iu/d 1st month, but averaging only ~8000iu/d in the first 3mo) did not achieve vigorous vit D bloodlevel, presumably because the loading dose of vit D3 in oil (540 000iu) was given by tube into the stomachs of critically ill patients; it would have better been given by transdermal injection, or else a much higher loading gastric dose given so as to speedily achieve a bloodlevel of around 70 (60 to 80) instead of half of this that was achieved in the crucial first few weeks .                                      from May 2010 through September 2012 at 5 ICUs the trial recruited  492 medical (60%) and surgical (40%)  critically ill adult white patients , 35% women, BMI mean 27, mean age  64.6 years (SD, 14.7) with vitamin D deficiency (≤20 ng/mL) assigned to receive either vitamin D3 540 000 IU, or  placebo    given orally or via nasogastric tube; ;  followed by monthly maintenance doses of 90 000 IU for 5 months- ie= about 18000iu/day for the first mo, then 90 000iu   mthly ie only 3000iu/d.           .     RESULT: on placebo the 25hydroxyvit D3 level doubled  from 13 at baseline to 17 at a month to 26ng/ml at 6mo.. By contrast, on vit D3 supplement it doubled to 34 at days 3 and 7 and day 28, but up to 46 at 6 months ie only 80% higher than the control group – thus 1/3 to 1/2 of the optimal target; with this, where 100% of patients were below 25OHvitD at baseline ie on admission to ICU, by 7 days, 87% were still in this bracket and none above 60ng/ml on placebo vs 25%  below 20  and 13% above 60 on vit D3; and by 6mo 35% were still that low on placebo, vs 5%  at that low, but 22% above 60 on vit D3. So it is not surprising that Median hospital stay 20 days was not significantly different between groups  Hospital mortality and 6-month mortality were also not significantly different (hospital mortality: 28% for vitamin D3 vs 35% for placebo; hazard ratio [HR], 0.81  P = .18; 6-month mortality: 35.0%  for vitamin D3 vs 42.9%  for placebo; HR 0.78  P  = .09). For the severe vitamin D deficiency subgroup analysis (n = 200), length of hospital stay was not significantly different between the 2 study groups: 19.5 days. Hospital mortality was significantly 40% lower with 28 deaths among 98 patients (28.6% ) for vitamin D3 compared with 47 deaths among 102 patients (46.1% ) for placebo (HR, 0.56 P for interaction = .04), but not 6-month mortality (34.7%] for vitamin D3 vs 50.0%  for placebo- ie 31% lower; HR, 0.60, P for interaction = .12). No serious adverse events were observed. The highest 25-hydroxyvitamin D levels measured were 107 ng/mL on day 7 and 106 ng/mL at month 6- well below the theoretical minimum toxic threshold of 150 or 250ng/ml..”

BUT  compared to the Austrian trial in overweight 27+kg BMI elderly whites given 540 000iu to start  by tube,              in   Salahudfin ea’s  randomized controlled trial in young emaciated   Pakistani men BMI 17.2kg, Vitamin D3 600 000iu  injection (which achieved twice the blood 25OH vit D3 level of the Austrian patients), had  accelerated clinical recovery from tuberculosis with  “impressive clinical (weight gain, chest xray and sputum clearing)  improvement  over 3 months on outpatient TB therapy (Directly Observed Therapy (DOTS) with 2 months of  4 antituberculous drugs followed by 6 months Isoniazid and Ethambutol)  with two doses 600 000iu vit D3 imi (vs placebo inj)  a month apart-  ie = ~20 000iu/d for the first 2 months, but equivalent to about 7 000iu/day over the 3 months treatment period . This dose  of vitamin D is as recommended for vitamin D supplement by the Pakistan Endocrine Society.  Trough  25OH vit D levels increased from about 20 to 90ng/ml.    After 12 weeks, the vitamin D supplemented pts (mean 28 yrs, BMI 17.2kg, 85% moderate to far advanced lung disease)  had  significantly greater mean weight gain (kg) + 3.75,  versus + 2.61, p 0.009; lesser residual disease by chest xray-  30% fewer zones involved 1.35 v/s 1.82 p 0.004,   and 50% or greater reduction in cavity size 106 (89.8%) v/s 111 (94.8%), p 0.035. Vitamin D supplementation led to significant increase in MTBs-induced IFN-g secretion in patients with baseline ‘Deficient’ vitamin D serum levels (p 0.021). Patients in the vitamin D arm and serum < 30 ng/mL (‘Insufficient’ and ‘Deficient’ groups) at enrollment had significantly greater improvements in TB severity scores compared to patients with normal baseline vitamin D levels; p 0.014.”

         “This corresponds with the earliest reports of the benefits of vitamin D in TB patients published in 1848 [21] that describes disease arrest, weight gain and reduction in mortality in patients with TB treated with cod liver oil compared to standard therapy alone. More recently, Martineau et al  [7]  demonstrated that a single oral dose of 2.5 mg (100,000 IU) of vit D2 significantly reduced growth of mycobacteria . A randomized, placebo controlled study on 67 Indonesian patients, by Nursyam et al , Jakarta  [22] reported that pulmonary TB patients given 420,000 IU of vitamin D over 6 weeks  ie 10 000iu/day had significantly higher sputum conversion rates as compared to placebo (p 0.002). Martineau et al. [8] showed that 100,000 IUs of 25-hydroxyvitamin D3 supplementation significantly improved sputum conversion rates in patients with the Taq1 25-hydroxyvitamin D receptor polymorphism of the tt genotype. ”                                                                    .

As Salahuddin ea note, the good results in Pakistan in only 3 months with vigorous  INITIAL dose vit D3  contrasts with Two recently published large randomised, controlled trials of conservative vitamin D3 over months  that achieved far lower blood vitamin D levels found no difference in clinical outcomes or mortality after 400,000 IU of 25-hydroxyvitamin D3 or placebo were given by   Martineau ea  in London, UK to 146 pulmonary TB patients – where mean (trough  or midpoint)  vit D level  (after 100 000iu vitamin D(3) or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment) – was surprisingly only  40ng/ml at 56days – ie after a mean of 7000iu/d by  56 days,  vs 10ng/ml  on placebo)- less than half of the bloodlevel  achieved on vit D3  in the Pakistan trial.

So the Austrian ICU patients would undoubtedly have done much better if given more effective  (ie in critically ill pts intramuscularly imi or subcutaneously) loading dose like the Salhuddin trial did.

 TIME   To SWOP FROM MISNAMED  “STRONG CALCIFEROL” VIT D2 TO THE REAL VIT  D3:     as the winter solstice approaches here, with fierce weather linking to  the expected influenza-like outbreak (while the MERS-CoV outbreak abates with summer in the severely vitamin D deficient Saudi Arabians), a new major study shows the supremacy of vitamin D3 for supplementation, and confirms that vitamin D2 benefit if any  is so mediocre as to be unethical..

Its sad that despite the strong evidence against using vitamin D2 supplement discussed last year,  it seems no one acted on  it despite the confirmatory paper from Bergen of last September.

Thus vit D3 is again confirmed as four times as potent as D2. But crucially, that giving vit D2 may actually SUPPRESS the optimal  serum vit D3  level.

We health professionals with our highly vulnerable populations in South Africa and worldwide   (epidemic/endemic  HIV, TB, cancer, drug addiction, MERS-CoV, asthma, diabetes, cardiovascular,  malnutrition, alcoholism and violence) therefore surely have no choice but to swop promptly from prescribing vit D2 “Strong Calciferol” (a dangerous misnomer) to prescribing vitamin D3 at vigorous dose (with if possible occasional blood level check of 25OHvit D3)- at a trivial imported and distributed cost (100cws)  to South African state clinics  of perhaps<1/4 of the cost of D2 eg  R1 per patient per month for a conservative 100 000iu monthly  (ie  after an appropriate germicidal  loading dose of eg 3000 iu/kg) if not the more realistic dose double that- still at only eg US$0.2 a month.

Health Authorities everywhere have an obligation to enforce the use of vitamin D3 and not vitamin  D2 globally ..

update 3 Sept 2014:  while the MERS outbreak in Arabia may at last be dying down, real highly infections plagues eg ebola malaria cholera typhoid, MRSA,  TB and HIV etc continue rampant, maiming and killing even more than the manmade wars raging on some continents. .

So it is ironic – or typical of the couldnt-care-less greedy politicians and potentates who run the world- that the medical authorities they employ  worldwide apparently continue to ignore the dramatic benefits of at least safe antimicrobial supplements like multivite, zinc, iodine, selenium,   and especially vigorous dose vitamin D3 at negligible cost, and highdose buffered vitamin C to tolerance, and colloidal silver.

Already 35 years ago Italian researchers published on Pubmed that vitamin D3 should be used orally  rather than injected D or as  oral vitamin D2:                   [Behavior of serum vit D in  humans after administration of vitamin D.   Boll Soc Ital Biol Sper. 1979   Coen G, Casciani CU ea.     “evaluated  Serum levels of 25 hydroxy-vit D  following injected and oral vit. D2 and D3 . While no rise in 25OHD3 serum levels was  observed after i. m. administration , a marked rise  was found following the oral administration. However the peak values were largely impredictable.”

We quote above  trials and evidence  that oral vit D2 may be actually harmful, that it is vit D3 in vigorous dose that is needed to at least treble if not quadruple the blood vit D level from the usual deficient levels we find, to between 60 and 100ng/ml during illness.  Unfortunately locally this is not only not grasped, but also the vit D assay kit  being used by  private laboratories measures only total 25OHvit D level, not the needed active 25OH vit D3 level  plus the potentially harmful (vitD receptor-blocking ) 25OHvit D2. This is a crucial omission which has been corrected by eg the Mayo Clini Lab, which routinely reports both D3 and D2 levels.

In the person not on vit D supplements, the mediocre ie insufficient total vit D level may mask that the crucial vit D3 level is actually seriously low- deficient.  In the person on vigorous vit D2 supplement (the spuriously named “strong calciferol” 50 000iu tab no longer prescribed in USA  but commonly in RSA,  that neglects to state it is D2 not D3), the total 25OH vit D assay will be even more misleading if the level  is well up, without the unwary being informed that it is harmful D2 that is elevated, and blocking the needed vit D3 level that the D2 is suppressing.

        15 June  2014 CRUCIAL EFFECTIVE VITAMIN D3 DOSING: A major new  metaanalysis of the benefit of Vitamin D3 and Respiratory Tract Infections RTI in PLOS 2013   at  Sweden’s Karolinska  Institute Bergman ea  showed that in the 11 relevant trials (published between 2007 and 2012 ie done through the first decade of this century) using vit D3,Overall, vitamin D showed a protective effect against RTI (OR, 0.64; 95% CI, 0.49 to 0.84). And the average vit D level at baseline was only 24ng/ml, but with the mediocre  vit D3 doses used then  of average 2000iu/d (300 – 4000iu/day) given for between 7wks and 3 yrs, the average bloodlevel achieved on replacement was only 50% higher at 36ng/ml”.

     This confirms more direct experience  with higher doses that blood level increment, and benefit,  is proportionate to vit D3 dose, at least up to the proven speculative  safe upper dose of at least 10 000iu/day (whereas the proven safe longterm daily dose is up to 50 000iu/day). “More important, the protective effect was larger in studies using once-daily dosing compared to eg monthly  bolus doses (OR = 0.51 vs OR = 0.86, p = 0.01)”. This concurs with our experience of major benefit  against respiratory infection that is  based on published studies giving a loading month’s dose of about 80-100 iu/kg/day  ie ~3000iu/kg; then that monthly dose split conservatively eg 50 000iu every week or two depending on mass, and severity of ill-health; to a more successful blood-level of 60 to 100ng/ml.

Similarly, the  2014 VIDA trial   across USA-    Effect of Vitamin D3 on Asthma Treatment Failures in Adults With Symptomatic Asthma and Lower Vitamin D Level, Castro ea,  showed “Vitamin D3 for 28 weeks did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma”But this trial had the same severe limitation as the Swedish metanalysis of vit D3 benefit- it also used only 4000iu/d. “While all were vitamin D insufficient ie below 30 ng/ ml  before the trial and half were deficient with levels below 20 ng/mL, supplementation brought levels above the 30 ng/mL threshold for 82% in that group – mean levels were 41.8 ng/mL at week 28 in the supplement group, while the mean stayed in the deficient range for those who got placebo. ”  So 4000iu/day merely doubled the bloodlevel to only about 40ng/ml – only about half of the putative optimal dose. 

These recent studies force us to conclude that bad weather, and  bad prevalent respiratory viruses,  and especially with major acute, or chronic illness as in those with or at risk of serious infections eg major trauma or sepsis,   MERS-CoV, Ebola, malaria, cholera, cancer, diabetics, smokers, asthmatics, bronchitics,   AIDS-TB., pneumonia and old age  sufferers, and especially hospital, laboratory  and clinic- health workers-  we should  give a loading dose of about 4000iu/kg, then 10 000 iu/d for an average 70kg adult,  or 50 000iu every 5 days, or more simply 75000iu (about 1.5ml of 100cws vit D3 powder) weekly; or at a stretch, 300000 if not 400 000iu monthly. . As  the common  imported powder concentrate  is 100 000 iu / Gm ie per 2 ml, it is simple to take the slightly sweetish powder up to  2 or more 4 ml teaspoons ie 200 000  -400  000 iu on the tongue.   

The majority of residents of developed countries now live urbanised with mechanized transport, do not live and work / walk  all day stripped in the sun. The poor malnourished  peasants  live crowded in ghettoes , and  the poorest are generally the darkest skinned and therefore make the least vitamin D3. So with rare exceptions, everyone needs the vigorous vitamin D 3 doses discussed above.

But at the prevalent bulk vit D3  powder price of  at most about  $0,o2 per 100 ooo iu, at a mean population age of around 20 to 25 yrs -outside  Europe- it would cost a country of eg 50 million people perhaps $o.5 per head per  year ie conservatively $25 million a year to prevent > 90% of common illnesses including drugging and violence consequences.  Of course no government can tolerate  such massive loss of jobs and taxes  in a decimated disease industry that turns over $ trillions annually – up to 18 % of national budgets.     So it’s up to individual adults, especially householders, educators and employees ,  to see that the cheapest cure- all  after clean water – vitamin D3 – is recommended and freely available.

We health professionals with our highly vulnerable populations in South Africa and worldwide   (epidemic/endemic  HIV, TB, cancer, drug addiction, MERS-CoV, asthma, diabetes, cardiovascular,  malnutrition, alcoholism and violence) therefore surely have no choice but to swop promptly from prescribing vit D2 “Strong Calciferol” (a dangerous misnomer) to prescribing vitamin D3 at vigorous dose (with if possible occasional blood level check of 25OHvit D3)- at a trivial imported and distributed cost (100cws)  to South African state clinics  of perhaps<1/4 of the cost of D2 eg  R1 per patient per month for a conservative 100 000iu monthly  (ie  after an appropriate germicidal  loading dose of eg 3000 iu/kg) if not the more realistic dose double that- still at only eg US$0.2 a month.
Health Authorities everywhere have an obligation to enforce the use of vitamin D3 and not vitamin  D2 globally ..

2 February 2014 VITAMIN D 3 DENIALISM:                                                       Dr John Cannell psychiatrist and nutritionalist  of the Vitamin D Council has posted a comprehensive rebuttal of the Autier review’s damnation of vitamin D at http://www.vitamindcouncil.org/blog/a-look-at-the-recent-lancet-review-study/.

Queries  and rebuttals    all over the world are questioning the negative French  (Autier ea)   Vitamin D status and ill health: a systematic review   published last month by the UK Lancet            Low serum concentrations of 25-hydroxyvitamin D (25[OH]D) have been associated with many non-skeletal disorders. However, whether low 25(OH)D is the cause or result of ill health is not known. We did a systematic search of prospective and intervention studies that assessed the effect of 25(OH)D concentrations on non-skeletal health outcomes in individuals aged 18 years or older. We identified 290 prospective cohort studies (279 on disease occurrence or mortality, and 11 on cancer characteristics or survival), and 172 randomised trials of major health outcomes and of physiological parameters related to disease risk or inflammatory status. Investigators of most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality. High 25(OH)D concentrations were not associated with a lower risk of cancer, except colorectal cancer. Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer. In 34 intervention studies including 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 μg per day or more did not show better results. Supplementation in elderly people (mainly women) with 20 μg vitamin D per day seemed to slightly reduce all-cause mortality. The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin D status is reported in a wide range of disorders. In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.

and the accompanying anonymous Lancet editorialchasing a myth?

Ongoing randomised clinical trials assessing the ability of vitamin D supplementation to reduce the risk of several non-skeletal disorders involve a population larger than that of Cambridge, UK, and will cost millions  of research dollars. VITAL, for example, will enroll 20 000 participants and has US$22 million in funding.  This vast investment of effort by patients, researchers,  and funders is laudable, as it is almost certain that it will be sufficient to answer a question that has long kept the medical community in the dark.
                 Vitamin D first became a medical success story when its importance in bone health and calcium homoeostasis was proven decades ago. Since then, epidemiological  evidence has been accumulating to support a role for vitamin D in the protection of individuals from various   non-skeletal disorders including cancer, cardiovascular diseases, autoimmune and inflammatory diseases, dementia, and diabetes; it might also reduce all- cause mortality. Many of these studies show a strong association between low vitamin D concentrations anddisease. However, the results of myriad recent small randomised controlled trials are almost unanimous in  concluding that vitamin D supplementation provides  protection from few, if any, of these outcomes.
      Vitamin D is a steroid hormone with pleiotropic and tissue-specific effects owing to the wide expression of  the nuclear vitamin D receptor in many different tissues,and the many genes that are targeted by its actions.  In the skeletal system, vitamin D promotes healthy development and remodelling of bone. In other tissues,   vitamin D is postulated to mediate potentially beneficial  effects via a wide variety of mechanisms: some evidence  suggests that it exerts anticancer activity by limiting hyperproliferation of certain cell types, that it promotes metabolic health by regulating lipid metabolism in adipocytes, and that it limits autoimmunity by  suppressing inappropriate immune responses.  In a systematic review in   The  Lancet Diabetes &  Endocrinology editorial , Philippe Autier and colleagues discuss a large number of observational studies suggesting  That high serum concentrations of vitamin D   might be protective.
      For example, those with high vitamin D had decreased risk of cardiovascular events      by up to 58%), diabetes (by up to 38%), colorectal  cancer (by up to 33%), and all-cause mortality (by  up to 29%). However, they also compare these findings with the results of randomised clinical  trials, which reveal a very different picture: no reduction in risk was found, even in trials involving adequate supplementation of participants with lowvitamin D levels at baseline (less than 50 nmol/L). Autier and colleagues also did a new meta-analysis  of 16 trials that assessed the effects of vitamin D supplementation on blood HbA1c, a biomarker mainly   used for monitoring disorders of glucose metabolism.
Although type 2 diabetes is associated with  low vitamin D, the results show that vitamin D supplementation does not reduce HbA1c
. Thus, it looks increasingly likely that low vitamin D is not a cause but  a consequence of ill health.
Despite the growing body of evidence indicating  that vitamin D is unlikely to prevent non-skeletal   disorders, there is strong support for its use from  many prominent members of the research community,  which is fuelled by the relatively low toxicity of vitamin D, the glimmer of positivity from some trials,and the large body of evidence from prospective  observational studies. For those who ‘believe’, the  lack of benefi t found in most trials completed thus  far can be attributed to issues including inadequate  supplementation, testing of a population not  sufficiently vitamin D deficient at baseline, incorrect
formulation, underpowering, or insufficient follow-up.  Vitamin D might not be safe in all settings, however.
Supplementing at high doses could cause harm in  people with already high concentrations of serum  vitamin D, particularly in those with liver, kidney, or  vascular problems. This is a concern, given the large  number of people taking vitamin D supplements (up  to 50% of adults in the USA).
Large clinical trials to assess the effects of vitamin D on non-skeletal health outcomes are  therefore justified. It would be a real boon to patients if the results are positive, but unless effect sizes for clinically important outcomes are large, the results will only confirm the neutral effect reported by most clinical trials thus far. Although this investment might  therefore have little effect on current guidelines, the results will at least allow the research community to  move on.
This French  review of Vitamin D is the sort of tactic regularly concocted by Big Pharma and the Disease Industry for the media,  to discourage patients and doctors  from taking/prescribing  effective doses of supplements (beyond a lowdose  multivite a day), instead force them to take Big Pharma poisons- synthetic new risky designer drugs- like antibiotics, antipain,  anticancer, anticholesterol, antiosteoporosis, antiplatelet,antihypertensive, vaccines, antiflu,  –    to make massive profits for the Disease Industry,  but not address or cure the deficiency causes of disease.     At the behest of Big Pharma like Roche, their lobbyists the FDA, the  European Medicines Authority and the UK NHS are  trying to push through legislation that will make anything but lowdose multisupplements available to the public solely on doctors’ prescription.
Meanwhile, Big Pharma companies are paying fines of over $10 billion  a year for promoting their snakeoil  prescription designer drugs by fraud, when these drugs are allowed to be registered for chronic use after small trials of only 6 to 12 weeks, and the researchers who  publish the trials for megadollar fees are regularly caught out, fired but rarely  jailed.                                                                            ……         The Big Pharma guys simply bill the cost of the fines into their marketing expenses- their bosses, and the politicians they buy off,  are too big to jail… Regulators then allow the drugs to be prescribed for years  until enough patients sicken and die for there to be an uproar and cancellation- as  happened recently with Prot(e)os the synthetic ranelate ‘osteoporosis’  snakeoil;.      Now a top Dutch researcher has been fired for falsifying trials to promote betablockers for hypertension – when these have been discredited as routine therapy  for this purpose  for over a decade.
yet the Regulators led by the FDA – which is massively funded solely  by Big Pharma as their ally- insists that vitamins, minerals and other long-proven natural supplement therapeutics, prime human hormones  like melatonin and physiological human sexhormone creams , have to undergo $multimillion trials before they can be marketed as already  long-evident safe effective therapies.

none of the vit D   trials used the dose of vit D3 now recommended on solid evidence  that we should all take   – 80 (to 100)iu/kg/day or 2400-3000iu/kg/month of vitamin D3- ie about 150 000 – 200 000 iu to start and then per month for average adults –  to maintain healthy 25OH vit D levels around 60-100ng/m (here our bloodlevels are usually between 10 and 20 !  because we take little dairy products, nuts and sunshine- we cover up and live indoors.)  .

Most  of the reported trials used only about 5% of the recommended  vit D  dose ie ~200 to 400iu/day ie 6 iu/kg/day!  this dose does nothing except partly prevent rickets-  in infants!  Pregnant women are still routinely given such weak near-nonsensical doses of vit D.

and as Cannell’s review of the Autier analysis  points out, the vitamin D  trials trials under way – * in USA-Boston VITAL study 20 000pts)   ,           Finland (FIND 18000 pts    and     UK(VIDAL 1600pts ) ,  in some 40 000 subjects, due for publication only  between 2017-2020-  are using only 1600 to  3200iu vit D a day or about 48  000 to 96000iu/month ie perhaps 32iu (25 to 40) /kg/day. So  they are testing still modest doses and blood level targets. .

Read about the fraud of the Disease Industry at https://healthspanlife.wordpress.com/2014/01/20/vitamins-c-d3-avoiding-vitamin-denialism/ – especially about the dodgy ” Strong Calciferol’ tabs (Lennons)- which are not what you expect (vit D3) but vit D2 (the label, and package insert, dont tell you this) . vit  D3 powder is half the price but apparently 4 times as strong as D2.

ideally you should check your 25OH vit D and calcium levels to make sure you are on the right dose- but always taking some magnesia supplement, and at least 2 liter of water/ sodawater/clear fluid a day to avoid dehydration, kidney stones and vascular disease (which  highdose calcium supplement eg 1000mg  & vit D3   400iu/day cause).

8 April 2013  UPDATE: VITAMIN D3 THE AMAZING SUPPLEMENT

It is sad to record that Dr Walter Stumpf died suddenly a few months ago during ongoing correspondence. The world  has lost a teacher  of the century in both biological sciences and the humanities, metaphysics and philosophy,..

This week – as flu mushrooms  in the southern hemisphere autumn- the Canadian Medical Association Journal  April 3-8 features  early-release articles on concerns about the Asian flu viruses and especially the SARS-nCorVirus. Is mass vaccination the answer?  or did this in fact worsen mortality in previous North American  epidemics of eg H1N1?  which brings us back to global protection against infections and all major diseases with lowcost safe VitaminD3 at say 50 000iu(~700iu/kg)/week plus the other all-system protective  supplements – eg multivitamins (especially vit C and K) and minerals especially  magnesium, zinc, idine  and selenium; and during epidemic times, major daily boost in vits D3 and C.

In December 2012 the University of San Diego published a useful researched update on vitamin D3 and breast cancer; pointing out again that while the increase in benefit obviously drops off with increasing dose, safe dose is up to at least 10 000iu a day or 70 000iu a week, to a bloodlevel around 100ng/ml; and toxic dose requires at least 40 000 iu a day chronically (if not 600 000iu/d as other evidence suggests). The projections for breast cancer reduction fit with the same team’s predictions in 2007.

So apart from maintaining good water intake, and avoiding taking ill-advised unbalanced solo calcium supplement, for optimal dosing   in those with cancer or any other high risk, blood levels of both 25hydroxy vit D3,   1,25 calciferol, calcium, phosphate  and creatinine, should be monitored occasionally, to avoid the rare risk of kidney stones and arterial/breast calcinosis.

Remember that magnesia, phosphate and vitamin C  and K2 supplements are amongst the most important of at least 40  to accompany vitamin D3.

Last month three new studies affirmed the importance of vigorous vitamin D3 levels for genetic, heart and all health.

Holick’s group at Boston University   show the profound .Influence of vitamin d status and vitamin d3 supplementation on genome wide expression of white blood cells. No studies have reported on how vitamin D status and vitamin D3 supplementation affects broad gene expression in humans. A randomized, double-blind, single center pilot trial was conducted for comparing vitamin D supplementation with either 400 IUs (n = 3) or 2000 IUs (n = 5) vitamin D3 daily for 2 months on broad gene expression in the white blood cells collected from 8 healthy adults.   in the winter.   CONCLUSION SIGNIFICANCE: Our data suggest that any improvement in vitamin D status will significantly affect expression of genes that have a wide variety of biologic functions of more than 160 pathways linked to cancer, autoimmune disorders and cardiovascular disease with have been associated with vitamin D deficiency. This study reveals for the first time molecular finger prints that help explain the nonskeletal health benefits of vitamin D

Tehran University  http://www.ncbi.nlm.nih.gov/pubmed/23517460  showed clearly that    Vitamin D Supplementation Improve the Severity of Congestive Heart Failure. In  100  heart failure patients with (NYHA) class I ,   Only 6% of the participants had a sufficient serum concentration of 25(OH) D >30 nmol/L. Patients with insufficient or deficient serum levels of 25(OH) D (<30 ng/mL and <20 ng/mL, respectively) received oral vitamin D3 for 4 months. Vitamin D supplement increased mean serum 25(OH) D from 12.6 nmol/L to 54 nmol/L (P<.001). After vitamin D supplement, the serum level of pro-brain natriuretic peptide markedly decreased (P<.001). Cholecalciferol significantly decreased high-sensitivity C-reactive protein level (P<.001). Restoration of serum 25(OH) D level was also associated with substantial improvement in hear tfailure (P<.001) and 6-minute walk distance (P<.001).

 and Robert Heaney’s group at Creighton University   http://www.ncbi.nlm.nih.gov/pubmed/23514768  that .  All-Source Basal Vitamin D Inputs Are Greater Than Previously Thought and Cutaneous Inputs Are Smaller.    

The magnitude of vitamin D inputs in individuals not taking supplements is unknown.. they reanalyzed 3000 subjects’  individual 25(OH)D concentration data from 8 studies involving vitD3  supplement.  The total basal input (food plus solar) was calculated to range from a low of 778 iu/d in patients with end-stage renal disease to a high of 2667 iu/d in healthy Caucasian adults. Consistent with expectations, obese individuals had lower baseline, unsupplemented 25(OH)D concentrations and a smaller response to supplements. Similarly, African Americans had both lower baseline concentrations and lower calculated basal, all-source inputs. Seasonal oscillation in 4 studies ranged from 5.20 to 11.4 nmol/L, reflecting a mean cutaneous synthesis of cholecalciferol ranging from 209 to 651 iu/d at the summer peak. We conclude that: 1) all-source, basal vitamin D inputs are approximately an order of magnitude higher than can be explained by traditional food sources; 2) cutaneous, solar input in these cohorts accounts for only 10-25% of unsupplemented input at the summer peak; and 3) the remainder must come from undocumented food sources, possibly in part as preformed 25(OH).

Update March 2010

August 2009  SUMMARY: Evidence is overwhelming  that the prime sun-induced steroid hormone Vitamin D3 cholecalciferol – soltriol- is  invaluable in  20fold   higher  dose ie   perhaps  5000 to 10 000iu/day rather  than has been preached to date (200- 400iu/d), as part of lifelong  hormone replacement  HRT to prevent all major chronic degenerative diseases in all humans living and working indoors.  Effective dose of vitamin D3 supplement can reduce deathrate and disease by an astonishing 20%- that is indeed a panacea almost as good as other natural micronutrient supplements eg  fish oil, metformin, and appropriate sex hormone replacement SHRT.   It is becoming clear that with rare exceptions everyone- especially those  with serious disease eg cancer, heart, lung, brain, nerve/muscle/bone/joint  or inflammatory bowel diseases or  chronic infections like TB  HIV  influenza  or human papilloma virus –   should take a daily supplement of about 10 000iu (1/4 mg)  vitamin D for as little as ~ R10 US$1  a month ; ideally  under supervision of some  health professional.  All that is required is occasional check of blood chemistry, and good diet and  fluid intake.

And obviously because of vitamin D3’s  benefits in lowering all diseases, when using vigorous dose vitamin D, one must  expect to need to lower  prescription drug treatments for diabetes, hypertension, depression, heart disease, lung disease, arthritis, infections  etc  as these ailments  improve from the vitamin D  replacement over months.

INTRODUCTION:  Battling to help some desperate patients this week – mostly women-  with cancer, vascular, rheumatoid, lupus, diabetic, depressive, osteoporotic  and infective disease- especially now the quadruple perils of infections  influenza; human papilloma virus; AIDS and tuberculosis – let alone nuisances like shingles  candida or  herpes –  prompts a thorough review of the polyfunctional vitamin of this decade- vitamin D3, cholecalciferol, soltriol (Stumpf WE).

This  review is especially appropriate on our Womens’ Day 9 August 2009 for a natural product so important for the health of women , that commemorates the year  1956 when 20 000 women marched in defiance of  male despots’  fascist apartheid pass laws. The ages-old discrimination against women is epitomized by the pragmatic liberal economist Professor Ken Galbraith’s lecture to the Royal Society of Medicine in 1973 on the problem of unequal development and centralization of power in male technostructure – profit maximization.

No-where in business is this better shown than in Big Business creating demand  by saturation marketing,  including the medicalization of health.  This  involves  disease-mongering through creating unnecessary  concerns so as to expand markets among the well  for  patents eg  blanket cholesterol or mammography or colonoscopy  screening,  or remedies   for eg female arousal disorder, anxiety, reactive depression, mild-to-moderate hypercholesterolemia – when very few have been proven to  need or benefit from such labels, procedures and drugs.

VITAMIN D3  SOLTRIOL : INFORMATION EXPLOSION:

The first  of 46200 entries on Medline  on vitamin D is  from Oxford by Heaton 1922 . There are 272 500 entries on vitamins since 1918,  the first specific one by Jack Drummond in 192o, but of course vitamin D was first identified by Mellanby 1919, preceded by vits A, B1 and C between 1909 and 1912. From a recent historical review (table 1) of hormones, vitamin D3  was  perhaps the 7th hormone recognized  after testosterone and  estrogen (China 2600 years ago) ,  thyroid (1891)  epinephrine secretin parathyroid and antidiuretic hormone.

Soltriol is an  exquisite description  for a sun-activated steroid, the  cardinal prohormone vitamin D3  made  from cholesterol via sunlight exposure. Soltriol is not in a 1964 Oxford Dictionary, nor is it’s etymology detectable on Google search; it was indeed invented by  the pioneer polymath neurologist Dr  Walter Stumpf . On Medline search for soltriol, the first result is  Corradino 1973…

It is intriguing to read that Dr Stumpf  graduated in medicine in 1952- and 50 years later  in 2005 he wrote on his website: “From the microautoradiographic target recognition and related actions it follows that vitamin D has healing potential for prevention and treatment of various deficiencies and ailments, including old age: a PANACEA? If there is any compound that deserves being designated a panacea, the multifunctional heliogenic vitamin D appears a suitable candidate.   Philosophical consideration: “Vitamin D”, the term does not reflect its significance. I have used instead SOLTRIOL in several publications as a more appropriate designation. – Is there not a link to Heraclitus emanation of “ ever-living fire ”? The cosmic solar fire (Soltriol) as the sustaining life force, providing wave length energies for Temperature, Visible Light , and Ultraviolet B “. ”  The Main Biological Role of Vitamin D is Seasonal Adjustment of Vital Functions: These include regulation of growth, reproduction, survival stress response; endocrine and exocrine secretion, cell proliferation, cognition and mood; neuro-motor, neuro-endocrine, and neuro-sensory functions, immune response, cardio-vascular and gastro-intestinal functions, regulation of calcium and other mineral levels, cell proliferation and protein synthesis-differentiation.

Considering the decades of vitamin D use for its other benefits, it is ironic that a 1999 University California website on The History of Vitamin D has never been updated to cover more than the anti-rickets protection from vitamin D. But as Prof Stumpf writes to  me today, ultimately it is the sun that is the panacea, transmitting it’s healing powers via the skin-activated messenger hormone vitamin D.

 

It is now almost  a year since this column last reviewed vitamin D3’s benefits against all major diseases   (see table) – during which year  scores of new randomized controlled trials RCTs of vitamin D have appeared- there are now some 1680 RCTs on it since  1965.  Carpenter 1999 reviews Forgotten Mysteries in the History of Vitamin D.

Women have a raw deal:  due to their prime role and innate sense for survival of the species, for nuturing and caring, they live  about 10% longer than their mates, but as a result endure far more illness, as well as assault, disability and murder (mostly  inflicted by the careless male).

PROTEAN STEROIDS, PROTEAN FUNCTIONS: Calcitriol is one of many human steroids that include the sex hormones, aldosterne and digoxin; as well as  nonhuman steroids which also have important medicinal use- like phytosteroids, equine steroids like the equilins eg premarin, and the important ecdysteroids in insects and some plants.   Stumpf has again stressed the wide distribution in humans  of vitamin D receptors VDRs, indicating their importance in protean human functions far beyond calcium regulation.

VITAMIN D AND ALL-CAUSE MORTALITY: it is just a year since Melamed ea from USA showed that  having low vitamin D (as opposed to high level)  increases all-cause mortality by 26%- thus taking submaximum safe dose of vitamin D  can improve chance of survival by about 20%.  This for as little as R10/month – $1-  in South Africa.

In 2000,  the Seven Country Study Group showed that  ” saturated fat,vitamin C and smoking are the major determinants of all-causemortality at the population level” ie the higher the fat and smoking intake and the lower the vitamin C, the higher the deathrate. We now know better-  serious vitamin D deficiency joins the list, which of course includes alcoholism. .

VITAMIN D AND CARDIOVASCULAR DISEASE CVD

Pizzorno 2009 reviews the strong evidence of the importance of balanced vitamins A D and K supplements in reversing the epidemics of both CVD and osteoporosis.

VITAMIN D AND DEPRESSIVE/NEURODEGENERATIVE DISEASE

over 20 articles already this year attest to the importance of vigorous vitamin D levels in reducing these diseases.

VITAMIN D AND AUTOIMMUNE / INFLAMMATORY BOWEL DISEASE AND MUSKULOSKELETAL DISEASE:

The much higher incidence of autoimmune diseases in women – especially SLE systemic lupus erythematosis and RA rheumatoid arthritis-    let alone far higher younger  female  risk for fractures- must have  been obvious for millennia.  So obviously genetic female factors play a major role in these diseases – now surely attributable   largely to  the reproductively necessary absence of the Y chromosome, and thus the 100fold lower testosterone: estradiol T:E2 ratio in women (perhaps 2:1) than in men (in youth, >200:1).. It is common cause that estrogen is immunostimulant whereas testosterone  and progesterone (like vitamin D) are immunomodulating. Hence testosterone and progesterone levels soar during pregnancy to prevent the mother rejecting her foetus. This partly also explains why vigorous vitamin D supplement also greatly improves fertility and pregnancy outcome.

VITAMIN D AND RHEUMATOID ARTHRITIS: many studies  show  the benefits of the prime anabolic steroids- vitamin D and androgen (Devis 1950)  supplements-  in treatment of all inflammatory disease, especially when inflammation itself weakens bone and all other tissues. The latest – last month (Chabchoub 2009)- shows “a possible role for XCI mosaicism in the pathogenesis of RA and thyroid disease  and may in part explain the female preponderance of these diseases”. But the first and only randomized controlled trial of the effect of vitamin D on modifying  RA  appears in  1973 (Brohult)  and the only open  trial (Andjelkovic  1999) in RA  showed that            “alphacalcidiol is a powerful immunomodulatory agent with fairly low hypercalcemic activity”.

VITAMIN D INTOXICATION:  The low toxicity of vitamin D3  is fortunate because while it is ideal to monitor vitamin D levels on effective replacement, the blood test costs about R660- $80- locally;  hence all one needs to do is exclude kidney problems (which may need even higher dose of vitamin D3), and risk of kidney stones- but perhaps checking blood calcium and creatinine  at baseline and occasionally, and ensuring balanced supplement of calcium-magnesium – boron-zinc-manganese-(iron if deficient)  and vitamins B, C, D and K.   Since vitamin D intoxication (toxic rise in blood calcium- hypercalcemia) in some opinions  requires ~>600 000iu/day for months, ths is inconceivable unless one were to swallow say twelve  50 000iu vitamin D every day for months.   So the only recognized form of vitamin D intoxication could be an industrial accident involving mistaken use of vitamin D concentrate in medicine.

HYPERCALCEMIA HIGH BLOOD CALCIUM: medical causes  are rare without gross calcium overdose (milk alkali syndrome) or other specific symptomatic diseases – eg primary hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma.And fortunately most patients with these diseases and hypercalcemia are far more likely to benefit from therapeutic treatment with vitamin D than worsen on it.

OVERDOSE:      HYPERVITAMINOSIS D: WIKI says   “Vitamin D stored in the human body as calcidiol (25-hydroxy-vitamin D) has a half-life of about 20 to 29 days.[17] Ordinarily, the synthesis of bioactive vitamin D hormone is tightly regulated, and prevalent thinking is that vitamin D toxicity usually occurs only if excessive doses (prescription forms or rodenticide[38] .   Serum levels of calcidiol (25-hydroxy-vitamin D) are typically used to diagnose vitamin D overdose. In healthy individuals, calcidiol levels are normally between 32 to 70 ng/mL (80 to 175 nmol/L), but these levels may be as much as 15-fold greater in cases of vitamin D toxicity. Serum levels of bioactive vitamin D hormone (1,25(OH2)D) are usually normal in cases of vitamin D overdose. Symptoms include Dehydration Vomiting Decreased appetite (anorexia) Irritability Constipation Fatigue.

Overdose of vit D3 has been observed at 1925 µg/d (77,000 IU per day). Acute overdose requires between 600,000 and 1,680,000 IU per day over a period of several days to months, with a safe intake level being 10,000 IU per day.

A 2007 risk assessment suggested that 250 micrograms/day (10,000 IU) in healthy adults should be adopted as the tolerable upper limit.[39] In adults, sustained intake of 100,000 IU can produce toxicity within a few months.[2] For infants (birth to 12 months) the tolerable UL is set at 1000 IU, and 40,000 IU has been shown to produce toxicity within 1 to 4 months.  All known cases of vitamin D toxicity with hypercalcemia have involved intake of or over 40,000 IU)[42].

Although normal food and pill vitamin D concentration levels are far too low to be toxic in adults, people taking multiples of the normal dose of codliver oil may reach toxic levels of vitamin A, not vitamin D, [43] if taken in an attempt to increase the levels of vitamin D. Most officially-recorded historical cases of vitamin D overdose have occurred due to manufacturing and industrial accidents.[42]

Some symptoms of vitamin D toxicity are a result of hypercalcemia caused by increased intestinal calcium absorption. Vitamin D toxicity is known to be a cause of high blood pressure.[45] Gastrointestinal symptoms of vitamin D toxicity can include anorexia, nausea, and vomiting. These symptoms are often followed by polyuria (excessive production of urine), polydipsia (increased thirst), weakness, nervousness, pruritus (itch), and eventually renal failure. Other signals of kidney disease including elevated protein levels in the urine, urinary casts, and a build up of wastes in the blood stream can also develop.[2] In one study, hypercalciuria and bone loss occurred in four patients with documented vitamin D toxicity.[46] Another study showed elevated risk of ischaemic heart disease when 25D was above 89 ng/mL.[47] Vitamin D toxicity is treated by discontinuing vitamin D supplementation, and restricting calcium intake. If the toxicity is severe blood calcium levels can be further reduced with corticosteroids or bisphosphonates. In some cases kidney damage may be irreversible.[2]

Exposure to sunlight for extended periods of time does not normally cause vitamin D toxicity.[42] This is because within about 20 minutes of ultraviolet exposure in light skinned individuals (3–6 times longer for pigmented skin) the concentration of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D that is produced is degraded.[48] Maximum endogenous production with full body exposure to sunlight is 250 µg (10,000 IU) per day.[42]”

VITAMIN D AND SEX:

Biologically, the most imperative function for species survival is sex- reproduction.   Vitamin D is clearly a potent  anabolic reproductive steroid like testosterone:   The first paper on this association on Pubmed appears in 1963 from Russia (Gokinaeva).

Stumpf 1989 at Univ N Carolina reported that “vitamin D (soltriol)  regulates and modulates reproductive processes in the female and male, controlling  reproductive processes from onset of puberty to  fertility, pregnancy, lactation, and probably sexual behavior.”

Mirzahossein in 1996 showed that,” given in the critical period of foetal imprinting, vitamin D  may  influence steroid hormone-receptor commanded events for life in a way similar to synthetic steroid hormone analogues”. So as with marine omega3., it is crucial that future parents take enough vitamin D.

Friedrich 2002 showed that  even prostate, colon and   normal cervical tissue and cervical cancer cells have VDRs – vit D receptors- and may be new targets for cancer prevention or cancer treatment.

Kalueff 2005 showed that it influences even neurological receptors eg grooming behaviour in mammals.

And now Blauer 2009 shows that it reduces growth by up to 60% in human uterus muscle and fibroids- leiomyomas.

VITAMIN D AND PAIN: this week Khan ea from Kansas University describe Effect of vitamin D supplement  on  joint pain and fatigue in women starting adjuvant letrozole treatment for breast cancer. But the first Pubmed reference on vitamin D and pain is from von Wendt 1951.  Gerwin 2005 recognized vitamin D deficiency as a cause of fibromyalgia- chronic fatigue syndrome.

and Glueck ea from Cincinnati show that vitamin D supplement for low vitamin D abolishes statin – induced  myalgia.

VITAMIN D AND SLE- SYSTEMIC LUPUS ERYTHEMATOSIS: on medline the first reference to immunosuppression with vitamin D was  by Bourdial  1963 on nasal allergy, and the first  for vitamin D and immunomodulation is by Nagler & Pollack 1986.:

However, the first paper  on the importance of Vitamin D3 deficiency   in  SLE appeared in Germany  1963, but the first paper in English and from an English country  only in 1979 (O’Regan).

The focus throughout has been on the benefit of vitamin D in reversing the hyperimmunity  of SLE, but of course vitamin D is equally important in preventing both the osteoporosis of inflammation, the fracture and wasting risks  of cortisone treatment, and the vascular disease associated with SLE.  In the last year alone there have been 10 such SLE – vitamin D major studies – 7 from the Americas and 3 from Europe.

SLE as well as plain lupus of the skin are  generally regarded as disease that requires protection from the sun.

Now this week Wright 2009 shows that in children,  SLE is  associated with vitamin D deficiency, particularly among those subjects with SLE who are overweight.

VITAMIN D, SUNLIGHT,  SLE AND CANCER:

The first case of SLE associated with cancer ( meningioma and cervix)-  is reported by Williams  1956. The latest – last month- highlights increased risk of  lymphoma, cervix and bronchus cancers.

Search for malignant melanoma MM and SLE finds the first reference in 1963. yet most of the papers are about reactions to interferon therapy, or immune markers- there is one solitary case report (1991 Sulkes, Israel) of a patient with indolent SLE who after 15 years developed and died of rapidly spread of MM. These authors comment on the infrequent association of SLE & solid cancers, the commonest  being uterus and bladder.

So it is exciting that while more sun exposure causes skin cancer and especially cutaneous melanoma  CMM, (Tuohimaa  2007),  sun exposure also improves survival from CMM-  and from a wide range of internal cancers – (especially stomach, colorectal, liver and gallbladder, pancreas, lung, female breast, prostate, bladder and kidney cancers). This favourable effect of more sunshine is obvious when comparing the lower cancer and heart disease deathrates in sunnier southern versus the darker northern countries. Only rare skin diseases eg porphyria cutanea tarda are contraindications to sun exposure of the skin. But at least one study Holme 2008 shows vitamin D deficiency in erythropoetic porphyria.

Professor Halstead 2008 (and many others)  conclude  that the high fructose corn syrup routinely used in fast foods and cooldrinks in first-world manufacturing is rapidly increasing obesity, lipidemia (and metabolic syndrome and cancer);  while folic acid  food fortification is causing low  B12 levels and thus possibly increasing dementia, vascular disease and advanced precancerous colorectal adenomas and breast cancer.   This trend is aggravated by at least  three scientifically unvalidated  obsessions of Regulators and the Medical hierarchy:

1.   low diet cholesterol in those with mild to moderate cholesterolemia;

ii.  low vitamin D –  low intake dairy products and less  sunlight exposure for fear of skin cancer; and

iii. warfarin (which blocks essential vitamin K) to reduce thromboses- whereas it worsens  both fracture risk  and vitamin D and K deficiency, and thus  arterial calcification, cancer and fractures;   all of which are reversed by vigorous vitamin B3-6-9-12 , C, D  & K supplementation.

Protection from both cancers and SLE is probably  associated with higher vitamin D level above ~100nmol/L.  Both lupus and cancers are due to altered immunity.  But SLE is due to increased autoimmunity- hence cancers   are infrequent during active SLE;  whereas cancers are due to reduced immunity – hence are associated with immune suppression, whether by cortisone (including stress) / chemotherapy, or deficiency of vitamin D – dietary and lack of sunshine..

It is now common cause that more  cancers occur with suppressed  blood  cholesterol – whether  the low cholesterol is cause d by or due to the cancer remains to be clarified; and at least one of the major statin cholesterol-lowering trials showed increase in breast cancer cases.

While there is no clear overall  relationship of statins to osteoporosis or cancer,  Kunitomo   1989showed that cholesterol reduces and corticosteroids enhance the toxicity of vitamin D in rats.  Montagnani 1994 showed that pravastain does not  interfere with the circulating levels of the main vitamin D metabolites.

VITAMIN D AND INFECTION:

For an acute infection, Cannell and Hollis 2008    suggest  vitamin D in an antimicrobial  dose of 2000iu/kg eg 120 000 iu a day for 3  days- to produce enough of the naturally occuring antibiotic cathilicidin.  Ginde 2009 show that those with high vitamin D levels have less respiratory infections. This column has previously reviewed the dramatic benefits of vitamin D on infection mortality in AIDs- TB patients.   Obviously one is going to be cautious pushing vitamin D  in a patient with known kidney stones, or hypercalcemia.

VITAMIN D : WHY THE INCREASING DEFICIENCY, NEED FOR SUPPLEMENT ?

Never mind the poor and chronically ill, the aging especially need much more vitamin D, and benefit the most. Even in a sunny fishing nation like Spain, elderly women do not get enough vitamin D from fish or other foods, and most have suboptimal blood levels of it.

Apart from  dietary intolerance and obsession reducing intake of cholesterol and dairy products, the vitamins and minerals in particular have been greatly depleted and imbalanced in commercially produced- and especially genetically-modified  food.   And while increasing longevity,  food scarcity -poverty and   mushrooming prices (cartel pricefixing that is ignored by well-paid politicians and regulators) – are prime causes,  Politicians and Regulators have worsened this by falling decades behind in ignoring the leading 20th pioneer nutritionist/ economists  like the USA’s Professors Linus Pauling the unique double Nobel prizewinner prophet of vitamin C and peace; Ken Galbraith; and  the UK’s  Sir Jack Drummond. The latter two respectively brought the Allies (under FD Rooseveld and WS Churchill)  through  WW2 by putting farming- healthy food production and pricing- as the painfully obvious priority- which selfserving  gluttonous politicians  like Nixon, Bush,  Kissinger, Mugabe and Mbeki, and most others leaders (who support, not just tolerate such despots)  simply ignore since they detest “surplus people”- the honest  poor;  if not also  hardworking farmers.

It is no coincidence that Pauling and Galbraith both graduated from agricultural colleges.  And no coincidence that all three nutritionists were the targets of  politician-business moguls because of the obstacles they posed to the profiteering national economic sabotage that is the lifeblood of ruthless businessmen-capitalists from before Nixon- Connolly- Reagan- Kissinger  and Thatcher, through to the Bushes and Blair and Montsano-GD Searle, Mbeki and Zuma,  and the arms, oil, banking, mining, media,  food, sex, tobacco-alcohol and medical-big pharma industry mafiosi cartel  who make or break  presidents and  governments.

James Ferguson makes a strong case for The Vitamin Murders, that Drummond (and his family) were butchered in  a Vitamin Industry contract  in France as a lesson to do-gooders because his advocacy of the primary role of good natural  nutrition and vitamins  was such an obstacle  to the fast food and synthetic drug industry.    Conspiracy theorists could argue that, like Pauling’s vitamin C, the Drug Industry have through the FDA managed to ensure that only this year is the FDA grudgingly moving to raise the Recommended daily Allowances of vitamin D (and C)  even fractionally above the present rickets- (and scurvy) preventing doses, as opposed  to their   modest 25 to 50fold  fold   higher intakes that have been known already for decades to be both safe and major benefit against all diseases.

John Le Carre’s The Constant Gardner echoes that ongoing conspiracy scenario, the battle between Big Pharma with it’s drug lobbyists (including the USA FDA and the European Union’s European Medicine’s Authority, and leading politicians) to promote their lucrative modern synthetic chronic  drugs (none of which have been shown to reduce all-cause disease and mortality as do natural supplements), versus nutritionists and informed consumers who know that broad natural supplements (vigorous vitamins, minerals and biologicals)  to bolster the failing adulterated food chain are more important and effective  than any patented designer drugs in combating all disease. Unfortunately the necessary advocacy for natural supplements has been muddied by fraudsters  like the Big Pharma- FDA- academia  cartel (who swamp the medical literature with trial and review papers favouring their snake oils), the Rath Foundation, and our local dissidents against reason  like  Mbeki, and Drs Manto Tshabalala-Msimang, Nkosasama Zuma and Olive Shishana.

CONCLUSION: In 2006 Dr Walter Stumpf in THE DOSE MAKES THE MEDICINE wrote:  “in recent years, discussion raged  about the negative effects of   estrogen-replacement therapy and its relationship to cancer.  In numerous articles, the side-effects of estrogen treatment were highlighted in a generalized fashion and, although consideration was given to the duration of treatment, the relationships to dose (let alone type and route of estrogen) were frequently left out. And yet, considerations of dose and time in pharmacology and toxicology are paramount.
Similarly, a
wareness of proper dosage is crucial to the development of future vitamin D therapies. Physiologic dosing of vitamin D does not cause hypercalcemia – hypercalcemia is related  to overdosing ie closer to 100 000iu/day. Considering the many target tissues that are unrelated to systemic calcium regulation, most therapeutic effects of vitamin D occur independently of the high-dose systemic calcium effects. Because of the biased focus on calcium, the many other effects tend to remain unnoticed and hidden.  Future research needs to give more consideration to dose-effect relationships by monitoring target functions independently of systemic calcium regulation.
New therapeutic applications of vitamin D can be established for cardiovascular, neurological, endocrine, immune, gastrointestinal, reproductive and other diseases, including posttraumatic and gerontological deficiencies, in which the polyfunctional effects of  the hormone not only come to bear, but can also be controlled and maximized for optimal health.”

Since the global population shift from rural to   city life and work the past century ie in our lifetispan,  humans have largely gone from being healthy longlived outdoor food-producing  workers living on their own fresh produce including organically grown unadulterated fresh  food and dairy products – or fish- (rich in micronutrients),   to working mostly indoors and consuming largely  micronutrient-depleted  food  as well as multiple noxious deliberate industrial pollutants- from sugar and alcohol  to estrogenics, pesticides, heavy metals, cornsyrup and aspartamate.

Like fish oil is the most important food extract we have (and businessmen are ruthlessly harvesting to extinction), vitamin D3  has become the anti-disease vitamin  of the past decade,  joining vitamins C & B as the  panacea vitamins that can and should be supplemented in far higher dose than anti-vitamin  “Regulators” and professional researchers and associations (with vested interests in protecting  their funder- Big Pharma) approve.

But as the more affluent age and increase in numbers,  the micronutrients that deplete (with longevity, the deteriorating food chain, and unnecessary drugs),- especially  vitamins  K, chondroglucosamine, N-acetyl cysteine, alphalipoic acid, Co-Q10, arginine, carnitine, carnosine,  riboseand the marine  EPA and DHA-   are  fast becoming the “vitamins”  of the next decade.

Tragically, edible marine products especially marine omega3 EPA+DHA are rapidly becoming so scarce that the vast majority of people  can  neither  source nor afford the minimum optimal gram a day, until science breaks through  to synthesize these uniquely beneficial free fatty acids. But at least the supply of minerals, and vitamins including D3, is inexhaustible and therefore freely available at reasonable cost.

ndb

dedicated to Dr Walter Stumpf, whose  >300 papers (~24% on vitamin D) on Medline apparently  span 1963 to 2008- on vitamin D the first  in 1979, the last  30years later appropriately on Vitamin D and the digestive system.  By comparison,  Pubmed lists only 3 papers by Albright,   in 1938-9.

UPDATE: COLORECTAL CANCER SCREENING IN LOWRISK PATIENTS- NO BENEFIT ON ALL-CAUSE MORTALITY. IS IT ANYTHING BUT A HUGE EXPENSE- AND RISK?

neil.burman@gmail.com

21 Dec 2014 Update: No response has been received from or published by  Annika  Steffens ea  of Australian universities in the past 2 months on the allcause mortality difference by CRC screening in their massive colorectal  cancer CRC screening study in an older population. .

But a number of autopsy studies the past 40 years throw more light on how infrequent CRC actually is elsewhere , Australia apparently having one of the highest rates at 0.125% pa.

As regards apparently undiagnosed cancer found at autopsy: colon cancer is very infrequent, and its import drops with age; and is no more common in sudden death potential organ donors than in others. In Japan over 20 years, the incidence of unsuspected colon cancer in 3600  routine autopsies  was only 0.03%pa. In Singapore in 1000 random autopsies on the other hand, incidental CRC was found in 10 ie a prevalence of 1%. In the Connecticut Cancer registry over 50 years, one cancer trebled the risk of a second cancer- especially  high risk of cancers of lung, larynx, mouth, pharynx; breast;colon, uterus,  ovary, cervix; suggesting a common etiology involving  smoking & HPV? , ie an intriguing link  between female genital tract, breast, airway  and colon but not prostate.. However studies since at least 2005  including from RSA 2007, do indicate a link between HPV and prostate cancer, the latest from Crete University 2014.

So smoking, alcohol and  STDs- especially HPV- are a deadly triad in   male-dominated  permissive countries like South Africa – but  likely worse in strict Islamic countries that keep citizens (subjugated women even more than men) overdressed ie minimize sunshine and thus lifegiving vitamin D3 levels.  .

refs: A  new study   from France asks:  Are suicide rates higher in the cancer population? An investigation using forensic autopsy data.  Med Hypotheses. 2014  de la Grandmaison,  Charlier ea Versailles Saint-Quentin University,    note previous population-based studies have identified increased suicide rates among cancer patients.  In total, 232 cases were included in both the suicide and the control groups.  Cancer was significantly more often found in the suicide group than in the control one (8.6% vs. 3.9%, p=0.03).  the presence of cancer increased the risk of suicide. Moreover, cancer was not known to the deceased in 70% of cases, while the most frequent mental disease found in cancer-related suicide cases was depression (75%). In the 20 cancer-related suicide cases analysed herein, it was difficult to ascertain whether malignancy was the only motive for committing suicide, as cancer could be considered to be either a major causative factor for suicide or an incidental finding.

Crit Rev Oncol Hematol. 2012 Cancer prevalence and mortality in centenarians: a systematic review. Pavlidis ,  Audisio  ea  Univ of Ioannina,Greece.   Data analysis demonstrates how cancer incidence and cause of death present a threefold decrease after age 90 and reach 0-4% above age 100. In addition, the number of metastatic sites are remarkably less and incidental malignant tumours or multiple primary cancers are more frequent, indicating that cancer in centenarians carries a more indolent behaviour. Cancer in the very elderly is relatively uncommon as a disease and as a cause of death. It is characterized by a slow growth and a modest life-threatening potential.

Arch Pathol Lab Med. 2009 Unexpected neoplasia in autopsies: potential implications for donor tissue  safety. Sens, Cooley ea University of North Dakota.-Medical examiner cases are increasingly used as tissue donor referral sources to meet ever-growing need for transplant tissues. Assumption is often made that traumatic and sudden deaths have minimal risk of unsuspected neoplasia.-A retrospective, 5-year review of 412 autopsies from a regional, primarily forensic, autopsy service to determine the incidence of unsuspected neoplasia, potential donor referral suitability. Unsuspected neoplasia rate at autopsy was 7% (29 of 412 patients); cancer was the cause of death in 41% (12 of 29 patients) of these individuals. In patients with a history of cancer, the discordance of cancer diagnosis was 44% (4 of 9 patients [11 patients with known cancer, 2 who refused medical evaluation were excluded from the study]). Nearly 60% (17 of 29 patients) of the unsuspected cancer cases had no apparent reason for deferral of tissue procurement before the autopsy examination.

Ueyama,Tsuneyoshi ea  Kyushu University, Japan.  During the past 20 yr, 17 colorectal carcinomas (0.47%) were incidentally detected among 3,638 autopsied patients without clinically evident colorectal carcinoma, including 2,232 males and 1,406 females, more than 40 yr old. Among the 15 male and two female index subjects, six (0.33%) were detected in the first and 11 (0.60%) in the second decade.

Cancer. 1988 Mar 1;61(5):1059-64.  Incidental carcinoma of the colorectum at autopsy and its effects on the incidence and future trends of colorectal cancers in Singapore.   Lee YS1 Ten incidental invasive carcinomas (two early carcinomas involving the submucosa, and eight advanced carcinomas involving the muscularis propria or beyond) of the large intestine were discovered in a series of 1014 consecutive autopsies. All occurred in Chinese aged 60 years and older, constituting a prevalence rate of about 3% in this age group. If unsuspected colorectal carcinomas in Chinese Singapore residents aged 60 years and older exist in those who died in 1984 to the same extent as that noted in this autopsy study, it was estimated that 146 additional cases would have been added to the Cancer Registry in that year. This would constitute 47.9% of the total number of colorectal cancers diagnosed in this age group in 1984. This potential contribution has to be taken into consideration in epidemiologic studies on the incidence and future trends of colorectal cancers in Singapore. It was observed further that incidental carcinomas were found predominantly in the ascending colon. With more frequent use of colonoscopy, the incidence of right-sided cancers of the large bowel may be expected to increase.

Natl Cancer Inst Monogr. 1985  Summary: multiple primary cancers in Connecticut, 1935-82.  Curtis,  Fraumeni ea   The risk of developing a second primary cancer was evaluated in over 250,000 persons reported to the Connecticut Tumor Registry (CTR) during 1935-82. The CTR has collected data on cancer incidence longer than any other population-based tumor registry and thus provided researchers with a unique opportunity to investigate the occurrence of second cancers among persons followed for long periods, in some cases for more than 40 years. When compared with the general Connecticut population, cancer patients had a 31% increased risk of developing a subsequent cancer overall and a 23% elevated risk of second cancer at a different site from the first. Little variation in risk was seen for the first 20 years of follow-up, although the risk for females averaged twice that for males (41% vs. 18%). Persons who survived more than 20 years after the diagnosis of their first cancer were at highest risk: 51% for females and 45% for males. Over 1 million person-years of observation were recorded, and the excess risk of developing a new cancer was 3.5 per 1,000 persons per year. Common environmental exposures seemed responsible for the excess occurrence of many second cancers, particularly those related to cigarette smoking, alcohol consumption, or both. For example, persons with epithelial cancers of the lung, larynx, esophagus, buccal cavity, and pharynx were particularly prone to developing new cancers in the same or contiguous tissue throughout their lifetimes. A notable finding was the high risk of cancers of the lung, larynx, buccal cavity, and pharynx observed among cervical cancer patients, which suggested a common etiology involving cigarette smoking. The intriguing association previously reported among cancers of the colon, uterine corpus, breast, and ovary was confirmed in our data, which indicated the possible influence of hormonal or dietary factors. Incidental autopsy findings were largely responsible for the observed excesses of second cancers of the prostate and kidney, and heightened medical surveillance of cancer patients likely resulted in ascertainment bias and elevated risks for some tumors during the early period of follow-up, most notably cancers of the thyroid. Interestingly, patients with prostate cancer were the only ones found to be at significantly low risk for second cancer development. However, this might be an artifact of case-finding because advanced age at initial diagnosis of prostate cancer was associated with an underascertainment of second cancers.

J Am Geriatr Soc. 1979   Cancer in the aged: an autopsy study of 940 cancer patients.    Ishii, Hosoda ea  In an autopsy study of 940 elderly cancer patients, 1,030 cancers were identified. The prevalence rate for overall cancer declined after age 85 in men and after age 75 in women. The chief sites of major cancers were the stomach, lung, esophagus, liver, and pancreas, in that order. Incidental cancers (chiefly of the prostate, thyroid, and colon) were found more often in patients over 80 years old. For multiple primary cancers, the prevalence rate was relatively constant until the age of 70, when it rose to a peak in the 80–84 age group before declining to the original level

4 Nov 2014  update: a new POSTAL study Colorectal cancer CRC  screening and subsequent incidence of colorectal cancer: results from the 45 and Up Study. by Steffen ea, from Australian universities shows the usual ~50% reduction BY SCREENING  in colorectal cancer occurrence, in a population mean age 60yrs followed for a mean of 3.78yrs in 741 000 screened pts , mean 60yrs at screening, mean BMI 27kg ie a high-risk population . .   But it glaringly omits  mentioning the most important data:     what was the allcause mortality reduction if any in the screened versus the unscreened cohorts after 3.78years? By this strange data omission, it must be assumed that the study showed no such benefit?.

All that the study confirmed is that it detected about 1000 new colon cancers in about 200 000 older people followed for almost 4 years ie an annual incidence of ~ 1 in 400 000 or 0.125% per year . This rate is similar to  the 0.12% cases pa ie per year  of early breast or  prostate cancer   claimed  in USA SEER data;  but the Australian CRC cancer rate reported is strangely almost three times the overall USA CRC incidence rate of about 0.04%pa found in USA men and women combined, similar to the lung cancer incidence reported there. . If the Australian data presented is correct, there must be something colotoxic (Perhaps their high beer and barbeque  intake?)  in the Australian diet compared to the European and USA population, since the great majority of all such citizens are of European “Caucasian”  origin?

This compares to South Africa where the latest stats for the whole population (NRC/CANSA 2007)   (assuming only maybe <1/4 of the population are 45yrs and up) are : prostate or breast 0.05%pa, lung or  CRC 0.01%pa, and cervix (much younger- due to abuse and STD) 0.05%pa. That study reported the lifetime risk of CRC in RSA as 1:115 in men, 1:199 in women, compared to , prostate 1:26 and breast 1:35, cervix 1:42,  uterus 1:176,  lung men 1:91  women  1:250.

There remains  no good evidence of lives saved ie reduction in all-cause mortality by such hugely costly population cancer screening for these commonest cancers. All that it achieves is the knowledge of previously silent cancer,  which would mostly have been buried unknown with the patient dying of other common causes- ie creating the worried well who have become “cancer survivors”.

we await response from the authors  on this primary issue .

Do any   studies show that there is   meaningful survival benefit from  costly mass screening for internal disease  of adults not at high risk, except for hypertension?  Mass CRC screening of people not at increased risk ( from family history, bowel symptoms or disease) is like breast and prostate screening, no apparent benefit on the most crucial issue, all-cause mortality.

19 Sept 2014   .    is there anything to update? CONCLUSION: not really. Conservatism urges avoidance of screening anyway in those with short lifespan from other major disease, or age eg above 75years- UNLESS there is good evidence of meaningful life extension. As we concluded in 2011, is such screening worth perhaps  1 month life extension in old age?

So far there is still no good evidence to support regular mass population screening in apparently well adults without risks for any degenerative disease  EXCEPT for hypertension;  glaucoma;   malignant melanoma; and  women at risk of cervix cancer ie sexually active at a younger age.

Health benefits and cost-effectiveness of a hybrid screening strategy for colorectal cancerDinh T,  Levin TR  ea 1Archimedes Inc, San Francisco  present a model rationale for FOBT screening from age 50yrs, with a single elective colonoscopy at 66yrs if FOBT remains negative – at a cost of US$10000 per putative QALY gained. .   Colorectal cancer (CRC) screening guidelines recommend screening schedules for each single type of test except for concurrent sigmoidoscopy and fecal occult blood test (FOBT). We investigated the cost-effectiveness of a hybrid screening strategy that was based on a fecal immunological test (FIT) and colonoscopy.   METHODS:  We conducted a cost-effectiveness analysis by using the Archimedes Model to evaluate the effects of different CRC screening strategies on health outcomes and costs related to CRC in a population that represents members of Kaiser Permanente Northern California. The Archimedes Model is a large-scale simulation of human physiology, diseases, interventions, and health care systems. The CRC submodel in the Archimedes Model was derived from public databases, published epidemiologic studies, and clinical trials.  RESULTS:   A hybrid screening strategy led to substantial reductions in CRC incidence and mortality, gains in quality-adjusted life years (QALYs), and reductions in costs, comparable with those of the best single-test strategies. Screening by annual FIT of patients 50-65 years old and then a single colonoscopy when they were 66 years old (FIT/COLOx1) reduced CRC incidence by 72% and gained 110 QALYs for every 1000 people during a period of 30 years, compared with no screening. Compared with annual FIT, FIT/COLOx1 gained 1400 QALYs/100,000 persons at an incremental cost of $9700/QALY gained and required 55% fewer FITs. Compared with FIT/COLOx1, colonoscopy at 10-year intervals gained 500 QALYs/100,000 at an incremental cost of $35,100/QALY gained but required 37% more colonoscopies. Over the ranges of parameters examined, the cost-effectiveness of hybrid screening strategies was slightly more sensitive to the adherence rate with colonoscopy than the adherence rate with yearly FIT.    .  CONCLUSIONS:  In our simulation model, a strategy of annual or biennial FIT, beginning when patients are 50 years old, with a single colonoscopy when they are 66 years old, delivers clinical and economic outcomes similar to those of CRC screening by single-modality strategies, with a favorable impact on resources demand.  Clin Gastroenterol Hepatol. 2013 Sep;:1158-66.

16 Sept 2014: PREVENT INSTEAD OF SCREEN: Dr  Ng  from DANA FABER CANCER INST, BOSTON MASS asks in .  Vitamin D for Prevention and Treatment of Colorectal Cancer: What is the Evidence?   Vitamin D insufficiency is highly prevalent in the U.S, particularly among colorectal cancer (CRC) patients- – studies suggest that higher vitamin D levels are associated with lower risk of incident CRC as well as improved survival in patients with established CRC. There remains a great need to improve prognosis for patients with CRC, and investigating vitamin D as a potential therapeutic modality is an attractive option in regards to safety and cost, particularly in this era of expensive and often toxic anti-neoplastic agents.  Curr Colorectal Cancer Rep. 2014 Sep 1;10:339-345

But as we know well from many studies, conventional “high” doses of vitamins C (eg  hundreds of  mgs/d)  and D (a few hundred to a few thousand iu/d)  have only modest benefit for prevention and against existing disease-  it requires about 10-15fold higher vit D3 ie 80-100iu/kg/day, and 100 to 500 more vit C ie a few to a few score gms vit C a day to have major impact. These must not be in isolation, as they may be limited by conditioned deficiency of other micronutrients especially vits K2. . We know well from eg the ATBC trial of vits A and E that too much and too late may be harmful, especially if these are not in natural balanced forms of all the vits A and E groups.

14 Sept 2014   A colleague is surprised that  at 72yrs I have never had a screening scope.

so I recheck the evidence after 3 years, since my 2011 review. Even The USA National Cancer Institute review of colon cancer screening  (updated to 24 July 2014) agrees  that Based on solid evidence, there is little evidence that screening for colorectal cancer (CRC) reduces all-cause mortality, possibly because of an observed increase in other causes of death, although in some studies it may reduce CRC mortality;   and there is always serious risk of harms. Overall, the NCI concludes that  On initial (prevalence) examinations, from 1% to 5% of unselected persons screened  with stool gFOBT guaiac faecal occult blood test (collected over 3 days, repeated up to yearly )   have positive test results ie 30 per 1000 recalled; of whom on imaging  2% to 10% have cancer and approximately 20% to 30% have adenomas,[26,27] depending on how the test is done.That translates to colon cancer detected in  about 3% of 6%  = 0.18% of the target population screened  – of whom 74% occur between 55 and 84 yrs. .

As a recent Spanish team review last year says, No strategy, whether alone or combined, has proven definitively more effective than the rest:   Economic evaluation of colorectal cancer (CRC) screening   Cruzado J1Carballo F. ea  1Colorectal Cancer Prevention Program for  Instituto Murciano de Investigación Biosanitaria,  Murcia, Spain Because of its incidence and mortality colorectal cancer represents a serious public health issue in industrial countries. In order to reduce its social impact a number of screening strategies have been implemented, which allow an early diagnosis and treatment. These basically include faecal tests and (then) studies that directly explore the colon and rectum. No strategy, whether alone or combined, has proven definitively more effective than the rest, but any such strategy is better than no screening at all. Selecting the most efficient strategy for inclusion in a population-wide program is an uncertain choice. Here we review the evidence available on the various economic evaluations, and conclude that no single method has been clearly identified as most cost-effective; further research in this setting is needed.. Best Pract Res Clin Gastroenterol. 2013 ;27:867-80.  

BUT:  Is aging per se a real risk factor for suffering colon cancer? No good evidence yet.  all cancers do increase with aging. But there is still no hard evidence of meaningful life extension from colon, breast or prostate  screening for silent risks in those without other cancer risk factors.

The NCI found four completed  trials of FOBT faecal occult blood testing since 2004 – in Minneapolis(46500), Denmark (31000), Sweden(68000) and UK(151000) – ie 300 000 older lowrisk adults- these   find no benefit in terms of increased length of life. The longest, –  30 year followup in Minneapolis – looks at the longterm mortality benefit of CRC screening– and as with breast and prostate screening for silent cancer in those without significant risk factors.   So organized mass population screening eg every 1  or 10 years from age 50 years does not save lives in the elderly at low risk ie no colon symptoms- at an enormous cost in the scores  of well people  – about 1.2 per 1000- needed to screen, with about 3% of these found positive needing imaging- at major risk of unforseen problems-  to find one cancer, shorten the lead time, save a life from silent cancer. We all die from something eventually. 99.82% of the population screened did not develop colon cancer.

In firstworld people the risk of colon cancer is generally below that of breast and prostate cancer respectively: Wiki sums it up-                                                                    Based on rates from 2007-2009, 5% of US men and women born today will be diagnosed with colorectal cancer during their lifetime.[95] The median age at diagnosis for cancer of the colon and rectum in the US was 69 years of age. Approximately 0.1% were diagnosed under age 20; 1.1% between 20 – 34; 4.0% between 35 – 44; 13.4% between 45 – 54; 20.4% between 55 a-64; 24.0% between 65 – 74;  25.0% between 75- 84; and 12.0% 85+ years. Rates are higher among males (54 per 100,000 c.f. 40 per 100,000 for females). about 20% of such cancer patients have a familial genetic risk.

so faecal screening would be the mass screening method of choice, with about 25% recall rate for costly colon imaging to find the 1.2  cases per 1000 in the target population. But that is supposed to uncover silent colon cancer 2 years earlier, allowing expected drastic reduction in the 75% mortality of clinically presenting colon cancer. So why do no trials of  colon cancer screening show reduction in all-cause mortality? Perhaps its because the lethal colon cancers occur  and present clinically younger in those with lethal genetic risks eg Lynch syndrome, or predisposing colon inflammation eg ulcerative colitis, Crohn’s; or those with multiple polyposis  who are more likely to bleed early.

But we know that real chronic colonic  disease is par excellence a western Saccharine Disease ie of our urban fastfood high sugars,  low fibre diet, inadequate water intake,  and slothful low sunshine ie couch potato  low vitamin D  constipated  lifestyle; with often smoking and alcoholism. . Naturally the Wiki review, written to favour regular screening to find profitable more  silent cancers (like breast and prostate screening) , does not mention this. .

Shaukat A1, Church TR ea  (in N Engl J Med. 2013;369:1106-14  Long-term mortality after screening for colorectal cancer    Minneapolis VA Health Care System USA).  In randomized trials, fecal occult-blood testing FOBT  reduces mortality from colorectal cancer. However, duration of the benefit is unknown, as are the effects specific to age.  METHODS:  In the Minnesota Colon Cancer Control Study, 46,551 participants, 50 to 80 years of age, were randomly assigned to usual care (control) or to annual or biennial screening with fecal occult-blood testing. Screening was performed from 1976 through 1982 and from 1986 through 1992. We used the National Death Index to obtain updated information on the vital status of participants and to determine causes of death through 2008.  RESULTS:  Through 30 years of follow-up, 33,020 participants (70.9%) died. A total of 732 deaths 2% were attributed to colorectal cancer: 200 of the 11,072 deaths (1.8%) in the annual-screening group, 237 of the 11,004 deaths (2.2%) in the biennial-screening group, and 295 of the 10,944 deaths (2.7%) in the control group. Screening reduced colorectal-cancer mortality (relative risk with annual screening, 0.68; 95% confidence interval [CI], 0.56 to 0.82; relative risk with biennial screening, 0.78; 95% CI, 0.65 to 0.93) through 30 years of follow-up. No reduction was observed in all-cause mortality (relative risk with annual screening, 1.00; 95% CI, 0.99 to 1.01; relative risk with biennial screening, 0.99; 95% CI, 0.98 to 1.01). The reduction in colorectal-cancer mortality was larger for men than for women in the biennial-screening group (P=0.04 for interaction).     CONCLUSIONS: The effect of screening with fecal occult-blood testing on colorectal-cancer mortality persists after 30 years but does not influence all-cause mortality. The sustained reduction in colorectal-cancer mortality supports the effect of polypectomy.

For mass Sigmoidoscopy screening,   Five sigmoidoscopy screening RCTs have reported incidence and mortality results.- Norway 2 trials;  and  United Kingdom; Italy; and the U.SA, in 166,000 participants in the screened groups and 250,000 controls. Follow-up ranged from only 6 to 13 years.   There was an overall 28% relative reduction in CRC mortality (RR, 0.72; 95% CI, 0.65–0.80), an 18% relative reduction in CRC incidence (RR, 0.82; 95% CI, 0.73–0.91), and a 33% relative reduction in the incidence of left-sided CRC (RR, 0.67; 95% CI, 0.59–0.76). There was no effect on all-cause mortality.

For mass colonoscopy screening, no trials have been completed to give any evidence of longterm mortality benefit.

One group proposes a screening program based on  periodic stool FIT faecal immunological test , with a single colonoscopy at 66yrs.  Dinh , Levin ea Archimedes Inc, San Francisco,( Clin Gastroenterol Hepatol. 2013 ;11:1158-66   Health benefits and cost-effectiveness of a hybrid screening strategy for colorectal cancer)  In our simulation model, a strategy of annual or biennial FIT, beginning when patients are 50 years old, with a single colonoscopy when they are 66 years old, delivers clinical and economic outcomes similar to those of CRC screening by single-modality strategies, with a favorable impact on resources demand.

UPDATE  20 Oct  2011 A chiropracter asks: what is the recommendation regarding screening colonoscopy, mammography, prostate for cancers? would MD’s and DO’s get one and if so in what circumstance?

My answer:

The only link between breast, prostate, bowel, ovary and womb cancers is that these organs (unlike cervix cancer) are genetically linked through common sex hormone influences; and (apart from the breasts) coincidentally abut ..

Prostate cancer associates with higher estrogen and DHT levels. As for usually estrogen-dependent breasts and  breast cancer screening in low-risk breasts discussed previously, the overwhelming evidence favours no screening at all without symptoms  or risk factors. Unlike for breast cancer,  treatment for prostate cancer (as for  colon cancer) seems to make no difference except when there is obstruction or bleeding. For asymptomatic PRCA the rule remains: watchful waiting. Like women and breast cancer, many men have undiagnosed ie asymptomatic prostate cancer at autopsy for other causes of death.

Colon cancer is different.   it is less common in women with estrogen replacement.

But unlike prostate and breast cancer where invasive screening of all lowrisk patients likely causes more harm  (including despondency) than good,  it is hard to find good colon cancer studies of asymptomatic lowrisk people that show no benefit of screening colon imaging. Studies of colon cancer imaging are inevitably by practitioners who have  a major commercial vested interest in such imaging.

But how many studies have been done comparing colon screening with no screening in patients who truly have none of the risk factors –  – heredity, meat diet, smoking, overweight, bleeding,  inflammatory bowel disease, polyps, diabetes?

Few articles are against such colon screening ie rationalize or philosophize against it .

A 2011 Medscape review from a New Jersey University team concludes cautiously: “In particular, education and intervention efforts for colon imaging should be focused on patients that have risk factors eg diabetes, obesity, or are former/current smokers. This population represents a sub-group of patients who are having CRC screening at a rate lower than the average-risk population. Significant reductions in CRC incidence and mortality might be possible by providing targeted screening interventions to increased-risk individuals and by educating physicians on the importance of recommending screening to these patients even in the face of multiple competing demands”. ie it  encourages  colon screening in  increased risk individuals. 

Search of Pubmed for “incidental colon cancer at autopsy” reveals only three  studies, >20 years ago,  two in the orient.

Ueyama ea, Kyushu University, Japan in Am J Gastroenterol.1991    Colorectal carcinomas incidentally detected in 3,638 autopsied cases and inpatients  during the past 20 yr.   17 colorectal carcinomas (0.47%) were incidentally detected among autopsied patients without clinically evident colorectal carcinoma, including 2,232 males and 1,406 females more than 40 yr old. Among the 15 male and two female index subjects, six (0.33%) were detected in the first and 11 (0.60%) in the second decade. During their survival periods, fecal occult blood studies were performed in 14 cases and positive in 12 (86%); however, two of them had gastric ulcers which were responsible for the occult blood. During the recent 11 yr, six cases (0.48%) of colorectal carcinoma (four of them males; two, females) also were detected among 1,249 inpatients who were examined by barium enema and/or colonoscopy, including 816 males and 433 females, 40 yr old, or more, in the Department of Radiology. Fecal occult blood was detected in four cases (67%) before colonic investigation. Compared with 708 surgically resected carcinomas, the incidental lesions from both sources were smaller, consisted of higher percentages of Dukes’ A type, and arose predominantly from the sigmoid colon and, rarely, from the rectum. These results indicate that the prevalence of colorectal carcinoma and its predominance in the sigmoid colon have not only apparently but actually increased in Japan, apart from improved diagnostic capabilities, and that false-negative rates with occult blood tests were surprisingly low in these autopsied cases and inpatients.

 Lee YS in Cancer 1988 studied Incidental carcinoma of the colorectum at autopsy in Singapore. . . Ten incidental invasive carcinomas (two early carcinomas involving the submucosa, and eight advanced carcinomas involving the muscularis propria or beyond) of the large intestine were discovered in a series of 1014 consecutive autopsies. All occurred in Chinese aged 60 years and older, constituting a prevalence rate of about 3% in this age group. If unsuspected colorectal carcinomas in Chinese Singapore residents aged 60 years and older exist in those who died in 1984 to the same extent as that noted in this autopsy study, it was estimated that 146 additional cases would have been added to the Cancer Registry in that year. This would constitute 47.9% of the total number of colorectal cancers diagnosed in this age group in 1984. This potential contribution has to be taken into consideration in epidemiologic studies on the incidence and future trends of colorectal cancers in Singapore. Incidental carcinomas were found predominantly in the ascending colon. With more frequent use of colonoscopy, the incidence of right-sided cancers of the large bowel may be expected to increase. The current underdiagnosis of ascending colon carcinomas has to be taken into consideration when any future increase in right-sided cancers of the large bowel is observed. 

Suen ea Cancer. 1974 studied Cancer and old age – autopsy study of 3,535 patients over 65 years old, in New York from 1960 to 1970 ie a decade earlier than the above oriental studies; they showed that men had cancer nearly twice as frequently as women (40% vs. 24%); and more incidental ie less aggressive neoplasms as age advanced. The most frequent cancers were those of the prostate (12% of men), gyne (7.5% of women- breast 3%) , kidney 3.5%, and colon 5.6%.. 70% of the cancers were already diagnosed in life ie 30% were incidental findings. Cancer tended to metastasize less frequently in the elderly.  The most common sites of latent asymptomatic cancer reported by Berg et al The prevalence of latent cancers in cancer patients. Arch. Pathol 1971. in their study of 5636 cancer patients with ages ranging from the teens to over 80,were prostate, thyroid, colon, and kidney. They further emphasized that cancer of the colon and kidney were the ones most easily missed clinically. In our study, the most frequent sites of incidental cancer, among the common cancers, were prostate (incidental 67%), kidney (51%), colon (31.5%), and breast 16.6%.

And  researchers from the Universities of California, North Carolina and Harvard –  Walter ea show in 2005  Screening for colorectal, breast, and cervical cancer in the elderly: Am J Medicine  that “characteristics of individual patients that go beyond age should be the driving factors in screening decisions… in one study -Selby ea A case-control study of screening sigmoidoscopy and mortality from colorectal cancer . N Engl J Med . 1992; .”For colorectal cancer screening, fecal occult blood testing has the strongest evidence of benefit in elderly patients, while flexible sigmoidoscopy reduces mortality from colorectal cancer by 59% .Flexible sigmoidoscopy has fewer complications than colonoscopy, with perforations occurring in less than 0.1 of 1000 examinations; .” But they did not report data on benefit of colorectal screening of lowrisk adults in terms of actual overall life extension ie reduction in all-cause mortality- which benefit has not been shown in rigorous analysis of xray screening mammography or screening blood and digital exams of lowrisk men for prostate cancer. .

Lack of significant life extension by breast and colon screening was shown by Rich and Black from Vermont USA in Clin Pract. 2000 When should we stop screening? Given a starting age of 50 years, screening throughout life has a maximum potential life expectancy benefit of 43 days for breast cancer and 28 days for colon cancer.

These 1 month extensions in life expectancy do not justify screening the entire population of older persons- surely only those of us with significant risk factors need be screened.

CONCLUSION: from the above references from autopsy series, the prevalence  of   incidental ie asymptomatic colon cancer at routine autopsy  in older deaths varies between about 0.5% and 3% in oriental and New York patients. So since I dont have any symptoms or risk factors listed, after 50 years in medicine I havent had colon or prostate imaging for a potential 4 week gain in life expectancy. I will do so promptly if I get colon symptoms.

I tell my older lowrisk patients the dubious potential benefit of cancer screening, and the serious risks, from overdiagnosis- polyps and lowgrade cancers that might never present in lifetime, to perforation ; while explaining to them that well-patient  breast, prostate  and colon cancer screening is hugely profitable universal policy.

For non-emergency consultations and especially costly and invasive procedures, doctors and patients need reminding that it’s the patient’s choice, not the doctors’..

This brings us to one of the ethical dilemmas of medicine: when our experience, and careful sifting of the hard evidence, conflicts with conventional wisdom- which is often based on belief and vested interests- evidence slanted hy bias- surely we practitioners have both a right to express our evidence-based personal conviction, and a duty to do so. Thus we surely have a duty  to give the patient the hard evidence both for and against- be it about the power of prayer and belief, about contraception and abortion, for and against statins for mild-moderate lipidemia, or in the low-risk patient, screening mammography, prostate or colon screening.

 

 

update Dec 2014: TIME TO MANDATE LOWDOSE RESERPINE+ LOWDOSE AMILOZIDE+- AMLODIPINE(/ DIHYDRALAZINE) AS FIRST LINE THERAPY OF AVERAGE HYPERTENSION.

TIME TO COMPELL FIRST LINE POLYTHERAPY OF COMMON  HYPERTENSION WITH LOWDOSE RESERPINE+ LOWDOSE AMILOZIDE; with AMLODIPINE as 4th add-on if needed.

dedicated;  for inspiration and help,  to: Drs YK Seedat; Roy Keeton;  Norman Kaplan; Colin Dollery, Harry Seftel; Josh Barzilay; Tony Bunn; Mark Blockman;  and pharmacists  Allan Taylor and Joe Talmud.

neil.burman@gmail.com    for previous reviews see  https://healthspanlife.wordpress.com/?s=reserpine+

https://healthspanlife.files.wordpress.com/2009/04/reserpine_table.pdf

update:  16 Dec 2014 THE RISKS OF MODERN ANTIHYPERTENSIVE DRUGS:  Pubmed search for ANTIHYPERTENSIVE DERMATITIS REACTIONS brings up >156 papers from 1970 (on practolol, propranolol, atenolol, labetolol, hydralazine, ACEI); we first encountered practolol (BBlocker) problems  in the ’70s;  and captopril (ACEI) dermatitis about 1980; Dermatitis  has also been reported since 1987 with calcium channel blockers. WHY USE ACEI/ARBS and BETABLOCKERS -with their added airways and circulatory risks -EXCEPT AS LAST RESORT?   when these are now routinely combined with other synthetic designer drugs clopidogrel (a sulfonamide) , or /and non-sulfonamide warfarin, aspirin, other NSAIDs and statins; sulphonylureas, glitazones, which cause serious multiple complications including dermatitis.

The problematic Bblockers, ACEI, ARBs, aspirin, NSAIDs,  clopidogrel, warfarin  and  statins are rarely indicated; whereas  the hypersensitiviy  risk with thiazide (hydrochlorothiazide – a sulfonamide – halflife ~10hrs  ) PLUS AMILORIDE (halflife ~7.5hrs,  not a thiazide)  is rare;  and reserpine (not a sulfa, half-life ~10days)  actually suppresses allergic risk;

and natural extracts- fish oil, coconut oil,  vigorous vitamins B, C, D3, E, K2;   magnesium, zinc, selenium, boron, iodine,   garlic, curcumin, gymnema, metformin, reserpine, cayenne, MSM/DMSO, arginine, carnitine, ribose, CoQ10, proline, alphalipoic acid, acetylcysteine- do far more good without harm (than heavily marketed designer synthetics) in addressing the root causes of the common degenerative  diseases of aging rather than addressing just their symptoms, as drug companies do. .

Refs: 1. Immunopharmacol Immunotoxicol. 2013 :35:447-50 “Cutaneous antihypertensive adverse drug reactions (ADRs) have been frequently reported. Vena,  De Simone ea  University of Bari, Italy reported Eczematous reactions due to angiotensin-converting enzyme inhibitors ACEIs or angiotensin II receptor blockers ARBs  in 23 hypertensive patients patients aged 66-87 years; 19 of them were taking another drug in addition to the suspected antihypertensive medication and 15 were on polytherapy with three or more drugs to treat multiple comorbidities. The antihypertensive culprit agents were (ACE) inhibitors in 9 patients, ACEI combined to hydrochlorothiazide (HCT) in 7 subjects, ARBs  alone in 2 patients and associated with HCT in 5 cases. Eczema was generalized in 16 patients and localized in 7 cases, with predominant involvement of lower limbs. Such lesions developed after a latency of 4-30 months and were associated with moderate-to-severe itch, usually unresponsive to oral antihistamines. Histopathology  was spongiotic dermatitis with possible associated psoriasiform skin changes.”

2.  In the Textbook  Adverse Drug Reactions 2nd Ed by Anne Lee, Pharmaceutical press 2006,  the chapter Drug Skin Reactions exhaustively lists all causative drugs – only  reserpine/ rauwolfia is not mentioned since it prevents hypersensitivity:

  3. J Exp Med. 1985 Dec 1;162:1935-53. Reevaluation of reserpine-induced suppression of contact sensitivity. Evidence that reserpine interferes with T lymphocyte function independently of an effect on mast cells. Mekori YA, Weitzman GL, Galli. Harvard & Tel Aviv Universities  “ reserpine blocks expression of delayed hypersensitivity (DH) by depleting tissue mast cells of serotonin (5-HT), preventing a T cell-dependent release of mast cell 5-HT necessary to localize and to amplify the DH response; findings strongly suggesting that whatever effects reserpine might have on immunologically nonspecific host cells, it’s effects on sensitized T cells are sufficient to explain its ability to block cell-mediated immune responses in vivo.

No recent review gives objective evidence-based opinion free of drug industry vested influence about optimal initial antihypertensive  drug therapy that contradict the above evidence.

13 December 2014: latest analyses of all antihypertensive trials confirm that LOWDOSE (potassium-sparing) diuretic- eg amilozide-   LOWDOSE reserpine, and if needed as 4th drug, calcium channel blocker eg amlodipine,  each  individually lower all major events including MORTALITY, ( and refractory lowers refractory pain).  Betablockers, ACEI and ARBs do not reduce mortality- and have major adverse effects. .

Thomopoulos ea (Univs Athens & Milan) J Hypertens Dec 2014   Effects of various classes of antihypertensive drugs on outcome incidence in hypertension, asks which  BP-lowering drug classes  are  effective in reducing MORTALITY?  In 55 RCTs (~200 000 individuals) all  common antihypertensive drugs lowered  BP , stroke,  and major cardiovascular events; but in 2014 use, only  a diuretic (even lowdose); and calcium antagonists  gave  significant reductions of all outcomes including mortality.

PAIN SUPPRESSED BY RESERPINE:    S Afr Med J. 1991;80:176-8.  Significant cost-saving with modification of antihypertensive therapy. Keeton & Monteagudo, Univ.Cape Town.    30 patients  on nifedipine for hypertension or chest pain were followed up for 6 months after alternative therapy- Reserpine combined with a thiazide- was instituted: blood pressure control improved and no serious side-effects were encountered. This  reduced the monthly cost by  73%. Although a self-assessment depression inventory was completed by 21 patients, our study does not fully evaluate the impact on quality of life. The likelihood of side-effects is  small–provided  the maximum daily dose of reserpine does not exceed 0.1 mg. A more considered approach is needed in the choice of antihypertensive agents.

Arch Inst Cardiol Mex. 1977 ;47:101-8. Prinzmetal’s angina Response to  treatment with reserpine. Review of physiopathological mechanisms. Guadalajara , Horwitz , Trevethan  present a case of Prinzmetal angina refractory to classic medical treatment, in which the angina attacks were suppressed with  reserpine .Coronary spasm due to alteration in the regulation of the coronary arterial tone from  autonomic nervous system illness is established, an abnormal coronary vascular reactivity is also reviewed. It is emphasized that Prinzmetal angina is an original entity, different from  coronary arteriosclerotic heart disease, which may coexist with it but which cannot be treated in the same way, because its physiopathologic mechanisms are different.

Cardiovasc Dis. 1974;1:194-201. PRINZMETAL ANGINA PECTORIS WITH NORMAL CORONARY ARTERIOGRAMS: EFFECT OF LONG-TERM RESERPINE TREATMENT.   Hernandez-Casas, Leachman ea . Baylor  St. Luke’s Houston, Texas

7 December 2014:  Medscape 2013 : the modern theory  Pathogenesis of essential hypertension HBP  is highly complex: Multiple factors modulate blood pressure (BP) for adequate tissue perfusion : Humoral (ie in the blood- hormonal, immune, nutritional), Vascular reactivity , Circulating blood volume, Vascular caliber, Blood viscosity, Cardiac output, Blood vessel elasticity, Neural – autonomic stimulation.                          Over the course of its natural history, essential HBP progresses from occasional to established HBP.  After a long invariably asymptomatic period, persistent HBP develops into complicated HBP, in which target organ damage to the aorta and small arteries, heart, kidneys, retina, and central nervous system is evident.

The progression of essential HBP begins with prehypertension in persons aged 10-30 years (by increased cardiac output) and then advances to early HBP in persons aged 20-40 years (increased peripheral resistance ), then to established HBP in persons aged 30-50 years, and finally to complicated HBP in persons aged 40-60 years.

Hence to prevent HBP becoming established and complicated by midlife, both the lifestyle/ nutritional factors, and the neural- stress and the RAAS renal-aldosterone- angiotensin systems – need to be optimized in young adulthood, in the early workplace  if not childhood ie at school: with reintroduction at  school of compulsory physical education/sport;  banning of  tobacco,  refined sugar  and retail salt sale; universal ingestion  3 times a week at least of a tsp of codliver oil  equivalent (before it becomes unobtainable;)  and a tblsp of virgin coconut oil; and if bloodpressure does not normalize, addition of at least 3 times a week 1/2 reserpine  ie 0,125mg and 1/2 amilozide ie 27.5mg , to address most of the risk factors, as detailed below a week ago. .

Kostis  ea, Univ Harvard; Rutgers,. Columbia,Texas, Am J Cardiol. 2014 Feb examined Competing cardiovascular and noncardiovascular risks and longevity in the Systolic Hypertension in the Elderly   Program SHEP with  chlorthalidone-based stepped care (n = 2,365) or placebo (n = 2,371) for 4.5 years,. all participants were advised to take active therapy thereafter. At the 22year follow-up,  gain in life expectancy free from CV death in the active treatment group was 145 days  ( p = 0.012). The gain in overall life expectancy was smaller (105 days)because of a 40-day (95% CI -87 to 161) decrease in survival from non-CV death. Compared with an age- and gender-matched cohort, participants had markedly higher overall life expectancy ( p = 0.00001) and greater chance of reaching the ages of 80 (81.3% vs 57.6%), 85 (58.1% vs 37.4%), 90 (30.5% vs 22.0%), 95 (11.9% vs 8.8%), and 100 years (3.7% vs 2.8%). In conclusion, Systolic Hypertension in the Elderly Program participants had higher overall life expectancy than actuarial controls and those randomized to active therapy had longer life expectancy free from CV death but had a small increase in the competing risk of non-CV death

The 2013 Statement by the International & American Societies of Hypertension( including all continents and South Africa) includes amiloride-HCTZide  ; and reserpine 0.1 mg/day in the array of drugs to be combined for optimal  BP control.  “Thiazide-like Diuretics: reduction of major cardiovascular CVD and  stroke events have been established. Main side effects are metabolic (hypokalemia, hyperglycemia, hyperuricemia), which  can be reduced by using low doses (eg, 12.5 mg or 25 mg of HCTZ) or by combining these diuretics with  potassium-sparing agents eg angiotensin-blockers, amiloride etc .    Note: Thiazides plus   b-blockers are also an effective combination for reducing blood pressure, BUT since both  increase blood glucose concentrations,  use with caution in patients at risk for diabetes.  Angiotensin-converting enzyme inhibitor ACEIs’ main side effect is cough (most common in women and in patients of Asian and  African background). Angioedema is an uncommon but potentially serious complication that can threaten airway function, and it occurs most frequently in  black patients.

Given the above -quoted longstanding established dangers of bblockers and ACEI; and that the  majority of older State chronic  patients around Cape Town are black and Asian women,  overweight hypertensive diabetic smokers, it is negligence on the part of State authorities that most State patients are treated with deleterious betablockers (atenolol), Angiotensin blockers and HCTZ ; instead of primarily with the longproven optimal lowdose reserpine, amilozide and amlodipine.

    30 Nov 2014  NEW  studies below  confirm  that the renin-angiotensin-aldosterone system RAAS  and the autonomic nervous systems ANS  are the two networks that primarily regulate bloodpressure.   In baseline treatment of common essential HBP, Increasing recent research points to the prime role of amiloride  –  thiazide combination  eg Moduretic, Amiloretic –  and arginine (nitric oxide stimulant) – addressing the RAAS;  – with reserpine  addressing the  ANS and anxiety.   

This combination overcomes much of the pathophysiology of  essential HBP ie raised cardiac output, and  aldosterone excess  sodium retention vascular load increase, potassium-magnesium wasting,  endothelial swelling ie stiffness  from low nitric oxide; vascular spasm;  and insulin resistance from aldosterone (and  thiazide and betablocker);  and counterbalances the harms of higher-dose thiazide (glucose intolerance-lipidemia, potassium-magnesium-wasting, hyperuricemia), but also avoids the numerous adverse effects of  spironolactone (a steroidal antihormone) and triamterene;

and the cardiorespiratory risks of betablockers, and ARBs. The evidence in fact supports use of amiloride lowdose preventatively in a highrisk prehypertensive population. just as the prohormone metformin is used preventatively in reversing weight gain to prevent diabetes, atheroma and PCOS inferti9lity..

refs: 1.  Nutr Hosp. 2014 Dec.   ALDOSTERONE: A CARDIOMETABOLIC RISK HORMONE?    Pereira Bressan  ea.University of Viçosa, Brazil..  Aldosterone is a component of the renin-angiotensin-aldosterone system, classically known for its role in sodium and water retention. Besides its renal effects, aldosterone is associated with the pathogenesis and progression of metabolic syndrome components. Diet can affect plasma aldosterone levels; high fructose and fat intake can lead to increased aldosterone levels, whereas the effect of sodium intake remains controversial. Adipose tissue, particularly visceral tissue, appears to produce a lipid-soluble factor that increases aldosterone production. Patients with metabolic syndrome have higher aldosterone levels; moreover, an increased cardiometabolic risk associated with insulin resistance could be partially mediated by the action of aldosterone via mineralocorticoid receptors. Even a subtle activation of this hormonal system may have deleterious effects on the glucose and lipid metabolism related to metabolic syndrome.

2. Semin Nephrol Sept  2014 . . Pathophysiology and Treatment of Resistant Hypertension: The Role of Aldosterone and Amiloride-Sensitive Sodium Channels.    Judd EK1, Calhoun DA2, Warnock DG2. University of Alabama.    Resistant hypertension is a clinically distinct subgroup of hypertension defined by the failure to achieve blood pressure control on optimal dosing of at least 3 antihypertensive medications of different classes, including a diuretic. In the absence of demonstrable renal, vascular and common endocrine causes, pathophysiology of hypertension can be attributed to aldosterone excess in more than 20% of patients with resistant hypertension. Dogma attributes increase in blood pressure seen with increases in aldosterone to its antinatriuretic effects. However, emerging research,  has identified and defines the function of amiloride-sensitive sodium channels eNaC and mineralocorticoid receptors in the systemic vasculature, challenges impaired natriuresis as the sole cause of aldosterone-mediated resistant hypertension. It thus highlights the cardinal role of amilozide in hypertension therapy.

3. Pflugers Arch. 2014 Nov:  Salt controls endothelial and vascular phenotype.Kusche-Vihrog ,  Brand ea. University of Muenster,  Germany. High salt (NaCl) intake promotes  development of vascular diseases independent of  rise in blood pressure, whereas reduction of salt consumption has beneficial effects for the arterial system. We focus on  endothelial Na+ channel (EnNaC)-controlled nanomechanical properties, since high Na+ leads to an EnNaC-induced Na+-influx and subsequent stiffening of endothelial cells. Mechanical stiffness of the endothelial cell (i.e., the endothelial phenotype) plays a crucial role as it controls the production of the endothelium-derived vasodilator nitric oxide (NO) which directly affects the tone of the vascular smooth muscle cells. In contrast to soft endothelial cells, stiff endothelial cells release reduced amounts of NO, the hallmark of endothelial dysfunction. This endothelium-born process is followed by the development of arterial stiffness (i.e., the vascular phenotype), predicting the development of vascular end-organ damage such as myocardial infarction, stroke, and renal impairment. In this context, we outline the potential clinical implication of arginine, direct (amiloride) and indirect (spironolactone) EnNaC inhibition on vascular function.

4. J Clin Hypertens (Greenwich). 2014 Jan  Epithelial sodium channel eNaC inhibition by amiloride on blood pressure and cardiovascular disease risk in young prehypertensives.   Bhagatwala , Dong  ea, Regents University, Augusta, GA.. Overactivity of epithelial sodium channel (ENaC) is considered to be one mechanism underlying obesity-related blood pressure (BP) elevation. In a nonplacebo-controlled clinical trial , the authors aimed to comprehensively evaluate the effects of amiloride monotherapy, an ENaC blocker, on BP and cardiovascular risk in young adults with prehypertension (n=17). Following 10 mg daily amiloride for 4 weeks, peripheral systolic BP (SBP), central SBP, and carotid-radial pulse wave velocity were significantly reduced by -7.06±2.25 mm Hg, -7.68±2.56 mm Hg, and -0.72±0.33 m/s, respectively, whereas flow-mediated dilation was significantly increased by 2.2±0.9%. Following amiloride monotherapy for 4 weeks, a significant increase in serum aldosterone was observed (5.85±2.45 ng/dL). ENaC inhibition by amiloride may be used as an early intervention to halt the progression to full hypertension and cardiovascular disease in young adults with prehypertension.
5. J Hum Hypertens. 2013 Nov Diastolic blood pressure reduction ontributes more to the regression of left ventricular hypertrophy: a meta-analysis of randomized controlled trials.  Zhang  Huang ea Sun Yat-sen University, ChinaLeft ventricular hypertrophy (LVH) is an independent cardiovascular risk factor; however, the key strategy necessary for LVH regression in hypertensive patients is not clear. A meta-analysis was conducted to study the effect of blood pressure reduction on LVH regression. A total of 17 randomized controlled trials comprising 2196 hypertensive patients (mean age, 56.3 years; 64.1% were men) were identified. The most significant decrease in LVH was seen in patients with a mean age over 60 years in the DBPM10 group. The renin-angiotensin system inhibitor was found to be the most effective antihypertensive drug for LVH regression. This meta-analysis result indicates that proper DBP reduction plays an important role in the regression of echocardiographic LVH in hypertensive patients.

6. Hypertension. 2012 .Double-blind, placebo-controlled, crossover trial comparing the effects of amiloride and hydrochlorothiazide on glucose tolerance in patients with essential hypertension. Stears, Brown ea University of Cambridge.    Hypertension guidelines advise limiting dose of thiazide diuretics and avoiding combination with β-blockade, because of increased risk of diabetes mellitus. We tested whether changes in the 2-hour oral glucose tolerance test could be detected after 4 weeks of treatment with a thiazide and could be avoided by switching to amiloride. . For similar blood pressure reductions, there were opposite changes in glucose between the 2 diuretics (P<0.0001).  There was a negative correlation between Δpotassium and Δ2-hour glucose (r=-0.28; P<0.0001). In 2 crossover studies, 4 weeks of treatment with a thiazide diuretic impaired glucose tolerance. No impairment was seen with K(+)-sparing diuretic or β(1)-selective blockade. Substitution or addition of amiloride may be the solution to preventing thiazide-induced diabetes mellitus.

7.   Am J Physiol Endocrinol Metab. 2008  Dimethyl amiloride improves glucose homeostasis in mouse models of type 2 diabetes.  Gunawardana , Piston ea .Vanderbilt University, Nashville, TN. Dimethyl amiloride (DMA) enhances insulin secretion in the pancreatic beta-cell. DMA also enhances time-dependent potentiation (TDP) and enables TDP to occur in situations where it is normally absent. As we have demonstrated before, these effects are mediated in part through inhibition of neuronal nitric oxide synthase (nNOS), resulting in increased availability of arginine. Thus both DMA and arginine have the potential to correct the secretory defect in diabetes by enabling or enhancing TDP. In the current study we  demonstrated the ability of these agents to improve blood glucose homeostasis in three mouse models of type 2 diabetes. The pattern of TDP under different conditions indicates that inhibition of NOS is not the only mechanism through which DMA exerts its positive effects. Thus we also have explored another possible mechanism through which DMA enables/enhances TDP, via the activation of mitochondrial alpha-ketoglutarate dehydrogenase.

8.  Circulation. 1995 Comparison of five antihypertensives and placebo on nutritional-hygienic therapy in  Treatment of Mild Hypertension Study (TOMHS). Liebson, Stamler ea . St Luke’s Medical Center, Chicago, in a double-blind, placebo-RCT  of 844 mild hypertensive participants randomized to nutritional-hygienic (NH) intervention plus placebo or NH plus one of five  antihypertensive agents: (1) thiazide (chlorthalidone), (2) beta-blocker (acebutolol), (3) alpha-antagonist (doxazosin), (4) calcium antagonist (amlodipine ), or (5) ACEI (enalapril).  Changes in BP averaged 16/12 mm Hg in the active treatment groups and 9/9 mm Hg in the NH only group. All groups showed significant decreases (10% to 15%) in LVM from baseline that continued for 48 months.  chlorthalidone  caused the greatest decrease in LVM at each follow-up visit (average decrease, 34 g),  (average decrease among 5 other groups, 24 to 27 g). Participants randomized to NH intervention only had mean changes in LVM similar to those in the participants randomized to NH intervention plus pharmacological treatment. The greatest difference between groups was seen at 12 months, with mean decreases ranging from 35 g (chlorthalidone group) to 17 g (acebutolol group) (P = .001 comparing all groups). 

9.  Arch Intern Med. 1981  Multiclinic comparison of amiloride, hydrochlorothiazide, and hydrochlorothiazide plus amiloride in essential hypertension. Multicenter Diuretic Cooperative Study Group.   [No authors listed}  A randomized, double-blind, multicenter study comparing amiloride hydrochloride, amiloride hydrochloride plus HCTZ, and HCTZwas conducted in 179 patients with mild to moderate essential hypertension (diastolic pressure, 95 to 115 mm Hg). After 12 weeks of treatment, significant reductions in pressure were observed for all three treatment groups. Systolic pressure reduction was greatest for amiloride plus hydrochlorothiazide. Baseline vs 12-week average supine pressures were 153/101 vs 139/93ie -14/8 mm Hg for amiloride, 160/100 vs 137/90 ie -23/10mm Hg for amiloride plus HCTZ, and 154/101 vs 134/89 ie -20/12mm Hg for HCTZ. Baseline vs treatment mean serum potassium levels were 4.24 vs 4.47 mEq/L for amiloride, 4.24 vs 3.86 mEq/L for the combination, and 4.15 vs 3.56 mEq/L for HCTZ. The changes in serum potassium level from the baseline for amiloride plus HCTZ were significantly different from those for HCTZ throughout the study (except for week 6). All drugs were well tolerated, and no drug-related toxic reaction was detected. This study demonstrates the efficacy of amiloride and amiloride plus HCTZ as diuretic antihypertensive potassium-conserving agents.

27 Nov 2014 THE IMPORTANCE OF NORMALIZING RESISTANT HYPERTENSION : THE ALLHAT TRIAL Furberg ea  December  2002 was the biggest  trial that compared a thiazide with other standard antihypertensive drugs in highrisk patients, and confirmed thiazide’s  superiority over amlodipine, lisinopril, and especially doxazosin. This was confirmed in the smaller shorter CONVINCE multinational trial Black ea a few months later, which showed that as single therapy, verapamil was inferior to a thiazide or atenolol.

The latest report of the landmark  5 year USA ALLHAT trial by Munter ea  now reports  on apparent   Treatment-resistant hypertension aTRH  and the incidence of cardiovascular disease and end-stage renal disease: “These results demonstrate that aTRH increases the risk for cardiovascular disease by almost 50%, doubled end-stage renal disease, and increased all-cause mortality- heart and peripheral circulatory failure  – by 30%. Although a high prevalence of aTRH has been reported, few data are available on its association with cardiovascular and renal outcomes. We analyzed data on 14684 (ALLHAT) participants to determine association between aTRH (n=1870) with coronary heart disease, stroke, all-cause mortality, heart failure, peripheral artery disease, and end-stage renal disease. We defined  Apparent treatment-resistant hypertension aTRH as blood pressure not at goal (systolic/diastolic blood pressure ≥140/90 mm Hg) while taking ≥3 classes of antihypertensive medication or taking ≥4 classes of antihypertensive medication with blood pressure at goal during the year 2 ALLHAT study visit (1996-2000). Use of a diuretic was not required to meet the definition of aTRH. Follow-up occurred through 2002.

24 Nov 2014  NOTE  how Big Pharma has lied in corrupting the Wikipedia section (in italics below)  on reserpine so as to try to further sideline this excellent natural drug: the adverse  highlights below  in red are based on ancient data from when Reserpine  was used decades ago in the West in 5 to 50 times higher doses than have been used without adverse effects in trials the past  20 years, and for centuries in India as the parent Rauwolfia:

Reserpine:because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely used today.Nonsense. This ignores the numerous side-effects of betablockers, ACEI, ARBs and CCBs other than amlodipine.  The reserpine-induced depression is considered by some researchers to be a myth, while others claim that teas made out of the plant roots containing ie lowdose reserpine has a calming, sedative action that can actually be considered antidepressant.[4] Notably, reserpine was the first compound shown to be an effective antidepressant in a randomized placebo-controlled trial.[5]      It may take the body days to weeks to replenish the depleted VMAT, so reserpine’s effects are long-lasting- a major advantage if patients take drugs irregularly. Tryptophan is the starting material in the biosynthetic pathway of reserpine, and is converted to tryptamine by tryptophan decarboxylase enzyme. Various enzymatic conversion reactions lead to the synthesis of reserpine from strictosidine.[8]

This depletion of dopamine can lead with reserpine overdose to drug-induced parkinsonism. THIS IS ONLY IN EXCESSIVE RESERPINE DOSE.  Reserpine has been discontinued in the UK for some years due to its numerous interactions and side effects. nonsense it was discontinued to protect Big Pharma newer antihypertensive drugs eg  Cardura, metoprolol, lisinopril; ARBs, Exforge etc .

“THE Reserpine-THIAZIDE  COMBINATION (WITH OR WITHOUT OTHER OLD DRUGS EG POTASSIUM-SPARERS AND HYDRALAZINE)  is one of the few antihypertensive medications that have been shown in randomized controlled trials to reduce mortality:

“The Hypertension Detection and Follow-up Program,[14] the Veterans Administration Cooperative Study Group in Anti-hypertensive Agents,[15] , the Systolic Hypertension in the Elderly Program, and now the Chinese reserpine trial 2011- which outstanding results  the Wiki article  doesnt bother to  mention. .

Reserpine is rarely used in the management of hypertension today. NONSENSE – that is merely the explicit wish and intent of Big Pharma.  Reserpine is listed as an option by the JNC 7.[17] Reserpine is a second-line adjunct agent for patients who are uncontrolled on a diuretic when cost is an issue.[18]   The daily dose of reserpine in antihypertensive treatment is as low as 0.1 to 0.25 mg – IN FACT 0.0625 t0 0,125MG/dAt doses of less than 0.2 mg/day, reserpine has few side effects, the most common of which is nasal congestion- SO WE NEVER PERSIST WITH  above 0.125mg/d

ONLY IN GROSS OVERDOSE:”There has been much concern about  Reserpine causing: depression leading to suicide; nasal congestion, nausea, vomiting, weight gain, gastric intolerance, gastric ulceration , stomach cramps,diarrhea.. . hypotension, bradycardia; Congested nose,erectile dysfunction drowsiness, dizziness,.. nightmares. Parkinsonism … General weakness, fatigue … may worsen asthma ; hyperprolactinemia… dangerous decline in blood pressure at doses needed for treatment. Early suggestions that reserpine causes breast cancer in women (risk approximately doubled) were not confirmed. . The above litany conveniently omits that these problems were reported in uncontrolled studies using reserpine doses averaging 0.5+ mg per day.[22][23] they do not occur at effective  low antihypertensive reserpine dose combined with lowdose diuretic. “

Nine years ago we reviewed in the BMJ  why reserpine plus thiazide is  The best-proven two-drug hypertension regime in primary care,

update 20 Nov 2014  the Sept  2014 influential French review Prescrire Int reviews the available evidence Treating essential hypertension- As in 2004, the first choice is usually a thiazide diuretic TZD  .. The current treatment threshold for hypertensive adults without diabetes or cardiovascular or renal disease is blood pressure above 160/90-100  mmHg. Apart from certain diuretic-based combinations, the use of combinations of antihypertensive drugs as first-line therapy has not been evaluated in terms of the complications of hypertension. systematic  meta-analyses of  tens of thousands of patients have compared the main classes of antihypertensive drugs against each other and against placebo. Compared with placebo, only low-dose TZDs and angiotensin-converting enzyme (ACEI) inhibitors have been shown to reduce all-cause mortality in hypertensive patients. They prevent  about 2 to 3 deaths and 2 strokes per 100 patients treated for 4 to 5 years. Systematic reviews conclude that neither calcium-channel blockers CCBs, ACEI nor beta-blockers BBs are more effective than thiazide diuretics TZDs  in reducing mortality or the incidence of stroke. The efficacy of the TZD chlorthalidone is supported by the highest-level evidence, three comparative clinical trials versus placebo, an ACEI, or a CCB, in more than 50 000 patients. In one of these trials, chlorthalidone was superior to the ACEI lisinoprilin preventing stroke; and  to the CCB amlodipine in preventing heart failure. The effect of hydrochlorothiazide HCTZ , combined with amiloride or triamterene, on cardiovascular morbidity and mortality has been demonstrated in three comparative clinical trials versus placebo, BBs, or a CCBHCTZ appeared more effective than the BB atenolol in reducing the incidence of coronary events.  Indapamide another TZD is less convincing that it is more effective than chlortalidone or HCTZ. None of the antihypertensive drugs appears to have a better overall adverse effect profile than the others. Thiazide diuretics can provoke hyperglycaemia and diabetes, although this does not reduce their efficacy in the prevention of cardiovascular events. As in 2004, in 2014, the first-choice treatment for hypertension in nondiabetic adults without cardiovascular or renal disease should be a thiazide, possibly combined with amiloride or triamterene. When a diuretic cannot be used, it is better to choose an ACEI: captopril, lisinopril or ramipril.

But TZDiuretic halflife is at best 15hrs (HCTZ); and for smoother hypertension control they need to be gentle and not major diuresis-inducing,  so that they do not disturb sleep or daytime function. and TZDs dont damp down compensatory heart speedup and arrhythmia, or lipidemia-hyperglycemia- which reserpine does. and lowdose reserpine doesnt cause the cough or breathlessness that ACEI, ARBs or BBs may.

This review needs to be read with Shamon & Perez‘  2009 University of British Columbia Canadian Cochrane report : the first systematic review of reserpine for essential hypertension  “Many antihypertensive agents exist today for primary hypertension (systolic blood pressure >/=140 mmHg and/or diastolic blood pressure >/=90 mmHg).  Reserpine was  a second-line therapy in some of those trials.   Included studies were truly randomised controlled trials comparing reserpine monotherapy to placebo or no treatment in patients with hypertension.  MAIN RESULTS: Four RCTs (N =237) were found that met the inclusion criteria. The overall pooled effect demonstrates a statistically significant systolic blood pressure (SBP) reduction on reserpine compared to placebo (WMD –8mm, 95% CI -14.05, -1.78).   None of the included trials reported withdrawals due to adverse effects.   AUTHORS’ CONCLUSIONS: Reserpine is effective in reducing SBP roughly to the same degree as other first-line antihypertensive drugs. But this analysis is outdated because it has long been common cause that  the best firstline treatment of hypertension is the balanced combination of reserpine with a potassium-sparing diuretic.

Lowdose Reserpine is the sole anxiolytic antidepressant antipsychotic antiserotoninergic antihypertensive drug that lasts, acts  for weeks  rather than days (amlodipine) or  hours (the TDZs, ACEI, ARBs)- and has no adverse effects; so it doesnt matter when it is taken;  when stopped, it takes weeks for it to completely wear off. And severe stress anxiety insomnia is so often a major component of severe essential hypertension. “Reserpine is an ancient tranquilizer, derived from a plant used in India for centuries. It has a powerful tranquilizing action, has been used to treat hypertension, and was found to be an antidepressant (Davies and Shepherd, 1955)”

Hence combining lowdose eg 0.125mg/d or less reserpine – even 3 days a week ie 0.05mg/d-  with amilozide 13-27mg/d as a morning or midday  dose  is ideal- especially when nighttime systolic hypertensionNSBP  is the strongest predictor of CVEs cardiovascular events, as shown in a new international study in Europe, Brazil, and Japan by Universities of USA, UK and Europe:  Roush, Zamalloa ea The ABC-H Investigators ; Journal of Hypertension (Oct 2014)   Prognostic impact from clinic, daytime, and night-time systolic blood pressure NSBP in nine cohorts of 13 844 patients with hypertension;     To determine which SBP measure best predicts cardiovascular events (CVEs- coronary artery disease CAD and stroke) independently, systematic review was conducted for all patients with hypertension,>1+ years follow-up..   Nine cohorts (n = 13 844) were from Europe, Brazil, and Japan. Results: Overall, NSBP’s dispersion exceeded DaySBP’s dispersion by 22.6% with nonoverlapping confidence limits. Within all nine cohorts, dispersion for NSBP exceeded that for ClinicSBP and DSBP ( P = 0.004)  Considered individually, increases in NSBP, DSBP, and CSBP each predicted CVEs: hazard ratios (95% confidence intervals) = 1.25 (1.22-1.29), 1.20 (1.15-1.26), and 1.11 (1.06-1.16), respectively. However, after simultaneous adjustment for all three SBPs, hazard ratios were 1.26 (1.20-1.31), 1.01 (0.94-1.08), and 1.00 (0.95-1.05), respectively. Cohorts with baseline antihypertensive treatment and cohorts with patient-specific information for night-day BP classification gave similar results. Within most cohorts, simultaneously adjusted hazard ratios were greater for NSBP than for DSBP and CSBP:  In hypertensive patients, NSBP had greater dispersion than DSBP and CSBP in all cohorts. On simultaneous adjustment, compared with DSBP and CSBP, increased NSBP independently predicted higher CVEs in most cohorts, and, overall, NSBP independently predicted CVEs, whereas CSBP and DSBP lost their predictive ability entirely. This trial confirms the 2012 Hosomi ea Japanese trial showing that to minimize (repeat) stroke from night BP variance, Antihypertensive medication taken in the evening or at bedtime is the most effective in treating morning hypertension when the patient adheres to the medication regimen.

Weiss’s Herbal Medicine  2001 pp 151-157 reviews why lowdose reserpine/rauwolfia is the prime baseline antihypertensive, via the central especially  autonomic nervous system as a major anxiolytic.

There is no evidence in chronic treatment of common essential hypertension to justify loop diuretics eg furosemide , as is common practice locally. .

update 12 Oct 2014     For the past decade we have advocated  for uncomplicated patients the gold-standard evidence-based combination of reserpine  0.0625 to 0.125 mg with  1/4  Amilozide (ie hydrochlorothiazide  HCTZ 12,5mg and amiloride 1.25mg) ie HAR daily as the most cost-efficient baseline treatment of hypertension.    Sometimes patients require the lower doses 1/4 tab each reserpine and Amiloretic 55mg) only 3 times a week for good control once on some cod liver oil, coconut oil and multivite-multimineral  to reverse arteriosclerosis, insulin resistance, reactive oxygen species,  and promote nitric oxide.

For more resistant cases we add  dihydralazine 25 mg/d or amlodipine 5 to 10mg as add-ons if required  – if necessary both-  occasionally for optimal HBP control around 120  to 130 systolic (the new international  Guideline target). With this regime of up to five drugs all more than 40 years in use, for hypertension we rarely find need to add the more costly / troublesome old eg methyldopa, or betablockers, spironolactone,   or new eg ACEI or ARBs ,  with   their  cardio-respiratory risks that are so rare with the  multi-low dose reserpine- amilozide- amlodipine- dihydralizane  combination.

There are now 250 000 antihypertensive drug studies on Pubmed since 1947.

 The latest  and definitive study  published on reserpine for HBP in Clin Drug Investig. 2011;31:769-77 is   Long-term efficacy and tolerability of a fixed-dose combination of antihypertensive agents: an open-label surveillance study in China a  massive  3 year (4500 patient-years) study  by  Wu Y, Li L. ea of   Peking University Health Science Center, China   .  A fixed-dose combination (FDC) of four compounds, hydrochlorothiazide  HCTZ 12.5 mg, triamterene 12.5 mg, dihydralazine 12.5 mg and  reserpine 0.1 mg (HTDR), is widely used as an antihypertensive treatment in China. Although used in China for more than 30 years, there have been few comprehensive evaluations of this treatment.          METHODS  open-label surveillance study in Shanghai in local primary healthcare settings. Subjects  with  essential hypertension, aged ≥35 years at the time of enrolment. Patients with secondary hypertension, myocardial infarction or stroke within 6 months of screening, impaired renal or hepatic function, history of cardiomyopathy or chronic heart failure, or were pregnant or lactating were excluded. HTDR was administered as one or two tablets per day in the morning. If necessary, additional HCTZ was added. Blood pressure (BP) was measured every 3 months.    RESULTS: A total of 1529 patients (65%  female; mean age 65.7 years) entered the study with mean BP 149/89. After the 36-month treatment period, 93.1% of patients had achieved the SBP target, 97.9% had achieved the DBP target, and 92.1% had achieved both. The mean decreases in SBP and DBP were 15.3 mmHg and 9.9 mmHg, respectively. Overall, 127 adverse events in 119 patients (7.8%) occurred during the follow-up period, most of which were mild to moderate. Plasma lipids, uric acid and potassium improved.                                                               CONCLUSION: HTDR was found to have good long-term efficacy and tolerability in Chinese patients with essential hypertension.

The mean  15/10  BP lowering  from a mean baseline BP of 149/89 after 3 years of the four-drug Chinese combination  in China   compares  starkly with the mean ~51/30 mm Hg lowering (from untreated HBP of 200/120 down to ~149/90)  over 4 months reported  below  by Alan Taylor in his 1989 thesis study in local rural Africans with similar doses of reserpine, HCTZ and dihydralazine- Taylor’s study achieving in rural Blacks  in 4 months the starting BP of the Chinese some 25 years later.  But  the long Chinese study speaks to to the tolerance of the HTDR combination.

The China reserpine study  of 1500 pts, 4500 pt years, strongly complements the ~13 trials  of reserpine   between 1977 (the Veterans’ Admin trial) and 1997(the German reserpine research group trials)  in 7500 patients for 1 to 3 years;   showing that low dose reserpine (and lowdose  thiazide ) together are  as good as or better than all more modern drugs- especially when augmented by amiloride.

(As Prof YK Seedat reported  here  in 2000), the China   paper reports zero noteworthy dihydralazine  risks at 12.5mg/d :     J Hum Hypertens. 2000 ;14:739-47. Hypertension in developing nations in sub-Saharan Africa. Seedat YK. University of Natal,  South Africa.  There is a rapid development of  ‘second wave epidemic’ of cardiovascular disease that is now flowing through developing countries and the former socialist republics. It is now evident from WHO data that coronary heart disease and cerebrovascular disease are increasing so rapidly that they will rank No. 1 and No. 5 respectively as causes of global burden by the year 2020. In spite of the current low prevalence of hypertensive subjects in some countries, the total number of hypertensive subjects in the developing world is high, and a cost-analysis of possible antihypertensive drug treatment indicates that developing countries cannot afford the same treatment as developed countries. Control of hypertension in the USA is only 20% (blood pressure <140/90 mm Hg). In Africa only 5-10% have a blood pressure control of hypertension of <140/90 mm Hg. There are varying responses to antihypertensive therapy in black hypertensive patients. Black patients respond well to thiazide diuretics, calcium channel blockers vasodilators like alpha-blockers, hydralazine, reserpine and poorly to beta-blockers, angiotensin-converting enzyme inhibitors and All receptor antagonists unless they are combined with a diuretic.  There are social, economic, cultural factors which impair control of hypertension in developing countries. Hypertension control is ideally suited to the initial component on an integrated CVD control programme which has to be implemented.  The existing health care infrastructure needs to be orientated to meet the emerging challenge of CVD, while empowering the community through health education.

Interestingly, a new  metaanalysis of HCTZ trials  by Musini ea Cochrane Database Syst Rev. 2014 May   Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension. shows that BP lowering  over the dose range 6.25 mg, 12.5 mg, 25 mg and 50 mg/day is 4/2 mmHg, 6/3 mmHg, 8/3 mmHg and 11/5 mmHg, respectively. For other thiazide drugs, the lowest doses studied lowered blood pressure maximally and higher doses did not lower it more. Due to the greater effect on systolic than on diastolic blood pressure, thiazides lower pulse pressure by 4 mmHg to 6 mmHg. This exceeds the mean 3 mmHg pulse pressure reduction achieved by ACE inhibitors, ARBs and renin inhibitors, and the 2 mmHg pulse pressure reduction with non-selective beta-blockers as shown in other Cochrane reviews. 

2009:     ABSTRACT: When modern antihypertensive drugs cost far more than the old and tried, and have around 40% risk of adverse effects (Girerd 2002 Paris),  and give inferior risk reduction, it is unethical for routine hypertension patients initially to  be  prescribed modern drugs singly or in combination in uncomplicated cases before trying the gold standard old risk-free lowdose reserpine-amilozide combination.

2009 has been a landmark year of published studies on first-line  hypertension treatment.

IT IS COMMON CAUSE THAT:

i. hypertension  (with or without overweight- excessive waist girth) is today the commonest presenting, simply detectable, monitorable and controllable chronic lifestyle degenerative disease;

ii. the bedrock prevention and therapy  of essential hypertension is  public- patient  education – exercise, stopping smoking,  and minimizing salt (since 1904) , sugar, alcohol and cooked fat intake so as to reduce overweight;

iii. genetics and the above risk factors aside, three  of the primary “endogenous”  and easily correctable causes of essential hypertension are water deficiency; marine omega3 (EPA eicosapentanoic and DHA docosahexanoic acid) deficiency; and insulin resistance if not frank adiposity/overweight and diabetes.

So adequate water intake, and fish oil, and metformin/galega to tolerance, (in appropriate adipose/overweight  cases) are cornerstones of antihypertensive therapy along with diet and lifestyle changes before any antihypertensive drugs are added.

Recently there have been contentious suggestion  (eg Law and Ward UK 2009)  that target bloodpressure should be that of youth- 120/70 down to 100/60 – as long as it does not fall so low that the patient gets dizzy on standing up. But the non-contentious gold standard remains  that no one should be left with bloodpressure above at most 140/90 sitting.

ANTIHYPERTENSIVE DRUGS: There are over 34 000 RCTs, reviews and metaanalyses  (since 1965) on Pubmed on these drugs.

Controlling   hypertension asymptomatically  before it causes damage and symptoms is the heart of successful prevention.

It is now claimed  that hypertension risk starts as low as >120/70, that we should be targeting this level if tolerated.

This can only be done gently and slowly, if possible by optimising diet , lifestyle and natural supplements.

But prevention in asymptomatic patients must especially be at most a once-a-day regime, and avoid causing symptoms, and still give stable cover even if taken erratically. Only reserpine provides gentle cover lasting weeks, thus avoiding wide BP variation due to erratic dosing.

Apart from the notorious adverse effects of the older antihypertensives like guanethidine, methyldopa and atenolol, search of Pubmed under  ‘ARBs, ACEI Cough;’ and under metaanalysis ‘antihypertensive cough’  with the established drugs, reveals 10 abstracts since the mid 1990s.

The nub of the matter is, the lowest-cost multiple-combination therapy (lowdose reserpine -amiloride – hydrochlorothiazide) gives the best bloodpressure and risk reduction with zero adverse effects – especially when combined with probably the best pluripotential drug of all,  fish oil..   A new Cochrane metaanalysis from Univ Brit Columbia confirms that lowdose thiazide gives the best reduction of all antihypertensives in both all-morbidity and mortality outcomes -RR 0.89 (CI 0.82-0.97, p=0.0067 = highly significant) . And that metaanalysis didn’t deign to mention reserpine in the abstract.

There are at least a dozen trials each of reserpine and thiazide  showing that they are the best,  ideally in lowdose combination .   As always, one fixed-dose combination pill (eg Brinerdin, Rautrax Imp) may work for many. But it is both cheaper, more efficient and scientific to prescribe the components separately so that reserpine and amilozide can  each be titrated individually to tolerance, starting with eg reserpine (0.25mg tab ) 1/4/day and amilozide (55mg tab) 1/4 a day (costing locally retail  perhaps US$0.5/month, $6/year) …

In some patients eventually this dose 3 days a week is all that is needed. With sensible advice about omitting sugar and smoking, and minimal alcohol, salt and cooked fats, and adding a multinutrient including magnesium, vitamins and the many favourable biologicals (including appropriate physiological sexhormone replacement), few patients need more than 1/2 a tab each of reserpine and amilozide for optimal BP and metabolic-vascular risk control. In the rare still- resistant cases, amlodipine is the next safest effective antihypertensive  drug to add, starting with 2.5mg/d. But of course in those with insulin resistance (ie most cases), metformin is the most appropriate pluripotential drug.

Yet no trial has shown  lower cost, and better superiority and safety  of any modern-drug  or combination over the triple-combination  lowdose amilothiazide (thiazide since 1956, amiloride since 1967)  with  lowdose reserpine (from the ages-old rauwolfia – extracted  as reserpine since 1949). Since the German Reserpine trials, and results of ALLHAT and SHEP showing that reserpine as add-on gave  by far the best clinical outcomes, no head-on trials against modern drugs dare be done by drug companies or the clinicians they employ.

Over a year ago this column   reviewed that fifty year old treatments of overweight -hypertension – diabetes are still best, echoing an SAMJ analysis 24 years ago of New antihypertensive drugs–blessing or costly nemesis? .

In 1989 pharmacist Alan Taylor published his MPharm thesis (Rhodes University)  on Cost Effective Antihypertensive Therapy at A Day Hospital. – showing in a prospective randomized controlled trial for 4 months that stepped outpatient care (starting with a mean untreated BP of about 200/120) achieved the target BP ( then <165/95) in 73% compared to 11.5% on individualized treatment, and with a cost saving of 36%, with somewhat lower incidence of side effects. Hydrochlorothiazide HCT 12.5 to 25mg/d was the first step;  methyldopa 250-500mg/d or reserpine  0.1mg/d  as the 2nd; hydralazine 10-50mg/d  low dose as the 3rd, alternatively atenolol  100mg as the 3rd or 4th step. Individualized treatment reduced bloodpressure by a mean  32.6/19 whereas stepped-care did so by 51.6/29.5mm Hg.. The HCT-Reserpine- Hydralazine-atenolol regime was the most frequently prescribed (in 61.6%),

Obviously today methyldopa, hydralazine  and atenolol have become last-ditch add-ons, with amlodipine being the 1st- choice 4th drug to add to reserpine and amilozide. ,

and  in 2007 Rayner, Blockman ea from the Hypertension Clinic    at Groote Schuur Hospital found that at two community  health clinics  in Cape Town, only 40% of patients achieved a bloodpressure below 140/90, on a mean of 2.4 drugs per patient   – clinics where reserpine and amilozide were unwisely  removed from the available drug list years ago, for no plausible reason, leaving hydrochlorothiazide, atenolol, hydralazine and amlodipine as the choices- with invariably poor results in poor patients attending such free clinics.

MODERN DRUGS?  But why should patients be subjected to the multiple and indisputable major risks of modern antihypertensive drugs compared to the gold standard lowdose reserpine and low dose amilozide?

eg

ABs angiontensin blockers – ACEI agiotensin converting enyme inhibitors and ARBs angiotensin receptor blockers like enalapril, candesarten  – pervasive cough, rashes, but far worse, lifethreatening angiodema, asphyxiation, skin sloughing; and now well-recognized acute or slowly progressive loss of kidney function- which doesnt always reverse on stopping the drug (Onuigbu ea  2008, 2009); Suissa ea  2006 at McGill University published the first major longterm – > 10year- followup (1982-1997)  of hypertensive diabetes patients, showing that compared to thiazide, only  ACEI increased the risk of endstage kidney failure 4.2 fold.

betablockers like atenolol, metoprolol – too slow heart rate, cold extremities, more depression, impotence,  asthma, glucose intolerance/ diabetes, heart failure, deaths;

and even calcium channel blockers -the gold standard of which is amlodiopine- have a formidable list of potential adverse effects (that lowdose reserpine and amilozide lack), of which some may be major nuisance if not dangerous eg (from the Sandoz product sheet): Often: dizziness; palpitations; muscle-, stomach– or headache; dyspepsia; nausea – in 1 in 100 users; Sometimes: blood disorders, gynecomastia, impotence, depression, insomnia, tachycardia – in 1 in 1,000 users;  erratic behavior, hepatitis, jaundice – in 1 in 10,000 users; Very rarely: hyperglycemia, tremor, Stevens-Johnson syndrome – in 1 in 100,000 users. ”

From the trials and experience, lowdose amlodipine is certainly the modern drug of choice to add if counselling plus ceiling doses of reserpine and amilozide, plus fish oil plus  metformin for underlying adiposity/insulin resistance,  do not adequately control hypertension and other risk factors.

Why use modern drugs with their major potential hazards  except for special circumstances last ditch?; when lowdose reserpine plus lowdose amilozide titrated to best effect rarely need a 4th drug added for good BP control;  and practically – unlike methyldopa, guanethidine and more modern drugs-  never causes persisting symptoms.

THIAZIDE ADVERSE EFFECT possible in even very low dose: anaphylaxis: Goetschalckx ea in 2007 could find exactly 49 case reports of allergic thiazide-induced pulmonary oedema in the literature after 50 years of use ie millions of patient-years. Thiazides are obviously sulphonamides, but fortunately serious- anaphylactic- reactions like lupus vascullitis and shock – are extremely rare. Wikipedia does not even mention these under thiazides, and no abstracts on Pubmed even guess at their rare  incidence. 50 cases in at least 10million patient years is an incidence of below 5 per million.

RESERPINE:   In 2007 Jos Barzilay ea documented Getting to goal blood pressure: why reserpine deserves a second look.

We last year examined closely the trials on thiazides and reserpine 1, 23.

and we published on line the only ever tabulation of all accessible trials  of thiazides and reserpine, showing in the ~12 thiazide trials between 1985 (the UK MRC trial)  and 2003 (the CONVINCE trial) that  in 115000 patients for a mean of 4 years,  thiazide is as good as or better than all more modern drugs;

and that reserpine in ~13 trials between 1977 (the Veterans’ Admin trial) and 1997(the German reserpine research group trials)  in 7500 patients for 1 to 3 years is as good as or better than all more modern drugs. Of course  the 2003 ALLHAT  and CONVINCE papers were by far the biggest trials validating thiazide as the gold standard in 50 000 patients for  3 and 5 years respectively;

and the VA trials of 1977, 1982 and  and 1990 in 1479 patients showing reserpine as equal or superior to betablockers,  and the German trials of 1997  in 400 patients (Griebenow, Pittrow ea 1997) validating reserpine as equivalent to thiazide or a CCB, and the combination of thiazide and reserpine superior to an ACEI.

Now in 2009:

Shamon ea’s Cochrane review last month confirms that reserpine  alone is at least equivalent  in antihypertensive effect to any  modern first line antihypertensive alone ;

Wald and Law’s metanalysis of single or combination antihypertensives confirms that  “The extra blood pressure reduction from combining drugs from 2 different classes is approximately 5 times greater than doubling the dose of 1 drug.”

Wright ea’s Cochrane review confirms that

“thiazides reduce all-cause mortality by 11%;   Low-dose thiazides (8 RCTs) reduced CHD  by 28%;

Beta-blockers and CCB reduced stroke by 17% and 42%, but not CHD  or mortality .        ACE inhibitors reduced mortality 17%; stroke  35%.

No RCTs were found for ARBs or alpha-blockers.”

However, that abstract does not enumerate the major adverse effects of betablockers and ABs.

Wright ea’s   ALLHAT reanalysis confirms that thiazide was superior to the ACEI, CCB, betablocker and especially the alphablocker doxazocin. neither alpha-blockers, ACEI nor CCBs  surpass thiazide-type diuretics (at appropriate dosage) as initial therapy for reduction of cardiovascular or renal risk. Thiazides are superior in preventing HF. new-onset DM associated with thiazides does not increase CVD outcomes.”

Costanzo ea’s Italian study confirms that CCBs reduce the risk of stroke by 14% compared to ACEI; reduce allcause mortality by a trivial 4%; increase heart failure by 17% compared with ‘active’ treatment;

Hoffman ea’s review from New York confirms that, in autopsies of Alzheimer cases, those on antihypertensives had far less plaques that those without hypertension.

Sozen ea confirms that “ABs- Drugs with blocking effects on the renin-angiotensin-aldosterone system –  do not improve endothelial dysfunction long-term in hypertensive patients”.

Mackenzie ea’s Comparison of the effects of antihypertensive agents on central blood pressure and arterial stiffness in isolated systolic hypertension shows that central Pulse Pressure was only reduced significantly by perindopril, lercanidipine, and bendrofluazide, whereas atenolol had no effect. Lercanidipine reduced the augmentation index, whereas atenolol increased it. Aortic pulse wave velocity was not changed by any of the drugs. In summary, despite similar reductions in peripheral systolic and PPs with the 4 classes of drug, changes in central pressure and augmentation index varied. Because central PP and increased wave reflections are considered important risk factors in patients with isolated systolic hypertension, the choice of therapy may be influenced by these findings in the future.”

Landmark’s Norwegian abstract confirms that thiazides (and betablockers)  increase insulin resistance and blood glucose risk (let alone lipidemia), but simply – selectively- as usual ignores that neither lowdose amilozide nor reserpine do this.

Nothing illustrates better why the triple combination of amilozide and reserpine is the best.

It has previously been pointed out that in the long term Cache County study, potassium-sparing diuretic was the only antihypertensive that lowered- in fact by 75% – the incidence of new Alzheimers disease;  and amilozide-like combinations are more effective than either component alone in safely and effectively lowering hypertension. – Patterson Dollery & Haslam in 1968; Rosenfeld in 1980; and the Multicenter Diuretic Cooperative Study Group in 1981.

CONCLUSION:  Reserpine has indisputable central and peripheral benefits in lowering central pressure via peripheral vasodilation, and via mild lowering of anxiety, cardiac rate and cardiac output; while thiazide and amiloride both lower both excessive body salt and water, while thiazide vasodilates and conserves calcium,  and amiloride  reverses the  potassium -magnesium depletion  seen in hypertension and with thiazide. .

Since the lowdose combination of reserpine and amilozide is superior to all other first-line drugs alone or in combination, and retail costs about   US$1 a month in South Africa, (with negligible adverse effects compared to all other antihypertensive drugs), this combination is the mandatory  firstline therapy for all  hypertensive patients, with rare exceptions. This regime  starts with amilozide 13.75mg (1/4 tab) and reserpine 0.0625mg (1/4tab) /d- and many patients can eventually be controlled with these doses just 3 days a week; with other antihypertensives added only if hypertension is not controlled with these increased to the ceiling tolerated eg of amilozide 27.5mg/d and reserpine 0.125 mg/d (maximum reserpine 0.25 mg 5/week ie 0.18mg/d if tolerated).

Since roleplayers are there to serve patients, not the Drug and Disease Industry, all roleplayers ( National Hypertension societies, provincial and national health and medical school authorities, medical schemes and all health practitioners)  have no choice but to obey the gold-evidence-based medicine set out herein, and reinstate reserpine and amilozide as mandatory 1st-line therapy of essential hypertension, with motivation  for alternatives to be provided in the  exceptional cases.

Unlike the USA and the East  where reserpine is still in national recommendations,  Authorities, regulators, suppliers and prescribers  in South Africa, Australia, the UK and Europe can no longer continue to defraud the public and deny patients this best treatment, since the two tablets (cheap amilozide and reserpine) are freely and universally available for  at most the retail South African prices quoted (less in bulk buy).

There is no shortage of reserpine, HCT or amiloride;  and the evidence for them over all modern antihypertensives  is binding under  rules of evidence and therefore medical ethics. The current evidence discussed shows that this  old lowdose combination is superior to all modern drugs and modern marketted combinations in both reduction of all-cause endpoints, adverse effects, and cost.

As Henry Black said recently, triple antihypertensive therapy is simply Back to the Past – and it can be both very low cost and risk-free..

And if proof is wanted, we must agree on a simple long term multicentre trial of the lowdose reserpine-amiloretic regime versus modern marketed combinations.- as in  ALLHAT but comparing combinations..But who is to pay for yet another trial to prove what is already so well proven?

35 years after Illich’s Medical Nemesis, it is very sad to have to be fighting overwhelming profiteering vested interests for what is now by far the commonest and most easily correctable major common degenerative disease – mild to moderate hypertension.

UPDATE: FOR MILDER PAIN, WHY USE NSAIDS (LET ALONE DICLOFENAC) OTHER THAN PARACETAMOL -ACETAMINOPHEN?

update

Aspirin,  paracetamol, other NSAIDs,  and codeine  in periodic conservative analgesic use have  not been reported to cause hypoglycemia eg a few gm a day solo or in combination  in well adults-  despite  deliberate overdose of these being  notorious for causing fatal bleeding or  liver failure with hypoglycemia, or respiratory failure.

But increasingly tramadol is incriminated in dangerous hypoglycemia: Tramadol Use and the Risk of Hospitalization for Hypoglycemia in Patients With Noncancer Pain Fournier, Suissa, eaJAMA Intern Med.December      Tramadol is an increasingly widely used  weak opioid analgesic , associated with adverse events of hypoglycemia.  Analysis  in United Kingdom Clinical Practice of treatnent with tramadol or codeine for noncancer pain between 1998 and 2012  included 334 034 patients, of whom 1105 were hospitalized for hypoglycemia during follow-up (incidence, 0.7 per 1000 per year) and matched to 11 019 controls. Compared with codeine, tramadol  associated with  increased risk of hospitalization for hypoglycemia  in the first 30 days of use (OR, 2.61 [95% CI, 1.61-4.23]). This 30-day increased risk was confirmed in the case-crossover analyses (OR, 3.80 [95% CI, 2.64-5.47]). Conclusions  tramadol (in contrst to codeine), TRIPLED risk of hypoglycemia requiring hospitalization. Additional studies are needed to confirm this rare but potentially fatal adverse event.

update 4 March 2013  BAN DICLOFENAC?  four years on, another call comes  for the virtual banning of diclofenac, from no less than the Canadian Medical Association Journal , based on a new metanalysis of NSAID risks by University  Toronto’s McGettigan and Henry .

As this column has long pointed out, diclofenac is apparently still the only NSAID that can kill suddenly without warning.  There are many far safer alternatives eg naproxen, ibrufen; and no compelling clinical evidence or reason to use it let alone cox2 inhibitors  except false beliefs and heavy marketing.

So as this columnist concluded in 2009,  it is blatant fraud, negligence and potential indefensible homicide  to continue recommending  let alone  using diclofenac simply for profiteering.

21June 2009 It is 4 months since this column last addressed nonsteroidal anti-inflammatory drugs NSAIDs.

A new study (from USA, UK and Canada – Ray 2009) of NSAIDs  claims that in those with ischemic heart disease, the popular NSAIDS -diclofenac, ibuprofen or rofecoxib(Vioxx) – increased serious heart disease/ death by about 50-67% compared to nonusers; whereas naproxen over some 111000 patient years of use gives no significant risk or benefit.

A new study from Denmark (Fosbol 2009) this year looked at a million healthy individuals with no hospital admissions or selected therapy. Compared to no NSAID use, ibruprofen and naproxen gave no added risk of death/ myocardial infarction; diclofenac gave 67% increased risks, and the two coxibs (rofecoxib Vioxx; celecoxib Celebrex)  increased risk 100%.

So we are led to believe that naproxen or ibuprofen is the NSAID  mild-to-moderate analgesic  of choice. Naturally the American Colleges and academia – who represent the Disease Industry, not patients- recommend yet other potentially toxic drugs- like  the magical proton pump inhibitors- to counteract the adverse NSAIDS..

But is this just a myopic view beloved of big pharma, to promote their snake oils.?

Another new study from Denmark (Gislason 2009) of 110 000 patients after admission for heart failure in the 12 years 1994-2005, showed that 57% died; 9000 (8%) were rehospitalized with acute heart attack  and 40 000 (38%) were rehospitalized with heart failure. Thus heart failure in a well-nourished population has a poor prognosis. In 36 000 who had used NSAIDs compared to non-users, risk of death was doubled on  diclofenac; increased~67% on  (rofe-or cele)coxibs; and was  significantly increased 22-31% by all other NSAIDs including naproxen and ibruprofen.

It is common cause after 20 years that injected diclofenac is the only NSAID that can unpredictably cause sudden death. So it’s administration risks culpable homicide when it is totally unwarranted. No cases of sudden death from any oral NSAID   including aspirin appear on Medline, apart perhaps from the risk of hyperacute asthma (Asamoto 1999).

But what of gastrointestinal bleeding  risks of NSAIDS? a 2007 study in Japan (Yajima) scoped all orthopaedic patients who took NSAIDs for more than 4 wks: oral diclofenac increased risk of erosive gastric lesions sixfold. A new review from Seattle (Schlansky 2009) refers to Helicobacter synergism in all NSAID use.

WHAT IS THE NEED FOR NSAIDS? The Wikipedia entry on NSAIDs  sums it up: it has almost four times as much text on the numerous  adverse effects of NSAIDs as on their uses- in fact the  article does not discuss the advantages of NSAIDS as analgesics; in fact it states plainly  that alone  just  “their gastrointestinal effects  are estimated to result in 103,000 hospitalizations and 16,500 deaths per year in the United States”.

All designer drugs are dangerous in overdose. Without overdose, paracetamol has no risk – and the Wikipedia entry thereon is balanced and highly favourable even for infants. We know well that paracetamol- a fatal liver toxin in overdose- should not be marketed without a built-in simple liver (and antineuritic) protective of  eg (carbo-or N-acetyl-)cysteine, alphalipoic acid and vitamin BCo.  But the Disease – Big Pharma Industry is not interested in prevention- Only Disease Pays. And Regulators, lobbyists and legislators  protect their source of work and income- the Drug Industry.

Fish oil (EPA+DHA) is probably  the most beneficial NSAID supplement we have (- perhaps ahead of other front-runners like vitamins C, D, magnesium and CoQ10-) halving all sudden deaths, and reducing by at least a third all major chronic degenerative diseases from CVD to diabetes, arthritis, learning, depression, behaviour disorders. Industry wont pay for head-on comparative trials. But the trial evidence suggests that fish oil and oral EDTA have better risk-benefit than aspirin and other antiplatelet agents, NSAIDs and warfarin.

We know that for moderate trauma and small – medium (even knee) joint pain/  contusions, self-massage with any natural NSAID like arnica or wintergreen is all that is needed, combined if necessary orally with up to 3 to 4gm paracetamol /day +- if needed a little codeine.   Prior 2002 found no significant difference in pain relief between paracetamol and naproxen in tension headache.

For more serious pain,  short of strong opioids, there is in fact no overall trial evidence that weak opioids or NSAIDs are better than eg hypnotherapy, or acupuncture,  or judicious paracetamol; to which latter if necessary a little codeine can be added as step-up analgesia. The latter  agents have none of the deadly risk of NSAIDs. Amadio 1984 showed that of Peripherally Acting Analgesics: ” paracetamol at up to 4 g per day compares favorably in analgesic potency to aspirin and other NSAIDs, and  should be considered the treatment of choice for mild-to-moderate pain”.  Skovlund 1991 showed no significant difference between naproxen and paracetamol in postpartum uterine spasms.

Six RCTs – five in mostly European peoples and one in Hong Kong- found paracetamol equal to diclofenac (Voltaren) – March 1994 in arthritis; Brevik 1999 and Kubitzek 2003 in dental surgery; Hoogewijs 2000 and Woo 2006 after trauma; and Munishankar 2008 after Caesarian section.  In a Cochrane analysis 2003, Towheed showed that in the one placebo-controlled RCT in osteoarthritis, paracetamol was clearly superior to placebo with a similar safety profile. And the general principle of therapy applies, that if required, combination of analgesics from different groups is better than single drug therapy. But given the many potentially fatal risks of the NSAIDs – compared to paracetamol, opioids and if indicated  aspirin –  there is no compelling reason to add NSAIDs  for pain.

We know that it is negligent to initially sentence people with  spontaneous mild-moderate head/neck/backache or tendonitis at the shoulder, elbow, knee etc to bedrest, NSAIDS, opioids or referral for xrays, scans or surgery. 95% will settle rapidly with reassurance, posture instruction and simple topicals and paracetamol analgesia. Otherwise most pain will disappear with firm reassurance with brief simple laying on of hands eg massage and traction with gentle rotational manipulation and instruction in auto-reinforcement –  pressure point eg earlobe pressure, or acupuncture, or hypnosis. And most of the remainder resolve quickly with  simple targeted injection with a little local anaesthetic plus depot steroid.

And we know that with judicious use, topical corticosteroid injection – never mind judicious brief systemic steroid (corticosteroid, calciferol, testosterone) has little or no risk and far greater target and multisystemic benefit than NSAIDs; and for chronic conditions, like fish oil at least address the underlying pathogenic mechanisms/causes- whereas NSAIDs and paracetamol ignore these.

Is drug-speeded resolution of inflammation essential and beneficial except for the drug vendor? A careful RCT by Bradley ea from Indiana University in 1992 observed that “joint tenderness and swelling, presumptive evidence of synovitis, may not be a priori indications for use of an antiinflammatory drug, or predict greater responsiveness to treatment with an antiinflammatory drug than to a pure analgesic, in symptomatic treatment of patients with knee osteoarthritis”.

So why are synthetic  NSAIDs and especially the Coxibs  still used? Why do academics and Regulators still allow, promote  them for  routine use, other than to profit Big Pharma, and cause perhaps a quarter million deaths a year globally?

SPECIALIST NATURAL MEDICINE CLINIC 2015

SPECIALIST NON-XRAY PAIN, BONE, BREAST, BRAIN,  HEART, CHEST, GENITOURINARY, HORMONE RISK SCREENING  @ NATURAL MEDICINE CLINIC

for appointments for consultations,   or non-xray procedures by registered practitioners :  Sure Touch breast prescreening on  Saturday mornings next on  7 February 2015  by Sister Zeneath Ismail – cash R650 (then R450 if followup scan desired within 3 months);   -QUS  ultrasound quantitative bone density  cash R450 -tariff item 3612-  anytime;  Unlike radiologists’  and thermography reports (which describe only  the imaging finding), the rates quoted include relevant breast or bone consultation and management planning  by specialist nurse & physician.

IF BOOKED TOGETHER, (not necessarily the same morning) then combined breast and bone screening is R1000.

OTHER SERIOUS health problems ARE DEALT WITH BY CONSULTATION DURING THE WEEK (OR ON A DIFFERENT SATURDAY MORN) : heart- ECG,  fatigue, HRT, sexual health, hypertension, depression, memory/dementia, lung & lungfunction, anaemia-haematology; kidney/bladder/pelvic, hormone-endocrine, depression, osteoporosis, sleep, diabetes, thyroid, adrenal; cramp; skin,  infection including STDs & HIV/AIDs, stroke, epilepsy-neurology, dizziness, heartburn/digestive/liver,  neuropathy,  sexual health, menopause, HRT, genitourinary; immune problems, or arthritis relief;

Thermography no-touch infrared screening  for suspicious  cancer /inflammatory  changes:  by Radiographer Melinda-next 23 March 2015.   R900 breasts; R1100  head and  upper;  or lower body & pelvis;  R1300 whole body.

Bookings/queries contact Evelyn/ Reyhana / Val at  the Natural Medicine Clinic, 1st Floor no 15, Grove Medical Bldg, opp ABSA (parking ABSA Parkade )  near Warwick/Cavendish  Square Claremont Cape Town RSA, ph +27216831465 or a/h +2783 4385248 or reyhanadaya@yahoo.com  .

For the disabled – by arrangement  drive  up the ramp  to the Clinic door on the Grove Bldg 1st floor  parking deck.

Under CMS Council for Med Schemes Reg 10(6), open Medical schemes eg hospital plans  have to pay from their own funds (not members’ savings) for appropriate outpatient consultation (tariff item 0191) for  PMBs ie major conditions eg  cancer,   depression, neck/spinal problems, serious heart, lung, other disease., etc. Breast and osteoporosis concerns are generally part of menopause consultations N95.9   (if not already eg breast cancer code C50) and thus are often billable  med scheme benefits. The menopause billable item only applies if you are 45yrs upwards, unless you have had total hysterectomy.

On patients’ requests, appropriate invoice can be prepared and submitted to your scheme for refund of your due benefits. Some schemes eg hospital plans  falsely deny due benefits until reported to their regulator  CMS. For medical plans where the billable tariff benefit rate is higher than the breast screening fee paid, the med plan rate 0191  will be charged eg R790 by the contracted  specialist,  and refundable by Discovery to the member. some basic schemes eg Keycare, Bonitas require preauthorization, or referral by their contracted GP  .

CAPE PENINSULA HYPERTENSION & HEADACHE CENTRE

CAPE PENINSULA HYPERTENSION & HEADACHE CENTRE (50 years of experience)      at       The Natural Medicine Clinic  NMC , 1st Floor, 15 Grove Bldg, Grove  Claremont, Cape Town- between  ABSA Parkade on Grove Ave, and Warwick Sq opp Cavendish. ph 0216831465/ 071202574 or email doctor@healthspanlife.com.

As the commonest silent killer of aging people in the world, pain, obesity  and often-resultant systemic  hypertension HBP deserve the best and cheapest treatment.     Headache is rarely caused by hypertension, but unlike hypertension, is usually easily controlled if not cured.

But precisely because HBP is so common- in half of us by old age, especially at night- it is a huge moneyspinner for Big Pharma and the Disease Industry.

so the last thing the HBP Industry wants is too successful too cheap treatment. Hence they (eg the WHO,  the SA Hypertension Society and medical schools- state clinics)-  blacklist  the best baseline treatment- lowdose amilozide and lowdose reserpine, to promote sales of ever-newer unproven drugs with multiple risks. .

But 60 years of experience (5 centuries in India) confirms that Rauwolfia and its extract reserpine remain the best and sufficient treatment for most patients provided it is combined with a mild diuretic eg magnesium-potassium; or     natural herbs eg  Green tea, cranberry juice, Apple cider vinegar , Dandelion, Nettle, Fennel, buchu, horsetail;

or a magnesium-potassium conserving equivalent- the recent  proven designer ie synthetic lowdose safe diuretic amilozide eg Amiloretic 55mg 1/4 to 1/2 tab, combined with natural  lowdose reserpine 0.25mg tab 1/4 to 1/2 tab, both initially daily, eventually perhaps only 3 days a week.  . These lower HBP and associated anxiety/depression  gently but surely to avoid complications.

The NMC is open  office hours  from 9 am 6 days a week, and offers objective electronic arm and leg bloodpressure measurement and if required urine and heart testing for causes and effects of hypertension etc. If desired, appointment can be made with a hypertension-metabolic  specialist physician.

see https://healthspanlife.wordpress.com/category/reserpine/ for further details to fight dementia, stroke, heart/kidney failure, heartattack, blindness, diabetes, gangrene, etc. The last thing the Disease Industry and hospitals, medical schools  want us to do is wipe out these common diseases with safe lowcost treatment..