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Statins, a critical review

LDL, the blood transport for cholesterol & fats
ldl-diagram.jpg

Pharma's myth and ignoring the cause 
  1. The cholesterol myth.  Numerous critics have pointed out that cardiovascular disease is not caused by higher levels of blood cholesterol or fats.  Pharma promotes the cholesterol myth and ignores the major causes.

  2. Major cause of cardiovascular disease is pathogens living within the middle layer of artery walls.  It initiates the immune response which involves LDL, HDL, and white blood cells. 

  3. It is in this immune function that the lipoprotein coating on LDL attaches to and neutralizes certain toxins produced by pathogens.

  4. Reactive chemicals such as simple sugar fructose and carbon monoxide can potentiate the process resulting in the formation of plaque within the artery walls by damaging the endothelial cells lining the artery walls thereby reducing the barrier of the endothelia cells to blood borne pathogens. 

  5. LDL is actively transported to the site of inflammation both to attach to toxins, and because its contents of cholesterol and fats are needed as part of the repair process.. 

For confirmation from journal articles on primary role of infective agent enter into http://scholar.google.com/ terms such as bacteria + atherosclerosis or go to http://healthfully.org/rl/id9.html for collection of articles

For confirmation of cholesterol myth enter into http://scholar.google.com/ or http://www.amazon.com/ cholesterol myth, or go to http://healthfully.org/rl/id5.html  for collection of journal articlesfor documentaries.

    Statins a 3 Page Critical Review   12/23/15 http://healthfully.org/rc/id6.html 

It is essential for you to understand how pharma (pharmaceutical industry) distorts, and controls medical information, and guidelines, thus the practice of medicine--see Market Science and Misinformation  side effects.  Marketing pitch for the statins is based on high Total Cholesterol (TC) and LDL causing heart attacks, strokes and, CardioVascular Disease (CVD); but CVD is caused by bacterial and viruses within the artery wall (tunica media) and the immune system’s response, thus lowering cholesterol doesn’t work--see Cholesterol Myth.  LDL has 2 functions, one is to as needed actively transport to cells cholesterol and triglycerides (fat), the other is its immune-system function:  it neutralizes (binds) toxins produced by pathogens—see.  LDL in the artery walls is a sign of pathogens causing inflammation.  Thus the presences of LDL, cholesterol, and triglycerides in the plaque of artery walls is because of LDL’s immune function.  LDL is like a fireman at a fire, a response.  Lowering LDL promotes damage by toxins.  Yes statins lower LDL and cholesterol, but that doesn’t benefit the patient.  The doggy clinical trials ran by pharma for marketing purposes fail to show significant reduction in deaths, so pharma markets statins based on lowering cholesterol and rigs the clinical guidelines.[1]  Marketing and influence trumps medical science.  The best-selling drug of all times is atorvastatin, marketed as Lipitor by Pfizer (US sales $12.4 billion in 2008, and world-wide total sales of $131 billion by 2007).  With 50% of the men and 36% of the women age 65 to 74 taking statins (CDC/NCHS, Health, US, 2010); their human costs is incredible; made worse because better alternatives[2] are shown harmful by pharma’s tobacco science.   The cholesterol myth and effective prevention get little space in the corp. media.—watch YouTube documentaries.

 

Statins discovery and approval casts doubts.  In the early 1970s an extract from a fungus was shown reduce serum cholesterol, but the Japanese research stopped because of animal toxicity & cancer.  Using a similar extract Merck in 1978 developed Mevacor (lavostatin).  This “’Statin produced significant toxicity at high doses in a variety of animal species” (ibid 520).  Animal studies showed it caused cancer (given the 20-year latency in humans, still a grave concern).  Merck tested low-dose Mevacor for homozygous familial hypercholesterolemia.  The FDA gave approval for this rare condition.  Once approved--as is the norm--the population base was expanded based on “marketing science”.  Because statins lower TC 30%, they were pushed as the only effective treatment for CVD.  But weak epidemiological association of elevated TC with CVD doesn’t demonstrate cause.   With in-house studies Merck and the manufacturers of the 9 me-too statins sold the world on “safe-and-effective”.  In Braunwald, Heart Disease, 8th Ed. P 2286: “safe, effective, and well-tolerated pharmacologic agents that have greatly expanded the therapeutic armamentarium available to the physician to treat disorders of lipid metabolism.”  But in Braunwald, p 1085 table, 3 of 4 listed studies didn’t support effective.  Merck’s JUPITER Study, 2008, is used to push primary prevention, but has major internal inconsistency:  the cooked results “do not support primary prevent of CVD”.  Moreover, “statin therapy and top athletics seem to be almost incompatible,”73% dropped out.  Statins don’t extend life and their side effects are grossly under-reported.  Because statins don’t treat the causes of CVD, they are ineffective; thus there is a chorus of marginalized critics.

19 NEGATIVE EFFECTS:  One, ED, it lowers testosterone , and  nitrous oxide thus causes ED; a similar effect upon women for the steroids are synthesized from cholesterol. Two, COX-2 inhibitor, just like Vioxx, which increased heart attacks (MIs) over 300%[3].  The American Heart Association warns: “accumulated evidence that non-steroidal, anti-inflammatory drugs [COX inhibitors], with the exception of aspirin, increase risk for heart attack and stroke”--promote atherogenesis. Three, blocks production of Q10, which enters LDL and inhibits oxidative damage that causes atherogenesis, and.  Four, Plaque instability:  “Vulnerability of plaques to rup­ture and thrombosis is of greater clinical relevance than the degree of stenosis they cause” (Corti et al., 2003).  Statins affect plaque stability in a variety of ways.  The meta-loproteinases degrade extra-cellular matrix components and thus “weaken the fibrous cap and destabilize the lesions” -- Goodman and Gilman pharmacology, 11th Ed, p 950.  Rupture of plaque causes over 80% of MIs.  Statins inhibit secretion MMP-1, 3, & 9 from SMC, and microphages make plaque less stable.   Five, reduction in ATP:  Q10 is needed for the conversion of APD to ATP (adenosine-5-triphosphate), the source of energy for muscles contraction.  “ATP is often called the ‘molecular unit of currency of intracellular energy transfer including muscle contraction and for chemical reactions.  ATP transports chemical energy within cells for metabolism--Wikipedia.  A reduction of 40% in CoQ10 is accepted.[4]  Six, The heart muscle under stress needs more ATP, not less.  This is why pharma excludes the elderly and those with coronary heart failure (CHF) from trials.   Thus, “the mean age of ME/CFS patients dying from CHF are 2.5 years younger than the control group.”  CHF death rate  has tripled since 1989.  In a review of statins on depletion of Q10 concludes:  “As the potency of statin drugs increases and as the target LDL cholesterol level decreases, the severity of Q10 depletion increases and heart-muscle function declines. This tragic scenario may very well be prevented by using supplemental Q10 with all HMG CoA reductase inhibitors [statins]” and, and. Thus “Lower cholesterol, poorer outcome in CHF patients.”  Pharma ignores Q10 side effect.  Seven, All Statins inhibit the rate controlling enzyme HMGCR of the mevalonate pathway.  This pathway generates a range of other products in addition to cholesterol, including coenzyme Q10, heme-A, [dolichol], the production of dimethylallyl prophosphate (DMAP),  &  isopentenyl pyrophosphate (IPP), which serve as the basis for the biosynthesis of molecules used in processes as diverse  as terpenoid synthesis, protein prenylation and isoprenylated proteins  which have pivotal roles in cell biology and human physiology and potential relevance to benefits as well as risks of statins.  Drugs, such as the statins, stop the production of mevalonate by inhibiting HMG-CoA reductaseWiki.  “The Mevalonate pathway is important for, cell membrane maintenance,  hormones, protein anchoring, and N-glycosylation.  It is also a part of steroid biosynthesisWiki.  Dolichols are isoprenoids  synthesized from mevalonate. They are vital to the process of Glycoprotein formation in the endoplasmic reticulum of cells. In this capacity it is critical to the formation of the Glycoproteins involved in neuro-peptides, cell identification, cell messaging and Immune defense.  Reduced bioavailability of dolichols can affect every cellular process in the bodyWiki.  And this is only a partial list.  Eight, Cholesterol is essential for life.  “It is the precursor for the biosynthesis of steroid hormones, bile acids, vitamin D, and is an essential component of cell membranes for proper permeability.  Effects include pancreatic and hepatic dysfunction, ED, diabetes[5], muscle weakness and myopathy (muscle disease). The myelin is a cholesterol base coating around nerve cells[6] (Wiki).  Nine, Cognitive, the reduction Q10 & cholesterol for the myelin sheath causes cognitive decline--especially in the elderly where it often leads to an incorrect diagnosis of Alzheimer’s disease and of neuropathy.  Ten, Causes Parkinson’s  and Alzheimer’s diseases.  These conditions are associated with low level of cholesterol—at Uffe p 56.   Eleven Causes cancer a confirmation of earlier animal studies—summary of cancers, and.  Twelve  Stimulates atherosclerosis and heart disease by blocking the vital CoQ10, heme A, vitamin K2 (the cofactor for matrix Gla-protein activation) and biosynthesis of selenium containing proteins, one of which is vital glutathione peroxidaseat 2015.  This article states that “statins stimulate atherosclerosis and heart failure”, and then provides the mechanisms.  Thirteen Causes Interstitial lung disease is similar to emphysema in that it is a progressive condition that affects alveolar epithelium and other tissues.  Of FDA reported side effects, it is 1/40th.  Fourteen, Causes cancer in animal studies, and thus in humans, at.  Fifteen, Polyneuropathy, damage affecting peripheral nerves, features weakness, numbness, pain, etc. is 26 times more common after 2 years on statins compared to general matched population—at.  Sixteen Side effects account for the poor compliance in the elderly (75% stop within  2 years).   Poor compliance also occurs with elite athletes (see 1st pg).  Seventeen treats the wrong cause, cholesterol doesn’t cause ischemic events or  atherosclerosis but rather infective agents (and) living in the tunica intima; thus statins are ineffective.  Three out of 4 major studies of secondary prevention (ALL-HAT, ASCOT, & PROSPER) failed to find life extension from statins (Table 42-78, Braunwald’s Supra, p 1085).  This table stands in opposition to the “safe & effective” claim (p 2286), which is pharma’s mantra, a mantra supported by their marketing studies and guidelines. Junk science is the norm (p 3) on TNT trial.  Eighteen, Primary prevention of high risk no benefit huge meta-study found, in JAMA.   Nineteen, drug interaction with serious side effects are common, considering that over half of senior in their 6th decade have taken statins, and seniors average age 72 average 6 drugs according to a hospital emergency admission study (polypharmacy).  

THREE POSITIVE EFFECTS:  1) Anti-inflammatory effect:  but because of effect upon prostaglandins statins like the NSAIDs doesn’t inhibit atherogenesis inflammatory process—see Vioxx, and.  2) Statin reduces the risk for thrombosis by affecting clotting, just like aspirin.  But rather than promote the sales of over-the-counter NSAID, pharma pitches lower TC.  3) For the rare familial hyperlipidemia extends life modestly at best—Prof. Ravnskov, Ignore the Awkward, chap. 3.

On statins:  Since “cholesterol synthesis occurs mostly at night” (Wiki), TC should be treated at night with short half-life[7] & low dose:  Zocor 2 hr. Mevacor 1.4 hr. Pravachol 1.75 hr. and niacin 35 min--avoid Lipitor 14 hr., Crestor 19 hr. 

Sorting it out, RECOMMENDATIONS:  Atherogenesis is caused pathogens within the artery walls.  This initiates  an inflammatory immune response by macrophages.  LDL which has an immune response is actively transported into the artery walls where it contents cholesterol from part of the resultant plaque.  Because of this transport process, lowering LDL doesn’t affect the formation of plaque, thus statins don’t stop plaque formation or remove it from within artery walls (see illustration).  The 32% drop in deaths from heart attacks and strokes (1960 to 1992) occurred prior to statins.  With statins’ wide use, mortality rate has remained constant.  Mevacor was approved in 1987 with only 60,000 taking it by 1990.  Reduced death rate was from less cigarettes and better treatment.  Statins reduce quality of life for the elderly: a large Canadian study had 75% dropout by 2 years, and 80% in a NJ study.  Very common and under reported side effects are:  fatigue, muscle weakness & cramps, mental confusion, pancreatic and liver dysfunction, diabetes, indigestion, cognitive decline, ED, & lower libido, especially for the elderly.  Lowering TC with statins doesn’t affect the young unstable plaque that cause 85% MIs because pathogens are the cause of the plaque formation.  .  What to do:  Don’t take a statin because they do not reduce mortality; they aren’t worth their side effects & expense.  Lifestyle changes of low carbohydrate-sugar diet lowers damage to endothelial cells on the artery walls.  Damage is caused mainly by glycation by fructose (7.5 times the rate of glucose).   Avoid carbon monoxide (cigarettes main source) which exacerbates the damage.  Endothelial cells block the migration of pathogens.  Saturated and monounsaturated fats are the best source of energy.  Everyone should take the antioxidants ascorbic acid and Q10, prevent oxidative damage.  Take 325 mg aspirin[8] with meals for its anti-inflammatory effect that prevents CVD; and aspirin prevents blood clots thus lowering ischemic events, etc5.  Low dose aspirin is ineffective because of tolerance after 1 year.  Take the natural estrogen (estradiol) & progesterone at menopause.   Estrogen[9] lowers risk of CVD 50%, osteoporosis and much more.  For elderly men testosterone lowers risk & increases survival from an MI.  Pharma attacks hormones & aspirin because they work.  Read Marking Science, be skeptical of medical “wisdom.”   If you still want to lower TC then take 250 mg slow release niacin or inositol hexanicotinate  at night, when it is effective.  Insulin produced following meals blocks the lipid lowering effect of niacin inositol & statins.  High dose during the day is a pharma ploy to reduce the use of niacin. 

JK has exercised vigorously since 1975; 325 mg twice daily aspirin since 1992; testosterone high dose 2003; low-sugar low carb diet 2014, 300 mg CoQ10 2012, and vitamin C 1000 mg (as calcium ascorbate) 2014.  Results:  JK is in 7th decade, excellent muscle tone and strength, no joint pain, blood pressure averages 125/75, BMI 23, and total cholesterol 165.  Pharma  has turned  hypertension, and cholesterol into medical conditions, and watch documentaries on YouTube.   



[1] New guidelines (3/2014) based on a 10 year 7.5% risk for MI would put 87% of men and & 56% of women age 60-75 on statins.  These pharma friendly guidelines exaggerate the risk of MI 175% and expand statins use to nearly all men over 50 years.

[2] See the 8-page paper ”On Lifestyle Diet and Drugs, or 2-page summation. Two studies have shown using raw data that positive bias is 32%.for pharma’s clinical trials. Pharma’s business model drives them to marketing patented drugs for chronic conditions, most of which are ineffective.  

[3] A reasonable assessment of total early deaths from the selective COX-2 inhibitors in the US would be over 200,000; and a much greater number for the non-selective COX inhibitors, the NSAIDs—but for aspirin.  Celebrex is still on the market, and though warnings about all COX inhibitors warning that they promote CVD, the oft-heard sales message prevails. 

[4] After 3 months treatment of healthy patients with a poor TC using pravastatin or simvastatin, the total cholesterol and CoQ10 (Q10) were lowered 40%, when compared to the placebo group.  “A diminution of Q10 availability may be the cause of membrane alteration with consequent cellular damage”Journal of clinical Pharmacology.  This finding is supported in other studies and widely accepted—summary article.  

[5] In a cohort study a 63% increased incidence of diabetes, Lancet 2015 also. The WHI trial found a 48% increase for women, see.        

[6]  The 2nd cause for neuropathy, the first low Q10.  The two are additive.

[7]  Half-life (t½) the time that it takes for the concentration in blood plasma of a substance to reach one-half of its initial measured level “(Wiki). 

[8]  Aspirin very significant risk reduction of most major cancers and Alzheimer’s disease, plus it reduces mortality from stage I, II, III cancer over 40%, and by 4 mechanism atherogenesis.  The long-term risk for stomach bleeding is about 4%; comparable to other NSAIDs and many other drugs.  Pharma’s attack with FDAs help is market driven.  Low does not have an anti-inflammatory effect and tolerance develops to its anti-platelet effect.

[9] For many benefits of natural HRT, and testosterone for men; and don’t believe the marketing science about hormones. 

cholesterol synthesis, statin (HMG-CoA) blocks
cholesterol-synthesis-flow-chart-sm.jpg
vital synthesis of ubiquinoe (Q10), etc.



^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^Non-technical summation                                             




Statins and cholesterol:  Cardiovascular disease (CVD) results from pathogens within the artery walls that cause an inflammatory response by macrophages those results in the formation of plaque.  The risk of infectious bacteria and viruses colonizing the artery walls is increased by artery endothelial dysfunction (cells which line the artery walls and thereby control the entry into the underlying tissue).   Major causal factors for endothelial dysfunction is a high blood sugar (especially fructose which is 7.5 more reactive than glucose) and high insulin level (insulin resistance).  Carbs through glucose increase insulin, and table sugar is a disaccharide consisting of fructose and glucose.  Thus low carb low sugar diet is the first line of prevention. Carbon monoxide--main source smoking—can significantly exacerbate endothelial dysfunction.  Both are reactive chemicals which damage the endothelial cells.   Macrophages are a type of white blood cell that scavenges damage cells and promote healing.  A lower level of cholesterol doesn’t prevent the active transport of LDL as part of the immune-healing response; thus statins do not affect the active transport process.  A large body of evidence has demonstrated that cholesterol and triglycerides are mere bystanders, and that statins though they lower cholesterol do not prevent CVDsee and watch documentaries.  Cholesterol and fats are present because of an immune response that goes on.  Statins are the biggest scam in pharma’s history.  And it made all the worse not only by chasing after causes which don’t protect against CVD, but also because of their affect upon quality of life, which very significantly affect those above the age of 60.  Cholesterol is used to synthesize numerous essential compounds and is part of cell membranes.  Lowering it production—typically 40%--has many common side effects.  Statins also lower the production of CoQ10 by 40%.  CoQ10 has an essential function in the production of ATP, the body’s energy molecule.  Statins for all these reasons should not be taken, especially among the elderly whose production of ATP has significantly dropped with age.     

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TERMS:  Primary prevention for those with high cholesterol only.  Secondary prevention for those with pre-existing cardiovascular disease (CV).  Opinion Leader: an authority in a specialty who receives substantial income from pharma.  Cardiovascular Disease (CVD) any disease, whether congenital or acquired, of the heart and blood vessels.  Cholesterol Profile (TC) the lab report listing the various components of cholesterol.  Coronary Heart Disease (CHD) atherosclerotic arterial deposits (atherosclerosis).   Congestive Heart Failure (CHF)/ heart failure (HF) occurs when the heart muscle is unable to maintain adequate circulation of blood in the tissues of the body or to pump out the venous blood returned to it by the venous circulation.  Myocardial Infraction (MI) a heart attack.  HMG-CoA reductase inhibitors (statins).


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Animal studies are a very good indicator for potential side effects in humans:  The original studies are done on animals to find out if a drug is effective and safe.  Unfortunately when pharma funded they own the results and as part of normal business do not published unfavorable results.  However, since such studies are fairly inexpensive, a number of them of animal studies are part of graduate work supervised by a professor, and are published.  Others, like this review are written by the manufacturer, in this case Merck.  The article mentions the side effects and then concludes that they don’t occur in “human therapeutic doses.”  A large body of evidence contradicts this rosy conclusion.  It is very disappointing that the top tier journal Nature published this article, which is a sales pitch for Lipitor, dressed up as a review of the research. (see the published summation below to dispel doubt)  For example the effects upon testosterone and CoQ10 are not mentioned—though there is significant literature on their suppression by Lipitor and other statins.   


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Below is an example of marketing science.  It is a review of the research on Mevicor (Lovastatin) by Merck (hardly unbiased in their dismissal of the relevance of animal studies).  Worth reading as to risk factors since animal studies have a high carryover to humans.   Tolbert left out the “c” word cancer, for which this side effect in animals is be repeatedly brought up.  Since most cancers have a 20-year lag time (such as cigarettes) from exposure, short-term clinical trials will not expose this risk.  It took for example 30 years for cancer to be associated with DES, a synthetic estrogen, and 50 years for MPA (methoxyprogesterone, which is still on the market). 


SIDE EFFECTS ANIMALS:  Statins produce significant toxicity at high doses in a variety of animal species. These effects include increases in hepatic transaminases, atypical focal hyperplasia of the liver, squamous epithelial hyperplasia [ORGAN ENLARGEMENT] of the rat fore-stomach (an organ not present in man), cataracts, vascular lesions in the central nervous system (CNS), skeletal muscle toxicity, testicular degeneration and, although the statins are clearly not genotoxic, tumours of the liver and other sites (details can be found in the product circulars of the individual statins). It has been shown, where it has been practical to conduct the experiment, that these effects can be prevented by administering mevalonate 29,30, the product of the reaction catalysed by HMG-CoA reductase.  This indicates that these toxic effects are mostly, if not entirely, attributable to extreme inhibition of the enzyme at high doses 29.  So Merck, and the regulatory agencies considering the marketing application submitted by Merck, were faced with a wide range of animal toxicological effects, as well as the history of compactin and the known central role of the cholesterol biosynthesis pathway in many physiological processes, including the production of steroids and cell membranes.  [The structure Lovastin is quite similar to compactin, whose toxicity in animal studies resulted from it not being tested clinically; nevertheless Merck went forward.]  Compactin was withdrawn from the market for ]   Fortunately, except for rare cases of myopathy and marked but asymptomatic increases in hepatic transaminases, none of the adverse effects found in animals occur at human therapeutic doses.” Nature Reviews Drug Discovery 2, 517-526 (July 2003) | doi:10.1038/nrd1112.  This Merck scientist is referring to life-threatening and rare muscle destruction caused by statins.  However, its impact upon quality of life for those above the age of 50 is gradual and thus subtle--the degree increases with age. 


Author’s affiliations: A. Tolbert, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Email: 
jonathan_tobert@merck.com




TERMS

Cardiovascular Disease (CVD) any disease, whether congenital or acquired, of the heart and blood vessels.

Cholesterol Profile (CP) the amounts of High density, low density, and very low density lipoproteins, of triglycerides, and other blood borne compound that are indicators for angiogenesis.   

Circulatory failure occurs when in the blood the concentration of oxygenated hemoglobin in the arterial blood, or the vascular bed is responsible for the inadequate cardiac output. 

Congestive Heart Failure (CHF) heart failure in which the heart muscle is unable to maintain adequate circulation of blood in the tissues of the body or to pump out the venous blood returned to it by the venous circulation.

Coronary Failure (CF) heart failure in which the heart muscle is deprived of the blood necessary to meet its functional needs as a result of narrowing or blocking of one or more of the coronary arteries.

Coronary Heart Disease (CHD) a disease of the heart and coronary arteries that is characterized by atherosclerotic arterial deposits that block blood flow to the heart, causing myocardial infraction. 

Endotoxin, the toxic protoplasm liberated when a microorganism dies and disintegrates.   Toxic substance bound to to the bacterial cell wall and releasedwhen the bacterium ruptures or disintegrates. Endotoxins consist of lipopoly- saccharide and lipoprotein complexes.  The protein component determines the antibody type that can react with the endotoxin molecule to produce an immune reaction.  Endotoxins are rarely fatal, although they often cause fever.   

Heart Failure (HF) is a pathophysiological state in which the heart is unable to pump blood at a rate commensurate with the requirements of the metabolizing tissues or can do so only from an elevated filling pressure.   I t is usually, but not always caused by a defect in myocardial contraction, i.e., by myocardial failure

HMG-CoA reductase inhibitors (statins), the enzyme they inhibit, which is the method by which lower cholesterol.

Meta-study consists of grouping together studies according to a set of criteria and then calculating the summation of finding.  Cochrane Library consists of hundreds of such meta-studies without funding from PhARMA. 

Morbidity rate the relative incidence of a particular disease in a specific locality

Myocardial Infraction (MI) heart attack

Primary prevention for those with high cholesterol, but no other health problems

Sarcopenia the loss of muscle mass causing weakness.  Statins contribute to this through lowering of CoQ10, and thereby affecting exercise and physical exertion, which are needed to maintain muscle mass and tone. 

Secondary prevention for those with pre-existing cardiovascular disease (CV)

Sepsis, the poisoned condition resulting from the presence of pathogens or their toxins.   The severe infection caused by pathogenic organisms, especially bacteria, in the blood or tissues.  If untreated, a localized infection, as in the respiratory or urinary tracts, can lead to infection in the blood stream and widespread inflammation, characterized by fever, chills, and other symptoms and later septic shock.  Chronic infection is a causal factor for CVD.

Thought Leader because of being PhARMA friendly a few administrators and researchers perform various well-paid services for PhARMA, such as a researcher, author of textbooks, head of clinic, and giving educationals.  They become known as an expert in their specialty.  
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Below is an example of marketing science.  It is a review of the research on Mevicor (Lovastatin) by Merck (hardly unbiased in their dismissal of the relevance of animal studies).  Worth reading as to risk factors since animal studies have a high carryover to humans.   Tolbert left out the “c” word cancer, for which this side effect in animals is be repeatedly brought up.  Since most cancers have a 20-year lag time (such as cigarettes) from exposure, short-term clinical trials will not expose this risk.  It took for example 30 years for cancer to be associated with DES, a synthetic estrogen, and 50 years for MPA (methoxyprogesterone, which is still on the market). 

.   

SIDE EFFECTS ANIMALS:  Statins produce significant toxicity at high doses in a variety of animal species. These effects include increases in hepatic transaminases, atypical focal hyperplasia of the liver, squamous epithelial hyperplasia [ORGAN ENLARGEMENT] of the rat fore-stomach (an organ not present in man), cataracts, vascular lesions in the central nervous system (CNS), skeletal muscle toxicity, testicular degeneration and, although the statins are clearly not genotoxic, tumours of the liver and other sites (details can be found in the product circulars of the individual statins). It has been shown, where it has been practical to conduct the experiment, that these effects can be prevented by administering mevalonate 29,30, the product of the reaction catalysed by HMG-CoA reductase.  This indicates that these toxic effects are mostly, if not entirely, attributable to extreme inhibition of the enzyme at high doses 29.  So Merck, and the regulatory agencies considering the marketing application submitted by Merck, were faced with a wide range of animal toxicological effects, as well as the history of compactin and the known central role of the cholesterol biosynthesis pathway in many physiological processes, including the production of steroids and cell membranes.  [Since the toxicity of the very similar in structure compactin, whose toxicity in animal studies resulted from it not being tested clinically, that the same occurred for Lovastin, but Merck went forward. Compactin was withdrawn from the market for ]   Fortunately, except for rare cases of myopathy and marked but asymptomatic increases in hepatic transaminases, none of the adverse effects found in animals occur at human therapeutic doses.” Nature Reviews Drug Discovery 2, 517-526 (July 2003) | doi:10.1038/nrd1112

Author’s affiliations: A. Tolbert, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Email: 
jonathan_tobert@merck.com

CHOLESTEROL    from http://en.wikipedia.org/wiki/Cholesterol

Cholesterol, from the Ancient Greek chole- (bile) and stereos (solid) followed by the chemical suffix -ol for an alcohol, is an organic molecule. It is a sterol (ormodified steroid),[3] and an essential structural component of animal cell membranes that is required to establish proper membrane permeability and fluidity. Cholesterol is thus considered within the class of lipid molecules. In addition to its importance within cells, cholesterol also serves as a precursor for the biosynthesis of steroid hormones, bile acids, and vitamin D.[4] Cholesterol is the principal sterol synthesized by animals; in vertebrates it is formed predominantly in the liver.

François Poulletier de la Salle first identified cholesterol in solid form in gallstones in 1769. However, it was not until 1815 that chemist Michel Eugène Chevreul named the compound "cholesterine".[5][6]  Since cholesterol is essential for all animal life, each cell synthesizes it from simpler molecules, a complex 37-step process that starts with the intracellular protein enzyme HMG-CoA reductase [what statins block]. However, normal and particularly high levels of fats (including cholesterol) in the blood circulation, depending on how they are transported within lipoproteins, are strongly associated with the progression of atherosclerosis.  For a man of about 68 kg (150 pounds), typical total body-cholesterol synthesis is approximately 1 g (1,000 mg) per day, and total body content is approximately 35 g, primarily located within the membranes of all the cells of the body. Typical daily dietary intake of additional cholesterol, in the United States, is 200–300 mg.[7]  Most ingested cholesterol is esterified, and esterified cholesterol is poorly absorbed. The body also compensates for any absorption of additional cholesterol by reducing cholesterol synthesis.[8] For these reasons, cholesterol intake in food has little, if any, effect on total body cholesterol content or concentrations of cholesterol in the blood.  Cholesterol is recycled. The liver excretes it in a non-esterified form (via bile) into the digestive tract. Typically about 50% of the excreted cholesterol is reabsorbed by the small bowel back into the bloodstream.

Function[edit]

Cholesterol is required to build and maintain membranes; it modulates membrane fluidity over the range of physiological temperatures. The hydroxyl group on cholesterol interacts with the polar head groups of the membrane phospholipids and sphingolipids, while the bulky steroid and the hydrocarbon chain are embedded in the membrane, alongside the nonpolar fatty-acid chain of the other lipids. Through the interaction with the phospholipid fatty-acid chains, cholesterol increases membrane packing, which reduces membrane fluidity.[11] The structure of the tetracyclic ring of cholesterol contributes to the decreased fluidity of the cell membrane as the molecule is in a trans conformation making all but the side chain of cholesterol rigid and planar.[12] In this structural role, cholesterol reduces the permeability of the plasma membrane to neutral solutes,[13] protons, (positive hydrogen ions) and sodium ions.[14]

Within the cell membrane, cholesterol also functions in intracellular transport, cell signaling and nerve conduction. Cholesterol is essential for the structure and function of invaginated caveolae and clathrin-coated pits, including caveola-dependent and clathrin-dependent endocytosis. The role of cholesterol in such endocytosis can be investigated by using methyl beta cyclodextrin (MβCD) to remove cholesterol from the plasma membrane. Recently, cholesterol has also been implicated in cell signaling processes, assisting in the formation of lipid rafts in the plasma membrane. Lipid raft formation brings receptor proteins in close proximity with high concentrations of second messenger molecules.[15] Cholesterol levels can change how quickly surface proteins move within the plasma membrane[16] and also the efficiency of magnetic capture of cells.[17] In many neurons, a myelin sheath, rich in cholesterol, since it is derived from compacted layers of Schwann cell membrane, provides insulation for more efficient conduction of impulses.[18]

Within cells, cholesterol is the precursor molecule in several biochemical pathways. In the liver, cholesterol is converted to bile, which is then stored in the gallbladder. Bile contains bile salts, which solubilize fats in the digestive tract and aid in the intestinal absorption of fat molecules as well as the fat-soluble vitamins, ADE, and K. Cholesterol is an important precursor molecule for the synthesis of vitamin D and the steroid hormones, including the adrenal gland hormones cortisol andaldosterone, as well as the sex hormones progesteroneestrogens, and testosterone, and their derivatives.[4] Some research indicates cholesterol may act as an antioxidant.[19]

Dietary sources

Fat intake also plays a role in blood-cholesterol levels. This effect is thought[by whom?] to come about by changes in the quantity of cholesterol and lipoproteins that are synthesized by the body. Isocalorically replacing dietary carbohydrates withmonounsaturated and polyunsaturated fats has been shown to lower serum LDL and total cholesterol levels and increase serum HDL levels, while replacing carbohydrates with saturated fat was shown to increase HDL, LDL, and total cholesterol levels.[29] Trans fats have been shown to reduce levels of HDL while increasing levels of LDL.[30] Based on such evidence and evidence implicating low HDL and high LDL levels in cardiovascular disease (see Hypercholesterolemia), many health authorities advocate reducing LDL cholesterol through changes in diet in addition to other lifestyle modifications.[31] The USDA, for example, recommends that those wishing to reduce their cholesterol through a change in diet should aim to consume less than 7% of their daily energy needs from saturated fat and fewer than 200 mg of cholesterol per day.[32] An alternative view is that any reduction to dietary cholesterol intake could be counteracted by the organs compensating to try to keep blood cholesterol levels constant.[33] Other research has found that an increase in the consumption of saturated fats and cholesterol decreases overall serum cholesterol. [34].

Regulation of cholesterol synthesis[edit]

Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood. A higher intake from food leads to a net decrease in endogenous production, whereas lower intake from food has the opposite effect. The main regulatory mechanism is the sensing of intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (sterol regulatory element-binding protein 1 and 2).[37]

 

Plasma transport and regulation of absorption

Cholesterol  is transported in the circulatory system within lipoproteins, complex discoidal particles that have an exterior composed of amphiphilic proteins and lipids whose outward-facing surfaces are water-soluble and inward-facing surfaces are lipid-soluble; triglycerides and cholesterol esters are carried internally. Phospholipids and cholesterol, being amphipathic, are transported in the surface monolayer of the lipoprotein particle.  In addition to providing a soluble means for transporting cholesterol through the blood, lipoproteins have cell-targeting signals that direct the lipids they carry to certain tissues. For this reason, there are several types of lipoproteins in blood, called, in order of increasing density, chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). The more lipid and less protein a lipoprotein has, the less dense it is.  VLDL molecules are produced by the liver and contain excess triacylglycerol and cholesterol that is not required by the liver for synthesis of bile acids. 

LDL molecules, therefore, are the major carriers of cholesterol in the blood, and each one contains approximately 1,500 molecules of cholesterol ester. LDL molecules, therefore, are the major carriers of cholesterol in the blood, and each one contains approximately 1,500 molecules of cholesterol ester.  Now within the cell, the cholesterol can be used for membrane biosynthesis or esterified and stored within the cell, so as to not interfere with cell membranes.  These LDL molecules are oxidized and taken up by macrophages, which become engorged and form foam cells. These cells often become trapped in the walls of blood vessels and contribute to atherosclerotic plaque formation. Differences in cholesterol homeostasis affect the development of early atherosclerosis (carotid intima-media thickness).[40] These plaques are the main causes of heart attacks, strokes, and other serious medical problems, leading to the association of so-called LDL cholesterol (actually a lipoprotein) with "bad" cholesterol.[39]

HDL particles are thought to transport cholesterol back to the liver for excretion or to other tissues that use cholesterol to synthesize hormones in a process known as reverse cholesterol transport (RCT).[41] Having large numbers of large HDL particles correlates with better health outcomes.[42] In contrast, having small numbers of large HDL particles is independently associated with  atheromatous disease progression in the arteries.  HDL particles (especially large HDL) have been identified as a mechanism by which cholesterol and inflammatory mediators can be removed from atheroma. Increased concentrations of HDL correlate with lower rates of atheroma progressions and even regression.

 

Metabolism, recycling and excretion

Cholesterol is oxidized by the liver into a variety of bile acids.[46] These, in turn, are conjugated with glycine, taurine, glucuronic acid, or sulfate. A mixture of conjugated and nonconjugated bile acids, along with cholesterol itself, is excreted from the liverinto the bile. Approximately 95% of the bile acids are reabsorbed from the intestines, and the remainder are lost in the feces.[47] The excretion and reabsorption of bile acids forms the basis of the enterohepatic circulation, which is essential for the digestion and absorption of dietary fats. Under certain circumstances, when more concentrated, as in the gallbladder, cholesterol crystallises and is the major constituent of most gallstones. 

 

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Disclaimer:  The information, facts, and opinions provided here is not a substitute for professional advice.  It only indicates what JK believes, does, or would do.  Always consult your primary care physician for medical advice, diagnosis, and treatment.