Category Archives: pain

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

update

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

MODERN SYNTHETIC PALLIATIVES- ANTIDEPRESSANTS,ANTIPSYCHOTICS, ANALGESICS, STATINS AND ANTI-INFLAMMATORIES – ARE RISKY NON-CURATIVE ESTROGENIC /FERTILITY ie METABOLIC ENDOCRINE DISRUPTORS

Accompanying his 32year old partner (with like her mother  BRCA+ breast cancer ), a   young man this week complains sorrowfully  of total erectile failure within three  days every time he resumes fluoxetine for longstanding depression.

This may suit those patients who eschew sexuality, who knowingly choose chemical castration.. But the drug doesnt fix the causes of depression, merely palliates, often no better than a placebo, sometimes worse- compared to natural multibeneficial  antidepressant supplements.

We already long  live in a sea of estrogenic endocrine disruptors decimating many species including humans,  like pesticides and PCBs, as so aptly described by Deborah Cadbury and Prof Nils Skakkebaek in classic books  eg The Feminization of Nature and The Estrogen Effect.

The commonest prescription  drugs (synthetics- antidepressants; major psychotropes;  amoxicillin,   oxidants ( betablockers eg atenolol;  nonsteroidal anti-inflammatory NSAID (which block antidepressant effects –the Paul Greengard hypothesis 2011 Rocherfeller Inst NY);  statins (cholesterol -steroid and insulin disruptors), and patent synthetic sex hormones-  are  now routine if not mandatory prescription  worldwide due to ruthless relentless marketing pressure-  disease-mongering for profit-  even in children, and worse,  in patients with cancers. The  commonest cancers- breast, prostate, uterus-  are estrogen-driven.

Such environmentally and biologically hostile designer patent drugs-for-profit   are increasingly detectable in surface wastewater globally  from human excretion, and thus drinking  water supplies .

Endocrine disruption studies of antidepressants  (eg fluoxetine Prozacs, mianserin Lantanon (its commercial analogue successor is now Remeron), Bupropion Wellbutrin Zyban;  Venlafaxine Effexor  and desimipramine)  in surface water in Canada,  USA,  Mexico, Brazil and Belgium since 2006, and longer for antipsychotics, statins  and NSAIDS, show estrogenic  ie antiandrogenic risks  for eg gender development and thus for breast/prostate cancer,   for  virility and fertility..

Doctors  mostly blithely  ignore that reproductive young females  have by evolutionary reproductive  necessity  100fold  lower androgenic:estrogenic balance (eg 3:1) than men (eg 300:1), and are also far more prone  than males both to estrogenic contraception prescription harm, and  to common  major depression and autoimmune disease like rheumatod arthritis and lupus, and thus to  the double peril of mutiple estrogenic  prescription.

Recently common NSAIDs eg ibrufen, diclofenac  and mefanemic acid have been shown to be estrogenic in fish.

But such elective  prescription of ( endocrine disruption) cancer- and infertility- promotors (antidepressants, NSAIDS, hormone contraception and HRT etc) ,  is hardly desirable or ethical  at any age, especially when patients and their parents  are not informed of the grave risks of these drugs with no proven longterm benefits (except for contraception).

new reviews  gives more insight  from a plastic surgeon into prevention, including the harms of xray mammography.

and into the gross dangerous overprescription  of diabetogenic depressing  hepato-nephro-myotoxic  statins for all.

Popular painkillers eg opioids like oxycodin, fentanyl, tramadol on the other hand are similarly also  powerful longacting hypoandrogenism–inducing drugs   promoting estrogen dominance – which further complicates the misery and depression of those in chronic pain or depression,  including from  cancer, especially in women as well as men;  who thus  require monitoring of gonadal hormone levels and, if deficient, testosterone replacement. Aloisi ea Univ Siena 2012.

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Reprod Toxicol. 2012:34:80-5. In vivo and in vitro estrogenic activity of the antidepressant fluoxetine.Müller JC, Imazaki PH, Boareto AC, Lourenço EL, Golin M, Vechi MF, Lombardi NF, Minatovicz BC, Scippo ML, Martino-Andrade AJ, Dalsenter PR.  University of Paraná,  Brazil.     .Recent years have seen an increase in the use of antidepressant drugs, especially fluoxetine (FLX), in sensitive populations, such as pregnant and lactating women. Although some evidence suggests a possible endocrine action of FLX, no specific studies have been performed to investigate this hypothesis. In the present study, we investigated the possible (anti)androgenic and (anti)estrogenic actions of FLX using Hershberger, uterotrophic (0.4, 1.7, and 17mg/kg), and reporter gene (7.6-129μM) assays. In the Hershberger assay, no differences were observed in androgen-dependent organ weights. However, the uterotrophic and gene reporter assays indicated a possible estrogenic action of FLX. Uterine weight increased in the 1.7 and 17mg/kg/day groups in the 3-day uterotrophic assay in immature rats. Additionally, noncytotoxic concentrations of FLX induced estrogenic responses and increased the estrogenic response of estradiol in MCF-7 breast cancer.    Recent years have seen an increase in the use of antidepressant drugs, especially fluoxetine (FLX), in sensitive populations, such as pregnant and lactating women. Although some evidence suggests a possible endocrine action of FLX, no specific studies have been performed to investigate this hypothesis. In the present study, we investigated the possible (anti)androgenic and (anti)estrogenic actions of FLX using Hershberger, uterotrophic (0.4, 1.7, and 17mg/kg), and reporter gene (7.6-129μM) assays. In the Hershberger assay, no differences were observed in androgen-dependent organ weights. However, the uterotrophic and gene reporter assays indicated a possible estrogenic action of FLX. Uterine weight increased in the 1.7 and 17mg/kg/day groups in the 3-day uterotrophic assay in immature rats. Additionally, noncytotoxic concentrations of FLX induced estrogenic responses and increased the estrogenic response of estradiol in MCF-7 breast cancer cells transfected with luciferase.
Pharmacol Biochem Behav. 2013103: 659-65..Participation of estrogen receptors in the antidepressant-like effect of prolame on the forced swimming test. Lemini C, Cruz-López B, Martínez-Mota L  Universidad Nacional Autónoma de México, Mexico.Estrogen therapy may produce antidepressant-like actions, but the side effects, such as thromboembolic events, may restrict its use among women. The 17β-aminoestrogens (AEs) [prolame [17β-(3-hidroxy-1-propylamino)-1,3,5(10)-estratrien-3-ol)], butolame [17β-(3-hidroxy-1-butylamino)-1,3,5(10)-estratrien-3-ol)], and pentolame [17β-(5-hidroxy-1-pentylamino)-1,3,5(10)-estratrien-3-ol)] induce estrogenic and anticoagulant actions, effects that could prove advantageous in an estrogen therapy; however, their antidepressant-like effects have not been described. The objective of this study was to determine the effect of these 17β-AEs (prolame, butolame and pentolame) in the forced swimming test (FST), an animal model sensitive to antidepressant drugs, and to establish the role of estrogen receptors in such actions. Ovariectomized female rats treated with prolame (10-200 μg/rat) showed a reduction in immobility and an increase in active behaviors in the FST, while this effect was not produced by butolame and pentolame (10-200 μg/rat). The antidepressant-like effect of prolame was similar to that of 17β-estradiol (E2, 5-20 μg/rat), sharing with it a biphasic profile but at higher doses. Antidepressant-like actions of prolame and E2 were not associated with changes in locomotor activity. With respect to a control group tamoxifen (15 mg/kg) by itself produced no changes in all behavioral evaluations, but canceled the antidepressant-like effect of prolame and E2. It is concluded that estrogen receptors participate in antidepressant-like effect of both estrogens in the FST. Antidepressant-like activity of different AEs is discussed considering their differences in chemical structure and the schedule used. Our results show additional central actions of prolame besides its pro-sexual, anti-coagulant, estrogenic and anxiolytic activity.
Aquat Toxicol. 2011:104::38-47. Selective uptake and biological consequences of environmentally relevant antidepressant pharmaceutical exposures on male fathead minnows. Schultz MM, Painter MM, Bartell SE, Logue A, Furlong ET, Werner SL, Schoenfuss HL  The College of Wooster, OH   USA   Antidepressant pharmaceuticals have been reported in wastewater effluent at the nanogram to low microgram-per-liter range, and include bupropion (BUP), fluoxetine (FLX), sertraline (SER), and venlafaxine (VEN). To assess the effects of antidepressants on reproductive anatomy, physiology, and behavior, adult male fathead minnows (Pimephales promelas) were exposed for 21 days either to a single concentration of the antidepressants FLX, SER, VEN, or BUP, or to an antidepressant mixture. The data demonstrated that exposure to VEN (305 ng/L and 1104 ng/L) and SER (5.2 ng/L) resulted in mortality. Anatomical alterations were noted within the testes of fish exposed to SER and FLX, both modulators of the neurotransmitter serotonin. Additionally, FLX at 28 ng/L induced vitellogenin in male fish–a common endpoint for estrogenic endocrine disruption. Significant alterations in male secondary sex characteristics were noted with single exposures. Effects of single compound exposures neither carried over, nor became additive in the antidepressant mixtures, and reproductive behavior was not affected. Analysis of brain tissues from the exposed fish suggested increased uptake of FLX, SER and BUP and minimal uptake of VEN when compared to exposure water concentrations. Furthermore, the only metabolite detected consistently in the brain tissues was norfluoxetine. Similar trends of uptake by brain tissue were observed when fish were exposed to antidepressant mixtures. The present study demonstrates that anatomy and physiology, but not reproductive behavior, can be disrupted by exposure to environmental concentrations of some antidepressants. The observation that antidepressant uptake into fish tissues is selective may have consequences on assessing the mode-of-action and effects of these compounds in future studies.

Aquat Toxicol. 2010 ;100:354-64    .Waterborne fluoxetine disrupts the reproductive axis in sexually mature male goldfish, Carassius auratus.nMennigen JA, Lado WE, Zamora JM, Duarte-Guterman P, Langlois VS, Metcalfe CD, Chang JP, Moon TW, Trudeau VL  University of Ottawa, Ontario, Canada.    Fluoxetine (FLX) is a pharmaceutical acting as a selective serotonin reuptake inhibitor and is used to treat depression in humans. Fluoxetine and the major active metabolite norfluoxetine (NFLX) are released to aquatic systems via sewage-treatment effluents. They have been found to bioconcentrate in wild fish, raising concerns over potential endocrine disrupting effects. The objective of this study was to determine effects of waterborne FLX, including environmental concentrations, on the reproductive axis in sexually mature male goldfish. We initially cloned the goldfish serotonin transporter to investigate tissue and temporal expression of the serotonin transporter, the FLX target, in order to determine target tissues and sensitive exposure windows. Sexually mature male goldfish, which showed the highest levels of serotonin transporter expression in the neuroendocrine brain, were exposed to FLX at 0.54μg/L and 54μg/L in a 14-d exposure before receiving vehicle or sex pheromone stimulus consisting of either 4.3nM 17,20β-dihydroxy-4-pregnene-3-one (17,20P) or 3nM prostaglandin F₂(α) (PGF₂(α)). Reproductive endpoints assessed included gonadosomatic index, milt volume, and blood levels of the sex steroids testosterone and estradiol. Neuroendocrine function was investigated by measuring blood levels of luteinizing hormone, growth hormone, pituitary gene expression of luteinizing hormone, growth hormone and follicle-stimulating hormone and neuroendocrine brain expression of isotocin and vasotocin. To investigate changes at the gonadal level of the reproductive axis, testicular gene expression of the gonadotropin receptors, both the luteinizing hormone receptor and the follicle-stimulating hormone receptor, were measured as well as expression of the growth hormone receptor. To investigate potential impacts on spermatogenesis, testicular gene expression of the spermatogenesis marker vasa was measured and histological samples of testis were analyzed qualitatively. Estrogen indices were measured by expression and activity analysis of gonadal aromatase, as well as liver expression analysis of the estrogenic marker, esr1. After 14d, basal milt volume significantly decreased at 54μg/L FLX while pheromone-stimulated milt volume decreased at 0.54μg/L and 54μg/L FLX. Fluoxetine (54μg/L) inhibited both basal and pheromone-stimulated testosterone levels. Significant concentration-dependent reductions in follicle-stimulating hormone and isotocin expression were observed with FLX in the 17,20P- and PGF₂(α)-stimulated groups, respectively. Estradiol levels and expression of esr1 concentration-dependently increased with FLX. This study demonstrates that FLX disrupts reproductive physiology of male fish at environmentally relevant concentrations, and potential mechanisms are discussed.

Pharmacol Biochem Behav. 2008 ;88:332-40.Estrogens participate in the antidepressant-like effect of desipramine and fluoxetine in male rats.Martínez-Mota L, Cruz-Martínez JJ, Márquez-Baltazar S, Fernández-Guasti A  Instituto Nacional de Psiquiatría  Mexico City In male rats, the antidepressant-like effect of fluoxetine (FLX) and desipramine (DMI) in the forced swimming test (FST) is reduced by orchidectomy and partially restored by testosterone (T). It is unknown if this modulation of T is produced by its estrogenic metabolites. The objectives of this study were to evaluate if the aromatase inhibitor, formestane, interferes with the antidepressant-like effect of DMI and FLX in intact male rats, and to analyze if 17beta-estradiol (E2) modifies the FST and interacts with the antidepressants in orchidectomized (Orx) males. Intact males received DMI (1.25-5.0 mg/kg) and FLX (2.5-10 mg/kg) alone or in combination with formestane (17.5 mg/kg). Orx rats received E2 (5, 10, 20 and 40 microg/rat) or the combination of E2 [at sub-threshold (5 microg/rat) and optimal (10 microg/rat) doses] plus sub-effective doses of DMI (2.5 mg/kg) or FLX (10 mg/kg). Serum testosterone and estradiol levels were measured in intact-control and -formestane treated animals as well as in castrated males replaced with various doses of E2. Formestane in intact males lacked of an action in the FST, but cancelled the antidepressant-like effect of DMI and FLX. E2 at the supra-physiological doses of 10 and 20 microg/rat produced antidepressant-like effects. E2 at 5 microg/rat (that re-established the levels of this hormone to physiological levels) and at 10 microg/rat restored the antidepressant-like action of DMI and FLX in Orx rats. It was concluded that estrogens participate in the antidepressant-like effect of DMI and FLX in the FST.

Chemosphere. 2006:;65:1836-45.. Effects of the antidepressant mianserin in zebrafish: molecular markers of endocrine disruption.van der Ven K, Keil D, Moens LN, Hummelen PV, van Remortel P, Maras M, De Coen W. University of Antwerp,  Belgium.    Due to their environmental occurrence and intrinsic biological activity, human pharmaceuticals have received increasing attention from environmental and health agencies. Of particular, ecotoxicological concern are drugs that affect nervous- and endocrine-systems. Zebrafish genome-wide oligo arrays are used to collect mechanistic information on mianserin-induced changes in gene expression in zebrafish. Gene expression analysis in brain and gonad tissue clearly demonstrated the estrogenic activity of mianserin and its potency to disrupt normal endocrine (estrogenic) signaling, based on induction of molecular biomarkers of estrogenicity (e.g., vitellogenin1 and zona pellucida proteins). The possible mechanism underlying this estrogenic activity of mianserin is disturbance of the Hypothalamo-Pituitary-Gonadal (HPG) axis by direct interference of mianserin with the serotonergic and adrenergic systems in the brain of zebrafish. Taking into account the importance of the HPG-axis, and considering the concept of ‘critical window of exposure’, our results reveal the importance for more elaborate testing of endocrine disruptive effects of aquatic antidepressants at different lifestages and during longer exposure periods (e.g., life cycle studies). Although there is a low concordance between the gene expression results in this study and previous cDNA microarray hybridizations, the global mechanistic expression patterns are similar in both platforms. This argues in favor of pathway-driven analysis of gene expression results compared to gene-per-gene analysis.

 

J Hazard Mater. 2013 Jun 15;254-255:242-51. .Effects of non-steroidal anti-inflammatory drugs on hormones and genes of the hypothalamic-pituitary-gonad axis, and reproduction of zebrafish.  Ji K, Liu X, Lee S, Kang S, Kho Y, Giesy JP, Choi K. Seoul National University,  Korea.This study was conducted in two experiments, to identify non-steroidal anti-inflammatory drugs (NSAIDs) with high endocrine disruption potentials, and to understand consequences of exposure to such NSAIDs in fish. In the first experiment, the effects of five NSAIDs on hormones and gene transcriptions of the hypothalamic-pituitary-gonad (HPG) axis were evaluated after 14 d exposure of adult zebrafish. Ibuprofen and mefenamic acids were identified to increase the concentrations of 17β-estradiol and testosterone in females significantly, while decreased those of testosterone among male fish. Significant up-regulation of fshβ, lhβ, fshr and lhr were observed in females, whereas down-regulation was observed in males exposed to each NSAID. In the second experiment, ibuprofen was chosen as a model chemical. Adult zebrafish pairs were exposed to ibuprofen for 21 d, and the effects on reproduction and development of offspring were examined. The egg production was significantly decreased at ≥1 μg/L ibuprofen, and parental exposure resulted in delayed hatching even when they were transferred to clean water for hatching. The results demonstrated that ibuprofen could modulate hormone production and related gene transcription of the HPG axis in a sex-dependent way, which could cause adverse effects on reproduction and the development of offspring.

University of Algarve, Portugal  .buprofen (IBU) is one of the most sold over-the-counter non-steroidal anti-inflammatory drugs (NSAID) and widely detected in the aquatic ecosystems. Nevertheless, the information regarding IBU effects in biota is still sparse. The goal of this study was to assess IBU potential effect as oxidative stress and endocrine disruption inducer in mussel Mytilus galloprovincialis applying a battery of biomarkers. Over two weeks of exposure to IBU (250 ngL(-1)), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), phase II glutathione S-transferase (GST) activities and lipid peroxidation (LPO) levels were determined in the digestive gland and alkali-labile phosphates (ALP) were carried out in sex-differentiated mussels’ gonads. The results confirm a transitory induction of antioxidant activities responses concomitant to lipid peroxide formation outline and an increase of ALP levels over time, particularly in exposed males which may lead to mussels’ reproductive fitness impairment highlighting a higher impact of IBU as an endocrine disruptor than as a short-term reactive oxygen species (ROS)-generator.

 

Aquat Toxicol. 2011 ;105:264-9..Non-steroidal anti-inflammatory drug (NSAID) ibuprofen distresses antioxidant defense system in mussel Mytilus galloprovincialis gills.Gonzalez-Rey M, Bebianno M   University of Algarve,  Portugal.Active pharmaceutical ingredients (APIs) are presently considered an emergent class of environmental contaminants. Ibuprofen (IBU) is one of the most applied non-steroidal anti-inflammatory drugs (NSAIDs) in the world. Several authors report the occurrence of IBU in influents and effluents of waste water treatment plants (WWTPs), surface, river and public tap water in numerous countries. However, very little is known about the risks and chronic effects of IBU exposure in non-target organisms. This approach undertakes the assessment of several oxidative stress biomarkers responses through the analysis of antioxidant enzymes activities (superoxide dismutase – SOD, catalase – CAT, glutathione S-transferase – GST, glutathione reductase – GR) and lipid peroxidation (LPO) levels in sentinel species mussel Mytilus galloprovincialis gills exposed for 2 weeks to an environmental realistic concentration of IBU. Results clearly show the significant induction and positive correlation between SOD activity and LPO in exposed gills, concomitant to an antioxidant defense depletion of CAT, GR and GST compared to controls. The integration of all biomarkers in mussels’ gills separates non- and exposed groups supporting the breakdown of the redox defense system and IBU’s pro-oxidant action. Further studies are needed to test possible endocrine disruption effects in mussels’ reproduction fitness as IBU is involved on prostaglandins biosynthesis inhibition.

BMC Med. 2013; 11:57..  The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. Schooling CM, Au Yeung SL, Freeman G, Cowling BJ. CUNY School of Public Health  York, .Statins are extensively used for cardiovascular disease prevention. Statins reduce mortality rates more than other lipid-modulating drugs, although evidence from randomized controlled trials also suggests that statins unexpectedly increase the risk of diabetes and improve immune function. Physiologically, statins would be expected to lower androgens because statins inhibit production of the substrate for the local synthesis of androgens and statins’ pleiotropic effects are somewhat similar to the physiological effects of lowering testosterone, so we hypothesized that statins lower testosterone.   METHODS:A meta-analysis of placebo-controlled randomized trials of statins to test the a priori hypothesis that statins lower testosterone. We searched the PubMed, Medline and ISI Web of Science databases until the end of 2011, using ‘(Testosterone OR androgen) AND (CS-514 OR statin OR simvastatin OR atorvastatin OR fluvastatin OR lovastatin OR rosuvastatin OR pravastatin)’ restricted to randomized controlled trials in English, supplemented by a bibliographic search. We included studies with durations of 2+ weeks reporting changes in testosterone. Two reviewers independently searched, selected and assessed study quality. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting.RESULTS:Of the 29 studies identified 11 were eligible. In 5 homogenous trials of 501 men, mainly middle aged with hypercholesterolemia, statins lowered testosterone by -0.66 nmol/l (95% confidence interval (CI) -0.14 to -1.18). In 6 heterogeneous trials of 368 young women with polycystic ovary syndrome, statins lowered testosterone by -0.40 nmol/l (95% CI -0.05 to -0.75). Overall statins lowered testosterone by -0.44 nmol/l (95% CI -0.75 to -0.13).    CONCLUSIONS:  Statins may partially operate by lowering testosterone. Whether this is a detrimental side effect or mode of action warrants investigation given the potential implications for drug development and prevention of non-communicable chronic diseases. See commentary article here http://www.biomedcentral.com/1741-7015/11/58.

 

Chemosphere. 2009 ;77 :1285-91.Occurrence and fate of rosuvastatin, rosuvastatin lactone, and atorvastatin in Canadian sewage and surface water samples.  Lee HB, Peart TE, Svoboda ML, Backus S. Aquatic Ecosystem Protection Research Branch, Environment Canada      Rosuvastatin (RST) and atorvastatin (ATO) are prescription drugs and members in the statin family used for the treatment of elevated cholesterol levels. A method using solid-phase extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the determination of ATO, RST and its metabolite rosuvastatin lactone (RSTL) in sewage and surface water samples has been developed. In the influent and effluent samples collected from 11 sewage treatment plants located in Ontario, Canada, ATO, RST, and RSTL were detected in all samples with median concentrations of 166 ng L(-1) (influent) and 77 ng L(-1) (effluent) for ATO, 448 ng L(-1) (influent) and 324 ng L(-1) (effluent) for RST, as well as 158 ng L(-1) (influent) and 41 ng L(-1) (effluent) for RSTL. Due to the inter-conversion between RST and RSTL, the total concentration of RST and RSTL in a sewage sample should be reported. The median removal rate by wastewater treatment was 66% for ATO and 22% for RST and RSTL combined. These statins were quite persistent in sewage. After a storage period of 21 and 62 days, there was only a slight decrease in ATO concentration and no change in the total RST concentrations. These three compounds were also detected in a number of surface water samples at low ng L(-1) concentrations. This is the first reported occurrence and fate of RST and RSTL in the Canadian aquatic environment.
Ecotoxicol Environ Saf. 2011;74:1216-25. Chronic exposure to diclofenac on two freshwater cladocerans and Japanese medaka.Lee J, Ji K, Lim Kho Y, Kim P, Choi  Seoul National University,  Korea.
Consequences of long-term exposure to diclofenac up to 3 months were evaluated using freshwater crustaceans (Daphnia magna and Moina macrocopa) and a fish (Oryzias latipes). Marked decrease of reproduction was observed at 25 mg/L for D. magna, and at 50 mg/L for M. macrocopa. Three-month exposure of fish to 0.001-10 mg/L of diclofenac resulted in significant decreasing trend in hatching success and delay in hatch. The hatching of the eggs produced from the fish exposed to 10 mg/L was completely interfered, while fertility of the parent generation was not affected. Gonadosomatic index (GSI) of female fish was also affected at 10 mg/L. Predicted no effect concentration of diclofenac was estimated at 0.1 mg/L, which is a few orders of magnitude greater than those observed in ambient water. Therefore direct impact of diclofenac exposure is not expected. However its bioaccumulation potential through food web should warrant further evaluation.\
J Toxicol Environ Health A. 2009;72(10):633-41. Life-cycle exposure of fathead minnows to a mixture of six common pharmaceuticals and triclosan.Parrott JL, Bennie DT Water Science and Technology Directorate, Environment Canada,Fathead minnows were exposed for a life cycle to environmentally relevant concentrations of a mixture of six common pharmaceuticals and one personal care product (nominal concentrations: 1,000, 300, 100, 30, or 10 ng/L). Mean measured concentrations of each chemical in the highest fish exposure aquaria were: naproxen 793 ng/L, gemfibrozil 662 ng/L, diclofenac 331 ng/L, ibuprophen 217 ng/L, triclosan 115 ng/L, salicylic acid 67 ng/L, and acetaminophen (chemical analysis inconclusive, nominal 1000 ng/L). Fish exposed for a life cycle even to the highest concentrations of the six pharmaceuticals and personal care product (PPCP) mixture showed no significant changes in growth and development compared to control. Length, weights, condition factors, liver weights, and gonad weights of PPCP-exposed fish were similar to water and solvent controls (0.000005% ethanol v/v). There were no marked effects of PPCP mixture exposure on external sex characteristics of the fish or on egg production. The only parameter that appeared to be affected was percent larval deformities in F1, which showed a significant increase in the 100- and 300-ng/L (nominal) PPCP mixture. Larvae from control fish had 4.7% (water controls) and 3.4% (solvent controls) deformities, compared to 9.3% in the 100-ng/L (nominal) PPCP mixture and 9.2% deformities in the 300-ng/L (nominal) PPCP mixture. Chronic exposure to environmentally relevant concentrations of seven PPCP most often detected in Canadian municipal wastewater effluents (MWWE) did not appear to affect fathead minnow survival, growth, or egg production, although it produced quantitative increases in deformities in the F1 generation.
Hum Reprod. 1993 Aug;8(8):1168-72.Autonomic nervous modulation and effects of a prostaglandin synthase inhibitor on human cervical secretion.Jonsson B, Hammarström  Karolinska Hospital, Stockholm, Sweden.Modulation of cervical secretion at ovulation time was studied in 10 women with regular menstruations. In an in-vivo model with repeated collection of mucus samples during three 90-min periods, the amounts of mucus in a control cycle and in three experimental cycles were compared. Drugs interacting with the autonomic nervous system and a prostaglandin synthase inhibitor were administered at time of ovulation. The cholinomimetic drug carbacholine significantly increased cervical secretion, while the anticholinergic drug butylscopolamine markedly inhibited this secretion. A long-lasting decrease in secretion was seen after administration of the prostaglandin synthase inhibitor diclofenac. Beside regulation of cervical secretion by the ovarian hormones, these results suggest an autonomic nervous modulation of cervical secretion, and in addition an impact on cervical by a prostaglandin synthase inhibitor. The effects on fertility regulation in the female are discussed.
Water Res. 2010 Jan;44(2):555-66.   Oxidative transformation of micropollutants during municipal wastewater treatment: comparison of kinetic aspects of selective (chlorine, chlorine dioxide, ferrate VI, and ozone) and non-selective oxidants (hydroxyl radical).Lee Y, von Gunten U. Federal Institute of Aquatic Science and Technology, Duebendorf, Switzerland.  Chemical oxidation processes have been widely applied to water treatment and may serve as a tool to minimize the release of micropollutants (e.g. pharmaceuticals and endocrine disruptors) from municipal wastewater effluents into the aquatic environment. The potential of several oxidants for the transformation of selected micropollutants such as atenolol, carbamazepine, 17 alpha-ethinylestradiol (EE2), ibuprofen, and sulfamethoxazole was assessed and compared. The oxidants include chlorine, chlorine dioxide, ferrate(VI), and ozone as selective oxidants versus hydroxyl radicals as non-selective oxidant. Second-order rate constants (k) for the reaction of each oxidant show that the selective oxidants react only with some electron-rich organic moieties (ERMs), such as phenols, anilines, olefins, and deprotonated-amines. In contrast, hydroxyl radicals show a nearly diffusion-controlled reactivity with almost all organic moieties (k>or=10(9)M(-1) s(-1)). Due to a competition for oxidants between a target micropollutant and wastewater matrix (i.e. effluent organic matter, EfOM), a higher reaction rate with a target micropollutant does not necessarily translate into more efficient transformation. For example, transformation efficiencies of EE2, a phenolic micropollutant, in a selected wastewater effluent at pH 8 varied only within a factor of 7 among the selective oxidants, even though the corresponding k for the reaction of each selective oxidant with EE2 varied over four orders of magnitude. In addition, for the selective oxidants, the competition disappears rapidly after the ERMs present in EfOM are consumed. In contrast, for hydroxyl radicals, the competition remains practically the same during the entire oxidation. Therefore, for a given oxidant dose, the selective oxidants were more efficient than hydroxyl radicals for transforming ERMs-containing micropollutants, while hydroxyl radicals are capable of transforming micropollutants even without ERMs. Besides EfOM, ammonia, nitrite, and bromide were found to affect the micropollutant transformation efficiency during chlorine or ozone treatment.
Toxicol Appl Pharmacol. 2007 Dec 1;225:142-53. .Modulation of steroidogenic gene expression and hormone production of H295R cells by pharmaceuticals and other environmentally active compounds.Gracia T, Hilscherova K, Jones PD, Newsted JL, Higley EB, Zhang X, Hecker M, Murphy MB, Yu RM, Lam PK, Wu RS, Giesy JP.Michigan State University,       The H295R cell bioassay was used to evaluate the potential endocrine disrupting effects of 18 of the most commonly used pharmaceuticals in the United States. Exposures for 48 h with single pharmaceuticals and binary mixtures were conducted; the expression of five steroidogenic genes, 3betaHSD2, CYP11beta1, CYP11beta2, CYP17 and CYP19, was quantified by Q-RT-PCR. Production of the steroid hormones estradiol (E2), testosterone (T) and progesterone (P) was also evaluated. Antibiotics were shown to modulate gene expression and hormone production. Amoxicillin up-regulated the expression of CYP11beta2 and CYP19 by more than 2-fold and induced estradiol production up to almost 3-fold. Erythromycin significantly increased CYP11beta2 expression and the production of P and E2 by 3.5- and 2.4-fold, respectively, while production of T was significantly decreased. The beta-agonist salbutamol caused the greatest induction of CYP17, more than 13-fold, and significantly decreased E2 production. The binary mixture of cyproterone and salbutamol significantly down-regulated expression of CYP19, while a mixture of ethynylestradiol and trenbolone, increased E2 production 3.7-fold. Estradiol production was significantly affected by changes in concentrations of trenbolone, cyproterone, and ethynylestradiol. Exposures with individual pharmaceuticals showed the possible secondary effects that drugs may exert on steroid production. Results from binary mixture exposures suggested the possible type of interactions that may occur between drugs and the joint effects product of such interactions. Dose-response results indicated that although two chemicals may share a common mechanism of action the concentration effects observed may be significantly different.

CHRONIC ILLNESS- MANAGED ANTIAGING & GENERAL PRACTICE CLINIC SOUTH AFRICA

update 6 April 2015

In Claremont  Cape Town

A  Specialist Family Internist Clinic offers consultations by appointment especially for managing (and ideally preventing)  the major chronic degenerative diseases of aging  and  maintaining physical, mental (and why not sexual?) vigour to a ripe and healthy old age; as well as preventing and managing acute disease at all ages.

The clinic (a specialist physician and a nutritionalist)  offers all-system evaluation and if available, natural  (as well as essential prescription orthrodox) prevention/treatment including metabolic – weight-endocrine-diabetes; heart-lung -kidney; hypertension; neurological-pain; joint & muscle; abdominal, immune system ie infection, cancer and auto-immune  support;  genito-urinary, & sexual problems;

and appropriate screening – ECG, non-xray ( no-touch thermography- eg thermomammogram;   SureTouch tactile) mammograms, non-xray (ie  ultrasound) BMD ie  bone fracture risk measurement, body composition, and appropriate hormone profiling/replacement.

Phone during office hours for appointment: for Claremont office  ph 021-6717415  or 6831465 (or 083-6299160) – at Grove Medical Bldg 1st floor no 15 (opp ABSA Bank Parkade c/o Grove Ave Pearce Rd)  , or neil.burman@gmail.com ;  or consultation by telephone/Skype or email .

by appointment only:        OFFICE HOURSby appt: ph office:  9am-5pm weekdays, 9am-1pm Saturdays.  AFTER  HOURS up to 9pm any day generally at office: –  email doctor   neil.burman@gmail.com  or ph 6am to 9pm  0836299160. EMERGENCIES  cannot be dealt with- acute emergencies and trauma, bleeding cases  must go to any  Emergency Unit .

Billing according to means ie specialist professional rates:  eg as a preferred provider for Discovery Health-  consultation procedure  0190; for needy patients, what the medical scheme pays  Detailed medical report and advice protocol provided at R300. Even Hospital Plans have to pay for outpatient consultation for scores of PMBs ie Prescribed Medical benefit conditions like Menopause.

 Needy patients desiring brief consultation can be seen by arrangement at GP rate.    Bone density scan  (covered by some medical schemes)  procedure 3612..  Non-xray mammograms are not yet covered by medical schemes codes: R650 for SureTouch including clinical consultation, R800 for thermomammogram.

update: BISPHOSPHONATES AND MALIGNANT BONE PAIN: REBUTTAL AND COUNTER-REBUTTAL

 neil.burman@gmail.com

update 2 Oct 2010: a practitioner asks what to do for a  white female 58years:
1998 ductal cell. lumpectomy, radiation, 15 nodes removed.  Tamoxifen  5 yrs.
2009  lobular cell. double mastectomy, nodes removed.  Aromasin  for next 5 yrs.
Osteopenia -2.3  found inside  1 yr .    on
Boniva ibandronate  4 yrs, stopped recently. 
 Doesn’t want to take IV drug for osteoporosis. 24 hr urine calcium  normal.  High vitamin d levels.
takes a lot of calcium,  vit d, vit c, vit b complex sups. Takes Prilosec omeprazole for reflux and hiatal hernia. chronic insomnia.
The questioner does not reveal her bodymass index or resting morning cortisol level or insulin resistance- all of which may well be raised; nor give her crucial vitamin D and C  intake or vitamin D  blood level. It is a question of evidence, not opinion – dogma- or laboratory average population ranges , as to what are optimal intakes and blood levels.

This column  has regularly reviewed the conflicting views and evidence  on osteoporosis;  BNP and breast cancer; and the safe multisystemic efficacy of using the score of natural supplements- including appropriate combined hormone replacement therapy – that safely oppose both osteoporosis – bone and muscle frailty-  and the associated chronic major involutionary diseases of aging especially vascular disease, dementia  and cancer. .

 The antireflux proton pump inhibitors PPI drugs notoriously aggravate osteoporosis; and for average reflux are not necessary with use of slippery elm, apple cider vinegar, simple calmag  and sensible diet and lifestyle.  It has been known for years that PPIs  more than double risk of osteoporosis, so why take them?. 

On the other hand, the pluripotential hormones of darkness and light –  vitamin D3 and  Melatonin – combined with the other mulibeneficial natural supplements that synergistically relieve/ reduce insomnia,  reflux pain,  cancer, depression, memory loss  and all other significant major chronic degenerative diseases of aging.

As this column regularly updates, Metformin too is a natural supplement (plant) co-hormone- a veritable panacea-  that reduces all major chronic disease and mortality by about a third- including cancer; and  dementia perhaps via reducing serum amyloid levels.let alone tissue oxidation, glycation, vasculopathy. BPN has none of these extraosseous benefits, only deadly risks.  

 Similarly, appropriate transdermal human estrogen but not oral xenoestrogen- CEE-  reduces serum amyloid in postmenopausal women,  while low testosterone raises serum amyloid in men.

So middleaged patients are at terrible risk of anxiety depression hypercortisolemia, frailty fractures, vascular disease , cancer and dementia after cancer, especially with sex hormone suppression or blockade. They do not need the myriad risky designer drugs touted for prevention of more cancer etc, all they need urgently and permanently is the scores of appropriate natural balanced supplements as this column regularly reviews- most of which supplements can simply be mixed in a tub of customized powder blend to be drunk twice daily. .

:Feb 13, 2009    In response to  Death-knell-for-bisphosphonates-for-osteoporosis-breast-cancer-time-for-class-action-against-bisphosphonate-damage last week,  a world-renown emeritus professor of radio-oncology comments:

“the action of the bisphosponates BPN is to inhibit osteoclastic action and thus reduces bone resorption; the patients tell the story- they get immediate and sustained relief from bone pain; if they  are on opiates the need is much reduced. Of course palliative RT is valuable, but often if pain recurs after RT the BPN give welcome relief, at least in my experience.

The  IV BPNs are also very useful in the oft-times encountered hypercalcemia often threatening myeloma- and other cancer patients. I am not however, too conversant with D3 in this setting!” But the first reference links are the latest in the clinical field of BPN and cancer.

Other than  in terminal cancer cases- when it doesn’t matter what convenient pain relief is used-  the problem with bone pain in cancer always is, what is the cause? either bone resorption from the catabolic effect of cancer (via eg high parathyroid hormone PTH);  OR cancer eating away at bone itself, OR something else common OP  unrelated to the cancer.?

But FOR CANCER-RELATED bone pain lesions – whether directly from cancer there, or from remote metabolic effect –  where are the trials comparing BPN with other antiresorptive antineoplastic ANTIINFLAMMATORY ANALGESIC ANABOLICS ie testosterone (or occasionally estrogen/ other antiandrogen)  and vitamin D3?

Obviously bone metastases are attacked with appropriate chemo-/ xray XRT, cortisone, testosterone AND if deficient, vitamin D3.

To put it the other way round: where is the evidence that BPN – at cumulative cost and risk-  adds benefit to the multiple attack? where the evidence that- unlike testosterone and vitamin D3- BPN has any benefit except on bone pain? Hypotheses based on in vitro and animal and human cell culture studies have  not translated into even good observational comparative evidence favouring BPN as good benefit:cost ratio for osteoporosis or cancer.

The oncologist answers in the traditional mode, by experience that BPN works. But evidence-based medicine EBM asks where is the comparative evidence for BPN to challenge the evidence that we have better multi-attack without BPN – when these supplements are not equally commercially promoted and tested in controlled trials for the usual commercial  reason ?

The dream of drug manufacturers is eternal, that their raincheque designer drug- statin or BPN or antihypertensive- will prove to be a safe multisystem panacea as is metformin and many  other supplements like vitamin D3 or testosterone. But after more than 30 years of BPN and statins, no trial in humans has yet shown this for BPN or  statin or any other original designer drug.

SIMPLE SAFE LOWCOST RISK MEASUREMENT AND CORRECTION: THE SOCIOECONOMIC IMPACT OF OSTEOPOROSIS

  neil.burman@gmail.com

Already just since April 2010, Pubmed (the on-line catalogue of peer-reviewed medical journal papers)  reveals four reviews – from USA, Mexico, Ireland and Cambridge UK-  on the huge socioeconomic impact of neglect  of long-available safe cheap measurement  and prevention of osteoporosis in aging populations. Especially that osteoporosis is underdiagnosed, and hence the need for improved use of diagnosis screening and preventatives.

And another study  from France reviews the deadly potential cutaneous (let alone gastrointestinal and other) risks of bisphosphonate and strontium drugs  prescribed for osteoporosis . Their  risk of serious adverse effects  may be <1:10 000 – but no study has ever been done comparing such $billion raincheck designer drugs with simple balanced lowcost safe combination of the score of natural supplements (some 7 vitamins, about 8 minerals and 5 human biologicals- costing as little as about US$10 a month) that are proven to prevent and heal osteoporosis let alone have major benefit on most major chronic diseases. .

The analogy is so simple- one does not treat :

anything but major pain with opioids or risky non-steroidal drugs  (or a sore throat with antibiotics) when simple safe modest-dose non-addictive analgesics and local therapy suffice; or

overweight,  or type 2 diabetes , or common mild to moderate hypercholesterolemia with any designer drug but metformin until control (with diet, lifestyle, supplements including metformin and appropriate other hormone adjustments)  is no longer good enough; or

 mild to moderate  hypertension requiring drug therapy with anything but perfectly safe lowdose reserpine plus lowdose amilozide – which suffice in almost 90% of mild to moderate cases- when more modern designer drugs (eg betablockers, angiotensin-converting – enzyme inhibitors and even the older methyldopa and calcium channel blockers) and newer drugs  both have infrequent but serious adverse effects, and are   less effective (they do not have the long duration and safety record of reserpine plus amilozide that makes it so effective even with erratic use) .

The socioeconomic model that measures the impact of a therapy only on one disease eg osteoporosis obviously also by intent supports the global profiteering and job-creation interests of Big Pharma and their well-rewarded allies – Government, Regulators, Universities, Research, Corporations and private practice. For these big-money industries, the use of a safe shotgun of unpatented and nonprescription supplements that more than halves the incidence, premature disability and mortality of both fractures AND all the common major aging degenerative diseases is anathema, since it reduces the Aging Diseases Industry from a $trillion goldmine in the aging who still vote, travel and earn, to a $billion expense when it matters far less- in the very old.

Hence Big Pharma is fighting a global war to abolish free choice of foodstuffs and supplements, conspire with governments to dictate what sources of foodstuffs must be eaten, and put all micronutrient supplement under doctors’ prescription! and above all else, suppress comparisons of designer prescription drugs with the gold standard old drugs and highly effective safe combinations of supplements.

This column has regularly published the growing irrefutable proof that high technology appliances and drugs are simply not needed to measure, prevent and treat common fragility fracture risk or any of the associated linked common chronic degenerative aging diseases.

And Guglielmi ea from Italian and Singapore Universities recently published another landmark review  confirming the voluminous evidence,  recent reviews from UK, that quantitative ultrasound QUS scan has replaced Dual Xray DXA bone mass density BMD  scan as the goldstandard fracture risk measurement test in common practice . Portable lowcost and therefore far more widely available QUS avoids the irradiation risk of costly centralized DXA, and the increasing overreading of bone density and hence risk score with aging due to accumulating calcification over the lower spine and hips.

It is of course intuitively and logically obvious that QUS devices that fix the target bone at a standardized site between the QUS heads as with eg the heelbone in eg the Norland CUBA footbox will eliminate most performer technique variation with a manually moved contact as in eg the Sunlight Beammed system.

Southampton University UK has also just published a study showing good correlation between peripheral QUS measurement and direct bone density measurement of excised fractured femoral heads from elderly hip replacement patients. .  .

And a Madrid team has just published a survey showing good correlation in children between 5 and 12 years between QUS measurements  and calcium-vitamin D intake.

CONCLUSION:  Safe and lowcost QUS can and thus should be used for bone risk measurement at all ages and locations – including schools and even the bedside;  in contrast to DXA which must not be used in those who are pregnant or not  at least post reproductive if not post-middle-aged.

Even in    the chronically frail or mentally dependent, periodic QUS screening is as crucial as eg bloodpressure screening since eg hypertensive , elderly, dementing or stroke patients share so many risk factors, and are thus are even more prone to osteoporosis- and incidental osteoporotic fracture easily converts the walking wounded  from needing supervised care to being totally wheelchair- or- bed- dependent.

UPDATES: HEALTHY LIVING

This  blog is irregularly updated   with the latest detailed pharmacological information on the ingredients of anti-aging preparations, the powder blend compositions, and mail-order/wholesale prices.

These are all detailed  on the page Product Details and Pricelists. but of course all the ingredients, as food supplements, can be ordered individually to US  or UK  or Japanese pharmacopoea standard anywhere from any reliable importer or manufacturer.

The prices listed are not updated weekly, they are a guide; and  dependent from day to day on imported costs which are mostly rising constantly .

For information email sales@healthspanlife.com (or contact 027836299160).

The public, as well as interested distributors/retailers, are invited to contact Healthspan Life!.

update: ACQUIRING/JUGGLING THE BEST SEX HORMONE HRT REGIME FOR WOMEN.

Joey Basson writes January 28, 2010

I used Primogyn Depot for about 20 years, but I believe it has been discontinued in South Africa. I am now really struggling to find something that really works for me.

The injection was perfect. Do you have any suggestions?

reply: Hi Joey,
DRUG COMPANIES GANG UP  TO SUPPRESS CHEAP EFFECTIVE AGENTS -AS THEY DID FOR 25 YEARS EACH WITH LITHIUM AND METFORMIN IN USA, STILL BLOCKING HUGELY BENEFICIAL USE OF CANNABIS; AND  at the end of 2008, without notice or warning,  they conspired to abolish  CHEAP APPROPRIATE  NON-ORAL HRT IN RSA- the depot injections MIXOGEN, DEPOTRONE, even PRIMODIAN DEPOT, PRIMOGYN DEPOT.

NOW APPROPRIATE NON-ORAL HRT COSTS ALMOST 5 TIMES AS MUCH TO USE, AS eg CREAMS, PATCHES, SPRAYS, IMPLANTS FOR BOTH MEN AND WOMEN- AND FOR WOMEN WITH FAR MORE BOTHER.

Now the only way we are going to get such injections back in RSA is if there is enough interest to fight through the red tape to import from overseas. But South African administration is now so degenerate   under the corrupt  Zumas that it takes 2 years to get desperately needed doctors and sisters registered here – and who cares about appropriate HRT for the aging? Certainly not the notorious “doctor” or “Rev”  Zumas since they dont give a fig for evidence or human -especially  the poor and womens’-  rights..

if you live too far away, we can do a personal consult by email+- phone +- skype – via the necessary questionnaire by email- for you to discuss and implement with your local GP.

see numerous updates the past year at  https://healthspanlife.wordpress.com/?s=HRT

22 March 2009

An update review by Barry Wren from an Australian Menopause Clinic again debunks the myth that appropriate HRT in postmenopausal women PMW increases the risk of breast cancer, cardiovascular  disease CVD and thrombosis. It  stresses that “benefits of HRT include  less:  symptoms of menopause;  osteoporotic fractures,  ischaemia and cardiovascular-related death, forgetfulness, dementia and colorectal cancer; and  improved well-being, quality of life,  vagina, sexual enjoyment and bladder capacity,  with increased longevity. Oral  OHT doubles the risk of thromboembolism”. But on it’s own  in the young women in the Womens’ Health Initiative, oral equine estrogen (premarin)  reduced all major risks even new breast cancers and death from breast cancer.

As we hear regularly in women who have unwisely followed hysterical advice to stop HT,  stopping appropriate HT leads to fairly rapid loss of many of the above benefits. It has been  obvious for a century if not millennia   that permanent appropriate Human Hormone Replacement HRT of any of the dozens of our hormones that run out   is  (like a complete supplement of all the vitamins, minerals and the biologicals other than HRT)  prudent if not essential.

But we have to understand the reasons, risks and different regimes available. Nobody may prescribe or administer any sex HT Hormone Therapy without the necessary up-to-date training and experience, ensuring that the patient is having the necessary periodic examinations to ensure both safety and that the SHRT is appropriate. So patients must not self-treat with over-the-counter  supplements.

But only doctors and pharmacists who have costly current dispensing licenses may dispense and compound any hormone creams. And oral HT including phyto/plant hormones are  under suspicion of promoting cancer long term, let alone hepatic first pass effects like thrombosis and gallstones, and fluid retention oedema and hypertension (Genazzani ea 2008) .

INJECTION: tiny safe self-injection of combined hormone subcutaneously  (like insulin) is easy every one to three weeks, as most men use for HRT.  Monthly injection of depot preparations that last about three weeks  is not advised for anyone, especially not women with a womb as they are liable to have break-through periods. But unlike men, many women prefer to use hormone creams daily. The Depot hormone injections have climbed in price – what is now available averages about R75 per month. BUT (unless she gets the injection from her doctor regularly & proportionately every 1 to 3 weeks), women have to lay out about R1000 for self-injection (since  pharmacists will not likely  split a multi-vial or a set of three vials).

Provided that they ensure that they are appropriately trained in such therapy, all doctors are licensed to give periodic chronic injections – which should always be exclusively by tiny subcutaneous injection to avoid the notorious ie potentially crippling complications of intramuscular injections. But if nothing else is required, doctors are entitled to charge about R100 fee for the responsibility of an injection visit. Like insulin, patients easily learn to give it themselves- for men about 160mg depot-testosterone every 2wks (as opposed to 1gm testosterone undecanoate Nebido every 3 months- or about 1/10th of the male dose for women deficient in testosterone).

Synthetic ie xenohormones – those not normally produced by humans- eg progestins, ethinylestradiol-  may be invaluable (although by no means essential)  for birth control; but should not be used for PMW, especially not orally.

USING CREAMS: it is indeed best for women to (initially) juggle the balance of the three hormones  (all of which are made to the highest standard in South Africa)  until you have determined what ratio and quantity suits you best.

For the slim small older woman who needs both hot flash control and energizing, memory, ache relief:  the first priority is to control hot flashes, skin & hair without arousing breast and womb discomfort:

so try the 0.25% Bies(trogen) (E2 + E3- usually 1:4 ratio)  initially 1/2 ml scoop 1 – 2 x/day with the progesterone 3% cream initially just ¼ to 1/3 ml scoop a day ie 4 to 1 or 3:1 . This is ideally rubbed into the face as makeup- or if you like, dilute them in simple aqueous cream. Increase the combined dose to double if necessary to get control of the flashes – but the higher the Biest dose, the higher the risk of waking the breasts and womb, or getting thrombosis and ankle swelling.

And (unless your androgen level is still high) use just enough Testosterone cream 0.5% eg 1/2 to 1 scoop once (or twice) a day – below the waist ie vaginally or between the thighs or on the soft sole of the foot – to energize, improve alertness, libido, muscle and bone strength. Supplementing estrogen and progesterone alone may suppress necessary androgen.

In the bigger plump younger woman, who desires memory, energy, fat loss and libido rather than hot flash and skin improvement, using testosterone below the waist and progesterone on the face in the above gradually increasing doses often suffices, without the fattening and breast-womb arousing risks of extra estrogen. Such women often make enough estrogen from testosterone and in their excess fat stores.

But once the average women is well past 60yrs, low-dose estrogen often becomes advisable anyway for balance.

Old women benefit from and tolerate perhaps 1/6th to 1/10th the doses of appropriate balanced  human sex hormones of younger women.

THE THREE PRIME HUMAN SEX HORMONES: there are no risks from any appropriate HRT, only risks from avoiding it. Progesterone alone lacks some of the benefits of testosterone and estrogen eg on muscle- bone and hearing. Of the three hormone types, only androgen protects and improves muscle mass and strength. Testosterone excess (hairy face, acne, anger, clitoris growth, husky voice) is easily avoided with sensible balanced dose adjustment. Progesterone and testosterone have major benefits that estrogen may lack eg on hyperimmunity and inner hostility- issues that may not concern the gyne surgeon.

(Bi)Estrogen excess-  especially if used  alone-  does the reverse (of testosterone): promotes endometriosis and breast activation; excess actually weakens muscle eg bladder leak by melting collagen; it fattens; has little benefit directly on depression (although it does reduce dryness and pain); may promote thrombosis since unlike testosterone it does not diminish clotting; and may promote anxiety, hostility- this is why progesterone cream is often the best for monthly PMS and for perimenopausal anxiety (against the raging hostility from estrogen swings).

Above all else, remember that estrogen stimulates both breasts and womb- so estrogen must always be balanced by enough progesterone and(/or) testosterone. And if the hormones are allowed to run out by widening the gap between injections beyond two weeks, or between cream doses by more than two days, vaginal bleeding likely will occur.

The initial outlay cost of the three different hormone creams is up to R500 retail- you find out for yourself how long each tub lasts; as opposed to having an experienced pharmacy eg the manufacturing AntiAging pharmacy in Gauteng  compound ie mix what you want in one or two tubs that will last a few months. Try your local pharmacy – but finding one with experience is difficult.

PREVENTION? OR WAITING FOR DISEASE FROM NEGLECT TO CRIPPLE YOU? Many  gynecologists (like urologists) are primarily surgeons concerned with reproduction, menstrual, pelvic and cancer problems, and treat the menopause years often with fattening hormone pills (HT- which have more risks) and surgery..  They do not have to deal with the much wider irreversible medical problems of old age (obesity-diabetic, insulin resistance, lipidemia, vascular, immune, fracturing, arthritic, visual and hearing loss,  depression, and dementias – and no least, common sudden premature death)# – which are largely AVOIDABLE with appropriate natural supplements from the beginning, including balanced non-oral human sex hormones. As a BBC news report this month  says, memory (ie cellular) deterioration  begins on average  before age thirty.

It is not the gynecologist, but patients  and Family/ general practitioners GPs and specialist physicians including endocrinologists and geriatricians who have to deal long term and medically (not surgically)  with these easily preventable crippling killer diseases..  Surgery cannot address the basic pathogenic cause of chronic degenerative disease.

The discomfort and fattening of the 5-10 MENOPAUSE years is a concern for all doctors – and the earlier the menopause (whether natural or surgical), the more important it is to start appropriate simple balanced non-oral HRT and other effective medical prevention of fattening and diabetes eg other insulin sensitizers like metformin. Avoiding the late postmenopausal  silent killer degenerative diseases of aging (# above) is crucial  essential duty of doctors – but mostly of patients themselves,  since- obstetrics and trauma  aside-  most doctors earn more by disease than by prevention..

ndb