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Pain

The Athlete’s Diet is a return to the Traditional view of health and the original intent of what the term diet really means. The beliefs, herbal practices, nutritional concerns and preventive medicine described in this book are based on principals and beliefs developed over the millennia. The following chapters will describe a methodology to live a healthy life. It is a program of exercise. The ingredients in its diet are those that best fuel and best meet the molecular needs created by exercise. These foods are described The Diet.

One of the unfortunate consequences of exercise is pain and inflammation. Unresolved inflammation in joints causes arthritis. The Athlete’s Diet recognizes that many athletes depend on drugs to exercise, especially those that infrequently or improperly workout. Many of the detrimental effects of exercise are cumulative or chronic in nature. These can be minimized or prevented by a botanical approach to healing. Pharmaceutical drugs better treat severe injuries and acute inflammation. This subject is discussed in The Athlete’s Health.

Antibiotics, drugs and surgeries predominate medical therapies. Others being developed involve cell based therapies and  genetic cloning. The potential that remains locked in stem cell research results from the government’s Neanderthal position. The number of scientists capable of conducting stem cell research with minimal capital is astounding. Leaving the door open for enterprising researchers is a prescription for disaster. Imagine terrorists training camps set amid protein sequencers, DNA analyzers and Pharmaceutical robots. 

Once the FDA approves a drug an avalanche of marketers take control of the product and insure its sale by convincing doctors of its validity. The marketing arm of Pharmaceutical companies  target patients as if they were the consumers of tissue paper.   The purpose for regulation was to prevent consumers from making diagnosis and treatment decisions. The flaws in the FDA policy and lack of corporate responsibility is described in America’s Health.

Pharmaceutical companies are dependent on physicians that believe in drugs. Physicians are taught to order tests and treat results. They are economically squeezed by the system and respond by increasing efficiency.  Efficiency translates into less time per patient. Hence the need for standardized treatment. The drugs they prescribe are influenced by the data and perks provided by Pharmaceutical reps. One of the most marketed therapies to both Physicians and consumers is pain relief. Every conceivable pain is portrayed in drug promotions along with the miracle cures they provide.

The Athlete’s Diet is different. It is a non-pharmaceutical approach to pain control. Its philosophy maintains that anti-inflammatory drugs should be used sparingly and certainly not at the first sign of pain.

Analgesic Drugs

Drugs such as acetaminophen (Tylenol), aspirin and ibuprofen (Motrin, Advil) represent a group of drugs knows as non-steroidal anti-inflammatory drugs (NSAIDs). These drugs produce adequate pain relief or analgesia without causing addiction. Instead of addiction, NSAIDs cause liver, kidney and gastrointestinal complications. The other group of drugs that are used to dull pain are the addictive opium narcotics or their derivatives (codeine, oxycodone, meperidine). The potential for abuse may discourage their use by doctors but the euphoria it produces encourages doctor’s visits.

All of the above mentioned drugs should never be used as a chronic or habitual remedy. Their ability to repress pain may be counterproductive to health since they also hinder the body’s ability to heal. All athletes that are currently taking these commonly prescribed pills should re-evaluate this practice. In addition to the stress placed on the kidneys, liver and GI tract in metabolizing and eliminating these drugs, they have other idiosyncratic drawbacks.

The Athlete’s Diet recommends natural botanical healing. Natural drugs are more easily metabolized with less harmful side effects. Their effectiveness is synergistic and increases over time. The pain and inflammatory repression they cause is less noticeable when compared to pharmaceutical as are the side effects.

It is generally agreed that all athletes need to recover following exercise. It maintains that athletes who replenish and restore themselves perform better and injure themselves less than those who don’t. The Athlete’s Diet considers preparation and replenishment as part of the exercise cycle and includes it as part of its program. As a preventive cure, The Athletes Diet recommends the habitual use of herbal anti-inflammatory products. Included are the non-herbal vitamins, minerals, amino-sugars, and other strengthening compounds. These metabolic intermediaries are believed to be important to cell repair. Adequate hydration in the period following exercise allows athletes to better replenish their bodies and remove toxic metabolites. The Athlete’s Diet stresses the importance of an athlete’s exercise cycle. In addition to a habitual period of intense activity, the diet requires a pre and post exercise regimen. Athletes that prepare their body for intense exercise by obtaining water and minerals and enough fuel will perform better than those who don’t. Athletes that include a period of time to relax, will rejuvenate and replenish their cells and thus be better prepared for the next cycle. These compounds are described in Natural Healing.

The Athlete’s Diet premise is that enhancement of athletic performance is a preventive strategy derived from Traditional healing. The Athlete’s Diet states that exercise improves health.

The Athlete’s Diet recommends natural methods to enhance exercise performance and improve long-term health. The Athlete’s Diet covers the quality of the substances imbibed and their subsequent digestion. It attempts to explain how these substances exert their effects and hence which ones to enjoy and which to avoid. The Athlete’s Diet believes that good eating habits promote harmony within while strengthening the body and relaxing the mind. Bad habits reinforce the unhealthy and selfish aspects of being, and causes imbalance and illness.

The Athlete’s Diet does expect fidelity to its foods. The gustatory pleasure of eating is one of the joys in life. To deny that, it to assure failure. Athletes are permitted to stray from healthy foods at times. The Athlete’s Diet is more of a moderation program than an elimination plan. Moreover, because it allows athletes to not be perfect, athletes can remain on the diet longer. Moderate the diet not the exercise!

The Athlete’s Diet describes a program to remain healthy and prevent disease. By following its diet, athletes will enhance their performance, reduce the severity of injuries and minimize the need for pain relievers. Its methodology requires intense exercise and sound nutrition. It is a diet that has a message for healthy athletes.

Heal thyself

This book is not intended as a substitute for medical diagnosis or therapy, which is only to be performed by a qualified health care professional.

Painkillers

Analgesics are pharmaceutical drugs that dull pain. They collectively earn over fifteen billion dollars annually for their makers. They are projected to earn over twenty-five billion annually in just a few years. Non-steroidal anti-inflammatory drugs (NSAIDs) represent a significant portion of those sales. The newest class of NSAIDs on the market is the coxibs. They are selective inhibitors of the enzyme cylooxygenase 2. A brief review of their mechanism of action is provided here. The consequences of inflammation are more thoroughly covered in The Athlete’s Health.

Inflammation

The central purpose of all NSAIDs is to repress inflammation in joints, tendons and ligaments. Reducing the redness, swelling and heat that characterize inflammation improves mobility and lessens pain.

Inflammation is the body’s response to irritation, injury or infection. Inflammation is characterized by the cardinal signs of heat, redness, and swelling, usually accompanied by pain at the injury site. Swelling is due to increased leakage of fluid from the blood vessels involved, while heat and redness are caused by the capillary dilation required to convey more blood to the site. 

Inflammatory mediators

Histamine, prostaglandins, thromboxane and leukotrienes are  four inflammatory compounds that illicit a strong biological response from the body. 

1.   Histamines are derived from the amino acid histidine and are released from white blood cells. Histamines produce vasodilation and increase the permeability of capillaries, thereby promoting the movement of substances out of blood vessels and into the site of the injury. 

2.   Prostaglandins are local hormone-like substances that

are actively synthesized at the site of injury where they intensify pain. 

3.   Thromboxanes are factors that initiate blood clotting in order to seal wounds. 

4.   Leukotrienes are very powerful inflammatory agents that constrict blood vessels.

Prostaglandins, leukotrienes and thromboxanes are referred

to as eicosanoids, due their derivation from arachidonic acid,

the 20-carbon chain fatty acid precursor.  

The Inflammatory Process

The inflammatory process begins when damaged cells release prostaglandins, specifically the E2 version abbreviated as PGE2.

PGE2. Prostaglandins belong to the eicosanoid family of compounds. PGE2 initiate a cascade of chemical reactions culminating in the migration of white blood cells (leukocytes) to the site of the injury. PGE2 formation depends on the activity of the cyclooxygenase enzyme system.

The inhibition or blockage of this enzyme system decreases prostaglandin production causing less white cell migration. This repressed prostaglandin production is basis for Vioxx’s anti-inflammatory activity.

Pharmacology

Cyclooxygenase is an enzyme system that results in the

formation of prostaglandins and thromboxanes from arachidonic acid. Cyclooxygenase enzymes are divided into COX-1 and COX-2 forms.

Prostaglandins represent a class of substances that function like hormones but are not. They are collectively known as prostanoids.

Discovery of Prostaglandins

The first of the prostaglandin compounds (prostanoids) to be identified and studied was prostaglandin, so named because it was first isolated from the prostate glands of sheep.

Prostaglandin was found to have a broad range of activities, with roles in inflammation, cells division, cell migration and muscle tone. Prostaglandin was only the first of many such substances to be isolated and described.

Prostanoids cause inflammatory cell migration to injured joints. The enzyme cyclooxygenase converts arachidonic acid to the precursor prostaglandin.

Prostaglandins are chemically synthesized from arachidonic acid. Arachidonic acid is derived from omega 6 fatty acids (linoleic). Omega 6 fatty acids are consumed in a diet rich in polyunsaturated oils.

The Athlete’s Diet recommends a diet higher in monounsaturated oils at the expense of both saturated

and polyunsaturated fat. This has the effect of lowering arachidonic acid production.

DRUGS

Pharmaceutical Arthritis Drugs

A profitable line of new drugs has been developed to treat arthritis. They are known as COX-2 inhibitors (coxibs) and are the subject under review by the FDA. The controversy surrounding their approval and their subsequent identification as a cardiovascular risk are discussed in America’s Health.

Sales of COX-2 inhibitor drugs have risen to over seven billion dollars a year. Arthritis is so prominent in America that over ninety percent of people over the age of forty has some form of it. Drug manufacturers recognize what millions of arthritis sufferers wanted and they developed it for them. Americans want better, more expensive and more effective drugs. They expected safe gastrointestinal behavior and instead got drugs that increase their risk of having a cardiovascular accident. The advertisements promised drugs to make their joints stop aching. Instead they delivered drugs that are unhealthy and no more effective than the ones developed decades ago.

There are over twenty NSAIDs on the market now that require a prescription, and three that don’t (aspirin, ibuprofen, naproxen). The use of NSAIDS in their natural or botanical form can be traced back to the Ancient Healers. Knowledge of their mechanism of action however, is only thirty years old. Recognition of two isoforms of the enzyme is less than fifteen years old with the search for a third COX enzyme in its infancy.

The search for the perfect arthritis remedy has centered on the development of selective cyclooxygenase inhibitors. They are into their second generation of drugs with no end in site. The present list of drugs approved for use  is Celebrex, Bextra, Dynastat, Arcoxia and Prexige. Each drug is supported with a specific safety trial that looked at one of the COX-2 inhibitors. They are called the VIGOR, CLASS, EDGE, and TARGET studies. APPROVe is a comparison study between Vioxx and Celebrex.  On the molecular level, arthritis is exacerbated by osteoclast activity. Drugs are thus being designed that increase the production of osteoprotogerin, a protein that lowers osteoclast activity. For now the methodology of choice in treating arthritis is by selectively blocking or repressing the cyclooxygenase 2 form of the enzyme.  COX is the first enzyme in the conversion of arachidonic acid to the pro-inflammatory prostaglandins.

Botanical Approach

The Athlete’s Diet prevents disease. It’s program is one of intense exercise and the proper nutrition to support it. Its foods contain a healthy diversity of essential phytonutrients. Foods that quench free radicals, dull pain, repress inflammation and improve mobility. The Athlete’s Diet does not recommend the use of Pharmaceutical drugs as an everyday method of controlling pain and inflammation. Used on a long-term basis, pharmaceutical drugs cause severe consequences with damaging side effects. Athletes who suffer from arthritis should follow a botanical regimen like the one described in The Athlete’s Diet. The chapter on Natural Healing presents products that best help athletes prevent inflammation following exercise. 

The Athlete’s Diet is an alternative program to pharmaceutical therapy and is based on plants. Specifically, on plants that in addition, to enhancing performance, improve endurance, repress inflammation and improve the health of an athlete’s joints. It is everyday medicine, a part of the diet. Botanicals are foods that moderate chronic disease not mask their effects. Pharmaceuticals are best used to treat acute inflammation and then only temporarily.  When I prescribed a painkiller or anti-inflammatory drug to ease a patient’s recovery following surgery, I was certain the drugs would work.

Botanical compounds are drugs found in herbs and foods. They are a safe and better alternative to taking NSAIDs.

The Athlete’s Diet believes the antioxidant and anti-inflammatory pigments contained in plants prevent chronic conditions from developing. 

There is always some lingering pain and inflammation from exercise despite a good diet. It becomes more manageable for athletes who have good dietary habits than for those who have bad habits. Botanicals produce a cumulative effect that slowly improves all aspects of health.

The Athlete’s Diet Black Box Warning

The Athlete’s Diet does not recommend the use of any selective COX-2 inhibitor. The Athlete’s Diet believes COX-2 enzyme activity is important to healing in ways that we don’t understand yet. Furthermore, The Athlete’s Diet does not believe that the entire arena of COX enzymes have been discovered, that a COX-3 enzyme is on the horizon. Until the safety concerns of the entire class of COX-2 inhibitors is resolved, the risks of these drugs outweigh their benefit and are to be avoided.

Herbal Cox Inhibiters

Certain herbs block the cyclooxygenase pathway to prostaglandins production and thereby possess anti-inflammatory activity. The Athlete’s Diet recommends the use of herbs to repress inflammation. These herbs include rosemary, turmeric, ginger, licorice, white willow, arnica basil, chamomile and green teas.  These herbs possess compounds that provide anti-inflammatory activity.

Some of them are included in topical anti-inflammatory ointments while others make up the many herbal substitutes for NSAIDs. This natural approach to pain control is safer than pharmaceutical drugs. This natural approach offers relief from the symptoms of arthritis without the side effects of drug.

THE Coxib CONTROVERSY

Pain is one residue of exercise that affects all athletes. The spectrum of NSAIDs is discussed with arthritis in Diseases and Therapies. Botanical Recovery is covered in Natural Healing.

Discovery of the Cox-2 Enzyme

In 1990 researchers at the University of Rochester Medical Center discovered the gene in humans that codes for an enzyme called COX-2. The team was lead by Donald Young, M.D., a physician and biochemist. The University received a patent in 2000, which they have been trying to collect royalties on.

Dr Young and his team discovered COX-2’s role in disease. They demonstrated the enzyme’s link to inflammation and proved  that selectively inhibiting or blocking the activity of the enzyme could repress inflammation. This discovery initiated a race between pharmaceutical companies to develop drugs that would inhibit the COX-2 enzyme and thereby reduce inflammation and pain.

The result of their efforts was the creation of a new class of drugs called COX-2 inhibitors (Coxibs). The original drugs or Coxibs are more commonly known by their brand names of  Celebrex® (celecoxib), and Vioxx® (refecoxib). The second generation of coxibs are known as Bextra® (valdecoxib),  Dynastat® (parecoxib), Arcoxia® (etoricoxib) and Prexige® (lumiracoxib)

The research that Young’s team worked on in 1990 also established a link between COX-2 and cancer.  Pharmaceutical companies are now researching coxibs for their potential to repress cancer. These phase IV trials have provided highly controversial data described later on.

The cyclooxygenase enzyme or COX is synthesized by every cell in the body.  Its activity is blocked by aspirin and other non-steroidal anti-inflammatory drugs.  Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are effective at controlling inflammation because they acted on the COX-2 enzyme. The unwanted side effects of gastrointestinal irritation and bleeding are caused by the NSAIDs’ effects on the original COX-1 enzyme. The full spectrum of effects and distribution of COX enzymes has not been established. They are known to exist in two forms and some researchers report a third isoform.

They are believed to involve platelet function, gastric secretion and inflammation. The COX-1 enzyme’s function is unrelated to inflammation. It’s role may be to repress the secretion of gastric acid in the stomach thereby protecting the stomach lining. In the absence of repression, acid is produced which irritates the cells that make up the lining.

Up until 1999 all NSAIDs including aspirin inhibited both the bad COX-2 form as well as the good COX-1 form.  This resulted in excess stomach acid, ulceration and gastrointestinal bleeding. In addition, there is the possibility of renal involvement either from the inhibition of the COX enzymes or though the removal of NSAIDs

The Young lab demonstrated that production of the COX enzyme is triggered by two kinds of molecular messengers. These inflammatory cytokines and growth factors cause the production of one of the two COX enzymes. The team genetically engineered the creation of two different types of cells. Each one synthesizing only one of the COX enzymes. This enabled the researchers to test compounds to determine if it could inhibit the gene that produced COX -2 without inhibiting the production of COX-1.

Pharmaceutical companies used the results from their research to identify new drugs that could inhibit only form of the COX enzyme, the COX-2 form. Pharmaceutical companies used Young’s cells to develop COX-2 inhibitors. The research by Young was the subject of a major patent infringement lawsuit against the drug’s makers, Pharmacia and the company that acquired it, Pfizer. The Supreme Court refused to hear the case without explanation and allowed the lower court’s ruling to stand.

The lower court ruled that Dr. Young and the University of Rochester’s work, did not blossom into a full-fledged complete invention. The University had committed over ten million dollars in the legal fight to gain billions in royalties. This illustrates how scientists and Universities are unable to win expensive lawsuits against the multilateral drug companies even when they own a break-through patent.

COX-2 Selective Inhibitor Development

Coxibs are a new type of non-steroidal anti-inflammatory drug (NSAID). They are based on COX inhibition, which is the methodology of choice for developing new arthritis drugs. COX-2 inhibitor drugs act by selectively blocking or repressing the cyclooxygenase 2 form of the enzyme (COX-2). COX in either form catalyzes the first reaction involving arachidonic acid. In the case of COX-2, the end product is a prostanoid (pro-inflammatory prostaglandin). Repressing this conversion results in less inflammatory compounds being produced.

Very simple idea, block the enzyme, block the pain stiffness and swelling it causes. What is not well understood is what other functions are the COX-2 enzyme involved with and what roles they play in health. Some of these activities may contribute to the dangerous side effects seen with the drugs that block this enzyme. The extent of COX-2 involvement in many tissues may never be known.  And since they are no more effective than over-the-counter medications in reducing pain and inflammation, The Athlete’s Diet sees no reason to support their use.

Although recovery from exercise is the last component of the exercise cycle The Athlete’s Diet will begin with the one ingredient in the Pharmaceutical armamentarium that is big news and which backs up the essential point of this book.

The coxibs (drugs that inhibit the COX-2 enzyme) have drawn considerable attention, not just because they have been linked to increased risk of heart attacks but also because these drugs were rushed to market by their makers and gained swift approval from the FDA. The coxib story is scary because of its implications. The FDA is at the center of the storm both in approving the drug Vioxx and its failure to act swiftly to protect the public once safety issues became known. During this debacle, A flood of leaks, whistleblowers testimony and anonymous letters has shook confidence in the US’s sole regulating agency.  One particularly disturbing news was the number of FDA scientists and researchers who claimed they were pressured to approve drugs despite their reservations concerning safety and effectiveness.

Cox-3 Possibility

In March of 1999, research by Dr. Dan Simmons and Nobel price laureate Sir John Vane, reported the possibility that a third isozyme of COX existed. The enzyme they theorize about has never been isolated or cloned.  The enzyme is immunologically related to COX-2 since COX-2 antibodies recognize and bind to it. COX-2 antibodies recognize only a specific amino acid sequence between residues 570-598 of COX-2. Is it conceivable that some of the protective effects of COX enzyme may be attributed to the function of COX-3. Researchers working in the field of eicosanoid science are pursuing this possibility and attempting to prove the existence of COX-3. If a third member of the COX enzyme family is discovered, then COX-3 will spawn the development of another generation of non-steroidal anti-inflammatory drugs.

This new therapeutic target for pharmaceutical exploitation will garner inordinate resources to develop new, more expensive and possibly more dangerous drugs. The COX-3 phenomenon can be explained by one of three scenarios. COX-3 may in reality be only a COX-2 or COX-1 variant, in other words there is no individual COX-3 enzyme or gene that codes for it. A third possibility, and the one that offers the most to Pharmaceutical science, is an actual gene that codes for a third COX enzyme.

Molecular Origins of The Coxibs

COX-2 inhibitors were developed to provide anti-inflammatory activity and produce analgesic effects to patients without damaging their gastric mucosa (stomach lining) or cause platelet dysfunction. The molecular origin of these inhibitors can be traced back to the search for a non-steroidal substitute for estrogen. Estrogen has the classic steroid nucleus made up of four rings of cyclic carbons. This skeleton defines the term steroid. Estrogen binding with an estrogen receptor causes growth. The search was for a drug that could bind with the estrogen receptor but not cause growth.

Unintended Consequences

The search produced the drug tamoxifen and a progenitor coxib. Tamoxifen is a non-steroidal agent that competes for the estrogen binding site. Tamoxifen is widely used to treat breast cancer because it selectively blocks the estrogen receptors. Another analogue that was deceloped had sulfur added to it, and displayed anti-inflammatory activity. This molecule would ultimately lead to the basic structure that is now known as a coxib. The substitution of side groups off the main three-ring structure provided drugs companies with novel ways to patent their own versions of the drug. Vioxx (rofecoxib), Celebrex (celecoxib) and Pfizer’s second-generation selective COX-2 inhibitor Bextra (valdecoxib), were the first ones to gain approval.

Because of the connection between the coxibs and estrogen receptors, other studies are underway to determine if coxibs can prevent cancer though its non-proliferative ability of blocking estrogen receptors and become a new therapy to treat breast cancer and polyps. It is also possible that the heart attacks and strokes that occurred with Vioxx is due to the loss of a cardiac protective effect that estrogen provides.

History of the Coxibs

In 1998-99 Merck and Pfizer were granted approval to sell and market two arthritis drugs.  These drugs, Vioxx (rofecoxib) and Celebrex  (celecoxib,) have made billions of dollars for their respective companies. Vioxx was voluntarily withdrawn in September of 2004 for increasing the risk of heart attacks and strokes. This was the largest prescription drug recall in history and a harbinger of things to come.  In December of the same year, Pfizer reported it was temporarily halting its marketing of Celebrex in light of its own studies that indicated a higher risk of heart attacks with high dose, long term use. In addition, Naproxen, a  painkiller sold under the brand name Aleve for over thirty years, also appears to increase the risk of heart attacks and strokes. In April of 2005, the FDA and the European Medicines Agency (EMA) took the unprecedented move to suspend the sale of Bextra because of serious cardiovascular risks. That makes four top selling pain-relieving drugs linked to cardiovascular risks in six months.

Coxibs are drugs that inhibit a specific isoform of cyclooxygenase, the COX-2 form. Cyclooxygenase is an enzyme in the pathway that produces prostaglandins from lipids. Prostanoids or prostaglandins are the mediators of inflammation.

Cyclooxygenase was discovered during the investigations of aspirin but its structure wasn’t determined till the early 1990’s.  The two isoforms of the enzyme were designated as COX-1 and COX-2. These enzymes differ by one amino acid in the main active site of the enzyme thereby providing a target for drug development. A drug that could block one form (COX2) and leave the other unblocked or uninhibited (COX1) would be very profitable. All non-steroidal anti-inflammatory agents or NSAIDs inhibit both forms of the cyclooxygenase enzyme. Coxibs are the only drugs that affect only the COX-2 enzyme. COX-1 enzymes are found in the lining throughout the gastrointestinal tract.

COX-1 enzymes are also found in platelets. Their effects are considered beneficial and their inhibition causes side effects such as ulceration and bleeding in the stomach as well as producing platelet clumping. COX-2 enzymes are found in other cells as well. The COX-2 enzyme when present in joints, promotes inflammation. Researchers do not know how many other cells require the COX-2 enzyme.

Drug developers created compounds that would inhibit only one form of the enzyme and thus represses inflammation without side effects. Or so it seemed. It was thought that inhibiting the COX-1 enzyme damages the stomach lining and inhibiting COX-2 enzymes decreases inflammation.  It is postulated that inhibition of COX-2 may also affect cardiac muscle and is the reason why the increased numbers of cardiovascular accidents.

COX development

Once the structure revealed the two isoforms, specific inhibitors of the COX-2 enzyme became the focus of drug development during the 90’s. The products that resulted from this research are pharmacological tools for the management and treatment of pain and arthritis. The COX-2 inhibitors or coxib drugs are the subjects of enormous controversy. This has focused the laser of media scrutiny on the development and testing of these drugs as well as the process that led to their approval.

Danger Sign

Although COX-2 was initially regarded as a source of only pathological prostanoids, new evidence indicates that this isoenzyme mediates other reactions than were not previously known. For example, COX-2 enzymes located in the endothelium (arterial walls) may confer a vasoprotective or anti-atherogenic action via the formation of prostacyclin, a potent inhibitor of platelet clumping. Prostacyclin also prevents the accumulation of cholesterol in vascular cells.

Phase IV Studies

The drug approval process is described in the Addendum. The last part of the process are the Phase IV trials. These trials are conducted after a drug in on the market. They are the lifeblood of the biotech business.  These small companies provide the Pharmaceutical giants with the sophisticated infrastructure needed to conduct these post-marketing trials. Many small and medium sized companies provide Big Pharma with their entrepreneurial and scientific talent to conduct Outreach studies.  

Phase IV studies are conducted after a drug is approved. Pharmaceutical companies conduct their own Phase IV studies to more fully understand how their drug compares to other drugs and to look for new ways to use a drug. The FDA rarely requires Phase IV tests although they can order one.  The FDA can require Phase IV studies on a large number of patients to evaluate a drug’s true safety, but they don’t.

The importance of phase IV trials is to ensure an enormous source of income for their manufacturers, not protect the safety of Americans. Fortunately, the results of the VIGOR and subsequent phase IV studies did protect the public, but not in the intended way.  Although it didn’t force the FDA into action, these tests did result in Merck’s lawyers recommending its voluntary withdrawal. It also focused attention on other similar drugs. In April 2005, the FDA and EMA ordered Pfizer to withraw Bextra based on strong evidence of increased cardiovascular risk and possible fatal skin reactions. The FDA also ordered strong warnings be placed on all NSAIDs.

From here on, it will be up to the legal arm of the pharmaceutical companies to both protect the executives from any criminality proceedings and defend their companies against lawsuits.

COX Chemistry

The enzyme cyclooxygenase (COX) catalyzes the first step in the synthesis of prostanoids (prostaglandins).  Early in the 1990s, COX was demonstrated to exist as two distinct isoforms. The two COX protein structures have much in common. Sixty percent of the amino acid sequence is identical and each form of the enzyme contains three separate binding domains (active sites). The three sites bind with different entities, two regulate the enzyme while, the main domain or active site catalyzes the reaction of arachidonic acid into prostaglandin E.

NSAIDs exert their effect by altering one or more of the amino acids at the active site.  The COX active site lies at the end of a hydrophobic channel that spans from the membrane-binding surface of the enzyme to the inner structure of the enzyme.

NSAIDs act at the COX active site by chemically altering amino acids or by causing a change in their spatial arrangement (conformational change).  Aspiri

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