Monthly Archives: September 2008

LOWER PROSTATE CANCER INCIDENCE, SIZE AND GRADE ON APPROPRIATE MONITORED TESTOSTERONE REPLACEMENT:

 

Further to the discussion  last week: on myths and realities of prostate cancer risk with appropriate hormone replacement HRT – testosterone replacement TRT,

the poster summarised  below was presented earlier this month at the German Society of Andrology.

 It may be the first published  controlled study  confirming the apparent prostate benefit  of appropriate testosterone replacement TRT  for a mean of 30 months  in hypogonadal men compared to comparably monitored eugonadal men. The numbers are small,  but show perhaps halving of the incidence (to 0.5% new prostate cancers per year) and severity of the cancers.

 

  As previously discussed in this column, this reduction in incidence and grade of malignancy  is what we have grown to expect with appropriate parenteral HRT, as also seen  in hypogonadal women to produce balanced testosterone:progesterone: estradiol levels and lesser breast cancer and cancer mortality. .

 

“No Higher Incidence of Prostate Cancer in Hypogonadal Patients being Treated with Exogenous Testosterone  1Aksam A. Yassin, 2 Farid Saad, 3 Ahmad Haider, 4 Osama Assaad.  1 Gulf Medical College UAE & Segeberger Kliniken, Noderstedt-Hamburg, Germany, 2 Gulf Medical College UAE, & Bayer Schering  Germany, 3 Urologic Office, Bremerhaven, Germany, 4 Mera Hospital, Moscow, Russia

Objectives  To evaluate incidence of prostate cancer in hypogonadal patients with erectile dysfunction, receiving long-acting injectable testosterone undecanoate TU (Nebido®, Bayer-Schering) in comparison with a similar group of controls.

Patients and Methods   154 testosterone deficient patients with average age 57 ± 2.1years with mean follow-up of 30 months (14-37 months), received  TU 1000mg and were compared with a control cohort of 160 men (average age 59 ± 1.6 years) with similar characteristics visiting our clinic for preventive medical check up.

 

TRT  patients underwent monitoring protocol at baseline and 3-monthly including assessment of  total prostate volume, and  ultrasound-guided biopsies when indicated by PSA velocity > 0.75 μg/L per year, or elevation over 4.0 μg/L.

Men visiting our clinic for preventive medical check up were examined assessing the same parameters at yearly intervals.

In all subjects in both groups, no abnormalities on rectal palpation were noted initially.

 

Results   At baseline, hypogonadal patients showed lower PSA values and lower prostate volumes (0.77 vs controls 2.1 μg/L and 27.6  vs control 39.5, respectively).

Patients in group I (hypogonadism and ED) whose PSA velocity on  follow up was > 0.75 μg /L above  baseline, underwent TRUS-guided prostate biopsy  according to protocol (10 cores 1.6 cm each).

In group I (154  hypogonadal), 11 biopsies were performed; finding CaP in 2/11 subjects, both of them unilateral and 5% tumor cells in a core. Gleason score 3+2 and 3+3, respectively. One

patient had a high grade PIN.

 In group II 160 control subjects, 12 biopsies were performed. 5 subjects (5/12) showed CaP, 4 of them bilateral, with a higher Gleason score of 3+3 to 4+4 and up to 75% tumor cells in a core.

In group I (hypogonadal), the 2 CaP patients underwent radical retropubic prostatectomy.

 In group II, all 5 CaP patients underwent radical retropubic prostatectomy.

 

Conclusions

1) Subjects with T-deficiency have initially lower prostate volume than eugonadal ones.

2) Subjects with T-deficiency have initially lower PSA levels than eugonadal ones.

3) Appropriate TRT does not increase the incidence of prostate cancer.

4) Smaller and less malignant (better differentiated) tumours were seen in the TRT men.

5) Patients on TRT under close monitoring may benefit as they are more likely to be diagnosed at an early stage.

 

 

 

 

 

 

 

 

 

Getting to Goal Blood Pressure despite Disaster Capitalism: Why Reserpine Deserves a Second Look

 Lets hear your comments for or against  a return to evidence-based medicine for hypertension, not marketing  hype:

Last week this op-ed column discussed the time-bomb of obesity–  overnutrition, and the wannabe panacea designer drugs of the Disease Industry.

Instead of the narrow Disease-Industry driven multiple designer  prescriptions for hypertension, lipidemia, vascular, depression, dementing and musculoskeletal diseases, the patient – and  lowering the costs of major disease- are far better served by recommending the natural supplements and the old and well-proven few prescription drugs often justified- lowdose amiloretic, lowdose reserpine, metformin., and appropriate parenteral HRT.  

The problem is that Politicians, Treasury, doctor and medicines Regulators, Stock-markets, the Media, Academics and practitioners are all far more impressed by the billion-dollar buying and marketing persuasions of Big Pharma than the truth that is in patients’ (but not the Disease Industry’s) interests.

 

It took 20 years to defeat the FDA-Drug Industry in USA and have old metformin and lithium registered there- so that these are  now worldwide the core drug therapies for type 2 diabetes and bipolar disease respectively  in most  patients.

Until lowdose reserpine plus lowdose co-amiloretic are  similarly restored as the initial therapy of essential hypertension world wide, the growing epidemic of essential hypertension remains in Noam Chomsky’s terms a Failed State of medicine, one of the prime successes of Kissinger-Rumsfeld-Cheyney-Bush- FDA type for-profit subversion of democracy and evidence in therapeutics – and blow the Innocent Casualties


The  August 2007  review summarized below  Getting to Goal Blood Pressure: Why lowdose co-thiazide-reserpine remain the first tier therapy review (which spells out all the acronyms)  from Kaiser Permanente and University clinics in three States,  is  crucial to managing the hypertension epidemic.

 

It amplifies the primacy  of the lowdose reserpine- lowdose co-thiazide diuretic combination over all other drug combinations with new data from the MRFIT study as well as from  the VA, HDFP, SHEP and ALLHAT trials – noting that in low dose these drugs have zero adverse effects (compared to methyldopa, betablockers, ACEI, CCB and ARBs) but a good BP control rate.

 

No antihypertensive drug acts  smoothly and safely for 24hours ie once a day dose except resserpine- which acts for many days; and no antihypertensive drug on its own normalises bloodpressure in the mjority of patients with mild to moderate hypertension.. Thus the ideal primary therapy remains lowdose reserpine plus lowdose coamiloretic.

 

The compelling year-old US review by Barzilay ea  omits a couple of crucial facts/ updates:

 

1. In South Africa, reserpine is still registered,   and recommended by experts as a valuable second-line antihypertensive- but – as in UK and Europe – it has been dropped from the State Clinics’ formulary, for which the responsible authorities ( in  RSA, UK and EU)  blankly refuse to give any scientific reason, since there are none.

This leaves the responsible decision-makers, by default of any other reason, tacitly admitting they bow to the financial enticements  of the pharmaceutical industry who prefer to research and sell more modern ie patented costly blocker drugs and especially patented combinations of the latter- although such combinations have never been proven to be anywhere as good as the lowdose reserpine- lowdose diuretic combination.

 

eg the ASCOT  trial merely confirmed  what was known,  that  brisk diuretic plus a BBlocker is not the best choice for the population tested.    ASCOT was done not in the average new middle-age hypertensive  in a temperate climate,   but like WHI, ALLHAT & SHEP, in  a highrisk older Anglo-Scandian  population mean age  63 yrs living in a much colder climate, many obese (mean BMI 28,3kg), 1/3 smoking, 80% already on therapy, and 60% already with (micro)proteinuria.

   there was no mention of  a good practice control  group ie on effective (eg Ornish- or DPP or UKPDS type) non-drug management, nor a control group on lowdose thazide-reserpine.+- eg amlodipine/ACEI for proper BP control.

Thus there s no basis to say that  a (combination of)  ACEI/ARB/CCB  should be universal firstline therapy.  Even compared to a bad combo like vigorous thiazide + atenolol,  in ASCOT the results of  Secondary endpoint (nonfatal AMI  excl silent AMI, + fatal CHD) barely reached  statistical significance, let alone the failure to achieve the primary endpoint significance (nonfatal AMI + CHD); and allcause mortality did not achieve POEM significance ie  2%pa on ThiazAten vs 1.8%pa on PerinoprilAmlod. (Patient Orientated Evidence that Matters – Shaughnissy & Slater).

      Most major endpoints were predictable, were to be expected in that population:

inappropriate BBlckade caused more PVD, bradycadia, cough, dyspnoea, periph coldness; heartrate was 11bpm higher on the peri/amlo combo, despite serum K level only 0.05mmol higher.  Inappropriate highdose thiazide + BB caused more erectile dysfunction, renal impairmnt & new diabetes-   yet there was no difference in chronic angina, hear failure, lifethreatening arrhythmia.

Perindopril on the other hand predictably caused joint swelling in 14% (vs 3% on thiaz-atenol); and the diuretic-free combo  predictably caused  periph oedema in 23% (vs 6%).  It is salutory that the discontinuaton rate due to adverse reactions was identical 24.7% for the two different regimes – confirming that the new patented combination is no better than even the old thisazide- bblocker one.

2. as hypertension experts  Drs Norman Kaplan, Marvin Moser, Jos Barzilay et al from USA, and South African Hypertension Society’s  Drs YK Seedat, Harry Seftel, Willie Mollentz,  Mark Blockman  et al agree in personal discussion, and by WHO pharmacy expert Kirsten Myhr  2002  and Urquhart 2003,   on what scientific  basis  is lowdose reserpine  restricted, no longer in the first tier combination for primary therapy of essential hypertension? 

It must stay first line both on economy and scientific grounds – although the Drug Industry wishes  it suppressed as has occurred in UK and WHO – EU and RSA State Drug lists, without any scientific reasons given.

Reserpine is not  “a tragic victim of myths, marketing, and fashionable prescribing” as Myhr quotes Fraser 1999 below. The analogy is lithium for bipolar disease, and metformin for diabetes and the prediabetes syndromes (overweight, hypertension,  infertility), which  gold standard old drugs were denied to the USA public  for twenty years  by the malignant control that Big Pharma wielded and still wields through it’s buying power  over the FDA and other Regulators. 

       The progressive suppression of reserpine by the EU and RSA can only be the result of disinformation spread by the New Prescription Designer Drug industry through it’s expert paid lobbyists in Academia, journals  and on Regulatory Committees. 

      Contrary to Fraser, there is no “fashionable prescribing” in socialist -controlled pharmacopoeas like the UK NHS, Europe or the state sector in South Africa- the (supra)national Authorities  have simply bowed to the financial might of manufacturers and banned  reserpine from their formularies, since governments (like the Disease Industry) earn far more from new designer drug registration and  tax revenues than from the old and proven like metformin, lithium and reserpine.

This is the essence  of Naomi Klein’s Disaster Capitalism (The Shock Doctrine 2007),  Al Gore’s The Assault on Reason (2007).

           But  for the same reason that even USA had to licence lithium and metformin – they are the best and proven therapies in their class-  lowdose reserpine must be reinstated as baseline therapy for hypertension in RSA and the EU.

3. Up to now on Medline,

          at least a dozen RCTs show that no single antihypertensive drug does better than lowdose (co-) thiazide. 

          at least a dozen RCTs show that solo lowdose reserpine is at least as good as if not better than any other single drug.

          at least 25 RCTs show that the combination of lowdose reserpine + lowdose co-thiazide/amiloride is unsurpassed

 

– so no drug company has dared to do any more head-on comparative trials .

 

             The latest of these trials – SHEP  and now ALLHAT – after the two definng German Reserpine Group  RCTs (Pittrow ea 1997)  –  show that even as third-line add-on ie in the most resistant cases, reserpine is unsurpassable.   

 

              The reserpine RCTs confirm that lowdose reserpine   corrects some of the metabolic adversity of higher-dose thiazide, without the adverse effects of the newer alpha/beta/ACE/ARB/CCB  blockers.  For safety and efficacy, amlodipine may be the nearest equal of reserpine – but it does not have all the  benefits of reserpine.. New studies confirm that lowdose reserpine is both major antidepressant-anxiolytic,  anti-parkinsonian, and a major anti-addiction herb extract.

 

4. and the Cache County study (2006)    showed that  “the use of potassium-sparing diuretics alone without any other antihypertensive medication was associated with a significant 90% reduction in Alzheimer’s Disease  risk   (aHR, 0.09; 95% CI, 0.01-0.41).

 

 

5. COSTING: Even in mid-2008, in South Africa a vigorous dose of co-amiloretic 13.5mg plus reserpine 0.1mg per day costs RETAIL as little as R15 or US2 a month – and many patients need only half those doses to control mild to moderate HBP. But if bulk bought by the RSA State for the millions of hypertensive state patients, the combination could cost as little as US$0.5 a year for actual ingredients. But in terms of disaster capitalism, such optimal therapy that  greatly improves healthspan and productivity suits  neither the pharmaceutical industry,  nor the State who depend on jobs, fees  and taxes  from a thriving pharmaceutical industry.  When we offered this option two year ago, the experts chose to ignore it…

 

6. IGNORING THE BROAD PATHOGENESIS OF AGING DISEASE: However, all the commercial ie prescription drugs discussed above hardly address the core pathogenesis of common essential HBP. 

The patented drugs deal with salt and water retention and  vasoconstriction, but  none work against obesity- metabolic syndrome, free radiclal lipoxidation inflammation, atheroma, and stress-related  hypercorticolism;  and only ACEI/ ARBs counter-act insulin resistance, tissue glycation ie reduce new diabetes.  

 

eg in the HOPE trial (2000) of ramipril vs placebo in ~66yr  old largely obese vascular-risk patients, the 5year death rate on placebo was 12.2% vs 10.4% on ramipril (-16%, p0.005)-  but if anything there were more noncardiovascular deaths on ramipril (4.3%) than on placebo(4.1%). New cases of diabetes were 1/3 lower on ramipril than on placebo (5.4%).

but  in the Univ Texas metaanalysis of ACEI and ARB trials (2006), these drugs reduced the incidence of new diabetes by only 20%.  

 

But  with marketed antihypertensive drugs, no reduction in the non-vascular scourges of the aging –  fractures, obesity, cancer or dementia –  was reported:

    neither the HYVET-COG trial  (2008) in those over 80yrs, nor the 2006 Cochrane metanalysis showed any benefit in lowering dementia with antihypertensives in hypertensive patients.

     In a 4year study from New Zealand Reid 2007  showed no significant improvement in hip or spine bone density from 50mg HCThiazide a day;    but a 2006 Canadian metanalysis   showed that thiazides  or betablocker or ACEI for hypertension reduced the incidence of any fracture by a significant 14 to 19%.

 

ADDRESSING THE PATHOGENESIS OF PREMATURE AGING DEGENERATIVE DISEASE: The insignificant results of focussing just on antihypertensives- no reduction in obesity, non-stroke dementia, cancer, and small reduction in fractures and dementia-

contrast with the result of 

*appropriate HRT in menopausal women in the WHI and Oulu 10year trials: about onethird reduction in all major events-  fractures, new diabetes, cardiovascular, cancer and dementing problems – and thus in all-cause mortality;

*and metformin in the three major diabetes prevention programs- about 50% reduction in new diabetes;

*and metformin in the UKPDS and Canadian 5 to 20year studies-   reduction of mortality by a third to half;

*and natural supplements for the depleting and polluted  food chain and environment – fish oil plus a simple appropriate blend of the 13 vitamins, +-13 essential minerals, and the ~25 invaluable other antioxidant nitric-oxide booster  biologicals which lower insulin resistance – lipidemia,   hypertension, obesity, free radical  lipoxidation and thus arteriosclerosis; and  all the  other major chronic degenerative diseases of aging: eg CoQ10, arginine, carnitine, ribose, proline,  N-acetylcysteine, malic acid, GABA, 5HTP, taurine, chondroglucosamine,  MSMethane, curcumin, galega, gymnema, coleus, sawpalm etc.

 

ndb

 

E d i t o r i a l  THE JOURNAL OF CLINICAL HYPERTENSION  2007: 9 591-4
Getting to Goal Blood Pressure:   Why Reserpine Deserves a Second Look
Joshua Barzilay,  Kaiser Permanente ea,

 This multiauthor editorial  reviewed several  hypertension trials in which reserpine therapy was used with good results,

and presented  new data from the Multiple Risk Factor Intervention Trial (MRFIT) that also demonstrate  the positive effects of reserpine.They believe that reserpine deserves reconsideration as an effective  antihypertensive medication, especially in combination therapy.


“By 2004, the prevalence of hypertension increased in USA  to 29% mainly as a result of increased  obesity and population age, while blood pressure (BP) control rates improved  to 37%.     Despite this recent success, BP control rates  remain low.  

Reasons for this include  lack of careful follow-up; failure to control systolic BP,  especially in older patients; and therapeutic inertia (ie, failure to increase the dose of medication  or add  another medication when BP is not at goal).

Until recently, even in the best clinical trials,  BP control rates of only 66% to 73% have been achieved even  with a 2-drug combination as initial therapy,

 

“One antihypertensive medication that could be used to improve BP control, especially systolic BP, is reserpine, a centrally acting adrenergic antagonist. It  fell into disfavor years ago, labeled  a relic from the past and an obsolete medication. While its use in westernized countries fell precipitously in the past decades despite its proven efficacy, reserpine is still used extensively  in nonwesternized countries, where health care expenditures are more costconstrained.
In South Africa, for example, it is a second-step hypertension medication after diuretic therapy. In India, low-dose reserpine, in combination with diuretics and hydralazine, is used effectively to prevent renal disease.

Several adverse effects –  depression, gastric bleeding, and breast cancer- attributed to reserpine  in the 1950s and 1960s led to its near demise. . Early in its use, recommended dosages of reserpine  varied from 0.75 mg to 10 mg/d;  but studies using   low dosages  0.05–0.1 mg/d usually in combination  with diuretics) show that reserpine is well tolerated

At current dosing levels, no increase in depression,  dyspepsia or breast cancer have been reported.

 

“The situation of reserpine is analogous in many ways to that of thiazide diuretic therapy. Early in their use, high dosages of diuretics (often up to 200 mg/d) were prescribed, and  associated with  high rates of adverse biochemical effects and little additional antihypertensive efficacy..

“Today, low-dose thiazide diuretics (ie, 12.5–50 mg/d) are the recommended first-step agents in the treatment of hypertension.

Early hypertension outcome studies, such as the Veterans Administration (VA) Cooperative Studies in the 1960s, the Hypertension Detection and Follow-Up Program (HDFP) in the 1970s, and MRFIT in the 1980s, established that low-dose reserpine therapy was an effective treatment for most hypertensives.

 

Table. Change in BP With the Addition of Step 2 Medication in MRFITa
                                                        SBP                                 DBP
STEP 2 MEDICATION     N         MEAN         SE                     MEAN              SE
Reserpine                         445        –7.8            0.6                     –6.5                 0.4
Methyldopa or propanolol 370      –4.1            1.1                     –3.8                 0.7

 

“Further analysis of the MRFIT dataset, presented here for the first time (Table), indicates that  reserpine add-on therapy in men treated with diuretic monotherapy through the first year of the  study was more successful in lowering systolic and diastolic BP than  propranolol or methyldopa..


“Several VA cooperative studies in the 1980s also demonstrated the efficacy of reserpine: In the Hypertension in the Elderly VA study, men aged 60 years or older, approximately 40% did not respond to thiazide monotherapy, and second-step medications were added. Results showed equal efficacy of methyldopa,
hydralazine, metoprolol, and reserpine and equal duration of action. Measures of cognitive behavioral effects, such as depression, diminished cognitive abilities, and changes in activities of daily living, did not differ between the groups; however, reported adverse effects and withdrawal due to drug intolerance were higher with methyldopa.

 

“With reserpine there were no reported adverse effects that were increased, but with reserpine  postural dizziness and headache were reduced, and serum cholesterol levels decreased  the most  (–16 mg/dL).

 

“The most recent clinical hypertension trial  reporting on the use of reserpine was the Systolic Hypertension in the Elderly Program (SHEP)  in more than 4700 adults aged 60+ years;  it  was the first to demonstrate the efficacy of low-dose antihypertensive medication in preventing stroke (by 35%) and cardiovascular events (by 32%) in people with isolated systolic hypertension (defined as systolic BP >160 mm Hg and diastolic BP <90 mm Hg). The active treatment group (n=2365) received a low dosage of chlorthalidone (12.5–25.0 mg/d) with a step up to atenolol (25.0–50.0 mg/d) or reserpine (0.05–0.10 mg/d), if needed. During the 4.5 years of average follow-up,  8% (n=193) received  reserpine over a mean exposure period of 1.7 years .For reserpine, the relative risk (vs nonuse of reserpine) and 95% confidence intervals were 0.65 (0.26–1.59) for mortality, 0.27 (0.04–2.26) for stroke, 0.93(0.29–2.96) for coronary heart disease events, and 0.55 (0.20–1.49) for cardiovascular disease events. 

All these  values are considerably lower than those associated with atenolol use (0.84;  1.34 ;1.04 and 1.07, respectively),  a medication still in wide use. These  results are similar to those of MRFIT.

Given the new results  from MRFIT and the results of the VA Cooperative trial and SHEP, it would appear that reserpine still has a role in the management of hypertension. The question arises: how should it be used?

 

“It is now commonly accepted practice to initiate antihypertensive therapy with 2
antihypertensive medications in persons with stage 2 hypertension.


“The most common combination  is a diuretic with either an angiotensin converting  enzyme (ACE)  inhibitor/angiotensin II receptor blocker (ARB) or a calcium channel blocker  (CCB).

 In many cases, especially in older persons and those with diabetes and obesity,

2 medications are not completely effective and ≥3 medications  may be required, as experienced in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial  (ALLHAT).  

 Persons with diabetes usually are obese. When obesity is centrally distributed, insulin resistance is present, and with it the metabolic syndrome. It has been estimated that among US adults aged 60 years or older, ≈65% have hypertension and ≈40% have the metabolic syndrome.

 One consequence of insulin resistance is increased sympathetic tone and thus elevated BP.

In these obese individuals,  blockade of increased sympathetic tone  with reserpine, through reduction of  peripheral and central noradrenaline stores, may have a salutary effect in BP control.

 

“Combining a diuretic, which decreases the excess fluid volume associated with the metabolic  syndrome,  and an ACE inhibitor/ARB or CCB,  which protects endothelial function and/or decreases vascular resistance,  represents an effective  treatment plan for the clinician in BP management.

This is in keeping with  growing awareness that combination therapy is an effective means of treatment  but more may have to be done in some patients. The use of reserpine, an additional option, may provide for improvement in management in these individuals. Reserpine is an effective BP-lowering agent. It
is most effective in the elderly and the obese, often when systolic BP is the limiting goal BP measure. It has a very long duration of action (days) and may therefore be helpful in partially adherent patients.

 

“At present, there are no pharmaceutical advocates for the use of reserpine or a clinical trial to test its effects on clinical outcomes. It will only be at the behest of the medical community that consideration be given for the use of low-dosage reserpine (0.05–0.10 mg once daily, often at bedtime) to better control BP. While the exact place for its use can be debated, we believe it deserves strong consideration.”

 

MEMORANDUM  From: Kirsten Myhr, MscPharm, MPH, Member Expert Advisory Panel on Drug Policies and Management http://archives.who.int/eml/expcom/expcom12/kmyhrmemo.docDate: 6 April 2002  To: Co-ordinator, WHO EDL Committee meeting April 2002

Subject: Revision of the essential drugs list

Reserpine

“I think there is documentation to support keeping it as a low cost alternative. Here are five relevant references from Medline, note in particular that it is included in the guidelines in South Africa, even after a recent revision of the guidelines.

1. Kronig B, Pittrow DB, Welzel D, Weidinger G. Different concepts in first-line treatment of essential hypertension. Comparison of  low-dose reserpine-thiazide combination with nitrendipine monotherapy. German Reserpine in Hypertension Study Group. Hypertension. 1997;29: 651-8.     

 2. Griebenow R, Pittrow DB, Weidinger G, Mueller E, Mutschler E, Welzel D.Low-dose reserpine/thiazide combination in first-line treatment of hypertension: efficacy and safety compared to an ACE inhibitor. Blood Press. 1997; 6(5): 299-306.

3. Manyemba J. A randomised crossover comparison of reserpine and sustained-release nifedipine in hypertension. Cent Afr J Med. 1997 Dec;43(12): 344-9.

4. Seedat YK. Hypertension in developing nations in sub-Saharan Africa. J Hum Hypertens. 2000 Oct-Nov;14(10-11): 739-47. Review.

5. Hypertension clinical guideline 2000. S Afr Med J. 2001 Feb; 91(2 Pt 2):163-72.

6. Fraser HS. Reserpine: a tragic victim of myths, marketing, and fashionable prescribing.
Clin Pharmacol Ther. 1996 Oct; 60(4): 368-73.

MYTHBUSTING: Androgen Risk for Prostate Cancer and AntiAndrogen therapy for Most (ie Older) Men with Prostate Cancer

          ARE  PHYSIOLOGICAL ANDROGEN LEVELS, OR ANDROGEN SUPPRESSION THERAPY ie ESTROGEN DOMINANCE, THE GREATER RISK FOR PROSTATE CANCER, QUALITY OF LIFE AND ALL-CAUSE MORTALITY?

Prostate -in 5% of men – and  breast cancer -in 4% of women-  are rarely  the cause of death or long term disability  in caucasians.  So with longevity a growing issue,  the adverse effect of post-midlife sex hormone depletion on other systems- quality of life, muskuloskeletal, mood, immunity and cardiovascular domains, let alone sexuality, is a growing issue. 

The oncologist, the urologist  or breast surgeon presented with a cancer must naturally focus on the immediate issue- deal with the cancer- which may include antihormone therapy. .

 

 The generalist clinician, the family practitioner and longterm carer eg the internist or geriatrician or psychiatrist, on the other hand looks far ahead to the chances of ensuring healthy multisystem longevity after the cancer- for which longterm goals balanced physiological hormone replacement often has merit. .

 

As regards  the risk factors for prostate cancer, Wikipedia sums it up nicely: “Prostate cancer presents clinically at an average age of 70years,  although  found incidentally in about 30% of men in their fifties and 80% of men in their seventies. Prostate cancer affected 18% of American men and caused death in 3% in 2005.  Pollution (eg environmental estrogenics, diethylstilbestrol exposure in utero,  Agent Orange) and genes play perhaps 20% to 80% role, which can hardly be prevented by the individual already in midlife:  In Japan, death from prostate cancer was one-fifth to one-half the rates in the United States and Europe in the 1990s. In India in the 1990s, half of those with cancer confined to the prostate died within ten years. African-American men have 50–60 times more prostate cancer and prostate cancer deaths than men in Shanghai, China. In Nigeria, 2% of men develop prostate cancer and 64% of them are dead after two years.”  

 Dietary:  blood levels of trans fatty acids, (in particular from hydrogenation of vegetable oils), are associated with an increased prostate cancer risk. Other dietary factors that may increase prostate cancer risk include low intake of vitamin E, vitamin D (incl. sunlight),  fish omega-3 fatty acids , and the mineral selenium.” .  

 

Hypocholesterolemia  – whether spontaneous or drug-induced – is associated with increased prostate cancer .

 

Combined vitamins C plus K (in ratio of 100:1)  (Jamison 2001) has also shown promise against prostate cancer.  

 

Huggins got the Nobel prize in  1966 for showing that androgen blockade extended life with  metastatic prostate cancer.

 

BUT what is the relationship between testosterone level and incidence/ severity of prostate cancer and quality of life thereafter?

 

 Oliver & Slater at London University showed already almost a decade ago that men presenting  with prostate cancer have testosterone levels below the average.

 

Abraham Morgantaler  from Boston Mass  this year reviews the increasing evidence that low testosterone, including testosterone blockade, actually increases  mortality from (highgrade) prostate cancer;   let alone the multisystem effects of avoidable sexhormone deficiency (on mood, mind, muscle, skeleton, cardiovascular and immune) that, as in women, probably lose years of healthspan if not also lifespan.

 

Major clinics following cohorts of men long term for well over  a decade  on appropriate physiological testosterone replacement  (after baseline exclusion of cancer markers) report  no increased prostate risk from such replacement , that if anything the incidence of new prostate cancer is half that of their peers; and no cases of subsequent death from prostate cancer in such supervised men have apparently yet been reported.

 

This year :

Shabsingh from Columbia Univ, Rhoden from Brazil  and Morales from Ontario  can still find no evidence that appropriate testosterone replacement increases risk of prostate cancer,  even when commenced after prostate cancer. 

 

Now:

 Dosoreth from Harvard shows the predictable corollary, that treating elderly prostate cancer with anti-androgens  plus radiotherapy XTR  actually gives  20% higher mortality than if   treated with XRT alone.  

 

Horwitz  from Philadelphia puts it practically – treat the cancer with XRT, but   add antiandrogen only if the PSA prostate specific antigen level  rises rapidly.

 

Lu-Yao 2008 shows from SEER USA data  that primary androgen deprivation for prostate cancer actually gave 20% lower prostate-cancer-specific survival over 10 years without reducing  all-cause mortality.

 

Kapoor 2008 and Traish 2008  motivate  that “ Androgen deficiency as a predictor of metabolic syndrome in aging men is an opportunity for intervention”.

 

So the evidence of the past ~70 years grows – as presented at the congresses of the world leaders, the International Society for  Study of Aging Males    and the  International Menopause Society  –  that  in older people, appropriate sexhormone replacement HRT (parenteral testosterone for men, testosterone plus estrogen plus progesterone for women)  to the physiological levels and balance  found before middle age  can actually reduce the risks of cancer death  as well as the risks of all other common  chronic major degenerative disease  (Morales 2008) .

Obviously this is provided HRT  is combined  both with appropriate other microsupplements (minerals vitamins and biologicals eg fish oil, chondroglucosamine, saw palmetto)  and with appropriate surveillance  for and management of cancer, mood, mind, cardiovascular and musculoskeletal systems – which is simple enough for the patient’s personal clinician to handle:  quality of life, memory, mood and sexuality; bloodpressure, bodymass index and waist girth/body fat; breast/pelvic/rectal examination; and occasional appropriate breast/ pelvic imaging, and blood screening- hemoglobin, lipids and PSA prostate specific antigen.    

AGAINST THE TIME-BOMB OF OBESITY: PANACEA GODDESS’ DRUGS: LONGEVITY HEAL-ALL HERBS?

 Adjusted simply and slowly up to the tolerated dose, metformin use in  type 2 diabetics for 30 years- without any major adverse effects longterm – lowers myocardial infarctions and deaths by 30%; over about 5 years it halves mortality, and reverses weight gain to maintain overweight about 6% lower than at baseline; and in prevention trials it halves incidence of new diabetes. .

Search under “disease time bomb” on Google brings up many  lurid reports on  heart, lung, liver, kidney, obesity, infection  threats etc;

eg last week:  :     “In a   new report published in the Lancet  Scientists say we need an  Integrated approach to tackle the chronic disease ‘time-bomb’. Salt and tobacco control, cheap combination drugs for cardiovascular disease as well as simple, easily-applied mental health interventions are all recommended to tackle the disease. The report claims a combination course of therapy involving several drugs for people at high risk of cardiovascular disease could cost as little as $1.10 per person, avert millions of  deaths  over the next ten years. Management of chronic diseases in primary health care was fundamentally different from that for acute care. Primary health care was probably more effective when complemented by effective public policies to tackle the major risk factors, such as tobacco use, obesity, and excessive salt consumption.
             
This month,  as the Paralympics enthral the world, six  new studies – gold medals-  reaffirm the primacy of galega officinalis- the origin of  galegine and thus metformin (Werner and Bell 1922)  – as the parent panacea herb ahead of all comers including statins:

 

1. A major trial  in St Petersburg Russia (Anisimov ea)  shows that feeding  female rats metformin  slowed down the switchoff of oestrus function and increased mean lifespan by 38% and maximum life span by 2.8months- despite failing to influence spontaneous tumour incidence.

 

2. A Swiss analysis  (Bodmerof 50 000 United Kingdom type 2 diabetics (mean age 61yrs at enrolment)  in  general practice in the decade to 2005 – ie mostly  after the 20year UKPDS trial to 1997 –  reassuringly confirms the safety of metformin as shown in the  uniquely long UKPDS.   .

 

3. The 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes  (Holman UKPDS 80)  shows that  after  up to 30years of use in 3277 diabetics, metformin in still attending enrolees continues to sustain  about 30% reduction in myocardial infarction and all-cause mortality – double the reductions by insulin-sulphonylureas- even though there was no longer difference in the HBA1c level achieved. .This  confirms that metformin has unique major benefits beyond lowering  raised blood glucose.

 

4. in Diabetes Vascular Disease Research, the diabetes editor Prof Cliff Bailey from Birmingham UK writes  about Metformin: A multitasking medication 

 

5. In a Veterans Affairs study (Gosmanova U Tennissee)  of 2200 diabetics patients over a mean of 5 years, after multivariate adjustment, metformin users had significantly  23% decreased  all-cause mortality compared with non-metformin users (P < 0.01).

 

6. The ALLHAT study (Rahman USA )  confirmed that In hypertensive patients with moderate dyslipidemia and impaired  kidneys, pravastatin was not superior to usual care in preventing clinical renal outcomes.

 

Safe reduction by 50 to 70% of progression of overweight and  the progressively  irreparable damage and risk that goes with type 2 diabetes (eg AGES- advanced glycation endproducts)  is obviously the mandatory duty of health workers, using promotion of healthy diet and lifestyle as well as pre-obesity  prediabetic  prescription of harmless (antioxidant-anticancer – antivascular disease pro-nitric oxide) insulin sensitizers like fish oil, metformin, vitamin C, carnitine, CoQ10, arginine  and appropriate human sex hormones .  

 

Already in 2000 Bell & Ovale  from Alabama calculated that “when monotherapy fails to control diabetes, combination therapy with a sulfonylurea and metformin is potentially effective in maintaining glycemic control and avoiding the addition of insulin or a thiazolidinedione for a mean duration of 7.9 years“. Thirty years of UKPDS followup has amply confirmed this-  even  in 1998 the UKPDS 24  concluded that “obese patients allocated to metformin gained the least weight and had the fewest hypoglycemic attacks. For all therapies, control achieved at 6 years was worse in the primary diet failure group than in the diet-controlled group. Because initial insulin therapy induced more hypoglycemic reactions and weight gain without necessarily providing better control, it may be reasonable to start with oral agents and change to insulin if goals for glycemic levels are not achieved

 

THE EFFECTIVE ANTIHYPERTENSIVE  PARADIGM:

       By contrast UKPDS 81 published simultaneously with UKPDS 80 last week  showed that in the hypertension study of the UKPDS, after another 10 years of followup of  hypertensive diabetics, the original (cardiovascular) benefit of tighter hypertension control was lost along with the loss of tighter bloodpressure control. 

 

Thus  in contrast to the pluripotential benefits of metformin beyond it’s glucose-regulating benefit, even the multiple antihypertensives used in UKPDS  patients (betablockers, ACEI,  furosemide,  nifedipine,  methyldopa or  prazosin) had no extra heart- or all-disease protection beyond that of tighter hypertension control (just as statins have no benefit other than via improving CVD  through lowering lipidemia; and bisphosphonates no benefit beyond lowering fractures via better bone density).

 

      This is in stark contrast to the gold standard triple best-ever treatment of mild-to-moderate hypertension  – lowdose reserpine about 0.05 (to 0,1)mg daily plus lowdose  6,25 (to12.5)mg hydrochlorthiazide plus 0.6  (to 1.25)mg  amiloride (ie amiloretic) daily-  as shown in numerous trials and studies from the 1970s Veterans to the 1990s German  Reserpine Group and  USA SHEP trials, and  the more recent ALL-HAT trial;   and the Cache County study .

 

     But because these agents are too effective and cheap- costing <US6/year – they  leave little market need for newer patented designer antihypertensive (and stress-blocking and calcium-magnesium- potassium sparing)  drugs that simply do not work as well – and mostly have  major potential adverse effects. So Regulators, academics  and Hypertension “Authorities” -certainly in Europe, UK and South Africa – who depend on the new drug industry for their living – have  simply and infamously  dropped them – see the UK -European and RSA State Formularies.

 

Even Wikipedia subtly mocks eg the UK- Europe cynical disaster capitalism   for dropping reserpine:

Reserpine has been discontinued in the UK for some years due to its vast interactions and side effects. (but..)  is one of the few antihypertensive medications that have been shown in trials  to reduce mortality: the HDFP,[5] the VA  Study Group in Anti-hypertensive Agents,[6] and SHEP.[7]  Reserpine is listed as a second line choice by the JNC 7.[8] . It is an excellent second agent for patients who are uncontrolled on a diuretic.[9]  It is also used to treat symptoms of dyskinesia in patients suffering from Huntington’s disease.[10]  In some countries reserpine is still available as part of combination drugs for the treatment of hypertension, in most cases they contain also a diuretic..  These combinations are currently regarded as second choice drugs. The daily dose of reserpine in antihypertensive treatment is as low as 0.1mg…  At doses of less than 0.2 mg/day, it has few side effects, most common is nasal congestion.[11]There has been much concern about it  causing depression leading to suicide.. however this was reported in uncontrolled studies using doses averaging 0.5 mg per day”.[12][13]

 

In SHEP the Systolic Hypertension in the Elderly Program  trial  in 4700 subjects from 1988 for a mean of 5 years,  even an ordinary thiazide diuretic significantly  lowered CV D mortality by 15%, with improved longterm outcomes. but more important, reduced stroke by 36%  and mortality by 40%..  And  reserpine 0.05 to 0.1mg/d as add-on in resistant cases approximately halved risks of stroke, CVD or mortality.  

 

ALLHAT The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial from 1994 to 2002 with >42, 000 patients was the largest antihypertensive trial. It confirmed  that a diuretic is still overall the baseline best therapy of essential hypertension compared to calcium channel (or beta-)  blocker or ACEI, even for metabolic risk factors ; and that adding a statin for mild to moderate lipidemia did not improve mortality or reduce renal decline ; and  as in SHEP, reserpine as backup add-on was unsurpassed. (Barzilay 2007: Getting to goal blood pressure: why reserpine deserves a second look  ;  J Clin  Hypertension: 2007:9:591-4)

 

Reserpine is criticised for many adverse effects in overdose. But what  foods and therapies do not have adverse effects in overdose?  As authorities here and elsewhere have to admit, reserpine and amiloretic have been sidelined simply because they are so powerful, low cost and safe in well below “traditional” dose – and they do not attract research funds because  they put modern  wannabe  baseline substitute drugs down to 4th-line add-ons. 

 

This does not contradict the  paradigm of good nutrition, that both drug  prevention and micronutrient  therapy should also be broadly based, multiagent for early and maximum control to prevent progression and irreversible damage,  as in eg hypertension, AIDS, vascular disease, tuberculosis, osteoporosis, arthritis, memory loss, osteoporosis etc. .

 

     Bodmer’s 2008 Swiss UK study  also confirms what other studies showed – the three continents’  Diabetes Prevention Program  DPP trials (Wenying 2001 Chinese J Endoc Metab, Knowler 2002 USA,  Ramachandran 2006 India);  the massive one-year COSMIC trial in USA in new diabetics (Cryer 2005); the Saskatchewan retrospective metformin study (Johnson 2002-2006),  the  ACCORD trial  2008, and now the Veterans’ Study 2008 –

     that apart from giving significantly better outcomes and thus survival in both diabetics and pre-diabetics (halving the incidence of new diabetes), metformin to tolerance is also uniquely safer than all other antidiabetic drugs in if anything protecting against co-incidental lactic acidosis (common in older diabetics; Lalau & Race 2000), and with sensible use not producing the  hypoglyemia  that plagues use of all other (ie hypoglycemic)  antidiabetic drugs..

 

METFORMIN AGAINST CANCER:

this column has in the past month reviewed the risk of drastic cholesterol lowering by statins increasing cancer risk.

The panacea role of metformin is  further strengthened by the June 2008  report (Gonzalez-Angulo) from the MD Anderson Cancer Centre Texas  that ” diabetic women who developed  breast cancer on metformin had treble the  pathologic breast cancer complete response rates ie up  from 8% to 24% compared to women not on metformin“. This is further evidence for starting metformin early and permanently in anyone who cannot maintain ideal body fat with diet and exercise alone.

and

a McGill University study (Gotlieb ea 2008) shows that metformin significantly inhibits the growth of ovarian cancer cell lines and potentiates cisplatin  .

 

METFORMIN AND FRACTURES:

the latest study, from Monami Italy 2008 again shows a trend to metformin reducing osteoporosis fractures.

 

METFORMIN AND LONGEVITY:

It has been known for at least 70 years (McKay 1935) if not millennia  that dietary caloric restriction (CR) is the only intervention conclusively  shown to slow aging and prolong  health and vitality in mammals and all species down to yeasts.  Ingram, Roth ea at the NIH  have confirmed  this (2001) “in primates with 2 deoxyglucose, and proposed it also with metformin (2005). Furthermore, it is not known whether CR extends longevity in long-lived species or in the already lean. There is evidence that CR in obese and lean subjects alike improves insulin sensitivity“.

 

Whether it applies equally or more so to good quality CR diet remains to be seen, since historically those subjected involuntarily  to CR have been on poor quality food.

          But very few  free-living species willingly   undergo  permanent  calorie restriction.

Mikhail Blagosklonny  (a medical  scientist  and basic science journal editor at the Ordway Research Centre at Albany Medical College who has authored over 140 publications especially in cancer)  comments last week (Cell Cycle. 2008 Sep;7:2615-8).  “Cancer and aging: more puzzles, more promises? “Anisimov  shows that metformin activates AMP-activated protein kinase, prolongs both mean and maximal life span and prevents reproductive aging of female mice. Unexpectedly, metformin did not decrease the incidence of cancer in this mice strain. Here, we discuss the relationship between aging and cancer, the mechanism of metformin action, and the prospects of using this compound for life span extension in humans.

 Last year Blagosklonny wrote (An anti-aging drug today: from genes to anti-aging pill. Drug Discov Today. 2007):   ”Numerous mutations increase lifespan in diverse organisms from worms to mammals. Most genes that affect longevity encode components of the target of rapamycin (TOR) pathway, thus revealing potential targets for pharmacological intervention. I propose that one target, TOR itself, stands out simply because its inhibitor (rapamycin) is a non-toxic, well-tolerated drug that is suitable for everyday oral administration. Preclinical and clinical data indicate that rapamycin is a promising drug for age-related diseases and seems to have anti-tumor, bone-sparing and calorie-restriction-mimicking ‘side-effects’. I also discuss other potential anti-aging agents (calorie restriction, metformin, resveratrol and sirtuins silent information regulator 2 proteins) and their targets, interference with the TOR pathway and combination with antioxidants.”     But unfortunately rapamycin while it is antifungal and pluripotential, does not have insulin-sensitizing weight-reducing benefits, is very costly (eg  Sirolimus 100mg US$199), and does not have the warranty of centuries of safe use as does galega/metformin.

His  and Anisimov’s work  proposes that  such antiaging regimes delay both senescence and cancer, so that when cancer does break through, the “longevity” regime no longer inhibits it. This concurs with the landmark supermouse studies of Lemon and Rollo at McGill who showed by 2005 that in genetically obese and shortlived mice,  a lifelong 31-ingredient  multimicronutrient supplement from infancy to death (including the evidence-based  vitamins, minerals, biologicals and herbs like flaxseed and DHEA – but not metformin nor fish oil), improved learning, and longevity by 28%, but many of the males developed lymphoma

  These pioneer rodent studies seem to work on the dosing principle that the metabolism of rodents is 10 times faster than  that of humans; so the 100mg/kg/day metformin that Anisimov’s group used equates to a modest 10mg/kg/day in humans, or 750  -1500mg/day in the overweight. It remains to be seen whether this modest dose will be effective in global anti-aging prevention for the average overweight person; as opposed to double that dose ie around 2650mg/day  achieved and tolerated  and needed by average overweight diabetics on metformin.

Using metformin for secondary prevention (ie for the still-well of any age who cannot sustain weight below a threshold of say BMI 25 or 27kg/sqm)-  long before the development of diabetes, obesity and PCOS polycystic ovary syndrome – remains the minefield for most health workers. Many health professionals – who should know better-  still propound the naive dogma that patients can  and must change their personalities and permanently stop smoking and start dieting and exercising strenuously enough to diminish  obesity. Yet do even 10% of patients achieve and maintain even 5% weight loss with such urging,  let alone get anywhere near optimal body composition?.

           This dilemma  of human inability to comply  is nicely summed up by Shelley Wood’s Medscape report on the   Lifestyle, Not Drugs, for Preventing Type 2 Diabetes “Gladiatorial” Debate at the EASD meeting last week. “Dr Zimmet argued  that “glucose-lowering drugs importantly prevent progression to diabetes… environmental, cultural, economic, and sociopolitical forces  work against lifestyle changes in developed countries, many of which are amplified in other parts of the world.         Preventing onset of type 2 diabetes is to reduce the risk of CVD, the clock starts ticking long before the line we actually call diabetes. And whether lifestyle changes alone will be enough to alter long-term effects remains unproven.  Lifestyle interventions can work, but maybe only where you  put people in prison and then rigorously control their exercise and diet regimen,” he said.

              Whereas continued metformin use for 30years in the UKPDS associated with 30% fewer myocardial infarctions  and deaths. 

 

   CONCLUSION:      Metformin is the only agent that has been shown (after about 80 years, and centuries as the parent herb galega) to safely and permanently  assist voluntary effort to restrict calorie intake so as to reduce weight gain and extend health – and has been strikingly successful in achieving and maintaining about 6 to 8% average weight loss in the obese (eg  Glueck 2006), while halving the incidence of new diabetes and halving the deathrate in diabetics,  adding maybe at least  a decade to health and life.

      No designer ie patented multi-tasking drug for chronic use since metformin  (- except possibly the too-cheap discarded combination of lowdose reserpine plus lowdose diuretic)  remotely matches the unique record of metformin plus fish oil, plus a multimucronutrient combination, plus  appropriate HRT in men and women, for reducing all major chronic degenerative diseases and mortality.  

 

TOWARDS THE UNIFYING HYPOTHESIS OF MANAGED ANTIAGING:

A gynecologist – the ultimate “midwife” of fertility, childbirth and womens’ successful midlife – asks: what are the pathogenetic mechanisms common to   the increasing fractures,   increasing stroke-cardiovascular and malignant  disease in the aging?

 

 It goes without saying that we humans are  our own worst enemies and the greatest threat to heathy survival of life. But bad choices and diet-lifestyle, Silent Spring,  and Oryx and Crake  aside:

 

CANCER – the least common clinically, that kills or cripples below 5%- is perhaps  easier to generalize: poisons like smoking, alcohol and asbestos aside, the common cancers  of the latter half of life  – the sex-hormone-related cancers- generally take decades to reach clinical significance, and involve many mechanisms including genetic, environmental, alcohol, smoking, lack of exercise, dietary and above all, random mutations and progressive dysregulation of aging and the millieu interieur.

 

 It is common cause that in both longterm historical followup clinics (Byrd & Burch; Schleyer-Saunders; Gelfand; Greenblatt Gambrell et al; the Nurses Study); and   in the trials- the Womens’ Health Initiative (2002, 2004) and the Oulu trial (Heikkinen 2006), women randomized to  appropriate conservative dose  oral estrogen-progestin from menopause and followed for up to 10 or more years had virtually one-third reduction in all common major diseases including breast and colon cancer, fractures, cardiovascular and dementing diseases, and in cancer- and all-cause mortality. Men followed for a decade and more from initiation of appropriate parenteral testosterone supplementation have similar striking reduction in prostate cancer and in cancer-and all-cause mortality (Behre & Nieschlag Germany; Carruthers London; Kaufman USA)  

 

CARDIOVASCULAR-STROKE DISEASE: it has been recognised for decades that  antioxidants,  and the three antihomocysteine vitamins (B6 B9 B12), and  the 150year old nitric oxide promoter nitroglycerin  NG are major benefit against chronic CVD and it’s  symptoms if not during acute myocardial infarction and stroke. NG remains the mainstay of treatment for angina.

     In acute myocardial infarction, the timing of intravenous NG seems to be crucial if it is to lessen morbidity and mortality (Jugdut Canada 1988), and similarly oral NG seemed to have no benefit following acute myocardial infarction  (Ishikawa  Japan 1996) except with heart failure (Fitzgerald 1990);  but  timeous transdermal NG may give beneficial improvement in cerebral bloodflow after subarachnoid hemorrhage (Reinert Switzerland 2006).

   There are apparently no  definitive randomized controlled trials on Medline  of chronic NG use in patients with chronic angina. But after angioplasty, restenosis angina responds well to NG (42% incidence)  compared to placebo (75%; p<0.003). NG lowered the repeat angiography rate from 23% to 4%.  (Doucet 2000).

 

OSTEOPOROSIS FRACTURES:

Ignoring  fracture incurred as a result of a stroke-induced fall, or visa versa; and ignoring disuse osteoporosis after stroke:

what factors contribute simultaneously to aging osteoporosis and stroke-cardiovascular disease CVD?

 

A forthcoming paper  (Kanawasa ea Japan Oct 2008)  “suggests that metformin can induce the differentiation and mineralization of osteoblasts via activation of the AMPK signalling pathway, and that this drug might be beneficial for not only diabetes but also osteoporosis by promoting bone formation”. It is common cause that  diabetes is associated with weaker bones and more fractures (Yamamoto 2006).

 

Metformin (Werner & Bell  1922) is dimethylguanidine- the only  synthetic drug (a tagged  antihyperglycemic  extract of  the galega officinalis plant) that has been proven to be a panacea against virtually all major diseases, a heavy-metal chelating,  antimicrobial fibrinolytic antineoplastic antihypertensive antioxidant   insulin sensitizer (without increasing C peptide)  that also reduces lipidemia;  and  bone resorption  (and thus unblocks  obesity-related delayed adolescent  growth) via promotion of nitric oxide synthase- possibly via AMP(Kim 2007).  It is the only designer drug  ever that has been proven in a 20 year randomized controlled trial RCT (mean 13.6yrs- the UKPDS, Holman ea 1998) to reduce all major adverse events including cancer and allcause mortality by 36% in diabetics; and reduce new diabetes by about 50% (30 – 70%) in major prevention trials in prediabetics over a mean of about 3 years in the USA, India and Chinese Diabetes Prevention Programs- without a singe major adverse effect. No other designer drug for chronic prevention  can claim such multisystemic benefits and lack of adverse effects in sensible tolerable dose.

 

By contrast, Osdoby ea  1994 reported that  the nitric oxide inhibitor “aminoguanidine also caused a loss of bone mineral density – Inhibition of NOS activity in vitro and in vivo resulted in an apparent potentiation of osteoclast activity”.  So while aminoguanidine was promoted a decade ago  as an antiaging antidiabetic drug against AGES Advanced Glycation  Endproducts   it has not  replaced metformin – despite promises, and thousands of papers  about it on Medline dating back to 1950, no clinical trial results have in fact been published  on Medline showing  aminoguanidine has any significant  longterm benefits.   The severe toxicity  reasons  (the ACTION ll trial) for this are detailed by Montagnani 2008.

 

Nitric oxide   is a key vasodilator, neurotransmitter and immunomodulator; it’s therapeutic level is boosted by nitroglycerine; metformin (Kanazawa 2008); human sex hormones and arginine.. Nobel prizewinner Ferid Murad ea 2008 note that “NO-mediated signalling is a recognized component in various physiologic processes (eg, smooth muscle relaxation, inhibition of platelet and leukocyte aggregation, attenuation of vascular smooth muscle cell proliferation, neurotransmission, and immune defence), to name only a few. NO has also been implicated in the pathology of many inflammatory diseases, including arthritis, myocarditis, colitis, nephritis and a large number of pathologic conditions such as amyotrophic lateral sclerosis, cancer, diabetes, and neurodegenerative diseases. Some of these processes (eg, smooth muscle relaxation, platelet aggregation, and neurotransmission) require only a brief production of NO at low nanomolar concentrations and are dependent on the recruitment of cyclic guanosine monophosphate (cGMP)-dependent signalling.”      So, as with oxygen, vitamins, minerals, biologicals, foods, alcohol  and all therapeutics, balance – the right amount- is everything.

 

Interestingly, while arginine and appropriate testosterone-estrogen supplements usually boost insulin sensitivity as well as  low growth hormone HGH levels and thus anabolism in bone, muscle etc, a nitric oxide promoter eg nitroglycerin in its own right  has the same benefit as ERT in preserving good bone mass (Hao ea China 2005). This was already shown in chicks by Osdoby ea 1994,  based on a postulate by MacIntyre ea 1991 . – who subsequently demonstrated this in rats (MacIntyre 2003).  

 

Estrogen is a known immunostimulator  whereas progesterone and testosterone are known immunomodulators.    In vitro, estrogen too may have  a dimorphic effect on nitric oxide (Walsh 2003; Shih 2006; Richette 2007).  But in postmenopausal women transdermal or oral  ERT  with or without cyclic progestin for 6 – months increases NO levels (Serin 2001; Kesim 2005).

 

Pance 2006 notes that “estrogen and progesterone  regulate the nitric oxide synthases (NOS) and, in turn, the NO produced has profound consequences on tumor cell homeostasis. On one hand, estrogen increases the activity of endothelial NOS (eNOS or NOSIII), while progesterone activates inducible NOS (iNOS or NOSII) expression. The data presented suggest that the low levels of NO produced by NOSIII mediate the proliferative effect of estrogen. On the other hand, the increase in apoptosis in response to progesterone could implicate the high levels of NO produced by induction of NOSII expression”

 

                Testosterone on the other hand is the well-known crucial  erectile stimulator of nitric oxide synthetase   (Shabsingh 2004)  . 

 

So  apart from genetic programming and accumulating levels of environmental toxins, there are  at least six  possible pathophysiologies common to  the  preventible aging comorbidities of  apoptosis, fattening-diabetes-cancer; osteoporosis-fractures, and CVD-stroke:

*catabolism by gonadopause deficiency without a balancing fall in catabolic cortisol levels;

*nitric oxide depletion;

*increased reactive oxygen species ROS due to depleting endogenous and dietary antioxidants; 

*common aging-related deficiency of minerals eg magnesium, zinc,chromium, lithium; vitamins; and human biologicals eg    chondroglucosamine, CoQ10, carnitine, ribose, arginine, carnosine, Nacetylcysteine;  

*insulin resistance – prediabetes, metabolic syndrome, diabetes; and

*accumulating multiple metal overload eg cadmium, iron, aluminium, mercury, lead, arsenic copper (even zinc and iron)  from  smoking, food and environmental  pollution  that can simultaneously promote cancer, neurovascular  and osteoporosis problems

 

Obviously the basket of natural supplements-  fish oil, cal-mag zinc boron, the vitamins A ( bcarotene) to K, and the human biologicals proline, CoQ10, arginine, ribose, carnitine  and appropriate  hormone balance with eg testosterone-estradiol, growth hormone, and galega extract,  are trophic in improving anabolism, antioxidation, optimal NO levels and preventing AGES, atheroma and arteriosclerosis as well as collagen and mineral loss from diverse muscle and bone – ie preventing many  of the risk factors for both fractures (frailty, weak  bones and muscles – skeletal and smooth ie  gastrointestinal and heart ) and vascular disease .

 

Given the common pathogenetic factors of all the common major aging diseases,  one should simply add natural arginine glutamine and proline,  in addition to the vitamins, minerals, glucosamine-chondroitin, and the other natural insulin sensitizers eg N acetyl cysteine, ribose, carnitine, CoQ10 and galega officinalis, to the natural supplements  to combat all aging diseases; and when hypogonadism becomes likely- with chronic illness, or from middle age- add appropriate parenteral balanced  physiological-dose testosterone-estradiol- progesterone to restore the average levels of healthy slim youthful adults.

 

While some of these above  may be chelators in their own right, the high prevalence of metal overload may justify routine addition to supplements (within recognized tolerance and safe limits)  of extra harmless putative chelators like calcium EDTA, carnitine, bromelain,  garlic,  malic acid, cysteine, lipoic acid, vitamin C, selenium, thiamine, magnesium, selenium, zinc and bromelain.

 

ndb

 

The first comment attached below is appropriately from

Professor  Frederick Naftolin MD, PhD, FACOG, FRCOG

past Chairman of OB/GYN at McGill and Yale Universities, then Prof of Biology at Yale,
now Professor of Obstetrics and Gynecology
Director, Reproductive Biology Research
Co-director Interdisciplinary program in Menopause Medicine
New York University School of Medicine

ARTHROSCOPY FOR MILD-MODERATE KNEE OSTEOARTHRITIS NO BENEFIT OVER MEDICAL RX

A new Canadian university  study (Kirkley 2008)  randomized some 170  patients with mild-to-moderate osteoarthritis  to arthroscopic debridement AD  of the knee or noninvasive medical – physical therapy. After 2 years of followup there was no signifiant difference in outcome between the operated and those treated conservatively. 

In 2008 so far, while there is no question of the value of arthscopic intervention for severe or blocked cases, especially in professional  eg “sports” workers, expert reviews conclude: 
 London University  (Axford   ” the treatment of depression and pain may be paramount to the successful treatment of knee OA”.
 
from New York (Lementowski 2008) focusses on the importance of reversing obesity.
 
from Israel (Bloom) “Osteoarthritis (OA) is the leading cause of knee morbidity. Age and overweight are the main risk factors for development of knee OA. The majority of patients respond to conservative treatment”
 
a Thailand Cochrane review of arthroscopic debridement (Laupattarakasem) found “There is ‘gold’ level evidence that AD has no benefit for undiscriminated OA (mechanical or inflammatory causes).
 
Creighton University (Gregory) concluded “most research suggests that glucosamine plus chondroitin  sulfate can improve symptoms of pain related to osteoarthritis, as well as slow disease progression in patients with osteoarthritis of the knee.  S-adenosylmethionine may reduce pain but high costs and product quality issues limit its use. Several other supplements are promoted for treating osteoarthritis, such as methylsulfonylmethane MSM, devil’s claw, Curcumin and ginger”,.
We have recently reviewed below (12 April, 24 June)  the good evidence that combined chondroglucosamine after a  few months reverses apparently intractible OA of the knees. Until the joint re-surfacing with  cartilage kicks in, natural analgesic antiinflammatories and overweight-reducing antidepressants  eg fish oil plus  5HTP plus MSM-curcumin-cat’s claw- bromelain-boswelia – pantothenic acid should be taken.

 

Vits B12, D3, FISH OIL, BRAIN DEVELOPMENT and PRESERVATION

Yesterday we reviewed the new data promoting vitamin D to the top pole position.
Supplements are about far more than promoting development, “wellbeing”, antiaging and longevity. None of these matter unless there is a good mind and spirit to work, enjoy and manage all.

 

                        While  correcting common Vitamin D3 deficiency may be the most important step needed against all common diseases including the commonest- vascular, infections, cancer, osteoporosis, autoimmune,
since the brain – mind, mood and function- is arguably the heart and meaning of  being and living, v
itamin D and it’s major food carrier fish oil’s  most important role may be in promoting and protecting the brain from conception to dotage.
                McCann and Ames from San Francisco’s Oakland Research Institute recently published an exhaustive review of vitamin D deficiency and brain dysfunction  in infant and adult rodents and humans; concluding that “while evidence has not yet fully satisfied causal criteria, vitamin D3 supplementation of at-risk groups including nursing infants, the very darkskinned,  and the elderly, appear warranted; with suggestion by some authorities that the threshold  for diagnosing vitamin D3 deficiency be raised even above a blood level of  77.5nmol/L  31ng/ml.   


Psychiatrist John Cannell also from California argues: “Apparent increase in prevalence of autism  the last 20 years corresponds with increasing advice to avoid the sun, advice that has probably lowered vitamin D levels and  lowered activated vitamin D  calcitriol levels in developing brains. Severe vitamin D deficiency during pregnancy disrupts dozens of proteins involved in brain development and leads to rat pups with increased brain size and enlarged ventricles, abnormalities similar to those found in autistic children… . Children with vitamin D deficient rickets have several autistic markers that apparently disappear with high-dose vitamin D treatment. Estrogen and testosterone have very different effects on calcitriol’s metabolism, differences that may explain the striking male/female sex ratios in autism. Calcitriol down-regulates brain production of inflammatory cytokines  that have been associated with autism. Consumption of vitamin D containing fish during pregnancy reduces autistic symptoms in offspring. Autism is more common with  impaired UVB penetration such as  in poleward latitudes, urban areas, high air pollution, high rainfall, and  dark-skinned persons (in whom maternal vitamin D deficiency is exceptionally common). Simple Gaussian distributions of the enzyme that activates neural calcitriol combined with widespread gestational and/or early childhood vitamin D deficiency may explain both the genetics and epidemiology of autism. If so, much of the disease is iatrogenic, brought on by medical advice to avoid the sun.”
 
Herndon et al from  University of Colorado ask  recently:  Does Nutritional Intake Differ Between Children with Autism Spectrum Disorders and Children with Typical Development?  they compared “Consumption of macro- and micronutrients and food group servings by children with autism spectrum disorders (ASDs; n = 46) and typical development (n = 31); Children with ASDs consumed significantly lower dairy servings, which deficit  persisted after controlling for child age and sex and parental dietary restrictions, and excluding children on the gluten-free casein-free (GFCF) diet. Large proportions of children in both groups did not meet national recommendations for daily intake of fiber, calcium, iron, vitamin E, and vitamin D.”
 
Now Vogiatzoglou, Smith ea from the Universities of Oxford, UK; Oslo, Norway; &  Australia publish “a prospective 5year followup  of 107 community-dwelling volunteers aged 61 to 87 years without cognitive impairment at enrollment, showing that  decrease in brain volume was greater among those with lower vitamin B12 levels and higher plasma homocysteine  levels at baseline, associations significant after adjustment for age, sex, creatinine, education, initial brain volume, cognitive test scores,  blood pressure, ApoE 4 status,  homocysteine and folate. Using the upper (for the vitamins) or lower tertile (for the metabolites) as reference in analysis and adjusting for the above covariates, vitamin B12 in the bottom tertile (<308 pmol/L) was associated with  sixfold increased rate of brain volume loss. High levels of homocysteine or low levels of folate were not associated with brain volume loss. Low vitamin B12 status should be further investigated as a modifiable cause of brain atrophy and of likely subsequent cognitive impairment in the elderly”. .
 
So while there are dozens of crucial factors before and after conception  in (neurological) structure, function and memory development and preservation-  from balanced foods and lifestyle including avoiding  trauma, smoking, alcohol, irradiation, microbial  and heavy metal excess to optimal nuturing and body composition including bloodpressure control- 
           safely measuring vitamin B12 and D levels, and  safely supplementing  low EPA eicosapentanoic acid EPA and docosahexanoic acid DHA ( as cod liver 4g/d) as well as low B12 and D levels into the  top quintile  of the “normal” range for pale skinned people in temperate climates- with eg vitamin D3  10 000iud and B12  eg 0.5mg/d-  may radically reduce the incidence of not just  childhood developmental, learning, behaviour, mood and aging memory/dementia problems.
        It will  also reduce  lifelong susceptibility to infection, fertility and growth disorders, osteoporosis, arthritis, common cancers (breast, prostate, skin),  autoimmune, vascular and skin diseases, and  premature aging. 
 
          These simple supplements- for below R2.50  a day,  US$10  a month-  may indeed radically improve fertility,  pregnancy, childhood,  work and successful aging outcomes.