(No emergencies or surgery- these must go to nearest polyclinic or hospital ER). .
or consultations by Telephone/email where appropriate.
or consultations by Telephone/email where appropriate.
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 :
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
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,
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
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
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
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
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.
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 high–dose 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. High–dose vitamin D (approximately 10,000 IU/day) in multiple sclerosis is safe, with evidence of immunomodulatory effects. This trial provides Class II evidence that high–dose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on high–dose supplementation. The trial, however, lacked statistical precision. , providing only Class level IV evidence for these outcomes.
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 2 months +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.
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.
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, Sydney: Adjuvant 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 .” 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. .
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
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.
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.
firstname.lastname@example.org for previous reviews see https://healthspanlife.wordpress.com/?s=reserpine+
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.
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 22–year 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.
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. Notably, reserpine was the first compound shown to be an effective antidepressant in a randomized placebo-controlled trial. 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.
“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 Hypertension Detection and Follow-up Program, the Veterans Administration Cooperative Study Group in Anti-hypertensive Agents, , 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. Reserpine is a second-line adjunct agent for patients who are uncontrolled on a diuretic when cost is an issue. 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/d. At 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. 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 CCB. HCTZ 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?
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.
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.
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.
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.
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.
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. .
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.
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.
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
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.
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.
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.
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.
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:
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.
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.
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.
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:
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 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.“