Category Archives: diabetes prevention

SPECIALIST FAMILY PRACTICE CONSULTATIONS IN CLAREMONT/ HARFIELD VILLAGE CAPE TOWN (& ONRUS)

Dr Neil D Burman MBChB(UCT) 1966, MRCP(UK 1974) Senior  Family General Integrative (all-ages) & Specialist Internist  practitioner in Claremont Cape Town,  has left Grove Bldg, moved his rooms to
 13 Stafford St Harfield  Village, 50m down from Harfield station subway above corner of 1st Ave. . (and occasionally by appointment at Onrus outside Hermanus).
Consultations  by appointment only 1600-1800, sometimes from 0900 weekdays and public holidays/weekends.  or consultations by Telephone/email  where appropriate.
(No emergencies or surgery- these must go to nearest polyclinic or hospital ER). . .  Holistic integrative chronic natural medicine practice (HRT, pain relief, infection eg HIV AIDS, TB, /cancer/obesity screening & prevention;
Banting & Supplement counsellor .

appts: ph Reception office hrs  021 6717797.   .
or
doctor personal email doctor@healthspanlife.com  or sms or whatsapp (or as last resort  try ph) 0836299160 all hrs 07.00 – 21.00. .    or fax to email 0865657215
Fellow of  Kronos Longevity Research Foundation Phoenix Arizona.

MEMBER OF SASIM SA Society of Integrative Medicine;      Royal Society SA; Kidney Association; Faculty of Consulting Physicians of South Africa; Kingsbury Hospital Forum;  and Local & International Societies for Study of: ; Menopause and Aging Males Andropause, Hypertension, Sexual Health, Vitamin D3-Autoimmune Disease  CGCoimbra network; LDN Trust; .  Insurance, and Professional Driving Permit Assessments. SASSA Disability Grant med officer .  (formerly practicing/lecturer  in Port Elizabeth;  Hypertension, Renal & Transplant  med   GSH UCT, Leeds Hospital  England: Tygerberg Hospital Univ Stellenbosch; Libertas Hospital G/wood; and Univ W Cape.

Preferred Provider: Discovery Health & FedHealth

THE NEGLIGENCE- MORTALITY AND MORBIDITY- OF WITHHOLDING APPROPRIATE HEALTHSPAN-EXTENDING PHYSIOLOGICAL HUMAN HRT FROM AGING MEN AND WOMEN

update 10 Dec 2015  a reader in Germany  responds:  “ Excellent! I wonder when lawyers will start suing for withholding hormone replacement. 
I think you have made a very strong point by stating that government, medicine and industry are more interested in disease than health.”
      HRT UPDATE 8 Dec 2015: THE NEGLIGENCE- MORTALITY AND MORBIDITY- OF WITHHOLDING APPROPRIATE PHYSIOLOGICAL HEALTHSPAN-EXTENDING HUMAN HRT FROM AGING MEN AND WOMEN :

its been a long time since this column last reviewed HRT for women (the KEEPS Trial) and for men, other than in the contexts of prevalent cancer phobiamongering.  Both our experience in practice, and longterm observational studies, are increasingly affirmative. Why should we be surprised?

Global pollution and overheating, antibiotic, alcohol and sugar abuse, and shortage of drinkable/arable water and therefore food are the dominant “natural” threats of the next decade let alone century. As a 2013 German-Chinese study says, Water-sustainability requires > 60% of arable land for soil water replenishment.
But thanks to worsening indoor living, sloth and food production policies, deficiency of antiinfection- anticancer antioxidant growth-promoting (not just rickets-and – goiter-preventing) microdose anabolic vitamin D3 and iodine have taken the lead , for the half of mankind who do not go hungry, in the essential needed mineral-vitamin microsupplements in life-and- lifequality-limiting micronutrient deficiencies for young and old. These micronutrient deficiencies are so easily and cheaply remedied for a few $ per person per year- but there is no incentive for high-tech profit-based government, medicine and industry to promote these since Only Disease Pays.

Now the recent October interview with leading Canadian andrologist Dr Alvaro Morales Testosterone Deficiency Focus of New Canadian Guidelines echoes what we have learned  the past 50 years over our career lifetimes about appropriate parenteral natural physiological HRT being as important for deficient aging men- testosterone replacement. This matches need for appropriate parenteral natural physiological HRT for postmenopausal women- for whom progesterone cream often suffices as the safe baseline, adding parenteral testosterone and parenteral estrogen only as selectively indicated.ie in both genders to conservatively restore physiological balanced baseline bloodlevels of healthy young adults. .
Its now 13 years since the USA hysterical banning (2002 then 2003) of all HRT after the badly designed and bad analyses and premature stopping of the Womens’ Health Initiative; which illogically tested unphysiological and long-discredited patent oral xeno- ie non-human hormones (premarin and medroxyprogestin) in mostly elderly women long past the Change- the midlife menopause and menopause symptom decade (ie late forties to late fifties).

Many of us in the International Menopause Society objected to this dangerous hysteria from 2002 onwards, but the Americans involved in the WHI refused to concede for a decade that they were wrong, since such admission would have opened them to culpable negligence claims.. . .

in 2013 co-editors Dr Nick Panay(UK) and Dr Ana Fenton (NZ) asked in the leading journal Climacteric about the Womens’ Health Initiative:WHI: have our worst fears come true? . This was based on ongoing analyses of studies eg by Drs Sarrell, Katz ea at Yale University that showed The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 50 to 59 years who were denied HRT.

Ongoing studies over 60 years (Schleyer-Saunders, Lee, Dalton, Greenblatt, Gelfand, Gambrell, Schneider, Davey, Shapiro, Cheifitz, Burger & Davis, Nieschlag & Behre, Notelowitz, Lunenfeld, Utian, Harman, Bhasin, Zitzman, Hader, Saad ea) have clearly confirmed what was apparent from experience in the 1940s, and Masters and Grody’s initial landmark HRT studies in the1950s in both sexes, that appropriate human parenteral balanced HRT (testosterone/ progesterone, plus estrogen for women) retard all risks of aging degenerative diseases in sex-hormone deficient aging people; and also extend both healthspan and longevity ie are antiaging.

           Now we have come full circle with longterm followup of stable physiological parenteral testosterone replacement- patches, fortnightly depotTT – or quarterly Nebido TUndecanoate – in 100 000s of men globally to a mean testosterone level around 18nmol/L (let alone to appropriate testosterone  replacement in women):

ongoing followup from a European observer personal communication last week is borne out by already published studies below: “there is no evidence from various registries of increased incidence and/or severity of prostate cancer with testosterone treatment.

      Increasing signals are that adequate testosterone treatment is protective, for the prostate as well as the immune, cardiovascular, nervous, musculoskeletal and cognitive-mood systems. One registry follows both hypogonadal men who refused testosterone treatment, and those on replacement. In 8 years follow-up of 296 elective hypogonadal men , 26% had major cardio-/vascular medical endpoints (21 deaths -19 = 6% cardiovascular, 30 =10% strokes, and 26 = 9% myocardial infarction, in total 77 events) . The elective Nebido testosterone replacement group (360 men) reported NO cardio/vascular endpoints ie no medical deaths, strokes, or heart attacks.(1 traffic accident death, 1 postsurgical complication death), q.e.d. p<0.0000…

REFS- in italics :
BOTH SEXES:
Clin Interv Aging. 2014 Jul 23;9:1175-86.. Off-label use of hormones as an antiaging strategy: a review. Samaras N1ea Geneva University Switzerland. Given demographic evolution of the population in modern societies, one of the most important health care needs is successful aging with less frailty and dependency. During the last 20 years, a multitude of anti-aging practices have appeared worldwide, aiming at retarding or even stopping and reversing the effects of aging on the human body. One of the cornerstones of anti-aging is hormone replacement. At present, women live one third of their lives in a state of sex-hormone deficiency. Men are also subject to age-related testosterone decline, but andropause remains frequently under-diagnosed and under-treated. Due to the decline of hormone production from gonads in both sexes, the importance of dehydroepiandrosterone (DHEA) in steroid hormone production increases with age. However, DHEA levels also decrease with age. Also, growth hormone age-associated decrease may be so important that insulin growth factor-1 levels found in elderly individuals are sometimes as low as those encountered in adult patients with established deficiency. Skin aging as well as decreases in lean body mass, bone mineral density, sexual desire and erectile function, intellectual activity and mood have all been related to this decrease of hormone production with age. Great disparities exist between recommendations from scientific societies and actual use of hormone supplements in aging and elderly patients. In this article, we review actual data on the effects of age related hormone decline on the aging process and age-related diseases such as sarcopenia and falls, osteoporosis, cognitive decline, mood disorders, cardiovascular health and sexual activity. We also provide information on the efficiency and safety of hormone replacement protocols in aging patients. http://www.ncbi.nlm.nih.gov/pubmed/25092967

     WOMEN: The latest of many are the Danish studies of up to 16 yearsfollowup ;        2008 http://eurheartj.oxfordjournals.org/content/29/21/2660.abstract

and
2012 http://www.ncbi.nlm.nih.gov/pubmed/?term=BMJ+%28Schierbeck+et+al+2012%3B345%3Ae6409,

the USA KEEPS RCT of lower-dose premarin vs estradiol patch +- parenteral progesterone in perimenopausal women by Harman, Naftolin ea http://www.keepstudy.org/publications/index.cfm,

and again
Clin Endocrinol (Oxf). 2014 Oct;81(4):621-8. doi: 10.1111/cen.12459. Epub 2014 May 5. Transdermal testosterone improves verbal learning and memory in postmenopausal women not on oestrogen therapy. Davis ea . Monash University, Australia. Randomized, placebo-controlled trial in which participants were randomized (1:1) to transdermal testosterone gel 300 mcg/day, or identical placebo, for 26 weeks. 92 postmenopausal women aged 55-65 years, on no systemic sex hormone therapy. Eighty-nine women, median age 60 years, were included in the primary analysis. Testosterone treatment resulted in statistically significantly better performance for the ISLT (improved verbal learning and memory) compared with placebo, adjusted for age and baseline score (mean difference 1•57; 95%CI 0•13, 3•01) P = 0•03 At 26 weeks, the median total testosterone was 1•7 nm (interquartile range (IQR) 1•1, 2•4) in the testosterone group and 0•4 nm (IQR 0•3, 0•5) in the placebo group. The small but statistically significant effect of testosterone treatment on verbal learning and memory in postmenopausal women provides the basis for further clinical trials.
Testosterone in women-the clinical significance. Davis & Wahlin-Jacobsen .Lancet Diabetes Endocrinol. 2015 (12):980-92. http://www.ncbi.nlm.nih.gov/pubmed/26358173.      Testosterone is as much an essential hormone for women, with physiological actions mediated directly or via aromatisation to oestradiol throughout the body. Observational studies indicate that testosterone has favourable cardiovascular effects measured by surrogate outcomes. Adverse cardiovascular effects have not been seen in studies of transdermal testosterone therapy in women. http://www.ncbi.nlm.nih.gov/pubmed/24716847

    MEN:
BJU Int. 2014;114:125-30. Long-acting testosterone injections for treatment of testosterone deficiency after brachytherapy for prostate cancer. Balbontin, Morgentaler ea With a median of 31-months follow-up, long-acting testosterone injections in men mean 62yrs with prostate cancer treated with brachytherapy produced significant clinical benefits. There were no cases of rising serum PSA, prostate cancer progression or recurrence.
J Urol. 2015;193:80-6. Incidence of prostate cancer in hypogonadal men receiving testosterone therapy: observations from 5-year median followup of 3 registries. Haider A1, Zitzmann M Yassin ea Germany In 3 parallel, prospective, ongoing, cumulative registry studies 1,023 hypogonadal men received testosterone therapy since 1996. Patients were treated when total testosterone was 12.1 nmol/l or less (350 ng/dl) with symptoms of hypogonadism. Maximum followup 17 years (1996 to 2013), median followup was 5 years. Mean baseline patient age was 58 years and 41 years. Patients received testosterone undecanoate injections in 12-week intervals. Prostate monitoring/ biopsies were performed according to EAU guidelines. RESULTS: A total of 11 patients were diagnosed with prostate cancer in the 2 urology settings at proportions of 2.3% and 1.5%, respectively. The incidence per 10,000 patient-years was 54.4 and 30.7 , respectively, ie mean 0.42% pa – well below that in the general population. No prostate cancer was reported by the andrology center. CONCLUSIONS:Testosterone therapy in hypogonadal men does not increase the risk of prostate cancer. If guidelines for testosterone therapy are properly applied, testosterone treatment is safe in hypogonadal men. http://www.ncbi.nlm.nih.gov/pubmed/?term=Incidence+of+Prostate+Cancer+in+Hypogonadal+Men+Receiving+Testosterone+Therapy%3A+Observations
Eur Heart J. 2015 Oct 21;36(40):2706-15. Normalization of testosterone level is associated with halved incidence of myocardial infarction and mortality in men. Sharma R1, ea University of Kansas retrospectively examined 83 010 male veterans with documented low TT levels http://www.ncbi.nlm.nih.gov/pubmed/26248567
Prostate Cancer Prostatic Dis. 2015 Dec;18(4):382-7. Preoperative low serum testosterone is associated with high-grade prostate cancer and an increased Gleason score upgrading.Pichon ea, France http://www.ncbi.nlm.nih.gov/pubmed/?term=Preoperative+low+serum+testosterone+is+associated+with+high-grade+prostate+cancer+and+an+increased+Gleason+score+upgrading+A+Pichon1%2C5%2C
Horm Mol Biol Clin Investig. 2015 Jun;22(3):101-9. Obesity and hypogonadism are associated with an increased risk of predominant Gleason 4 pattern on radical prostatectomy specimen. Neuzillet , ea France http://www.ncbi.nlm.nih.gov/pubmed/26047422
BJU Int. 2013;111:880-90. Prostate-specific antigen (PSA) concentrations in hypogonadal men during 6 years of transdermal testosterone treatment. Raynaud ea france http://www.ncbi.nlm.nih.gov/pubmed/23294726
Exp Clin Endocrinol Diabetes. 2015 Nov;123(10):608-13. The Effect of Metformin and Metformin-Testosterone Combination on Cardiometabolic Risk Factors in Men with Late-onset Hypogonadism and Impaired Glucose Tolerance.Krysiak ea Poland . No previous study has investigated the effect of metformin, administered alone or together with testosterone, on cardiometabolic risk factors in men with hypogonadism. The study included 30 men with late-onset hypogonadism (LOH) and impaired glucose tolerance (IGT) who had been complying with lifestyle intervention. After 12 weeks of metformin treatment (1.7 g daily), the participants were allocated to one of 2 groups treated for the following 12 weeks with oral testosterone undecanoate (120 mg daily, n=15) or not receiving androgen therapy (n=15). before and after 12 and 24 weeks of therapy with the final dose of metformin. Patients with LOH and IGT had higher levels of hsCRP, homocysteine and fibrinogen than subjects with only LOH (n=12) or only IGT (n=15). Metformin administered alone improved insulin sensitivity, as well as reduced 2-h postchallenge plasma glucose and triglycerides. Testosterone-metformin combination therapy decreased also total and LDL cholesterol, uric acid, hsCRP, homocysteine and fibrinogen, as well as increased plasma testosterone. The effect of this combination therapy on testosterone, insulin sensitivity, hsCRP, homocysteine and fibrinogen was stronger than that of metformin alone. The obtained results indicate that IGT men with LOH receiving metformin may gain extra benefits if they are concomitantly treated with oral testosterone. http://www.ncbi.nlm.nih.gov/pubmed/26600057
Swiss Med Wkly. 2015 Nov 24;145:w14216. Hypotestosteronaemia in the aging male: should we treat it? Christe N1, Meier CA1.Switzerland http://www.ncbi.nlm.nih.gov/pubmed/26599486 The term male hypogonadism is defined as the failure to maintain physiological concentrations of testosterone, a physiological quantity of sperm or the combination of both. Aetiologically, androgen deficiency can originate from the testes (primary hypogonadism) or from the hypothalamic-pituitary regulation of the testicular function (secondary hypogonadism). The causes of hypogonadism are very diverse .. But how about the aging male? It is known that there is a highly variable age-related decline in testosterone levels; whether this represents a variation of normality or has a true disease value requiring therapy has been disputed over more than a decade. The key questions surrounding this debate concern not only the age-dependent threshold for serum testosterone but, more importantly, the risks and benefits of testosterone replacement therapy in the aging male. randomised controlled trials of testosterone administration in aging males with a size of at least 100 patients and a follow-up of at least 6 months, identified eight studies. These studies mostly tried to evaluate the effect of testosterone on bone density, muscle strength and body composition, rather than clinically meaningful endpoints. Moreover, these trials have provided evidence for relevant cardiovascular adverse events in elderly men. This supports the need for further studies to define the treatment threshold for testosterone levels in the aging male, as well as with regard to the long-term risks and relevant benefits of testosterone therapy in this population. Until we have more solid data in aging males, testing for testosterone deficiency and testosterone replacement should remain reserved for patients with predisposing conditions, symptoms and signs of bona fide hypogonadism.
Rev Endocr Metab Disord. 2015 Nov 21. The complex and multifactorial relationship between testosterone deficiency (TD), obesity and vascular disease.Traish AM1, Zitzmann M2.Boston & Germany Univ. Testosterone deficiency (TD) is a well-established and recognized medical condition that contributes to several co-morbidities, including metabolic syndrome, visceral obesity and cardiovascular disease (CVD). More importantly, obesity is thought to contribute to TD. This complex bidirectional interplay between TD and obesity promotes a vicious cycle, which further contributes to the adverse effects of TD and obesity and may increase the risk of CVD. Testosterone (T) therapy for men with TD has been shown to be safe and effective in ameliorating the components of the metabolic syndrome (Met S) and in contributing to increased lean body mass and reduced fat mass and therefore contributes to weight loss. We believe that appropriate T therapy in obese men with TD is a novel medical approach to manage obesity in men with TD. Indeed, other measures of lifestyle and behavioral changes can be used to augment but not fully replace this effective therapeutic approach. It should be noted that concerns regarding the safety of T therapy remain widely unsubstantiated and considerable evidence exists supporting the benefits of T therapy. Thus, it is paramount that clinicians managing obese men with TD be made aware of this novel approach to treatment of obesity. http://www.ncbi.nlm.nih.gov/pubmed/26590935
Cancer Causes Control. 2015 Nov 20. Serum androgens and prostate cancer risk: results from the placebo arm of the Prostate Cancer Prevention Trial. Schenk JM1, EA USA & Australian Univ. examined whether pre-diagnostic serum androgens were associated with PCA risk in the placebo arm of the Prostate Cancer Prevention Trial. In this 3 yr nested case-control study, cases (n = 1,032) were primarily local-stage, biopsy-detected cancers, and controls (n = 1,025) were biopsy-confirmed to be PCA-free.. We found no significant associations between serum androgens, estrogen-to-testosterone ratios, or SHBG and risk of total, low (Gleason <7) or high-grade (Gleason 7-10) PCA. http://www.ncbi.nlm.nih.gov/pubmed/26589415
by contrast,

seer.cancer.gov/statfacts/html/prost.htm reports:
In recent years, the number of prostate cancer deaths IN USA was 21.4 per 100,000 men per year ie 0.021%pa . c/f apparently no prostate cancer deaths in the TRT studies. These rates are age-adjusted and based on 2008-2012 cases and deaths. Lifetime Risk of Developing Cancer: Approximately 14.0 percent of men will be diagnosed with prostate cancer at some point during their lifetime, based on 2010-2012 data

4 August 2015 VITAMIN D: FOR INDOOR TYPES, HOW MUCH eg 50 000iu/d IS ENOUGH, AND SAFE? & 2million iu loading dose is not toxic for adults. Especially for infants, acute illness- ICU, INFECTIONS:

 VITAMIN D REVIEW: WHAT DOSE IS ENOUGH ?   INSUFFICIENCY vs DEFICIENCY, VIT D RESISTANCE?    COMBINATION OF ANABOLICS?     ACUTE LOADING DOSE eg FOR INFECTION, ICU, BURNS, BRONCHIOLITIS?     SAFE vs OVERDOSE-TOXICITY DOSE & LEVELS?  VIT D ALLERGY?

neil.burman@gmail.com

see previous vit D updates:  at  23 Mar 2015 womens’ day: the crucial role of vitamin D as HRT in reducing all major diseases . Salute Dr Walter Stumpf

and    https://healthspanlife.wordpress.com/2009/10/29/is-there-a-vitamin-d3-conspiracy-of-suppression/

and 17 JUNE 2015 VITAMIN D DEFICIENCY VIRUS EPIDEMICS.

PREFACE WARNING: nb black italics are abbreviated quotes; for the link click on blue italics  eg McKenna ea.            NB conclusions depend, are based on, apparently reliable formal  randomized controlled RCTs trials  and team experiences, (but RCTs, metaanalysis, reviews and case reports   are also notoriously  vulnerable to vested interests of authors and sponsors, statistical errors, omission of inconvenient results, even subtle blatant fraud and fabrication;  to small numbers, heuristics and bias   – confusing causality, type 2 statistical errors ie sheer random chance; per  eg per Nobel prizewinner – the American  Daniel Kahneman : Thinking, Fast and Slow: New York 2011; the Briton   Oliver  Gillie 2014; Vit D, Sunlight, mortality, causality  and The Scots   Paradox, the Swiss Paradox;  the Flu, MERS, AIDs-TB-ebola epidemics: Can Sun Exposure, or  Lack of it, Explain Major Paradoxes in Epidemiology; https://www.linkedin.com/in/olivergillie;biography); the Semmelweis Paradox;  the current epidemics in Central and South Africa, Saudi Arabia, South Korea, cities & refugee camp  ghettos, 1918-19 et seq;  the German Gerd Gigenzer  http://www.gocognitive.net/interviews/gerd-gigerenzer-decision-making.

4 August 2015 update: why do new trials/ reviews keep referring to mediocre dose vitamin D3 as high dose?    Karen Hansen’s  Univ Wisconsin  trial compared placebo, with baseline  vit D3  24000iu /month and as high dose 5 fold more ie  124000iu/month- finding no significant benefits. BUT  124000iu/month is still only about 4000iu/day, which on average increases 25OH Vit D3 only by about 40ng/ml. This is hardly high dose when vigorous levels are at least double this ie close to 100ng/ml; and vigorous safe dose long term is around 50 000iu/day ; with up to 150 000iu/day, up to above 250ng/ml blood level,  having been taken for decades, or single dose of 2million units,  without toxicity... Of course safety depends on adequate water, magnesium and vit K2 intake, and not adding  calcium supplements since average city diet is low in magnesium, iodine  and vit K2, not calcium or toxic fluoride or bromine. 

                      2015 Aug 3  JAMA Intern Med. . Treatment of Vitamin D Insufficiency in Postmenopausal Women: A Randomized Clinical Trial. Hansen, Marvdashti ea http://www.ncbi.nlm.nih.gov/pubmed/26237520 . Experts debate optimal 25-hydroxyvitamin D (25[OH]D) levels for musculoskeletal health. Objective  randomized, double-blind, placebo-controlled clinical trial was conducted at a single center in Univ Wisconsin   from  2010, completed 2014. A total of 230 postmenopausal women 75 years or younger with baseline 25(OH)D levels of 14 through 27 ng/mL and no osteoporosis were studied.  Interventions: Three arms included daily white and twice monthly yellow placebo (n=76), daily 800 IU vitamin D3 and twice monthly yellow placebo (n=75), and daily white placebo and twice monthly 50,000 IU vitamin D3 (n=79). The high-dose vitamin D regimen achieved and maintained 25(OH)D levels ≥30 ng/mL. Main  Results:  After baseline absorption was controlled for, calcium absorption increased 1% (10 mg/d) in the high-dose arm but decreased 2% in the low-dose arm (P = .005 vs high-dose arm) and 1.3% in the placebo arm (P = .03 vs high-dose arm). We found no between-arm changes in bone mineral density, trabecular bone score, muscle mass, and Timed Up and Go or five sit-to-stand test scores.  High-dose cholecalciferol therapy increased calcium absorption, but the effect was small and did not translate into beneficial effects on bone mineral density, muscle function, muscle mass, or falls. We found no data to support experts’ recommendations to maintain serum 25(OH)D levels of 30 ng/mL or higher in postmenopausal women. Instead, we found that low- and high-dose cholecalciferol were equivalent to placebo in their effects on bone and muscle outcomes in this cohort of postmenopausal women with 25(OH)D levels less than 30 ng/mL.
26 JULY 2015 UPDATE:
1,   Calcium supplements are no longer recommended for adults:  they promote vascular calcification and worse.

J Intern Med. 2015 Jul 14. Calcium supplements: benefits and risks. Reid , Bristow , Bolland .University of Auckland, New Zealand. Calcium is an essential element in the diet, but Calcium Study demonstrates no relationship between dietary calcium intake and rate of bone loss over 5 years in healthy older women with intakes varying from <400 to >1500 mg day. Thus, supplements are not needed within this range of intakes to compensate for a demonstrable dietary deficiency, but might be acting as weak anti-resorptive agents via effects on parathyroid hormone and calcitonin.  As a result, anti-fracture efficacy remains unproven, with no evidence to support hip fracture prevention (other than in a cohort with severe vitamin D deficiency) and total fracture numbers are reduced by 0-10%, depending on which meta-analysis is considered. Five recent large studies have failed to demonstrate fracture prevention in their primary analyses. This must be balanced against an increase in gastrointestinal side effects (including a doubling of hospital admissions for these problems), a 17% increase in renal calculi and a 20-40% increase in risk of myocardial infarction. Each of these adverse events alone neutralizes any possible benefit in fracture prevention. Thus, calcium supplements appear to have a negative risk-benefit effect, and so should not be used routinely in the prevention or treatment of osteoporosis.
        Rather it is vits D3, C,  K2 ;  and magnesia supps that are recommended for multisystem benefits-  magnesia especially for prevention of common renal stones- since the classic paper from Harvard  Am J Clin Nutr. 1967;20:393-9. Effect of daily 200mg MgO   and 10mg vitamin B6   administration to patients with recurring calcium oxalate kidney stones. Gershoff & Prien.
2. for preventing eg calcium stones and mortality etc, vit D3 in high enough dose to switch off hyperparathyroidism. eg Clin Nutr. 2015 Mar 24.    Vitamin D3 supplementation and body composition in persons with obesity and type 2 diabetes in the UAE Sadiya , Abusnana ea The study was executed in 3 phases in two arms vitamin D arm (n = 45) and placebo arm (n = 42); in Phase 1 the vitamin D arm received 6000 IU vitamin D3/day (3 months) followed by Phase 2 with 3000 IU vitamin D3/day. During follow up (phase 3) both the arms were un-blinded and supplemented with 2200 IU vitamin D3/day for another 6 months . On supplementation no significant changes in anthropometric dimensions was observed. S-25(OH) D peaked in phase 1 (77.2 ± 30.1 vs 28.5 ± 9.2, p = 0.003) followed by a decrease in phase 2 (62.3 ± 20.8, p = 0.006) paralleled by a decrease in parathyroid hormone in phase 2 (5.9 ± 2.4 vs 4.5 ± 1.8, p < 0.01) compared to baseline in vitamin D group. Supplementation was safe, improved s- 25 (OH)D also reducing the incidence of eucalcemic parathyroid hormone elevation.
      Crit Care Med. 2015 Jul 16.   A Randomized Study of a Single Dose of Intramuscular Cholecalciferol in Critically Ill Adults.  Nair, Center ea   Univ Sydney & Brisbane, Australia.  LMU, Munich, Germany.    To determine the effect of two doses of intramuscular cholecalciferol on serial serum 25-hydroxy-vitamin-D levels and on pharmacodynamics endpoints.Prospective randomized interventional study.
Fifty critically ill adults with the systemic inflammatory response syndrome.Patients were randomly allocated to receive a single intramuscular dose of either 150,000 IU (0.15 mU) or 300,000 IU (0.3 mU). Secondary hyperparathyroidism was manifested in 28% of patients at baseline. Parathyroid hormone levels decreased over the study period with patients achieving vitamin D sufficiency at day 7 having significantly lower parathyroid hormone levels (p < 0.01).  Although in-hospital mortality rate did not differ between the groups, patients who did not mount a parathyroid hormone response to vitamin D deficiency had a higher mortality (35% vs 12%; p = 0.05). No significant adverse effects were observed.
     3  universal vitamin D3 deficiency:   our local population, as in virtually all populations worldwide who no longer work and live bare in the sun and eat plenty of raw fish(eg unfiltered cod liver) (oil) have average blood 25 OH vit D levels at or below 20ng/ml, whereas it is  incontestable that all diseases decline steadily as this marker vit D3 level is elevated by sunshine to the probable maximum natural achievable level around 40ng/ml- and with vigorous supplements eg 50 000iu/wk  up to around 80ng/ml, but in sickness to around >100ng/ml.
 4.    But the vit D overdose literature shows that while the highest adult vit D3 doses that have been prescribed are about 640 000iu as monthly dose (Salhuddin N ea , Karachi Pakistan 2013- with 40% improvement in TB recovery after only 2 months compared to TB pts given antiTB Rx alone), and 40 000iu/day in South America for months  for serious pemphigus and albinism. The Pakistan Endocrine Society is a pioneer professional group in endorsing vigorous vit D3 dosing.
But the threshold for toxicity- hypervitaminosis D– seems to be above 2million units single dose in nonagenarians (Netherlands 2 pts) or 88 000iu/day longterm (Canada); and blood 25OHvit D above 250 – 500ng/ml. one 70yr old women was reported to present with Hypervit D only after 10 years  taking 100 000ium/d ie over ~300million iu.. Another women was reportedly  unharmed after 5  times that ie @ 150 000iu/day ,  1.5 billion vit D2 iu over 28yrs –Stephenson & Peiris 2009.
small Subcontinent people–  Pakistanis, Indians etc may be more prone to overdose with vit D, often from massive doses given by injection weekly ie no chance of reducing absorption plateauing as oral overdose increases, as normally happens.
 
VIT D2 VS D3:  note that as one of the most backward Govts in the world, RSA   STATE  authorities- at least in W Cape eg state hospitals and  day hospitals- still distribute and promote vit D2 for osteoporosis, altho these tabs falsely labelled Strong Calciferol are in fact fraudulently labelled,  only their manufacturer website Lennons-Aspen reveals that they are in fact ergocalciferol vit D2, which experts have long condemned as only about 1/4 the strength of vit D3, and which D2 in two studies actually worsens not improves rheumatoid arthritis. This in contrast to the all-disease beneficial  anabolic steroid vit D3 which wholesales in bulk at around R200/kg.a different independent website eg http://www.ndrugs.com/?s=lennon-strong%20calciferol does reveal that Strong calciferol is in fact D2, but not that it is a xenohormone manufactured only by yeasts, not animals; and that it elevates 25OH vit D2– not D3- in our blood, thus blocking both our D3 receptors and formation.   Wiki does detail that it is made only by lichen, mushrooms and alphalpha- but not by any animals.
Already in 2006 Houghton and Veith (Univ Toronto Canada) published The Case Against vitamin D2.. Vitamin D2, or ergocalciferol, should not be regarded as a nutrient suitable for supplementation or fortification… no successful clinical trials to date have shown that vitamin D2 prevents fractures..The poorer stability of and greater impurities in vitamin D2 powders may also lead to a higher risk of toxicity than that associated with the vitamin D3 metabolites. However, it is more likely that the weaker affinity of vitamin D2 metabolites to DBP produces higher and more biologically available proportions of free 25(OH)D2 and 1,25-(OH)2D2 and may thus be responsible for the greater risk of D2 toxicity .  Taken together, the most plausible explanations for the greater bioefficacy of vitamin D3 are conceivably due to the higher affinities of vitamin D3 and its metabolites than vitamin D2 for hepatic 25-hydroxylase, DBP, and VDR and because vitamin D3 is not directly metabolized to 24(OH)D as is vitamin D2.”D2may be safe in mega-overdose, but this  2009 abstract from a Tennessee Veterans’ Admin unit  begs the question of whether the D2 tablets were indeed genuine vitamin D, of any benefit to the patient? who apparently consumed over a billion iu of vit D2 in  half a lifetime – at least 20 times the aggressive dose of 50 000iu/week. :

South Med J. 2009 Jul;102:765-8..  The lack of vitamin D toxicity with megadose of daily ergocalciferol (D2) therapy: a case report and literature review.   Stephenson & Peiris .The maximum daily dose of vitamin D currently recommended is 2000 IU. Ergocalciferol (D2) 50,000 IU orally weekly for 8-12 weeks is often used to treat vitamin D deficient patients (25(OH) vitamin D <20 ng/mL). The lack of vitamin D toxicity after massive doses of ergocalciferol has yet to be reported in the literature. We report a case of a 56-year-old woman who received supratherapeutic doses of ergocalciferol (150,000 IU orally daily) for 28 years without toxicity. We discuss the possible mechanisms which may account for a lack of toxicity despite intake of massive daily doses of ergocalciferol in this patient.
                    1 July 2015 update:  The  2008  report from Kimball & Veith, Toronto concludes:  The lowest observed adverse effect level for vitamin D, said to cause hypercalcaemia in normal adults, is officially 95 mg/day ie 4 000iu/d. But collective  reports  indicate that serum 25(OH)D concentrations need   to exceed 700 nmol/L ie 280 ng/ml chronically   before vitamin D3 toxicity becomes  evident ie from at least ~40 000iu D3 /day or perhaps a million iu monthly. .

update 30 June 2015: The Univ Toronto team  in the previous decade published more evidence of safety and benefit  of vit D3 up to 40 000iu a day 280 000iu/week; but   not 88 000iu/day: the warning is that calcium supplement should be avoided in such high vit D3 dosage. They were not yet advising supplement vit K2 and magnesium.                       Neurology . A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis.   Burton JM1, Kimball S, Vieth R   ea  St  Michael’s Hospital, Toronto, Canada.     Low vitamin D status has been associated with multiple sclerosis (MS) prevalence and risk; .  to assess the tolerability of highdose oral vitamin D prospectively, an open-label randomized prospective controlled 52-week trial matched patients with MS to treatment or control groups. Treatment patients received escalating vitamin D doses up to 40,000 IU/day (280 000iu/wk) over 28 weeks to raise serum 25-hydroxyvitamin D [25(OH)D] rapidly and assess tolerability, followed by 10,000 IU/day (12 weeks).. Calcium (1,200 mg/day) was given throughout the trial. Endpoints were mean change in  biochemical measures,  biomarkers, relapse events, and Expanded Disability Status Scale (EDSS) score.    RESULTS:   Forty-nine patients (25 treatment, 24 control) were enrolled [mean age 40.5 years, EDSS 1.34, and 25(OH)D 78 nmol/L]. All calcium-related measures within and between groups were normal. Despite a mean peak 25(OH)D of 413 nmol/L 164ng/ml, no significant adverse events occurred. Although there may have been confounding variables in clinical outcomes, treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell proliferation compared to controls.   Highdose vitamin D (approximately 10,000 IU/day) in multiple sclerosis is safe, with evidence of immunomodulatory effects.    This trial provides Class II evidence that highdose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on highdose supplementation. The trial, however, lacked statistical precision. , providing only Class level IV evidence for these outcomes.

          Ann Clin Biochem. 2008;.   Self-prescribed highdose vitamin D3: effects on biochemical parameters in two men.     Kimball S1, Vieth R.   , University of Toronto, Toronto, Canada. ..  The lowest observed adverse effect level for vitamin D, said to cause hypercalcaemia in normal adults, is officially 95 microg/day 4000iu/d. Serum 25-hydroxyvitamin D (25[OH]D) concentrations associated with hypervitaminosis D remain undefined. Reported 25(OH)D concentrations resulting from prolonged excessive vitamin D3 intakes have exceeded 700 nmol/L 280ng/ml. We report self-prescribed high dose of vitamin D3 over 5-6 years by two men.               Subject 1 had been taking 100 microg/4000iu day for 3 years followed by 3 years of 200 microg/8000iu/day. Serum 25(OH)D concentrations averaged 130 nmol/L 52ng/ml while taking 100 microg/4000iu day of vitamin D3. While taking 200 microg/8000iu/day of vitamin D3, mean serum 25(OH)D concentrations were 260 nmol/L 102ng/ml with no hypercalcaemia or hypercalcuria over the 6 years of vitamin D3 intake.                                                  Subject 2 was a 39-year-old man diagnosed with multiple sclerosis.  his own dose-escalation schedule  increased from 200ugm 8000iu  to 2200 microg/ 88000iu/day over 4 years. The  evidence of a potential adverse effect was that urinary calcium:creatinine ratios showed an increasing trend, which preceded serum calcium concentrations above the reference range (2.2-2.6 mmol/L). His serum 25(OH)D concentration was 1126 nmol/L 450ng/ml  when total serum calcium reached 2.63 mmol/L. He stopped vitamin D3 supplementation at this point. Two months later, all biochemistry values were within reference ranges; serum 25(OH)D concentrations fell by about one-half, to 656 nmol/L 260ng/ml . These results help to clarify the human response to higher intakes of vitamin D3. Close monitoring of biochemical responses confirmed that an increase in urinary calcium:creatinine ratio precedes hypercalcaemia as serum 25(OH)D concentrations rise.

update 28 June : a landmark trial in Brazil 2 years ago finally shows what a really high dose of Vit D3 – 35000iu/d  can do safely over 6 months, a cumulative safe dose of 6million iu A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis:  Dermatoendocrinol. 2013  Finamor,  Coimbra ea    University São Paulo, Brazil     Autoimmunity has been associated with vitamin D deficiency and resistance, and vitamin D metabolism gene polymorphisms   frequently described. May high dose vitamin D3  compensate for inherited resistance to its biological effects?.  To assess the efficacy and safety of prolonged high-dose vitamin D3 treatment of patients with psoriasis and vitiligo, 25 patients with psoriasis or  vitiligo received vitamin D3 35,000 IU once daily for six months ie >1million iu/mo,  >6 million iu over 6mo  in association with a low-calcium diet (avoiding dairy products and calcium-enriched foods like oat, rice or soya “milk”) and hydration (minimum 2.5 L daily). Psoriasis patients were scored according to “Psoriasis Area and Severity Index” (PASI) . All patients presented low vitamin D status (serum 25(OH)D3 ≤ 30 ng/mL) at baseline. After treatment 25(OH)D3 levels significantly increased (from~16 to ~120ng/mL)  ie increase of +- 100ng/ml by 35000iu dly – a flattened highdose response curve, only 10ng/ml rise per 3500iu/d;    and PTH levels significantly decreased (from ~57 to 27 pg/mL. PTH and 25(OH)D3 serum concentrations correlated inversely. The PASI score significantly improved in all nine patients with psoriasis. 14 of 16 patients with vitiligo had 25–75% repigmentation. Serum urea, creatinine and calcium (total and ionized) did not change and urinary calcium excretion increased within the normal range. High-dose vitamin D3 therapy may be effective and safe for vitiligo and psoriasis patients. WHAT WAS THEIR BMI? my 25OHvit D level runs at ~90ng/ml on ~9000iu vit D3 a day; and my  patient’s level runs at ~150ng/ml on ~15000iu/d… so perhaps the Brazilians with these skin disorders (unlike us) have  resistance genes that block higher levels of 25OHvit D. So without doing costly genotyping, we in practice need to check vit D level response early where very high dose is indicated in severe disease. .

Mediocre chronic dose vit D3 supp  eg 2000iu/d , 25OHvitD well > 30ng/ml-   is not enough– it needs high loading eg >400 000- 600 000iu  for acute illness, and good maintenance dose eg >5o 000- 75 000iu/wk  for blood level >60ng/ml, for chronic prevention, to maintain good vit D level and thus real protection:    BMJ Open Respir Res. 2015 Jun   Association between prehospital vitamin D status and incident acute respiratory failure in critically ill patients:  retrospective cohort study.  Thickett , Christopher ea:      Boston, Massachusetts , USA     Intensive care units of Boston teaching hospitals.  1985 critically ill adults admitted between 1998 and 2011    Exposure of interest was prehospital serum 25(OH)D categorised as ≤10 ng/mL, 11-19.9 ng/mL, 20-29.9 ng/mL and ≥30 ng/mL.  In the cohort, the mean age was 63 years,     25(OH)D was ≤10 ng/mL in 8% of patients, 11-19.9 ng/mL in 24%, 20-29.9 ng/mL in 24% and ≥30 ng/mL in 44% of patients. Eighteen per cent (n=351) were diagnosed with acute respiratory failure.  Prehospital 25(OH)D  30ng/ml  in our critically ill patient cohort.  

Thorax. 2015 Jun 10.Double-blind randomised controlled trial of vitamin D3 suppl for the prevention of acute respiratory infection ARI  in older adults and their carers (ViDiFlu).    Martineau , Griffiths ea.Univ London.  clinical trial of high-dose versus low-dose vitamin D3 supplementation for ARI prevention in residents of sheltered-accommodation housing schemes and their carers in London, UK.    137 individuals were allocated to the active intervention (vitamin D3 2.4 mg = 100 000iu once every 2months +10 μg =400iu daily for residents= 62 000iu/mo; carers 3 mg once every 2 months =60 000iu/mo);  and 103 participants to placebo once every 2 months +vitamin D3 10 μg daily = 12000iu/mo for residents, placebo once every 2 months for carers) for 1 year. RESULTS:Inadequate vitamin D status was common at baseline:  92% of 240  participants had serum 25(OH)D concentration < 30ng/ml. The active intervention did not influence time to first ARI (adjusted HR (aHR) 1.18, 95% CI 0.80 to 1.74, p=0.42). When URI and LRI were analysed separately, allocation to the active intervention was associated with 50% higher  risk of URI (aHR 1.48, 95% CI 1.02 to 2.16, p=0.039) and increased duration of URI symptoms (median 7.0 vs 5.0 days for active vs control, adjusted ratio of geometric means 1.34, 95% CI 1.09 to 1.65, p=0.005), but not with altered risk or duration of LRI.   CONCLUSIONS: Addition of intermittent bolus-dose vitamin D3 supplementation to a daily low-dose regimen to average  ~2000iu/d did not influence risk of ARI in older adults and their carers, but was associated with increased risk and duration of URI  over 400iu dly ie 12000iu spread over the month.

Thorax. 2015 May.   Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs).  Martineau ,Griffiths ea    London  University UK. Asthma exacerbations are commonly precipitated by viral upper respiratory infections (URIs). Vitamin D insufficiency associates with susceptibility to URI in patients with asthma.  randomised controlled trial of vitamin D3 supplementation for  prevention of asthma exacerbation and URI. 250 adults with asthma in London, UK were allocated to receive six 2-monthly oral doses of 120 000iu 3 mg vitamin D3 (n=125) or placebo (n=125) over 1 year.   206/250 participants (82%) were vitamin D insufficient at baseline. Vitamin D3 did not influence time to first severe exacerbation (adjusted HR 1.02, 95% CI 0.69 to 1.53, p=0.91) or first URI (adjusted HR 0.87, 95% CI 0.64 to 1.16, p=0.34). No clinically important effect of vitamin D3 was seen on any of the secondary outcomes listed above. The influence of vitamin D3 on coprimary outcomes was not modified by baseline vitamin D status or genotype. Bolus-dose vitamin D3 supplementation – 60 000iu/mo = average 2000iu/d – did not influence time to exacerbation or URI in a population of adults with asthma with a high prevalence of baseline vitamin D insufficiency.

update 27 June 2015  another review Safety of vitamin D3 in adults in multiple sclerosis  Kimball ,Vieth ea  2007 University  Toronto, Canada confirms that  up to at least 40 000iu daily for 28 weeks  is safe. Patients’ serum 25(OH)D concentrations reached twice the top of the physiologic range without eliciting hypercalcemia or hypercalciuria. The data provide objective evidence that vitamin D intake beyond the current upper limit is safe by a large margin.

      update  20 June 2015 : the  10th  HIGHDOSE VIT D STUDY  (100 000 to  600 000iu stat, or up to 55 000iu/day):       Quraishi,  Bhan ea 2009 Harvard Univ Boston: Effect of  Highdose VIT D Supplement on Vitamin D Status and Cathelicidin Levels in Sepsis: Crit Care Med. 2015 Jun 17: RCT  to compare changes in vitamin D status and cathelicidin (LL-37) levels in 30  adult ICU patients given  Placebo (n = 10) vs 200,000 IU cholecalciferol (n = 10) vs 400,000 IU cholecalciferol (n = 10), within 24 hours of new-onset severe sepsis or septic shock in a single Boston, MA teaching hospital.  Blood samples  at baseline (day 1) and on days 3, 5, and 7. At baseline, median (interquartile range) plasma 25-OHvitD  was 17 ng/ml,  peaked by day 5 in  intervention groups.  On day 5, median change in biomarkers for placebo, 200,000 IU vit D3 cholecalciferol , and 400,000 IU vit  D3 groups, respectively, were as follows: 1) total 25OHvitD, 3% (-3% to 8%), 49% (30-82%), and 69% (55-106%) (p < 0.001); 2) bioavailable 25OHvitD, 4% (-8% to 7%), 45% (40-70%), and 96% (58-136%) (p < 0.01); and 3) LL-37 : -17% (-9% to -23%), 4% (-10% to 14%), and 30% (23-48%) (p = 0.04). Change in high-sensitivity CRP levels did not differ between groups. A positive correlation was observed between bioavailable 25OHvit D and LL-37 (Spearman ρ = 0.44; p = 0.03) but not for total 25OHvitD and LL-37. CONCLUSIONS:High-dose vitD3 supplement rapidly and safely improves total  and bioavailable 25OHvitD  levels in patients with severe sepsis or septic shock. Changes in bioavailable 25OHvitD are associated with concomitant increases in circulating LL-37 levels.

Clin Nutr. 2015 Apr 14.    Increases in pre-hospitalization serum 25(OH)D concentrations are associated with improved 30-day mortality after hospital admission: A cohort study in Boston, Mass.. Amrein , Christopher ea   in two Boston univ. hospitals .Pre-hospital vitamin D status may be a modifiable risk factor for all-cause mortality among hospitalized patients.  4344 adults hospitalized between 1993 and 2011..  INTERVENTION(S):  None.  The main outcome was 30-day all-cause mortality.  In an adjusted logistic regression model, absolute changes of ≥10 ng/mL in patients with initial 25(OH)D  < 20 ng/mL (n = 1944) decreased the odds of 30-day all-cause mortality by 48% (adjusted OR 0.52, P = 0.026).  A causal relation may not be inferred from this observational study.
      Conversely, another new study this month confirms the hazard of gross overdose of anything:   Kaur, Mithal ea .India Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency  Clin Endocrinol (Oxf). 2015 Jun “Vitamin D toxicity, wrongly  considered rare, can be life-threatening,  with substantial morbidity, if not identified promptly. In 16 patients with vitamin D toxicity seen between January 2011 and January 2013  Clinical manifestations included nausea, vomiting, altered sensorium, constipation, pancreatitis, acute kidney injury and weight loss. Median (range) age was 64.5 (42-86) years. Median  serum 25(OH)D level  371 (175-1161) ng/ml, serum total serum calcium level  13.0 (11.1-15.7) mg/dl . Irrational Overdose of vitamin D caused by prescription of mega doses of vitamin D was the cause of vitamin D toxicity in all cases. Median (range) cumulative vitamin D dose was 3,600,000 (2,220,000-6,360,000)”– but the abstract doesnt mention the timespan . Generally, after loading dose for urgent risk,  maintenance dose  need  not exceed about 80 iu/kg/d eg 7000iu/day ie ~50 000iu/wk or 2500 000 iu/yr, ideally with ideally occasional blood vit D, calcium & creatinine tests. .

           UPDATE FOR KIDS: Pediatr Rheumatol Online J. 2015 May .  Vitamin D-update for the pediatric rheumatologists.    Vojinovic J1, Cimaz R2. University of Nis, Serbia.   ” So in accordance with new vitamin D recommendations, we recommend that a child with rheumatic disease, especially if treated with steroids, needs at least 2-3 time higher doses of vitamin D than the dose recommended for age (approximately 2000 UI/day). Vitamin D supplementation has become an appealing and important adjunct treatment option in PRD

      17 June update : Proc Natl Acad Sci U S A. 2015 Jun 15. pii: 201500909.           High-dose vitamin D3 reduces deficiency caused by low UVB exposure and limits HIV-1 replication in urban Southern Africans.  .Cape Town, South Africa, has a seasonal pattern of UVB radiation and a predominantly dark-skinned urban population who suffer high HIV-1 prevalence. This coexistent environmental and phenotypic scenario puts residents at risk for vitamin D deficiency, which may potentiate HIV-1 disease progression. Coussens ,  Jablonski   ea  from Univ. Cape Town & Stellenbosch conducted a longitudinal study in two  Cape Town ethnically distinct groups of healthy young adults, supplemented with 50 000iu weekly  vitamin D3  for 6 weeks  in winter, to determine whether vitamin D status modifies the response to HIV-1 infection and to identify the major determinants of vitamin D status (UVB exposure, diet, pigmentation, and genetics). Vitamin D deficiency was observed in the majority of subjects in winter and in a proportion of individuals in summer, was highly correlated with UVB exposure, and was associated with greater HIV-1 replication in peripheral blood cells. High-dosage oral vitamin D3 supplementation attenuated HIV-1 replication, increased circulating leukocytes, and reversed winter-associated anemia. Vitamin D3 therefore presents as a low-cost supplementation to improve HIV-associated immunity.
    16 June 2015  REVIEW: ADULTS: WHAT VIT D DOSE IS ENOUGH? Because of our increasingly government-encouraged soporific  TV lifestyle and western processed- food-factory low-fat high-carbs HCLF diet, vitamin D has turned out to be as important as >vitamin C as the seriously deficient primary major nutrients in far higher than scurvy/rickets prevention doses.
Just as we ‘only’ need vitamin C 10mg/d to prevent scurvy, the historical DAILY recommended allowance RDA dose of vitamin D for rickets is ‘only’ ~10mcg 400iu/d.
But current expert opinions advocate  effective multisystem chronic prevention against infections, cancer, neurological, cardiovascular and bone disease in adults  vit C between 1gm  and 30gm/day; and

       vit D between 100mcg 4000iu and 250mcg 10 000iu/d (ie 80-100iu/kg/d); or about 25000 to 70 000iu/week or equivalent spacing;
to a blood 25hydroxyvit D 25OHvitD level of ~60 (40 to 80ng)/ml for global prevention; but around ~100ng/ml depending on severity of illness being targeted.

     DONT REJECT A SUPPLEMENT AS OF NO VALUE JUST BECAUSE IT TESTED INEFFECTIVE  IN  LOW DOSE:   eg Martineau , Griffiths ea.Univ London Thorax. 2015 Jun   Double-blind randomised controlled trial of vitamin D3 supplementation for the prevention of acute respiratory infection in older adults and their carers (ViDiFlu). CONCLUSION: Addition of intermittent bolus-dose vitamin D3 supplementation to a daily low-dose regimen did not influence risk of ARI in older adults and their carers, but was associated with increased risk and duration of URI.   BUT like so many trials,this trial in  240 London Seniors and carers is not about high dose, but mediocre dose, in small numbers: it  confirms that 100 000iu vit D3 every 2 mo ie average ~extra  1666iu/d is no better protection than just 400iu dly ie 12000iu spread over the month.

Since like all steroids the many vitamin Ds are vitamin C-cholesterol-derived oils stored and carried in fat, the fatter the patient the higher the maintenance dose vit D3 (eg 100 iu/kg/d) to maintain a good steady optimal bloodlevel.                                Fortunately, unlike the other essential physiological human anabolic steroids (eg androgens, progesterone and estrogens that are poorly absorbed , and trans-hepatically dangerous if swallowed), vitamin D3 is well absorbed either by mouth, by injection; or transdermally / intranasally; and apparently not degraded to risky byproducts in the liver as are the “sex” steroids. .

And of course for best absorption, fat-soluble essentials like vits A, D, E , K; CoQ10 & alphalipoic acid ALA are best eaten with fat not carbs eg veggies, cereals or on empty.
To minimize risk of stones and vascular calcification from imbalance, it is important to take vit D3 with                                                                                      *liberal water, magnesia and vitamin K2; perhaps                                                 *~30gms fresh marine oil /wk eg a tsp of cod liver oil 3 x a week; and                       * a few tsp/d of virgin coconut oil (and for cooking/frying in);
*at least half of daily non-protein energy as FATS- animal, dairy and avocado &
*while minimizing moderate omega6 as nuts and raw olive/ oil; and avoiding/minimizing diabesogenic insulin-resistance-causing refined carbs, and synthetic junk fats like margarine, and other seed oils- eg sunflower and canola – certainly not for frying.

A new university study from Ireland ( Endocr Connect. 2015 June. McKenna ea) confirms that average vitamin D levels there are still well below sufficiency let alone good levels, although it finds Rising trend in vitamin D status from 1993 to 2013: “The Institute of Medicine 2011 Dietary Report specified higher Vitamin D intakes for all age groups compared to 1997, but also cautioned against spurious claims about epidemic vitamin D deficiency and against advocates of higher intake requirements. 40 years have seen marked improvement in vitamin D status, but we are concerned about hypervitaminosis D. Time series sequence chart demonstrated a steady upward trend with seasonality. The average 25OHD increased by ~50% from ~15ng/ml in 1993 to ~23ng/ml in 2013. CONCLUSIONS: Vitamin D status improved over the past 40 years, but there is a dual problem:                             *groups at-risk of vitamin D deficiency, who need public health preventative measures; and                                                                                                     *random members of the public  taking unnecessarily high vitamin D intakes for unsubstantiated claims. “

       Last year Autier, Mullie ea from Lyon France and Bolland, Reid ea from Auckland NZ published major reviews concluding that “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 “vitamin D supplementation with or without calcium does not reduce skeletal or non-skeletal outcomes in unselected community-dwelling individuals by more than 15%. Future trials with similar designs are unlikely to alter these conclusions
But Gillie from Health Research Forum, London 2014 in Controlled trials of vitamin D, causality and type 2 statistical error  rebuts Autier ea, Bolland ea:    “In Lancet Diabetes Endocrinol, Autier, Mullie ea. (2013) , and Bolland, Reid ea. (2014) , concluded that low levels of vitamin D are not a cause but a consequence of ill health brought about by reduced exposure to the sun, an association known as ‘reverse causality’ Denial of the possible benefits of vitamin D, as suggested by insistent interpretation of studies with reverse causation, may lead to serious harms, some of which are listed.” So Gillie affirms the focus of this June 2015 review on vigorous dose vit D without chronic toxic overdose, that Autier ea and Bolland ea overlook, that their conclusions were based on lowdose vitamin D, not vigorous dose eg loading dose 600 000iu  monthly with or without ~50 000iu weekly that has been increasingly validated.

         COMBINED BALANCE ALWAYS BEST:
While  human sex hormones in good youthful balance are all essential physiological anabolic ie growth-promoting steroids, Atif ea at Emory University, Atlanta, 2009  and 2015   showed that in rats, Vitamin D with progesterone P4 supplement affords significantly better brain protection against excitotoxicity in cultured cortical neurons  and in traumatic brain injury in vivo than progesterone or vit D alone. In their 2009 braincell culture experiment, the optimal ratio of the hormones given was Prog:Vit D 1000:1 (Prog 20 umol/L: vitD 20nmol/L); whereas in their 2015 in life study the ratio was 8000:1– the rats were injected intraperitoneally  Prog 16mg/kg and VitD 1ug  one and 6 hours after the brain injury, and at 24 hours after brain injury they were killed and the brain damage compared. The optimal ratio, balance of the two steroid  hormones  for rat brain protection (1000:1 in a bench cellculture  and 8000:1 in an acute living rat model) is noteworthy for human dosing although the absolute doses cannot be extrapolated to living humans.   In humans this review below shows that the optimal acute dosing thus far reported seems to be  about 1000mg progesterone injection ie ~13mg/kg (some disputed trial evidence for protecting human brain injury after 50 years of research), and vit D for acute global protection about  600 000iu = 10 000iu/kg= 250 ug /kg ie P:vitD ratio about 50:1.

But vit D3, & androgens, and progesterone (eg Roeder 1986 & Starkov 1997), are the classic muscle-bone anabolic (ie growth- protein-water-salt-retaining) steroids. So we should always combine them in appropriate dose if needed for men, and even women. Estrogen is essential for reproduction, bone strength and femininity, but is muscle-anabolic only for the female reproductive tract; and for fat and glandular tissue ie breasts: estrogenic  dominance doubles cancer; adiposity;  sarcopenia;  and urinary incontinence ie weakens the pelvic floor; so should never be given unopposed by progesterone/androgen and vigorous vit D3 .

          ACUTE LOADING DOSE OF VIT D?: Like antibiotics, for acute (antimicrobial or ICU metabolic eg vascular, brain, cancer ) disease, adult vitamin D3 LOADING dose 540 000 to 600 000iu monthly – but not much lower loading dosing – has been recommended and proven major benefit, eg

1. New Zealand 2009 Osteoporos Int. ;20:1407-15.. Bacon ea :              High-dose 500 000iu oral vitamin D3 supplementation in the elderly were concerned that: vitamin D doses are frequently inadequate; compliance with daily medication is likely to be suboptimal; large loading doses of vitamin D(3) rapidly and safely normalize 25OHD levels; and monthly dosing is similarly effective only after 3-5 months. With baseline 25OHD > 20ng/ml, vitamin D supplement does not reduce parathyroid hormone PTH levels. This randomized double-blind trial RCT compares “high-dose” vitamin D3 regimens and estimates optimal 25OHD levels, from changes in PTH & procollagen type I propeptide (P1NP) in relation to baseline vit D . Sixtythree elderly participants were randomized to three regimens of vitamin D supplementation: a 500,000-IU loading dose; the loading dose plus 50,000 IU/month; or 50,000 IU/month. the Loading and Loading + Monthly groups showed increases in 25OHD of 23+/- 11ng/ml from baseline to 1 month. Thereafter, levels gradually declined to plateaus of 27 +/- 2 ng/mlL and 36 +/- 2 nmol/l, respectively. In the Monthly group, 25OHD reached a plateau of ~32 +/- 8 ng/dl at 3-5 months. There were no changes in serum calcium concentrations. PTH and P1NP were only suppressed by vitamin D treatment in those with low baseline 25OHD level.. CONCLUSIONS: Large loading doses of vitamin D(3) rapidly and safely normalize 25OHD levels in the frail elderly. Monthly dosing is similarly effective and safe, but takes 3-5 months for plateau 25OHD levels to be reached.

2, Pakistan 2013 Salahuddin N ea:  600 000IU Vitamin D monthly for 2 doses improves clinical recovery from tuberculosis. 259 patients with pulmonary TB were randomized to receive either 600,000 IU of Intramuscular vitamin D3 ie ~20 000iu/day, or placebo for 2 doses. After just 12 weeks, the vitamin D supplemented arm demonstrated significantly greater ~40% improvement: mean weight gain (kg)+3.75, (3.16-4.34) versus+2.61 (95% CI 1.99-3.23) p 0.009 and lesser residual disease by chest radiograph; number of zones involved 1.35 v/s 1.82 p 0.004 (95% CI 0.15, 0.79) and 50% or greater reduction in cavity size 106 (89.8%) v/s 111 (94.8%), p 0.035.

3. Austria 2014  Amrein ea, 540 000iu loading dose in 475 ICU pts significantly reduced morbidity and mortality by 40% in 492 vit D deficient pts,  ie is anabolic ie reverses muscle wasting – sarcopenia. as also found by Aganostis 2015 metanalysis

4. Canada/USA universities 2014 Ekwaru, Holick ea: “in a survey, 17,614 Healthy volunteers reported vitamin D supplement ranging from     0 to    55000iu/day= ~1.65million iu/mo; and had serum 25(OH)D levels ranging from 4 to 160ng/ml. The dose response relationship between vitamin D supplementation and serum 25(OH)D followed an exponential curve. On average, serum 25(OH)D increased by 5ng/ml per 1,000 IU in the supplementation interval of 0 to 1,000 IU /day; and by 92% less eg 0.4ng/ml per 1,000 IU in the supplementation interval of 15,000 to 20,000 IU per day. BMI, relative to absolute body weight, was found to be the better determinant of 25(OH)D. Relative to normal weight subjects, obese and overweight participants had serum 25(OH)D that were on average 8 and 3 ng/ml lower, respectively (P<0.001). We observed no increase in the risk for hypercalcemia with increasing vitamin D supplement.”

5. Pakistan 2015 April 22nd Endocrine Society seminar RCT : Vit D3 up to 600 000iu loading dose : Prof Muhammad Masood, Consultant Endocrinologist of Aga Khan University : “ How Much Vitamin D We Need?” vit D deficiency VDD has resurfaced as significant health problem in recent years. In Pakistan region, VDD is very prevalent despite adequate sunshine throughout the year. A huge number of studies associate Vitamin D deficiency with almost any disease. Recently, concerns about the safe upper level of vitamin D have been raised and a reverse J or U shaped relation has been described with 25-OHD level and mortality. Increasing number of patients are being reported with vitamin D toxicity because of excessive intake of vitamin D resulting from misinterpretation of prescription, manufacturing errors, inappropriate prescription of excessive vitamin D doses for vague musculoskeletal complaints without monitoring 25-OHD concentrations. A study conducted at our center revealed important implications, first a dose of VD3 ranging from 200,000-600,000 IU given orally or IM will correct the deficiency in more than 70% of individual at 2 months. A dose of vitamin D 600,000 IU given IM will correct the deficiency in more than 90% of individuals and maintained levels > 20ng/ml in 84% of individuals at 6 months. Multiple mega doses may pose the risk of toxicity.”
6 Belgium 2014.:Vitamin D status after a 100 000iu highdose cholecalciferol in healthy and burn subjects. Rousseau ea Burns patients are at risk of vitamin D (VDD) deficiency and may benefit from its pleiotropic effects in acute phase. Two groups received an oral dose of 100,000IU VD3 RESULTS:A total of 49 subjects were included: 29 in GHealth and 20 in GBurns. At D0, prevalence of VDD was higher in GB: 25OH-D was 21.5 (10.1-46.3) ng/ml in GH vs 11 (1.8-31.4) ng/ml in GB. DBP and ALB were lower in GB. At D7 In GB, changes in 25OH-D extended from -36.7% to 333.3% with a median increase of 33.1%. This study highlighted the differences in VD status and in response to a high dose VD3 in burn patients when compared to healthy patients. 25OH-D measurement needs cautious interpretation, should not prevent burn patients to receive VD supplements during acute care. Higher doses than general should probably be considered

7 Canada 2015 Jan; up to 300 000iu vit D3 loading: McNally Univ Ontario ea Rapid normalization of vitamin D levels: a meta-analysis.. systematic review of pediatric clinical trials of high-dose vitamin D with 25[OH]D.., selected 88 Uncontrolled and controlled trials reporting 25(OH)D levels after high-dose (≥1000 IU) calciferol. 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 >30ng/dl within 1 month. Nine of 10 studies evaluating loading therapy (>50 000 IU) achieved group 25(OH)D levels >30ng/dlL. Adverse event analysis identified increased hypercalcemia risk with doses >400 000 IU, but no increased hypercalcemia or hypercalciuria with loading doses 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). Loading doses >300 000 IU should be avoided until trials are conducted to better evaluate risk and benefit.
Australia: some Australians are fearful in claimed cautious ignorance: Sanders ea University of Melbourne 2013 ask Is high dose vitamin D harmful? With potential to minimize risk of many chronic diseases, and apparent biochemical safety of ingesting doses of oral vitamin D several-fold higher than current recommended intakes, recent research has focused on supplementing intermittent, high-dose vitamin D. However, two recent randomized controlled trials (RCTs) both using annual high-dose vitamin D reported an increase, rather than a decrease, in the primary outcome of fractures.” So annual megadose doesnt help in prevention?.
but they are planning bold highdose trial:                                                                                    8. BMC Cancer. 2014 Saw ea Melanoma Institute, SydneyAdjuvant therapy with 500,000 IU high dose vitamin D following primary treatment of melanoma; Patients with primary cutaneous melanomas that are ulcerated and >2 mm in thickness, or nodal micrometastases, have few options for adjuvant treatment. Recent studies suggest a role for vitamin D to delay and improve overall prognosis. This pilot placebo-controlled randomised phase II trial will assess feasibility, safety and toxicity of an oral loading dose of Vitamin D (500,000 IU) followed by an oral dose of 50,000 IU of Vitamin D monthly for 2 years in patients treated by wide excision…”

        9 INDIAN PEDIATR 2014 :   300,000 IU or 600,000 IU RCT. Mittal ea Delhi. 76 children (median age 12 mo) with rickets. Oral vitamin D3 as 300,000 IU (Group 1; n=38) or 600,000 IU (Group 2; n=38) in a single day. 25(OH)D levels increased from baseline to 12 weeks after therapy :[Group 1: 7.58 to 16.06 (12.71– 20.29) ng/mL, P<0.001]; Group 2: 6.57 (4.66–9.25) to 17.60 . ie 25(OH)D levels were deficient (

But while all the data above are too heterogenous to do a metaanalysis, we now know as well as the South Africans, Pakistanis, Indians, Americans, Canadians, ANZIOs and Austrians do from this literature analysis and collective experience that a level of 25OHvit D of 20 or 40ng/ml is not adequate protection; conversely a bloodlevel of ~>200ng/ml has to be exceeded long term to incur risk. And a loading adult dose orally in adults of at least 600 000iu vit D3 – more likely >1 million iu- (that’s 6gm of 100cwt vit D concentrate powder, costing perhaps $0.25 in South Africa) taken with fat -may be needed to achieve safe high enough bloodlevel to have acute protective effect- and the vit D bloodlevel will drop below vigorous levels within weeks without maintenance doses, as the Austrian study used after their loading dose 540 000iu..

so even 50 000iu every week – my standard chronic illness adult maintenance dose that I take- is ineffective initially for acute protection in eg TB adults (Daley ea India 2015) or ICU . It seems such adults (pneumonia, TB, acute AIDS, ICU) need ? 600 000iu (or ? a ~ million iu orally) to start, then eg 100 000iu/wk till better, then drop to maintenance. .

            VIT D & INFANTILE BRONCHIOLITIS
Infantile bronchiolitis is a severe and common occurrence and killer under a year of age in South Africa as in the northern hemisphere; especially in tiny premmies; in the majority due to RSV respiratory syncytial virus rather than coronavirus, ‘flu etc; with no conventional therapy except support- leaving the doctor actively doing nothing except comfort, while the nurse nurses…
BUT eight papers since 2011 on Bronchiolitis strongly support vit D: that vitamin D deficiency/ polymorphism plays a major role from pregnancy on:
Three studies from 2011-2014 show that such bronchiolitis infants have low vitamin D or vitamin D polymorphisms that make them vulnerable; Two studies in 2014, from Harvard (Randolph ea ) and Ottawa (McNally ea) Universities in RSV bronchiolitis infants show vit D-binding haplotype, or Vitamin D receptor (VDR) polymorphisms;      And a 2011 study from Belderbos ea Utrech Univ Netherlands 2011 that Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis- Neonates born with 25-OHD concentrations <20ng/ml had a sixfold (95% confidence interval: 1.6-24.9; P = .01) increased risk of RSV LRTI in the first year of life compared with those with 25-OHD concentrations ≥ 30ng/dl. These studies thus point to brisk vitamin D supplement as likely major benefit against both RSV and subsequent asthma./COPD.

and Five recent team reviews 2011 to 2014 of RSV bronchiolitis from Italy—Baraldi ea ;   Canada- Poon ea ; Ireland – Clancy ea; and USA: Herzog ea-Cornell Univ NY, and Massachusetts-Maxwell ea – thus encourage the use of vigorous vitamin D and A and omega3 supplements in pregnancy or infancy to prevent  our  high RSA risk of bronchiolitis and future asthma/COPD.  eg
Curr Drug Targets. 2011.Herzog ea Cornell Univ. Immunologic impact of nutrient depletion in chronic obstructive pulmonary disease. Maternal smoking may diminish interferon response secondary to micronutrient deficiency, particularly of Vits A & D, and support persistence of RSV into adult life , Muscle wasting and cachexia systemic features of COPD. Nutritional depletion is related to poor survival and is a rational target for therapeutic intervention also in advanced and critically ill patients. Preliminary studies and suggest that supplementation with omega-3 and Vitamin A, Vitamin D3, and zinc may have beneficial effects in COPD.

now    2015  Salimi ea in Iran show in  Association between vitamin D receptor polymorphisms and haplotypes with pulmonary tuberculosis  in  Biomed Rep.   “The vitamin D receptor (VDR) is an important factor in activating immune response in different infectious diseases. Case control study on 120 PTB patients and 131 healthy controls with  Genetic analysis  by polymerase chain reaction.. The VDR Fok1 Ff genotype was associated with TB and the risk of PTB was two times higher in individuals with the Ff genotype. A higher frequency of f allele was observed in PTB patients and therefore, the f allele may be a risk factor for PTB susceptibility. In addition, haplotype analysis showed that the f-T-B and f-t-b haplotypes (Fok1, Taq1 and Bsm1) may have the potential to increase PTB susceptibility. In conclusion, the Ff genotype and f allele of the VDR Fok1 polymorphism were associated with PTB susceptibility. In addition, the f-T-B and f-t-b haplotypes may be the susceptible haplotypes for PTB.”

     THE RSA HOLOCAUST ESPECIALLY FOR WOMEN AND KIDS:  This new cumulative data above  is crucial given that while men fight ruthlessly for power, sex, money- even wars- the high birthrate in poor malnourished teenage girls in RSA, (especially with prevalent violence, alcohol, smoking and other drug abuses, AIDS and pulmonary and abdominal/ meningeal TB), who are thus ill-equipped both to breastfeed and parent with the myriad burdens of illiteracy and joblessness poverty, single parenting, starvation, male violence, refugee squatter survival, and then having to take ARVs, antiTB drugs or at least INH, cotrimoxazole and frequent other antimicrobials.

It is controversial, but Marks DF1.Br J Health Psychol. 2007 Department of Psychology, City University, UK argues that Literacy not intelligence moderates the relationships between economic development, income inequality and health: ” Kanazawa (2006) presented data allegedly supporting a racist version of evolutionary psychology that claims that the populations of wealthier and more egalitarian societies live longer and stay healthier, not because they are wealthier and more egalitarian, but because they are more intelligent. The objectives of this study are: (i) to determine the relationship between IQ and literacy in Kanazawa’s sample of countries and (ii) to reanalyse Kanazawa’s dataset using measures of literacy in lieu of national IQ test scores. RESULTS:National literacy scores across the countries in the sample are highly skewed. In spite of this, the literacy measures are highly correlated with alleged differences in national IQ (r = .83-.86). The measure of literacy together with economic development (GDPpc) and income inequality (Gini coefficient) control at least 59-64% of the variance in national life expectancy at birth.CONCLUSIONS:There is no scientific justification for believing that alleged intelligence differences play any role in explaining international differences in health status. Measures of alleged national IQ scores are highly confounded with differences in literacy. Literacy is a key factor in the health of any community and policies designed to enhance the literacy of a population are expected to lead to significant improvements in health status.
For these intellectually challenged illiterate women from remote rural villages  – many of whom cannot even write their initials let alone a signature, or understand English or Afrikaans-   anything but their tribal dialect-  pregnancy and AIDS/TB are the only relative escape from starvation and manual ie servile labour- which marginally paid drudgery is disappearing with the government-caused collapsed SA economy, power supply and industry. But the disability grant of ~R1500 ($125pm ie <$1/work hour) ) pm, and child welfare grant of perhaps R300 ($25)pm, is a drop in their ocean of despair. And given the mushrooming STD rates and costs thereof from male recklessness , from worsening corrupt central-government- led illiteracy and effective mass unemployment – state HIV-TB clinics and hospitals seldom have a little B6 or C to give these women, let alone regular supplies of ARVs or essential healing nutritionals eg vits A, Bco, minerals D, iodine, zinc, and biologicals eg  cod liver oil etc.

In the private sector, medical aid schemes also dont pay for supplements, only synthetic designer drugs that ignore underlying causal immunodeficiencies – since Only Disease Pays.
OVERDOSE? Between the two topic headings Hypervitaminosis D and Vitamin D toxicity, there are already 1798 refs on Pubmed alone. Hypervitaminosis D  428 reports on Pubmed since the first, from Harris & Moore, The Nutrition Lab, Cambridge 1929; Hypervitaminosis and vitamin balance: ..        and there are 1436 entries under Vitamin D toxicity since the first Vitamin D Toxicity by Leake 1936 at  UCLA .
ADULTS: But experts and numerous overdose reports ( only a few of which are noted below) reveal the truth,  that at least oral DAILY, well over 50 000iu to 1 MILLION iu/d of vitamin D for months, LONGTERM to up to 100 000IU/D for months to 365 million iu over 10 years has to be taken to cause illness ie symptomatic hypercalcemia .
Conversely, Chakraborty ea at Roy Research Center, Kolkata, India, report (Lab Med. 2015) A nontoxic case of vitamin d toxicity, a woman who developed very high serum Vitamin D levels (746 ng/mL, RI: 20 to 50) as a result of medication error. In spite of such high serum concentrations the patient was without any clinical symptoms and had normal serum calcium. The evidence base regarding the safety profile of Vitamin D supplementation in humans has been build through case reports, not dose titration RCTs to astronomical levels- which would be unethical.

So while routine maintenance dose eg 600 000iu/month, or 4000- to 10 000iu/d, or 100 000iu/wk in adults has never been reported to cause overdose toxicity,
on vigorous chronic vitamin D3 (not calcium or D2) dosing for disease, obviously ideally baseline (or at least after say 2-3 months of trial of conservative vitamin D replacement) calcium, vitamin D and kidney function levels should be measured since very rarely, unexpected silent hypercalcemia may already be present. .
But numerous reports eg from Netherlands 2014 show that a single overdose of even 2million iu vit D (=~100 000iu/d over 30days given the T 1/2 of vit D of 2 wks to 2 months), while kicking the bloodlevel up a few hundred ng/ml, does no harm even in two Dutch nonagenarians.

Relative hypovitaminosis D (bloodlevel below 30ng/ml) is prevalent locally and internationally in an indoor-working sunburn-fearing over-dressed city population not taking supplements more than the usual 400iu vit D in a daily multivite – especially in alcoholics, and the undernourished poor, and those following the government -recommended disease- promoting diabesogenic high- carbs low- fat diet marketed by commercial interests and bad science the past 50 years..

Already in 1999 Vieth at Univ Toronto wrote in Am J Clin Nutr. “Vitamin D supplementation, 25-OH vit D concentrations, and safety. . for adults, the 5-microg (200 IU) vitamin D RDA may prevent osteomalacia in the absence of sunlight, but more is needed to help prevent osteoporosis and secondary hyperparathyroidism, and prevention of some cancers, osteoarthritis progression, multiple sclerosis, and hypertension. Total-body sun exposure easily provides the equivalent of 250 microg (10000 IU) vitamin D/d, suggesting that this is a physiologic limit. The assembled data from many vitamin D supp. studies reveal a curve for vitamin D dose versus serum 25(OH)D response that is surprisingly flat up to 250 mcg (10000 IU) vitamin D/d. To ensure that serum 25(OH)D concentrations exceed 40ng/ml, a total vitamin D supply of >100 microg (4000 IU)/d is required. Except with conditions causing hypersensitivity, there is no evidence of adverse effects with serum 25(OH)D concentrations <55ng/ml, which require a total vitamin D supply of 250 microg (10 000 IU)/d to attain. Published cases of vitamin D toxicity with hypercalcemia, for which the 25(OH)D concentration and vitamin D dose are known, all involve intake of >/= 1000 mcg (40 000 IU)/d. Because vitamin D is potentially toxic, intake of >1000 IU/d has been avoided – even though the weight of evidence shows that the currently accepted, no observed adverse effect limit of 2000 Iu)/d is too low by at least 5-fold ie >10 000iu/d long term.”
O/Dose INFANTS: to avoid vitamin D poisoning and permanent damage to infants, of course dose needs to be scaled down accordingly on the 100iu/kg/d basis; but infants have a much bigger body surface area and thus meds requirement & tolerance. Human breast milk vit D is usually inadequate especially for swaddled darker-skinned babies and mothers; so conventionally at least 1000iu/d supplement vit D is for babies up to 6 months, 2500iu/d above 1year, and 4000iu/d from 9 years; or a pro rata loading dose, is advised eg Canada http://www.cps.ca/documents/position/vitamin-d and USA Heaney ea http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/. Conversely, serum 25(OH)D concentration consistently >200 ng/mL is considered to be potentially toxic [5].” Without a fingerprick vit D and calcium assay (lab cost here is ~R300 ie $25), monitoring here is tedious and costly…
ALLERGY TO VITAMIN D3? That vigorous vitamin D3 replacement can improve immunodeficiency and even relieve dermatitis is common cause.
But since Vit D’s discovery in 1914 (USA McCollum and Davis) and soon commercial production and marketing the past 90 years, not a single documented verified ALLERGY case (not overdose) can be found on Pubmed or Google?.Such true allergy cannot be anything but very very rare, since with vit D3, like all other bioidentical human hormones, and vitamins, allergy (unlike overdose) is almost inconceivable- although receptor loss or blockade may create resistance to eg thyroid, testosterone, vit D etc. . Allergy could conceivably occur to some carrier/ additive to the vitamin D3- but not even in the lungs from inhalation of old high-vit D oil droplets in fish factory workers
VitaminDwiki puts it in perspective. Designer ie prescription synthetic meds, and common foods, and tap water, are more likely to cause problem.

None of the 14 refs on Pubmed reports allergy to vitamin D. Google merely notes some anecdotes from users.

The last and urgent word today  -on medical and parental responsibilities- is by Wolfgang Högler ,Birmingham Children’s Hospital, UK ,Clin.Endoc. 2015: Complications of vitamin D deficiency from the foetus to the infant: One cause, one prevention, but who’s responsibility? The supplier of bone Calcium and phosphorus is the hormone calcitriol, which originates from vitamin D, itself made by sunshine in human skin. Requirement for bone minerals is highest during phases of rapid growth, and no one grows faster than the foetus and the infant, making them particularly vulnerable. Deprivation of calcium, whether through low calcium intake or low vitamin D, leads to serious health consequences throughout life, such as hypocalcaemic seizures, dilated cardiomyopathy, skeletal myopathy, congenital and infantile rickets, and osteomalacia.                                                                                                                    These 5 conditions are often summarised as ‘symptomatic vitamin D deficiency’, are fully reversible but also fully preventable. However, the increasing prevalence of rickets and osteomalacia, and the deaths from hypocalcaemic cardiomyopathy, demand action from global health care providers. Clarification of medical and parental responsibilities is a prerequisite to deliver successful prevention programmes.     The foetus and infant have the human right to be protected against harm, and vitamin D supplementation has the same public health priority as vaccinations.

And Dr John Cannell of The Vitamin D Council comments today : Dr. Hogler does not discuss the growing evidence that maternal and infantile vitamin D deficiencies may lead to neurodevelopmental disorders such as autism. I have always thought that the only way obstetricians and pediatricians will prescribe adequate doses of vitamin D is if they are charged for malpractice from failing to identify and treat vitamin D deficiency. If it is established that vitamin D deficiency causes autism, the malpractice attorneys will swarm like sharks to blood. Given increasing evident harms from numerous vaccinations, and often lack of real longterm supporting evidence of good eg the (swine and seasonal) flu and cervix HPV vaccines, we must consider vitamin D supplementation as far more proven benefit and safety than intensive multiple vaccinations.
-And on sepsis and brain salvage:  Dr Cannell promotes   –  vitamin D is a viable treatment for sepsis?, the landmark work of Drs William Grant and Ray Matthews.

The evidence is strong that vigorous natural supplements (vits, minerals, human hormones and some natural biological like marine oil and chondroglucosamine) are priorities especially in both acute emergencies, chronic diseases and prevention, from conception at all ages, over vaccinations and antibiotics and all synthetic designer drugs. .

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REFS:
BMC Cancer. 2014 ;14:780 Adjuvant therapy with high dose vitamin D following primary treatment of melanoma at high risk of recurrence: a placebo controlled randomised phase II trial Saw RP1, Thompson JF. ea Melanoma Institute Australia,North Sydney , Australia. .

  Indian Pediatr. 2014 ;51:265-72. 300,000 IU or 600,000 IU of oral vitamin D3 for treatment of nutritional rickets: a randomized controlled trial. Mittal , Gupta ea University College Medical Sci,, New Delhi.
Calcif Tissue Int. 2013 ;92(2):191-206. Is high dose vitamin D harmful? Sanders KM1, Nicholson GC, Ebeling PR., University of Melbourne

Med J Aust. 2005 Jul 4;183(1):10-2. Annual intramuscular injection of a megadose of cholecalciferol for treatment of vitamin D deficiency: efficacy and safety data. Diamond TH1, Ho KW, Rohl PG, Meerkin M.University of New South Wales, Australia.

Geriatr Orthop Surg Rehabil. 2011 May;2(3):94-9. . Improving mobility and reducing disability in older people through early high-dose vitamin d replacement following hip fracture: a protocol for a randomized controlled trial and economic evaluation. Mak JC1,  Cameron ID ea. , University of Sydney, Australia .Hypovitaminosis D is particularly common among older people with a proximal femoral (hip) fracture and has been linked with poorer lower extremity functioning, falls, and fractures.

     J Nutr. 2014;144:2002-8. Vitamin D deficiency is associated with progression of knee osteoarthritis. Zhang FF1, McAlindon TE EA2.usa uNIVERSITIES

    Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2014 ;28(14):1031-3. [Effect of nasal instillation of vitamin D3 on patient with allergic rhinitis symptoms]. [Article in Chinese] Gong, Jiang Y EA

      Nutrients. 2014 ;6(9):3403-30. doi: 10.3390/nu6093403. Does sufficient evidence exist to support a causal association between vitamin D status and cardiovascular disease risk? An assessment using Hill’s criteria for causality.Weyland PG1, Grant WB2, Howie-Esquivel J3., University of California,
Eur J Clin Nutr. 2014 ;68(5):632-4..Pharmacokinetics of daily versus monthly vitamin D3 supplementation in non-lactating women.Meekins ME1,, Thacher TD2Mayo Clinic, Rochester,& University of Witwatersrand, Johannesburg,
Mol Med. 2009 ;15(9-10):328-36. Vitamin D affords better neuroprotection against excitotoxicity in cultured cortical neurons than progesterone alone. Atif F1, Sayeed I, Ishrat T, Stein Emory University, Atlanta, Georgia, USA
.
Am J Clin Nutr. 2008 ;87(6):1952-8. Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Aloia, Yeh ea Winthrop University Hospital, NY.
Am J Clin Nutr. 2008:87(3):688-91.Pharmacokinetics of a single, large dose of cholecalciferol.  Ilahi M1, Armas LA, Heaney Creighton University Omaha, .
Curr Opin Lipidol. 2007 ;18(1):41-6. Vitamin D and vascular calcification.Zittermann Schleithoff Koerfer Ruhr University Bochum, Germany.
J Am Coll Nutr. 2003 Apr;22(2):142-6. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. Heaney RP1, Dowell MS, Hale CA, Bendich A.Creighton University, USA.

         Diabetes Care. 2015 May. pii: dc150323. Effect of LOWDOSE Vitamin D Supplementation on Glycemic Control in Patients With Type 2 Diabetes (SUNNY Trial): A Randomized Placebo-Controlled Trial. Krul-Poel YH1, Simsek S7 eu .

          Horm Metab Res. 2015 May 4 Effects of High-Dose Vitamin D Supplementation on Metabolic Status and Pregnancy Outcomes in Pregnant Women at Risk for Pre-Eclampsia. Karamali M1, Asemi Z ea.
J Am Geriatr Soc. 2014 ;62(8):1546-50..Effectiveness and safety of a high-dose weekly vitamin D (20,000 IU) protocol in older adults living in residential care. Feldman F1, Green TJ.ea. Simon Fraser University, Burnaby, BC, Canada.

    Maturitas. 2015 Mar 27. Sarcopenia in post-menopausal women: Is there any role for vitamin D? Anagnostis P1, Goulis DG ea Greek Universities http://www.ncbi.nlm.nih.gov/pubmed/?term=aganostis+Sarcopenia
J Adolesc Health. 2015 Apr 11. Vitamin D =<2000iu/d Fail to Increase 25-Hydroxyvitamin D Levels or to Alter Cardiovascular Risk Factors in Obese Adolescents: A Pilot Study.
Shah S1, Wilson DM2, Bachrach LK2.

     Lancet Infect Dis. 2015 May;15(5):528-34.Adjunctive vitamin D 400 000iu in 6 weeks for treatment of active tuberculosis in India no benefit : a randomised, double-blind, placebo-controlled trial. Daley P1, Vieth R4, , Mathai D ea .
Thorax. 2015 May;70(5):451-7. doi: 10.1136/thoraxjnl-2014-206449. Epub 2015 Feb 27.
PLoS One. 2015 Feb 23;10(2):e0117123. doi: 10.1371/journal.pone.0117123. eCollection 2015. Vitamin D₃ supplementation in Batswana children and adults with HIV: a pilot double blind randomized controlled trial. Steenhoff AP1, Stallings ea .
Eur J Endocrinol. 2015 Mar;172(3):235-41. doi: 10.1530/EJE-14-0870.Vitamin D3 increases in abdominal subcutaneous fat tissue after supplementation with vitamin D3. Didriksen , Jorde R3 ea

44-9987.12279. Epub 2015 Feb 6. Effects of a single, high oral dose of 25-hydroxycholecalciferol on the mineral metabolism markers in hemodialysis patients. Merino , 2, Quereda ea, .
Pediatr Neurol. 2015 ;52:160-4.Vitamin D supplementation in children with epilepsy and intellectual disability. Snoeijen-Schouwenaars , Majoie MH ea .:.
J Acad Nutr Diet. 2015 Feb;115(2):225-30. .Dietary fat increases vitamin D-3 absorption.Dawson-Hughes B, Rasmussen H.
Eur J Clin Nutr. 2015 ;69(2):193-7 The effect of a single, large bolus of vitamin D 250,000 IU in healthy adults over the winter and following year: a randomized, double-blind, placebo-controlled trial.Kearns MD1, Tangpricha V3

.
Sleep Breath. 2015 May;19(2):579-83. doi: 10.1007/s11325-014-1049-y. Epub 2014 Aug 23. The effect of vitamin D supplements on the severity of restless legs syndrome. Wali S1, Krayem A.

Endocr Pract. 2014 ;20(12):1258-64..The vitamin d dose response in obesity.Dhaliwal R1, Aloia JF1.

BMC Infect Dis. 2013;13:22. Vitamin D accelerates clinical recovery from tuberculosis: Salahuddin N ea.
VIT D & INFANTILE BRONCHIOLITIS
Curr Drug Targets. 2011;12(4):489-500. Immunologic impact of nutrient depletion in chronic obstructive pulmonary disease. Herzog R1, Cunningham-Rundles , Cornell University, NY.

    Ital J Pediatr. 2014 Oct 24;40:65. Inter-society consensus document on treatment and prevention of bronchiolitis in newborns and infants. Baraldi , Corsello EA -Società Italiana per le Malattie Respiratorie Infantili, Italy. http://www.ncbi.nlm.nih.gov/pubmed/25344148
Pharmacol Ther. 2013;140(2):148-55.Vitamin D deficiency and severe asthma. Poon AH1, Mahboub B, Hamid Q. McGill University, http://www.ncbi.nlm.nih.gov/pubmed/?term=Vitamin+D+deficiency+and+severe+asthma.+++Poon+AH
Clin Exp Allergy. 2014 Feb;44(2):231-7. doi: 10.1111/cea.12247.Vitamin D-binding protein haplotype is associated with hospitalization for RSV bronchiolitis. Randolph, Bont EA Harvard Medical School.
Pediatr Pulmonol. 2014;49(8):790-9. Vitamin D receptor (VDR) polymorphisms and severe RSV bronchiolitis: a systematic review and meta-analysis. McNally1, Little ea. Univ Ottawa, Canada.
Pediatrics. 2011;127):e1513-20. Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis. Belderbos, Bont ea, University Utrecht,Ndl. http://www.ncbi.nlm.nih.gov/pubmed/?term=Cord+blood+vitamin+D+deficiency+is+associated+with+respiratory+syncytial+virus+bronchiolitis.+Belderbos

     J Matern Fetal Neonatal Med. 2013;26;639-46.Vitamin D and neonatal immune function. Clancy ea Ireland http://www.ncbi.nlm.nih.gov/pubmed/?term=Vitamin+D+and+neonatal+immune+function.
Nutr Rev. 2012;70:548-52. Better newborn vitamin D status lowers RSV-associated bronchiolitis in infants.Maxwell CS1, Carbone ET, Wood RJ. University of Massachusetts, Amherst, USA. http://www.ncbi.nlm.nih.gov/pubmed/?term=.+Better+newborn+vitamin+D+status+lowers+RSV-associated+bronchiolitis+in+infant
OVERDOSE
Am J Clin Nutr. 1999 ;69:842-56.Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Vieth.   University of Toronto, Canada.

     Clin Endocrinol (Oxf). 2015 Jun . doi: 10.1111/cen.12836. Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency. Kaur, Mithal ea Delhi.

     J Steroid Biochem Mol Biol. 2015 Apr;148:14-8. Iatrogenic vitamin D toxicity in an infant–a case report and review of literature. Ketha, Singh EA

    Einstein (Sao Paulo). 2014;12(2):242-4. Vitamin D intoxication: case report.
[Article in English, Portuguese] Marins TA1, Korkes H1.ea Hospital Israelita Albert Einstein, São Paulo, Brazil.
J Clin Endocrinol Metab. 2011;96(12):3603-8. .Vitamin D intoxication with severe hypercalcemia due to manufacturing and labeling errors of two dietary supplements made in the United States.Araki T1, Holick MF, Newman LG.ea

Ann Pharmacother. 2011 ;45(10):e52. Hypervitaminosis D associated with a vitamin D dispensing error. 4.5million iu over 3 mo. Jacobsen , Schilling ea.

Am J Public Health. 1995 ;85(10):1418-22.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1615632/pdf/amjph00448-0092.pdf Subclinical health effects in a population exposed to excess vitamin D in milk. Scanlon, Falk H.ea
N Engl J Med. 1992 ;326(18):1173-7. Hypervitaminosis D associated with drinking milk. Jacobus CH1, Holick MF, Seely EW.:ea .

Q J Med. 1986 Oct;61(234):911-9. The osteodystrophy of hypervitaminosis D 365million iu over 10 years: a metabolic study. Davies M, Mawer EB, Freemont AJ. A patient received 2.5 mg vitamin D2 ie 100 000iu/d daily for 10 years ie 365 million iu total, presented with increasing skeletal pain and hypercalcaemia. The limbs were painful to touch especially at the insertions of ligaments and tendons, and radiographs showed osteosclerosis with calcification in the periosteum, blood vessels, tendoachilles and plantar fascia. A negative external calcium balance was documented in the presence of enhanced intestinal calcium absorption and an increase in urinary hydroxyproline excretion. Cortisone improved calcium balance and corrected the hypercalcaemia by reducing serum 1,25-dihydroxyvitamin D levels and urinary hydroxyproline excretion.

Nouv Presse Med. 1981;10(36):2965-7.[Vitamin D metabolites in a new case of drug-induced hypercalcemia (author’s transl)]. [ French] Ulmann A, Bourdeau A, Lair M, Bader C. the authors report on a new case of severe hypercalcaemia induced by prolonged oral treatment with high doses of vitamin D2. (6 mg ie 240 000iu/day ie for 9 months ie 23million iu).

     Lancet. 1978 ;2(8090):621-3. The continuing risk of vitamin-D intoxication.
Davies, Adams . Eight cases of vitamin-D poisoning are described.
.
Arch Intern Med. 1975 Jul;135(7):986-8. Protracted vitamin D intoxication.
Shetty , Hagen ea   A 56-year-old woman underwent subtotal thyroidectomy for Graves disease in 1963. After the operation, hypoparathyroidism developed and therapy was begun with vitamin D2 (ergocalciferol), 100,000 units daily.  Four months later, ie 12 million iu vit D, after hypercalcemia (14 mg/100 ml) had been noted, vitamin D therapy was discontinued

    Dtsch Med Wochenschr. 1975 ;100(9):415-6, 419-23. [Observations in vitamin D and dihydrotachysterol poisoning]. [German] Ziegler R, Delling ea. In three women intoxication with vitamin D or dihydrotachysterol occurred. Two patients died from complications despite successful lowering of the serum calcium, the third died after a pulmonary embolus during hypercalcaemia 5 months after cessation of vitamin D. .

    Br Med J. 1972 ;3(5820):205-7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1785685/pdf/brmedj02214-0027.pdf Vitamin D intoxication treated with porcine calcitonin. Buckle RM, Gamlen TR, Pullen IM.Southampton UK Porcine calcitonin was used to treat three Southampton women in their sixties with hypercalcaemia due to accidental chronic vitamin D intoxication with 30 000 to 500 000iu/d for 4 to 13 weeks (vit D 9 million iu over 4wks; 4.5million iu over 13 week; and 29 million iu over 2 months). Normocalcaemia was achieved in 3 to seven days, with rapid full recovery.

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.

All Artificial Sweeteners Raise Your Risk of Diabetes by Altering Your Gut Microbiome

why we must avoid all artificial sweeteners – if you must sweeten, use only the natural ie herbal intense sweeteners  stevia;  xylitol or  lo han go. available from Natural Medicine Clinic, 15 Grove Bldg, Grove Ave, Claremont Cape Town ph +27216831465)

By Dr. Mercola Oct 1st 2014: Artificial Sweeteners Raise Your Risk of Diabetes by Altering Your Gut Microbiome

Both artificial sweeteners and certain gut microbes have previously been linked to obesity, and according to the latest research, artificial sweeteners may raise your risk of diabetes by disrupting your intestinal microflora. According to the authors of the widely publicized study:1
“[W]e demonstrate that consumption of commonly used non-caloric artificial sweeteners formulations drives the development of glucose intolerance through induction of compositional and functional alterations to the intestinal microbiota.
The researchers found that artificial sweeteners alter certain metabolic pathways associated with metabolic disease, and that it can induce gut dysbiosis and glucose intolerance in otherwise healthy people.
Glucose intolerance is a condition in which your body loses its ability to cope with high amounts of sugar, and it’s a well-known precursor to type 2 diabetes. It also plays a role in obesity, because the excess sugar in your blood ends up being stored in your fat cells.
The fact that artificial sweeteners may exacerbate metabolic disorders like diabetes is a severe blow to diabetics who dutifully follow recommendations to switch to diet foods and beverages in order to control their diabetes.
The fact that artificial sweeteners are NOT a dieter’s nor a diabetic’s best friend has been known by researchers for some time. The problem is that it hasn’t received the necessary traction in the media—until now.2, 3
“Collectively, our results link non-caloric artificial sweeteners (NAS) consumption, dysbiosis and metabolic abnormalities, thereby calling for a reassessment of massive NAS usage,” the researchers note.
Artificial Sweeteners Can Cause Glucose Intolerance by Altering Your Microbiome
The researchers initially started out testing the artificial sweeteners saccharin, aspartame, and sucralose in mice, and were “surprised” when the mice developed glucose intolerance.
As noted by New York University microbiologist Martin Blaser,4 no one had previously considered that artificial sweeteners might exacerbate metabolic disease by way of the microbiome.
Of the three non-caloric sweeteners tested, saccharin had the most pronounced effect on glucose levels. This led to a human trial, in which data from 400 people enrolled in a nutritional study were assessed.
Those who consumed high amounts of artificial sweeteners were found to have higher levels of HbA1C—a measure of blood sugar—compared to non-users or occasional users of artificial sweeteners.
Seven volunteers who did not use artificial sweeteners were then recruited, and asked to consume the equivalent of 10-12 single-dose packets of artificial sweeteners daily for one week.
Four of the seven people developed “significant disturbances in their blood glucose,” according to the researchers. Some became pre-diabetic within just a few days!
The reason for this dramatic shift was traced back to alterations in gut bacteria. Some bacteria were killed off, while others started proliferating. As noted in the featured NPR article:5
“It could be that for some people who responded negatively to the artificial sweetener, the bacteria that got crowded out were helping to keep glucose in check.”
This mirrors previous research,6 which has found that bacterial populations in the gut of diabetics differ from non-diabetics.
Another 2008 study demonstrated that sucralose can alter the microbiome in rats by reducing colonies of beneficial gut bacteria, and research published in Clinical and Experimental Rheumatology7 in 2012 revealed a potential link between aspartame and irritable bowel syndrome (IBS). Imbalanced gut flora has also been linked to obesity.
Compelling Results Suggest We Should Reconsider Widespread Use of Artificial Sweeteners
In sharp contrast to many other studies, this one was actually able to clearly show causality, meaning there’s a direct cause and effect relationship between consuming artificial sweeteners and developing elevated blood sugar levels. As reported by The Scientist:8
“Four weeks of treatment with gut bacteria-depleting antibiotics reversed the glucose intolerance in mice that continued to receive saccharin. This led the team to examine whether the microbiomes of the mice were somehow altering glucose metabolism.
Transplantation of feces from non-antibiotic-treated mice that consumed saccharin- or glucose-containing water into germ-free mice within six days induced the same blood-sugar elevations in animals that were never themselves exposed to the sweeteners.
‘This is the elegant and home run experiment that shows causality in mice,’ said [pathologist Cathryn] Nagler.
Using shotgun metagenomic sequencing on the fecal samples, the researchers showed that mice given saccharin or those that received a fecal transplant from saccharin-fed mice had a different microbiome composition compared to mice given sugar or no sweeteners.”
Cathryn Nagler, who wrote an accompanying commentary9 in the journal Nature, said the findings were “very compelling,” noting that “the study suggests… we should step back and reassess our extensive use of artificial sweeteners.”
Aspartame Raises Insulin Levels as Much as Sugar
Other studies have also linked artificial sweeteners to metabolic alterations that promote type 2 diabetes—contrary to conventional thinking and health recommendations.
For example, one 2012 study10 found that chronic lifetime exposure to aspartame, commencing in utero, produced changes in blood glucose parameters in mice. Not only was aspartame found to decrease insulin sensitivity compared to controls, it also wrought havoc on brain function…
Another study published in 2007 in the journal Diabetes Care11 found similar results. Here, the researchers investigated the effect of different macronutrient compositions on plasma glucose and insulin levels during an acute bout of exercise in men with type 2 diabetes.
They hypothesized that using fructose or aspartame would have a lower impact on insulin release and glucose response than a sucrose-sweetened meal. Those of you who have been reading my articles featuring experts on sugar and fructose like Dr. Richard Johnson and Dr. Robert Lustig will immediately recognize this as a fatally flawed hypothesis. And indeed, that is what they discovered. According to the authors:
“Contrary to all expectation, the aspartame breakfast induced a similar rise in glucose and insulin levels at baseline than the sucrose meal, even if the aspartame meal had the same taste, and was 22 percent lower in calories and 10 percent lower in carbohydrates, with an inferior glycemic index… Considering the lack of evidence on the aspartame utilization in patients with type 2 diabetes, we consider that these clinical observations, in an exercise setting, raise important concerns regarding the safety of aspartame as suggested by international guidelines.”
Obesity Continues to Rise
According to a recent JAMA study,12, 13 the obesity rate among American adults has continuously climbed over the last decade. Between 1999 and 2012, the average age-adjusted waist circumference increased from 95.5 centimeters (37 19⁄32 inches) to 98.5 centimeters (38 25⁄32 inches). Abdominal fat also rose from 46.4 percent in 1999-2000 to 54.2 percent in 2011-2012. The United Kingdom is facing a similar health crisis. According to September 17 article in Mail Online:14
“Obesity is a ‘slow-motion car crash’ which is threatening to bankrupt the NHS, according to its chief executive. Simon Stevens said the problem is now more deadly than smoking and causing millions to suffer life-long illness and disability. He also revealed that – absurdly – the NHS is spending far more on drastic weight loss surgery than trying to prevent the problem in the first place. A quarter of adults and a fifth of children are now considered obese and the rates have almost doubled in 20 years…
Next month, Mr. Stevens will publish a set of plans to tackle the problem which will see the NHS and private firms urged to do more to help staff lose weight. Doctors and nurses will be encouraged to be healthy role models for patients and hospitals told to ban junk food from canteens. NHS trusts and private companies will also be urged to help staff lose weight by holding slimming classes, running clubs or just providing bike racks at work. Mr. Stevens, who took up post last April, said: ‘Obesity is the new smoking, and it represents a slow-motion car crash in terms of avoidable illness and rising health care costs…” [Emphasis mine]
Artificial Sweeteners Can Severely Hinder Weight Management Efforts
Those who switch to artificial sweeteners are typically carrying extra pounds and/or are diabetic, or prone to these conditions. Unfortunately, this may be the absolute worst diet change you could implement if you’re overweight or diabetic. Research has repeatedly shown that artificially sweetened no- or low-calorie drinks and other “diet” foods tend to stimulate your appetite, increase cravings for carbs, stimulate fat storage and weight gain, and promote insulin resistance and diabetes.
There are a number of different reasons for this. First of all, artificial sweeteners basically trick your body into thinking that it’s going to receive sugar (calories), but when the sugar doesn’t arrive, your body signals that it needs more, which results in carb cravings. This connection between sweet taste and increased hunger can be found in the medical literature going back at least two decades (see list of selected studies below). But artificial sweeteners also produce a variety of metabolic dysfunctions that promote weight gain—and now we can add gut dysbiosis and altered microbiome to that list!
In 2011, the UT Health Science Center in San Antonio publicized the results of two important studies, saying:15
“In the constant battle to lose inches or at least stay the same, we reach for the diet soda. Two studies presented [June 25, 2011] at the American Diabetes Association’s Scientific Sessions suggest this might be self-defeating behavior. Epidemiologists from the School of Medicine at The University of Texas Health Science Center San Antonio reported data showing that diet soft drink consumption is associated with increased waist circumference in humans, and a second study that found aspartame raised fasting glucose (blood sugar) in diabetes-prone mice…
‘Data from this and other prospective studies suggest that the promotion of diet sodas and artificial sweeteners as healthy alternatives may be ill-advised,’ said Helen P. Hazuda, Ph.D., professor and chief of the Division of Clinical Epidemiology in the School of Medicine. ‘They may be free of calories but not of consequences.’” [Emphasis mine]
Sampling of Studies Refuting ‘Diet’ Claims
Here’s a sampling of some of the studies published through the years, clearly refuting the beverage industry’s claims that diet soda helps with weight management. The 2010 review in the Yale Journal of Biology and Medicine16 is of particular relevance here, as it offers a great historical summary of artificial sweeteners in general, and the epidemiological and experimental evidence showing that artificial sweeteners tends to promote weight gain. It also illustrates that as usage of artificial sweeteners has risen, so has obesity rates—despite all these “diet friendly” products.

Source: Yale Journal of Biology and Medicine June 8 2010: v83(2)
Preventive Medicine 1986 Mar;15(2):195-20217
This study examined nearly 78,700 women aged 50-69 for one year. Artificial sweetener usage increased with relative weight, and users were significantly more likely to gain weight, compared to those who did not use artificial sweeteners—regardless of their initial weight. According to the researchers, the results “were not explicable by differences in food consumption patterns. The data do not support the hypothesis that long-term artificial sweetener use either helps weight loss or prevents weight gain.”
Physiology and Behavior, 198818
In this study, they determined that intense (no- or low-calorie) sweeteners can produce significant changes in appetite. Of the three sweeteners tested, aspartame produced the most pronounced effects.
Physiology and Behavior, 199019
Here, they found that aspartame had a time-dependent effect on appetite, “producing a transient decrease followed by a sustained increase in hunger ratings.”
Journal of the American Dietetic Association, 199120
In a study of artificial sweeteners performed on college students, there was no evidence that artificial sweetener use was associated with a decrease in their overall sugar intake either.
International Journal of Obesity and Metabolic Disorders, 200421
This Purdue University study found that rats fed artificially sweetened liquids ate more high-calorie food than rats fed high-caloric sweetened liquids. The researchers believe the experience of drinking artificially sweetened liquids disrupted the animals’ natural ability to compensate for the calories in the food.
San Antonio Heart Study, 200522
Data gathered from the 25-year long San Antonio Heart Study also showed that drinking diet soft drinks increased the likelihood of serious weight gain – far more so than regular soda23 On average, for each diet soft drink the participants drank per day, they were 65 percent more likely to become overweight during the next seven to eight years, and 41 percent more likely to become obese.
Journal of Biology and Medicine, 201024
This study delves into the neurobiology of sugar cravings and summarizes the epidemiological and experimental evidence concerning the effect of artificial sweeteners on weight.

According to the authors: “[F]indings suggest that the calorie contained in natural sweeteners may trigger a response to keep the overall energy consumption constant. …Increasing evidence suggests that artificial sweeteners do not activate the food reward pathways in the same fashion as natural sweeteners… [A]rtificial sweeteners, precisely because they are sweet, encourage sugar craving and sugar dependence.”
Yale Journal of Biology and Medicine, 201025
This review offers a summary of epidemiological and experimental evidence concerning the effects of artificial sweeteners on weight, and explains those effects in light of the neurobiology of food reward. It also shows the correlation between increased usage of artificial sweeteners in food and drinks, and the corresponding rise in obesity.
Appetite, 201226
Here, researchers showed that saccharin and aspartame both cause greater weight gain than sugar, even when the total caloric intake remains similar.
Trends in Endocrinology & Metabolism, 201327
This report highlights the fact that diet soda drinkers suffer the same exact health problems as those who opt for regular soda, such as excessive weight gain, type 2 diabetes, cardiovascular disease, and stroke.28, 29 The researchers speculate that frequent consumption of artificial sweeteners may induce metabolic derangements.
Nature, 201430
This study was able to clearly show causality, revealing there’s a direct cause and effect relationship between consuming artificial sweeteners and developing elevated blood sugar levels.

People who consumed high amounts of artificial sweeteners were found to have higher levels of HbA1C—a long-term measure of blood sugar—compared to non-users or occasional users of artificial sweeteners.

Seven volunteers who did not use artificial sweeteners were then recruited, and asked to consume the equivalent of 10-12 single-dose packets of artificial sweeteners daily for one week.

Four of the seven people developed “significant disturbances in their blood glucose,” according to the researchers. Some became pre-diabetic within just a few days.

The reason for this dramatic shift was traced back to alterations in gut bacteria. Some bacteria were killed off, while others started proliferating.
Are There ANY Safe and Healthy Alternatives to Sugar?
One of the best strategies to kick the sugar habit is to implement intermittent fasting, and to make sure you’re eating enough healthy fats. Once your body has the proper fuel, your sweet cravings will radically diminish. If you need a sweetener you could use stevia or Luo Han, both of which are safe natural sweeteners. For a comprehensive review of the best and worst sweeteners, please see my previous article, “The 4 Best, and 3 Worst Sweeteners to Have in Your Kitchen.” Just remember, if you struggle with high blood pressure, high cholesterol, diabetes, or extra weight, then you have insulin sensitivity issues and would benefit from avoiding ALL sweeteners.
If you’re having trouble weaning yourself off soda, try Turbo Tapping. Turbo Tapping is a clever use of the Emotional Freedom Technique (EFT), specifically designed to resolve many aspects of an addiction in a concentrated period of time. Last but not least, if you experience side effects from aspartame or any other artificial sweetener, please report it to your National or Regional Health Dept without delay. It’s easy to make a report — just go to your National  Consumer Complaint Coordinator page, find the phone number for your state, and make a call reporting your reaction.

METFORMIN REDUCES ALL CHRONIC DISEASES, INCLUDING IMPROVING THYROID FUNCTION.

this new report Metformin and low levels of thyroid-stimulating hormone in patients with type 2 diabetes mellitus from  McGill University; Montréal, Quebec. says nothing that is seriously clinically significant, it is merely common sense.

It does not show that metformin causes any heart or thyroid dysfunction ie change in thyroid hormone levels,  merely that it reduces TSH  in those on thyroid replacement.- indicating that  thyroid dose may be able to be tapered.    

A parallel new study from Italy  Metformin-induced thyrotropin suppression is not associated with cardiac effects  confirms there is no heart risk- quite the contrary.

People tend to fatten and slow down as they age, and these people tend to  metabolic syndrome ie obesity, cholesterolemia, hypertension, vascular disease and thus diabetes- same as patients with hypothyroidism. So type 2 diabetes, hypothyroidism (sometimes preceded by hyperthyroidism) and aging go together- usually without demonstrable direct cause and effect.

This new McGill University metformin study does not claim any cause and effect.  The link may be simply  that metformin (which is simply a carbon-hydrogen -nitrogen molecule)  improves all metabolic functions- antioxidant, nitric oxidant- including iodine/TRH/ TSH / thyroid/insulin   hormone responses. .

So as with all nutritional supplements and exercise  that improve metabolism, metformin may improve treated hypothyroidism by improving peripheral thyrooxine receptors , and thus lower need for thyroid replacement.
Metformin or the parent galega a medicinal plant extract used for many centuries reduces new diabetes and all diseases and deaths by 1/3 to 2/3.

it is among other things a prohormone regulator, improving common insulin resistance.

the definition of low TSH is arbitrary. If much below 1, it is suspicious of thyroid overactivity, excess thyroid hormones-
but rarely may reflect central ie pituitary failure to produce enough TRH/TSH and thus cause central hypothyroidism.

so TSH unless way outside the ‘normal’ range of 1 to 2 is a poor guide to health and disease, which is based on clinical  state and the thyroid hormone and antibody levels.

Most aging people develop some degrees of thyroid underactivity, which generally responds to replacement of deficient selenium, iodine and sex hormones without addition of risky thyroid hormones- for which conventional blood levels are a poor guide.

so as in all patients whatever their state and treatment, thyroid function should like all other functions be considered periodically.

ndb.


  Metformin and low levels of thyroid-stimulating hormone in patients with type 2 diabetes mellitus  McGill University; Montréal, Quebec.

Background: Small cross-sectional studies have suggested that metformin, a first-line oral hypoglycemic agent, may lower thyroid-stimulating hormone (TSH) levels. Our objective was to determine whether the use of metformin monotherapy, when compared with sulfonylurea monotherapy, is associated with an increased risk of low TSH levels (< 0.4 mIU/L) in patients with type 2 diabetes mellitus.

Methods: Using the Clinical Practice Research Datalink, we identified patients who began receiving metformin or sulfonylurea monotherapy between Jan. 1, 1988, and Dec. 31, 2012. We assembled 2 subcohorts of patients with treated hypothyroidism or euthyroidism, and followed them until Mar. 31, 2013. We used Cox proportional hazards models to evaluate the association of low TSH levels with metformin monotherapy, compared with sulfonylurea monotherapy, in each subcohort.

Results: A total of 5689 patients with treated hypothyroidism and 59 937 euthyroid patients were included in the subcohorts. Among patients with treated hypothyroidism, 495 events of low TSH levels were observed during follow-up (incidence rate 119.7/1000 person-years). In the euthyroid group, 322 events of low TSH levels were observed (incidence rate 4.5/1000 person-years). Compared with sulfonylurea monotherapy, metformin monotherapy was associated with a 55% increased risk of low TSH levels in patients with treated hypothyroidism (incidence rate 79.5/1000 person-years v.125.2/1000 person-years, adjusted hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.09–2.20), with the highest risk in the 90–180 days after initiation (adjusted HR 2.30, 95% CI 1.00–5.29). No association was observed in euthyroid patients (adjusted HR 0.97, 95% CI 0.69–1.36).

Interpretation: In this longitudinal population-based study, metformin use was associated with an increased incidence of low TSH levels in patients with treated hypothyroidism, but not in euthyroid patients. The clinical consequences of this need further investigation.

HORMONES 2014, 13(2):252-258
Carlo Cappelli,1 Mario Rotondi,2 Ilenia Pirola,1 Barbara Agosti,3 Ana Maria Formenti,1 Pasquale De Cata,2 Massimo Salvetti,1 Luca Chiovato,2 Maurizio Castellano1

1Department of Medical and Surgical Sciences, Endocrine and Metabolic Unit, University of Brescia; 2Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Superiore Prevenzione e Sicurezza Lavoro Laboratory for Endocrine Disruptors, University of Pavia; 3Diabetic Unit, Spedali Civili di Brescia; Italy  http://www.ncbi.nlm.nih.gov/pubmed/24776625

Abstract

OBJECTIVE: Metformin treatment may induce a decrease/suppression in serum TSH levels, mimicking sub-clinical hyperthyroidism (SHT). The aim of the present study was to retrospectively evaluate changes in several electrocardiographic indices in euthyroid subjects with diabetes who, after starting metformin treatment, developed a low serum TSH as compared to patients with SHT resulting from an underlying thyroid disease or TSH suppressive treatment with L-thyroxine.
DESIGN: Heart rate, P wave duration, P wave dispersion, QTmax, QTmin and QT-dispersion were assessed in 23 patients with diabetes treated with metformin before and after 6 months of TSH-suppression and in 31 control patients with SHT.
RESULTS: No significant changes in electrocardiographic parameters were observed from baseline to the TSH-suppression measurement. A significant difference in P wave duration (102.9±7.4 vs. 92.1±5.8 ms, p<0.001), P wave dispersion (13.1±3.4 vs. 7.1±3.5 ms, p<0.001), QTmax (399±18 vs. 388±16 ms, p=0.024), QTmin (341±14 vs. 350±17 ms, p=0.038) and QT dispersion (49.9±9.6 vs. 30.9±9.2 ms, p<0.001) were observed between the control group with SHT and the group of diabetic patients with low serum levels of TSH.
CONCLUSIONS: Our results show that the TSH-suppressive effect observed in patients taking metformin is not associated with peripheral markers of thyroid hormone excess, at least at the cardiac level.

THE STATIN- FOR- ALL -SENIORS HOAX: FOR WHOM TOLLS THE BELL? FOR WHOM ARE STATINS EXCEPT RARE HIGH-RISK PATIENTS’ SEVERE HYPERCHOLESTEROLEMIA, AND PROFITEERING? FURTHER DISCREDITED FOR PRIMARY PREVENTION:

neil.burman@gmail.com

19 Sept 2014 update:     ABSTRACT:  readers  of this column recently commend its statin commentary, last updated in June, about the controversy of statins  in primary prevention of cardiovascular disease CVD. This update now  reviews crucial major recent evidence that the marketing hype  of “statin deficiency” in the average aging population is a  dangerous fabrication (eg Vytorin) of the $billion Disease and Drug corporate industry  – especially when statins inhibit omega3  and CoQ10 which like other human micronutrient protectors- magnesium, iodine, arginine, carnitine, ribose, vitamins , B, D3, C & K2,   and human  sex hormones – are increasingly deficient  or imbalanced in an aging western population and urban convenience food  diet.

     The prizewinning immunologist   Dr Duncan Adams from Univ Otago   in the elite QJM 2011 pithily demolishes The Great Cholesterol ie Statin Myth, commends the statin trials metanalysis of  Ray ea from Cambridge 2010 that showed no benefits of statins in mild to moderate cholesterolemia. .     More evidence says  dont use  natural supplements along  with statins to reduce statin risks and enhance statin benefits, but better to avoid the risks  from statins, smoking and excessive alcohol eg ROS reactive oxygen species , in an aging slothful  fattening population:  with improved exercise, more water, a Banting-type low-carbs high-fat and -greens – fermented (ie high in vit K2)  diet, a multivite-multimineral plus vigorous well-tolerated supplements of CoQ10,vits D3 and C, fish oil,  magnesium, sulphur, coconut oil, and appropriate metformin and human sex hormone replacement.
     Rather than  Big Pharma’s promotion of  Statinopause, statin deficiency ,  we need to address the multiple age-and diet-related deficiencies (and some excesses)  that lead to the preventible degenerative diseases of aging- and which are worsened by the Food Factory chain  promotion that has dictated the (Gary Taubes’  Diet Delusion  and Nina Teicholtz’ The Big Fat Surprise) expose  of processed grain-fed nutrient-depleted (but fructose-loaded) foods, high carbs low animal fat/cholesterol diet for forty years. This has   compounded the deficiency of -fat-soluble micronutrients   like vitamins D3, CoQ10, A,  E & K2,  lecithin and marine omga3 – EPA and DHA; and naturally compounded pollution  by environmental-  radioactivity, electromagnetic and radiofields-,   and air, foodchain and drug pollution the past 50 years years by plastics, CO2 and volatile emissions, mercury, aluminium, fluoride, lead, bromide;   micromineral depleted salt, fatally potent endocrine disruptors, antibiotics, xenohormones, pesticides  and numerous other synthetic drugs launched on the public until they are recognized to kill humans.        
                                                                                    

  Margaret McCartney  general practitioner, Glasgow writes : We lack the tools to help patients decide about statins BMJ 2014; 349 doi:     The National Institute for Health and Care Excellence (NICE) recently approved atorvastatin for people in England and Wales who have a 10% risk of a cardiovascular event within 10 years; it had previously been a 20% risk.1 GPs are advised to treat such people—which includes everyone older than 85—and to continually review everyone else in case they pass the 10% threshold.

          This decision on funding statins is based primarily on cost effectiveness to the NHS.2 The press release from NICE mentioned the potential benefit to the population (namely, it “could help prevent up to 28 000 heart attacks and 16 000 strokes each year”3) but not the absolute benefit to the individual.

But life is more complicated than that: people make choices for multiple reasons. Many patients stop taking statins after starting them4; others, faced with the choice of taking a drug with a small chance of benefit, would rather not do so; and some people will want to take them no matter how low their risk may already be.

We lack the tools to accurately predict individual risk at such low thresholds—leading to overtreatment and, to a lesser extent, non-identification of risk.5 The general practice cake is finite; cutting a bigger slice for healthy people at lower risk means a smaller slice for people who have symptoms and are unwell. The chance of a longer life is offered to people who are willing to take tablets consistently, but we know that these compliant patients are already more likely to live longer, even when taking a placebo.6 7 This policy, which benefits people who are already the healthiest, has the potential to widen health inequalities.

       Who is keeping an overview of where NICE is taking us? The conflicts of interest among the members on its drafting panels are buried in minutes rather than in the guidance itself, and we still lack public access to most of the trial data that NICE uses.8 But we are told to press ahead regardless when, most bewildering of all, we don’t have a decent shared decision aid—designed and tested for the five million more people advised to take statins—about the benefits and harms of statinisation and the management of cardiovascular risk.

      “Should I take statins?” is a question asked of GPs every day. We urgently need better tools to allow guidance to guide, rather than dictate new targets. Our lack of resources to deal with such a common question simply isn’t acceptable.

Background:
2013 Italian  Statin HMGA   study Pasin ea shows that statins- cholesterol-busters- do not help patients with sepsis.
A 2010   review Yue ea of all published studies in  3,022 postmenopausal women (mean age, >62.7 y), showed  that statin use doesnt prevent fractures or increases bone density.

why should synthetic designer metabolic poisons – statins-  be expected to help peripheral  conditions like fracture risk and menopause?  when statins promote diabetes – insulin resistance, and  block healthy  metabolism throughout the body, in brains, muscles, kidneys, skin- but especially  lowering liver manufacture of cholesterol that is one of our top lifegivers  for our needed reproductive and adrenal steroids- including our two prime anabolic steroids( vitamin D3 and androgen). And statins increase the risk of highly malignant Merkel Cell skin carcinoma by 25%, as well as dermatitis eg Ma .  ..

We have known for  ~forty  years that while anticholesterol drugs  are  valuable for  rare people with severe hypercholesterolemia HCH risk of  vascular disease, statins’  longterm adverse effects are numerous, and there has never been evidence to justify their routine mass  use  for mild to moderate HCH- ie CVS risk below ~15 to 20% in 10 years-   despite the Cholesterol-statin industry investing multimillions in their promotional trials and in their lobbyists.

The Sheffield Cholesterol  and Multiple Risk Table by Jackson ea 25 years ago in the Lancet  was impressive  as a guide to  life extension by taking a statin permanently. When used for secondary prevention of coronary heart disease CHD , treatment with an inhibitor of hydroxymethylglutaryl-coenzyme-A reductase HMGA results in worthwhile benefit that clearly exceeds any risk in patients whose risk of coronary death is 1.5% or more per year ie >15% per 10 years. This evidence can be extrapolated logically to primary prevention of coronary disease provided that treatment is targeted at those with similar or higher risk. The table highlights the predominant effect of age on coronary risk; a person who is free of vascular disease and younger than 52 years is unlikely to have the specified degree of risk. Even in older people (60-70 years) several risk factors are generally required to attain this degree of risk. Some people are candidates for lipid- lowering drug treatment with serum cholesterol as low as 5.5 mmol/L, whereas others with cholesterol as high as 9.0 mmol/L are not. Although cholesterol lowering is a powerful method for preventing coronary events in people at high risk, cholesterol measurement by itself is not a good way to identify those with high risk. At that stage I had already been advised for 20 years , and declined on the evidence,  to take an anticholesterol drug , since in my early 50s despite my cholesterol of 6-7, my normal weight, HDLC, Hcy, Lpa,  bloodpressure, blood glucose, lifestyle and diet  put me at low risk
.Now the updated Sheffield 2011 Table  is  by  Jackson et al  in the prestigious QJM. At my age and low risk factors (no FH of CHD despite familial risks  (diabetes, atrial fib and mild lipidemia), my  Sheffield score of about 10 barely  puts me into the statin benefit range of 5 months gained. My coronaries and carotids are clear of plaque at last imaging, on all the natural supplements mentioned in this review, but not statin or any other designer hypolipidemic drug. If my patients have already been started elsewhere on a statin, I suggest they try just 5mg/day to minimize risks. . .
ADVERSE EFFECTS:  by design, they are antimetabolic;  oxidant ie increase ROS reactive oxidant species;  reduce CoQ10 by 39%.  Although these adverse effects are dose dependent and may be rare, they are cumulatively serious against muscle, liver, kidneys, memory, mood,  pancreas,  skin, sexual function; they cause diabetes, neuropathy and perhaps worsen cancer.  Thus they are like cancer chemotherapy, only for severely ill patients ie those with severe familial hypercholesterolemia..
     As  Beyond Health summarizes last year,      “Cholesterol does not cause heart disease. The French  Paradox- they have the highest average cholesterol in Europe, around 250mg(6mmol/L), but the lowest incidence of heart disease and half the heart attacks we have here in the U.S. In Crete, the home of the healthy Mediterranean diet, a 10-year study failed to find a single heart attack despite average cholesterol levels well over 200 (5 mmol). There are as many heart attacks in people with cholesterol levels over 300 (7.5mmol) as those whose levels are under 200 . Half of all heart attacks occur in people with normal cholesterol levels.   Cognitive problems affect about 15 percent of statin users, including episodes of temporary amnesia called transient global amnesia (TGA). Statins have an adverse effect on tau, a protein made by brain cells that helps maintain their structure. Abnormal tau proteins are linked with neurodegenerative diseases like Alzheimer’s, Parkinson’s and ALS.  Statins  cause progressive cognitive decline, ranging from mild to severe, and anxiety, depression, inability to deal with stress, and violent behavior. Statin-takers are more likely to develop peripheral neuropathy, and to experience tremors and vertigo.  Other health issues linked with statins include cancer, suppressed immunity, cataracts and optic nerve problems, liver damage, impotence and loss of libido, hypersensitivity reactions that can lead to the autoimmune disease lupus, birth defects if taken by pregnant women, skin rashes and dryness, hair loss, gastrointestinal problems, insomnia, and pancreatitis. “
LESSONS FROM FAMILIAL HYPERCHOLESTEROLEMIA:
Wiki says In FH, Initial studies showed increased activity of HMGA but more showed that this did not explain the very abnormal cholesterol levels in FH patients. The binding of LDL to its receptor, and effects of impaired binding on metabolism  proved to be the underlying mechanism for FH.  Heterozygous FH is a common genetic disorder inherited   in 1:500 people in many “European”   populations – the Afrikaner, French Canadians, Lebanese Christians, and Finns have high rates of specific mutations that make FH particularly common in these groups. Homozygous FH is much rarer, occurring in 1 in a million births. Heterozygous FH is normally treated with lipid lowering agentsstatins, bile acid sequestrants.. . Homozygous FH often does not respond to medical therapy and may requires radical  other treatments.
 
       But search of Pubmed and Google  for STATIN mortality reduction IN FAMILIAL HYPERCHOLESTEROLEMIA gives few reports showing  that statins meaningfully reduce mortality  and add  QALYs quality life years.
                        A current comprehensive  Medscape review August 2014 Familial Hypercholesterolemia Medication  does not specify any  % reduction in mortality on statins or any other drugs, despite lowering LDLc levels 50-60%.
and  Familial Hypercholesterolemia.  Youngblom E, Knowles JW. Editors.  GeneReviews® Univ. Washington 2014 Jan  says Familial hypercholesterolemia (FH) is characterized by severely elevated LDL cholesterol (LDL-C) levels that cause atherosclerotic plaque deposition in arteries and a markedly increased risk of coronary artery disease at an early age. In FH, the more common CVD is coronary heart disease (CHD), which may manifest as angina and myocardial infarction; stroke occurs more rarely. Heterozygous FH is relatively common (prevalence 1:200-500). Persons with untreated FH are at an approximately 20-fold increased risk for CHD. Untreated men are at a 50% risk for a fatal or non-fatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years. In contrast, homozygous FH (HoFH)  is much rarer (prevalence 1:160,000 to 1:1,000,000). Most individuals with HoFH experience severe CHD by their mid-20s. The rate of either death or coronary bypass surgery by the teenage years is high.
Indeed,  Fred Raal, Dave Marais ea from their clinics’  long term results at   Wits and UCT showed Reduction in Mortality in Subjects With Homozygous Familial Hypercholesterolemia Associated With Advances in Lipid-Lowering TherapyCirculation 2011 but the ~60% reduction in mortality in the statin era in this rare group (187 such subjects, mostly Afrikaners, very few smokers) was even so statistically barely significant. When the patients lost to follow-up in the statin-naive group were included in the analysis and censored on the date that statin therapy became available, the hazard ratio for the end point of death remained barely significant at 0.38 (95% CI 0.15–0.94; P 0.04), and the hazard ratio for the end point of MACE was not significant 0.54 (95% CI 0.25–1.18; P=0.12)
However, a  new JAMA study   from the Netherlands paints a gloomy picture- following almost 277  kids from age ~14 years for  Ten-Year Follow-up After Initiation of Statin Therapy in Children With Familial Hypercholesterolemia, after 10 years twice as many of those on statins were smoking  compared to their “normal” sibs, but worse, the FH sibs on statins, despite 20% lower cholesterol,  had the same increase in carotid artery thickening as their sibs without FH.
 
Nordestgaard, Tybjærg-Hansen ea for the European Atherosclerosis Society Eur Heart J. 2013 say . Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population:  to prevent coronary heart disease: consensus. .  Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, LDLC targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counseling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD.                                                                                                                                                            
THE FAILURE OF EZETIMIBE, VYTORIN:
But ezetimibe as an addon to statin eg in  Vytorin has been thoroughly discredited.  As Forbes.com said last year,   Pharma & Healthcare 2013   The Fate Of New Cholesterol Drugs Depends On IMPROVE-IT   “.But  Improve-It was not completed as planned in 2013. The new American  guidelines delivered a strong statement questioning the increasingly controversial theory that LDL lowering by itself is beneficial. “We found that non-statin therapies really didn’t provide an acceptable risk reduction benefit compared to their potential for adverse effects in the routine prevention of heart attack and stroke,”  IMPROVE-IT is the large, seemingly endless outcomes trial studying Vytorin, which has been a blockbuster drug for Merck. But the drug’s reputation, and its sales, have diminished in recent years because of a raging controversy over the lack of any evidence for clinical benefit. Vytorin lowers LDL cholesterol but no one knows if it improves outcomes. The IMPROVE-IT trial is supposed to resolve this controversy next year, but it will do so only as the patent on the drug nears expiration.     There’s a really good analogy to help understand the way IMPROVE-IT could impact the fate of the PCSK9 inhibitors. Just recently supporters of Amarin’s fish oil pill Vascepa thought the drug would coast to approval for a broad new indication. Their optimism was based largely on an agreement with the FDA that did not require a large outcome study before approval. But over the past few years several large outcome trials– not entirely dissimilar to IMPROVE-IT– failed to demonstrate clinical benefit for drugs that, like Vascepa, lowered triglycerides. The FDA tore up its earlier agreement with Amarin. In all likelihood Vascepa will not gain the new indication it seeks until an ongoing outcome study is successfully completed. The other Merck CVS drug trial of Tredaptive, a combination of simvastatin and niacin B3 vitamin, failed to show the new drug was better than a statin alone.

However, the Improve-It trial already failed when it showed no significant target benefits of more intensive LDLC lowering by it’s planned   2.5  years finish ie  2010 ; so numbers  (10 000 to 18000)  and time were increased to 18000 subjects, to finish now.. The latest is that results will be released  17 November…

what do other  STATIN  trials show? A Canticle for Statins?

COMPARISON OF THE 2011 CAMBRIDGE METANALYSIS AND  2013 COCHRANE STATIN METANALYSES:

 Ray et al from Cambridge Univ UK in Arch Intern Med. 2010:  a   meta-analysis of 11 randomized controlled trials (Jupiter, Allhat, Ascot, Mega, AfCaps, WOSCOPS, ASPEN, CARDS, Prevend-it, PROSPER, HYRIM) involving 65,229 participants  ie ~244,000 person-years , mean age 62yrs,  systolic BP 141, LDLC 3.45, mean duration 3.7yrs (Jupiter only 2.2yrs), 19% diabetics,   found no  benefit of statin therapy on all-cause mortality in a high-risk primary prevention set-up.
and 3  years later Taylor ea (London Univ Cochrane Database Syst Rev. 2013)  concluded  in   their abstract: Statins for the primary prevention of cardiovascular disease THAT  Evidence available to date showed that primary prevention with statins is likely to be cost-effective and may improve patient quality of life. In Eighteen randomised control trials   in  56,934 participants , mean age 57yrs, cholesterol baseline 6.17mol/l, LDLC 4.1;  duration 1 to 5.3years ie mean about 3.15 years ( they did not report mean bloodpressure). . Fourteen trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). All-cause mortality was reduced 14%  by statins (OR 0.86, 95% CI 0.79 to 0.94).  as was combined fatal and non-fatal CVD RR 0.75 (95% CI 0.70 to 0.81) There was no evidence of any serious harm caused by statin prescription .                         

BUT
t
heir full published paper tables   showed that statin use – in a mean time of only 3 years-   ” increased Diabetes 18% from 2.4% on placebo to 2.9% on statin; with  more fatal strokes,  liver, renal, arthritis adversity. and all-cause mortality from 5-1 to 4.4%; NUMBER NEEDED TO TREAT NNT 96. THE ABSTRACT DOES NOT GIVE THESE GLUM NUMBERS, that statins benefit  only 1 in a hundred.  BUT the dull paper states  Only the JUPITER trial showed strong  evidence of a reduction in total mortality.
As this column has previously pointed out, the Jupiter Trial was clearly flawed when we first reviewed it, and further debunked by diverse major groups by 2011/2 .
so while  the Cochrane study patients were 5 years younger but had baseline LDLC 19% higher,  than in the Cambridge analysis,   ie by age and LDLC, the Cochrane analysis could still not show meaningful reduction in mortality other than in the disputed Jupiter study.. But the Cochrane trials had only 1/8th of the diabetics in the Cambridge analysis.
 
     The 2013 Cochrane statin review’s   evidence for using statins for primary prevention in higher-risk persons without CVD  admits it’s antimortality benefit   is based solely on the weight of the seriously flawed Jupiter trial. But while the Taylor Cochrane analysis used only 8 of the trials (skipping PROSPER, ASCOT and ALLHAT)  analysed in the Ray Cambridge analysis, the Cochrane analysis added another 10 trials. Despite covering 7 more trials than the Cambridge 2010 analysis, the Cochrane analysis included 25% fewer patients than the Cambridge analysis,

     So  what the innocuous abstract of the London  UK  Cochrane review   failed to say is that, in their full paper (available on application)  weighted by the biased Jupiter trial,   to lower mortality by 14% in about 3.5years, to avoid one death,   96 well people need to take fairly vigorous dose statin for 1 to 5.4 years – or 1 patient for a few hundred years–   with serious risks of diabetes (up 18%), liver, kidney, myopathies, peripheral neuropathy, intracerebral hemorrhage (ICH), and other diseases of the central nervous system (eg  cognitive impairment, depression, sleep disorders, nightmare, and headache- . mood (suicide risk increased 2.5 fold – Davison & Kaplan 2014 Canada );

and (unlike the anticancer benefits of metformin and vitamin D3) no benefits in reducing cancers rates. Such bad risk: benefit ratio confirms what  has always been known, that there is no place for mass long-term consumption of statin whether in a mythical Polypill (Wald and Law 2003–   with adverse Bblocker, ACEI and aspirin,) or even more farfetched added to our diet staples- water, bread etc..

It is common cause that diabetes increases major  risks 4 fold; so advocating  96 well people to take a statin to lower  mortality  by 1 case in 3.5 years ie 330 patient-years while >3% develop diabetes, stroke, depression, myositis, hepatorenal  and other major complications,  is  negligence,  when patients do so much better on metformin plus other natural proven life-extending  supplements like fish oil, coconut oil, vitamins esp vit D3 & K2,  minerals etc. 

As Pubpeer said on 27  July 2014, its a crisis of  trust in what top journals (in this case the Cochrane Review) publish. For TRUST read distrust…

This is in contrast to metformin prevention in similar overweight well people,  which lowers all risks by at least a third, with no adverse effects  provided dose is started low and titrated to tolerance ie ~250 to 2500mg a day. THE BMJ STATIN FUROR JUNE 2014:
Just last month, the long-awaited independent review of the BMJ June 2014 STATIN publication (of articles denouncing the value of statins for mass primary prevention ) confirmed  that the BMJ editors under  Dr Fiona Godlee were correct in  standing by the June papers  that there is no mortality benefit from statin treatment in people at less than a 20% 10-year risk of cardiovascular disease, as Canada implements.,
The panel, chaired by Dr Heath with  six internationally renowned experts, concluded the journal had handled the two articles appropriately and that its processes were timely and reasonable. 

Now  three new 2014  studies put more wolves  among the Big Pharma profiteering disease-mongering sheep:
one from India describing many promising new competitors to displace statins;  one from Oxford University warning yet again of the adverse effects of anticholesterols, this time by CETP inhibitors; and one from New York University mocking the wannabe Statinopause, statin deficiency:

      George,  Elangovan  ea in India  J Cardiovasc Pharmacol Ther. 2014 Jul  Look  into the Crystal Ball -Upcoming Drugs for Dyslipidemia: say: . Although statins are effective anti-dyslipidemic drugs, their use is fraught with issues such as failure of adequate lipid control in 30% of cases and intolerance in select patients. The limited potential of alternatives such as fibrates, bile acid sequestrants and niacin has spurred search for novel drug molecules with better efficacy and safety, eg  promising cholesteryl ester transfer protein CETP inhibitors such as evacetrapib and anacetrapib; (MTP) inhibitors eg lomitapide; Apo CIII inhibitors eg  mipomersen;  PCSK9 inhibitors eg evolocumab, alirocumab; farnesoid X receptor modulation; and Lp-PLA2 inhibition. While it may not be an easy proposition to dismantle statins from their current position as a cholesterol reducing agent and as a drug to reduce coronary and cerebro-vascular atherosclerosis, our improved understanding of the disease and appropriate harnessing of resources using sound and robust technology could make rapid in-roads in our pursuit of the ideal anti-dyslipidemic drug.

BUT
Miller NE. University of Oxford, UK   in F1000Res.2014 Jun   warns  Time to think again about .  CETP inhibitors and cardiovascular disease:   Inhibition of cholesteryl ester transfer protein (CETP) lowers plasma LDLC concentration and raises HDLC, suggesting it might prevent CVD. From the outset, however, the concept has been controversial owing to uncertainty about its effects on HDL function and reverse cholesterol transport (RCT). Although there has long been good evidence in rabbits  that CETP inhibition reduces atherosclerosis , the first information on CETP as a CVD risk factor in a prospectively followed cohort was not published until after the first Phase 3 trial of a CETP inhibitor had begun. The worrying finding that in humans CVD incidence was related inversely to plasma CETP has since been reproduced in each of five further prospective cohort studies. Similar results were obtained in subjects on or off statin therapy, for first and second CVD events, and for mortality as well as CVD morbidity. Additionally, two recent studies have found alleles of the CETP gene to be associated with an increased risk of myocardial infarction. Meanwhile, CETP gene transfer in mice was found to increase RCT from peripheral macrophages in vivo, and human plasma with high CETP activity was shown to have a greater capacity to remove cholesterol from cultured cells than plasma with low activity. This mounting evidence  in humans and mice for a protective function of CETP has been given remarkably little attention, and indeed was not mentioned in several recent reviews.  It appears to show that CETP inhibition does not test the HDL hypothesis as originally hoped, and raises a pressing ethical issue regarding two Phase 3 trials of inhibitors, involving more than forty thousand subjects, which are currently in progress. As the weight of evidence now clearly supports an adverse effect of CETP inhibition on CVD, an urgent review is needed to determine if these trials should be discontinued.
and
Han, Weinberger, SutinNew York University. J Gen Intern Med. 2014 Aug. warn:  Statinopause.        Statins are the cornerstone of lipid-lowering therapy for CVD prevention. The  American College of Cardiology (ACC) and American Heart Association (AHA) 2013 guidelines represent a fundamental shift in how statins will be prescribed; recommending  statins for nearly all older patients up to age 75 years, including healthy adults with low normal lipid levels and no atherosclerotic cardiovascular disease (ASCVD) risk factors other than age. Under the 2013 guidelines, age becomes a main determinant for initiating statin therapy for primary prevention among older adults. Specifically, according to the new guidelines, white males aged 63-75, white females aged 71-75, African American males aged 66-75, and African American females aged 70-75 with optimal risk factors would be recommended for statin treatment for primary prevention. Based on the new guidelines, one could term these older adults as having “statin deficiency,” a condition warranting statin treatment. We call this putative condition of age-related statin deficiency “statinopause.” After careful examination of the trial evidence, we find very little support for the new recommendations for primary prevention. The lack of evidence underscores the need for clinical trials to determine the risks and benefits of statin therapy for primary prevention among older adults.                                                                                                                                                           
HALF OF PATIENTS DISCONTINUE STATINS WITHIN A YEAR IN REAL LIFE:     Already in 2009    Goldenberg N1, Glueck C: wrote  in real life practice, about half of patients who are prescribed statins discontinue the medication by the end of the year. from the  Cholesterol and Metabolism Center,  Jewish Hospital, Cincinnati, Ohio, USAin  Vasc Health Risk Manag. .    Efficacy, effectiveness and real life goal attainment of statins in managing  CVS  risk. Statins became available in 1987 for the treatment of hypercholesterolemia .   Multiple, well-designed, placebo-controlled, double-blind studies revealed that each 1% reduction in serum cholesterol level was associated with about 1% reduction in risk of CVS events. Low-density lipoprotein (LDLC) cholesterol reduction to less than 78 mg/dL may be associated with reduction of atheroma burden. Patients with high levels of high specificity C-reactive protein and having LDLC less than 3.4 mmol/L (130 mg/dL) in primary prevention settings benefited from aggressive LDLC reduction with rosuvastatin over a 2-year period.  Medication adherence is lower in younger patients, women, and absence of known CHD. Personal features of the prescribing physician and dispensing pharmacies also affect patients’ compliance. More studies are needed to evaluate if “compliance packets” would benefit patients in a real life situation.
STATINS DEPLETE  Co10, OMEGA3 AND OTHER ESSENTIALS:.
     Coenzyme q10 therapy 2014  .Garrido-Maraver J1,  Sánchez-Alcázar ea . at Seville Universities say coenzyme Q10 (CoQ10) have  key role in mitochondrial bioenergetics; antioxidant; obligatory cofactor for uncoupling proteins and a modulator of the mitochondrial transition pore; expression of genes ; human cell signaling, metabolism and transport. CoQ10 deficiencies are due to autosomal recessive mutations, mitochondrial diseases, aging-related oxidative stress and carcinogenesis processes, and statin treatment. Many neurodegenerative disorders, diabetes, cancer, and muscular and cardiovascular diseases have been associated with low CoQ10 levels as well as different ataxias and encephalomyopathies. CoQ10 causes no serious adverse effects in humans.  Oral a CoQ10 is a frequent  antioxidant used in many diseases that may provide a significant symptomatic benefit.

        Statin treatment and new-onset diabetes: a review of proposed mechanisms. Brault ,  Daskalopoulou ea .2014  at McGill and Harvard say   New-onset diabetes has been observed  involving statin therapy. To explain this association, three major mechanisms have been proposed . First, certain statins affect insulin secretion through direct, indirect or combined effects on calcium channels in pancreatic β-cells. Second, reduced translocation of glucose transporter 4 in response to treatment results in hyperglycemia and hyperinsulinemia. Third, statin therapy decreases other important downstream products, such as coenzyme Q10, farnesyl pyrophosphate, geranylgeranyl pyrophosphate, and dolichol; their depletion leads to reduced intracellular signaling.

     Michel de Lorgeril ea .Universite Joseph Fourier, Grenoble France  BMC Med.2013 ask: do statins inhibit omega-3?. Recent findings on the health effects of omega-3 fatty acids and statins, and their interactions. .Early randomized controlled trials (RCTs) demonstrated the health benefits of omega-3 fatty acids (n-3), whereas recent RCTs were negative. We now address the issue, focusing on the temporal changes having occurred: most patients in recent RCTs are no longer n-3 deficient and the vast majority are now treated with statins. Recent RCTs testing n-3 against arrhythmias suggest that n-3 reduce the risk only in patients not taking a statin. Other recent RCTs in secondary prevention were negative although, in a post-hoc analysis separating statin users and non-users, non-significant protection of n-3 was observed among statin non-users whereas statin users had no effect. Recent RCTs testing statins – after the implementation of the New Clinical Trial Regulation in 2007 – are negative (or flawed) suggesting that the lack of effect of n-3 cannot be attributed to a parallel protection by statins. Finally, statins favor the metabolism of omega-6 fatty acids (n-6), which in turn inhibits n-3; and contrary to n-3, they increase insulin resistance and the risk of diabetes. Thus, n-3 and statins are counteractive at several levels and statins  inhibit n-3.

ie statins undo the proven benefits of omega3 and CoQ10. .

VITAMIN D AND CHD:

 Charles Glueck ea at the same Cincinnati Jewish Hospital. in  Med Hypotheses. 2011 describe HOW Vit D repletion reverses statin intolerance in 91% of statin-intolerant patients. Symptomatic myositis-myalgia in hypercholesterolemic statin-treated patients with concurrent vitamin D deficiency leading to statin intolerance may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle.   Myositis-myalgia is the most common cause of statin intolerance, leading to cessation of statin use, with consequent failure to lower LDL cholesterol to target levels for primary and secondary prevention of cardiovascular disease (CVD). Despite published and new empirical evidence, the medical establishment has refused to accept it, requiring placebo-controlled, double-blind studies, none having been reported to date.

Glueck’s promotion of vitamin D as antidote or alternative to statin is borne out by at least 5 papers on Pubmed since 2003 (Kajinami), Yavuz 2009 ea ) –  some of which show that vit D level may rise significantly on statin.
       Now a  major review from Universities of Newcastle UK and Harvard by Kunadian, Manson ea   Am Heart J. 2014 of  Vitamin D deficiency and coronary artery disease: concludes: Coronary artery disease being the leading cause of death in developed countries, older patients are at particularly high risk of poor outcomes following acute coronary syndrome,  and impaired nutrition, including low vitamin D levels, may play a role.  Longitudinal studies have demonstrated increased cardiovascular mortality and morbidity associated with vitamin D deficiency. Low vitamin D levels have been linked to inflammation, higher coronary artery calcium scores, impaired endothelial function and increased vascular stiffness. Most available trials have tested only low doses of supplementation in relatively low-risk populations.


Specific Critiques of the Jupiter study and Contrasting results from other studies: :
 Wiki quotes Dr. Michel de Lorgeril, et al  In 2010,  published “a critical reappraisal” of the JUPITER Trial in the Archives of Internal Medicine,  what they saw as flaws in the trial, pointing out that the cardiovascular mortality rate and the case-fatality rate for myocardial infarction were much lower than they expected; they also questioned whether the study had been biased and perhaps manipulated because it was sponsored by a pharmaceutical company with a strong commercial interest in the outcome. They concluded that, “The results of the trial do not support the use of statin treatment for primary prevention of cardiovascular diseases and raise troubling questions concerning the role of commercial sponsors.  In addition, some prior and some subsequent studies have contrasted with the JUPITER trial results.       Five  other major university papers in prestige journals  also criticized the Jupiter study in 2011/12: Samson ea Florida State, Serebruany Johns Hoplins; Ridker Harvard, and  Morrissey ea Cedars-Mt Sinai;  while Lopez and Wright from Spain and Canada published an exhaustive debunking of the Jupiter claims of significantly reduced mortality.
            as we have long questioned about mass use of statins, Jay Cohen MD 2014 Aug 4th asks in  the MedicationSense E-Newsletter again: what is The Truth About Crestor: Is Crestor Dangerous And, if so, Why?  Crestor is the newest statin and the strongest statin yet. Statins are highly touted drugs for reducing cholesterol. Studies clearly show that statins improve cholesterol numbers (by lowering LDL and raising HDL) and may reduce C-reactive protein. Statins impede atherosclerosis, reduce heart attacks and strokes, and cardiac death. Thus, the statins Lipitor and Zocor are not only the #1 and #2 top-selling drugs in America, but also household names.  Other statins include Pravachol, Mevacor, and Lescol–and now ultra-potent Crestor. Until 2001, there was another statin: Baycol. It was then the newest statin and a potent statin–until it was withdrawn because of dozens of deaths. Is Crestor another Lipitor or another Baycol? Although Crestor has been on the market only a year, it has already been linked to numerous cases of severe muscle breakdown, kidney toxicity, and deaths. Public Citizen recently petitioned the FDA to ban Crestor...
 

       Conclusion: these references reviewed confirm that  is no justification for the myth of routine use of statins for primary prevention in the average population, especially in view of their risks, especially  increase in diabetes, and the availability of safe and far more globally healthgiving natural antiaging antioxidant energizing  insulin-sensitizing supplements that do a far better job of reversing both CVD and all other major diseases. .

update  16 June 2014 as this column has argued since 2008 (and this author for 40 years in refusing to take them for lack of proof)-  given their numerous serious and nuisance harms-  there never has been good enough evidence to justify synthetic designer cholesterol-busters for primary prevention with mild-to-moderate cholesterolemia ie without the presence of cardiovascular disease;

in contrast to   harmless multipurpose (antiatheroma antidiabetic antithrombotic antihypertensive anticancer all-disease prevention) micronutrient supplements like fish oil, coconut oil, DMSO, metformin,  vitamins esp C D & K2, minerals esp magnesium, chromium, zinc, iodine; , human nonoral HRT, CoQ10, arginine, carnitine, carnosine ; numerous mixed medicinal herbs; etc.

In the Statin-use debate creates furor at BMJ    CMAJ  on June 16, 2014,   Carolyn Brown argues  “Statins are beneficial for people with proven coronary artery disease, but a recent BMJ article questioned their use as a prophylactic measure.            “Are statins going to have a big impact on coronary artery disease or are they going to be one of the big mistakes that the medical profession has made?” That’s the question asked by Dr. James Wright, a Canadian who co-authored an analysis of the evidence on statins that appeared in the British Medical Journal (BMJ) in October 2013. 

      ” It seems like a straightforward question, but that article has led to a furor in the United Kingdom, with a well-known researcher calling for its retraction and the BMJ editor-in-chief Fiona Godlee defending the journal’s publishing process on radio and television. At issue is the clinical uncertainty about the preventive use of statins. “We’re fairly certain that benefits outweigh the harms in people with proven coronary artery disease (CAD). That’s based on a highly statistically significant but modest reduction in total mortality,” says Wright, who is managing director and chair of the Therapeutics Initiative (TI) at the University of British Columbia. But he says most prescriptions for statins are aimed at preventing CAD.

               “The evidence for this is not as rigorous and serious adverse effects have been documented. The UK’s National Institute for Health and Care Excellence (NICE) recently proposed extending preventive use of statins from patients who have a 20% chance of developing CAD in the next 10 years (its current guideline) to those with a 10% risk. This has led to a debate over the accuracy of risk calculators, unnecessary prescribing in seniors (since age is a major risk factor) and adverse effects. Canada’s guidelines recommend statin therapy in patients with risk below 20% only if their levels of cholesterol or other indicators exceed certain thresholds. Wright believes the statin issue has become heated because “so many people are taking them. They have been in the news so much and there [is] so much money being spent on them.” “Publication of our article has reignited the debate,” says Dr. Kamran Abbasi, international editor of the BMJ, who spoke on behalf of Godlee. “There are people who disagree vehemently on this issue. They can’t reach any sort of consensus on it at the moment.” The BMJ article re-analyzed data from the Cholesterol Treatment Trialists (CTT) Collaboration meta-analysis and cited adverse effects rates from various studies.

             ” Sir Rory Collins, a researcher at Oxford University and head of the CTT group, corresponded directly and met with Godlee in December 2013 about the article, calling for a retraction. He has also stated his view in media interviews. As a result of Collins’ complaint, the article was corrected, as the authors agreed that they had erred in reporting rates of side effects from the observational study. Wright says, “The issue around side effects is just that there is some harm.” The analysis had cited a rate of statin-related adverse effects of 18%; in fact, the original study found 17.4% of patients had a “statin-related event” but only approximately 9% discontinued statin therapy as a result. The correction affirmed that the CTT study failed to show that statins reduced the overall mortality risk in patients with a less than 20% risk of CAD over 10 years. Godlee also published an editorial explaining the journal’s decisions on how to handle the controversy and appointed an independent panel to rule on whether a retraction is warranted. Collins says he has submitted detailed material to this panel and maintains that there remain “extensive problems” with the analysis paper, beyond what the correction addressed. Charlotte Haug, vice-chair of the Committee on Publication Ethics (COPE).

update 2010   A new review, this time from a top team in France, further demolishes the deceptive  Jupiter trial promoting rosuvastatin Crestor, confirming that it was fatally flawed:

Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER Crestor controversy: a critical reappraisal.

Michael de Lorgeril ea conclude: ” The results of the trial do not support the use of statin treatment for primary prevention of cardiovascular diseases and raise troubling questions concerning the role of commercial sponsors.”

This concurs with the fraud of modern medicine increasingly pursued by combined Drug Industry and Government Regulator conspiracy, including www.lef.org/…/Media-Attempts-to-Misrepresent-Scientific-Findings.htm

and

Justice Dept declares war on doctors.

and why use a drug that can cause cancer , and tendinopathy, and  thrombocytopenia? Pubmed  shows at least 7 causally linked case reports since 1992 and 2008 , including one  now for rosuvastatin.

and Univ California San Diego alone reports 300 cases of statin-related myopathy.

contrast this with the trial report last week from a hypertension unit in Israel where a simple combination of vits C & E, coQ10 and selenium for 6 months – with no risks- lowered arterial stiffening, hypertension, lipidemia and glucose.

so why use statins except in severe familial lipidemia?

Feb 4th 2010 

 Early last year this column pointed out that the JUPITER trial was another nail in the coffin of primary use of statins.

Now a University California    Davis team concur further   in “Another look at the results of the JUPITER trial…  that many of the participants did not receive care consistent with current standards. Thus, the benefit of statin therapy would have been more difficult to demonstrate if standard therapeutic recommendations had been followed. In conclusion, these considerations cast doubt on the contention that statin therapy should be initiated in apparently healthy individuals on the basisof elevated high-sensitivity C-reactive protein levels.