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March 21, 2005

Treatment of Inflammation Stricken by the Law of Unintended Consequences
Foreseeing all consequences of one's decisions is impossible

Inflammation and its treatment have been one of the major tasks of medicine since its inception. The new student of medicine learns the litany of tumor, dolor, and rubor and applies these ancient descriptive terms in the analysis of possible inflammation.

Since the diagnosis and treatment of inflammation is so ubiquitous to the practice of medicine its treatment has seen methods and medications too numerous to list here. Since the problem persists despite all these years of effort the makers of medications continue to attempt to treat this problem with all manner of new drugs. Studies of inflammation showed the beneficial effects of aspirin in the 1800's and proceeded to many other drugs uses as antipyretics (anti-fever), analgesics (anti-discomfort) and anti-inflammatories. These all became known as aspirin-like and the term non-steroidal anti-inflammatory drug was first used for phenylbutazone when it was introduced into clinical practice in 19493 The mechanisms of action of these drugs was found to involve activity of the enzyme cyclooxygenase (COX) which mediates the synthesis of endogenous prostaglandins. However there is still not complete understanding of these medications in the treatment of inflammation. In 1992 a new enzyme was cloned from human and animal sources and was called cyclooxygenase-2 (COX-2). This was found to be increased by inflammatory cytokines and decreased by glucocorticoids. Prostaglandins are ubiquitous substances involved in inflammation. They form a group of fatty acid derivatives called prostanoids. A critical step in the production of these prostanoids involves the COX-1 and COX-2 prostaglandin endoperoxide H synthase-1 and synthase-2. PGHS-1 or COX-1 was presumed to be the major target of NSAIDS and it wasn't until the existence of two different cyclooxygenases was found in 1991 with the isolation of the COX-2 isoenzyme that differences in the two were described. 3 COX-1 was found to be a general prostaglandin related to the maintenance of gastric mucosa, vascular hemostasis and autocrine response to hormones. COX-2 was an inducible enzyme upregulated a great deal by various inflammatory stimuli. These results led to the concepts that the anti-inflammatory actions of NSAIDS were due to COX-2 inhibition and the unwanted side effects due to inhibition of COX-1. This information then led the pharmaceutical companies to develop specific anti-COX-2 medications and thus was born Vioxx®, 5 , Celebrex® and others.

The use of these medications skyrocketed and those with inflammatory conditions liked the effectiveness of these medications. Then as more and more patients used these medications and more years of patient use experience were accumulated the precautionary notes in the article on COX-2 inhibitors in the Therapeutics Letter of 2001/2002 began to be recognized.4 These unforeseen consequences of the uses of these drugs demonstrated once again the law of unintended consequences. This Law was first discussed by Robert Merton in 1936 2 and more recently discussed by Rob Norton.1

This bumping up against the wall of things not thought of is always sobering. In today's climate of responsibility oriented adverse outcomes analysis it can be devastating. Soon there were reports of adverse cardiac events. The actual statistical risk of these adverse events only seems to occur in about 1.9% of patients and then only with long term use.

However there has been a huge decrease in the use of these COX-2 inhibitor drugs and now with new evidence of a benefit of COX-2 there may be a re-orientation of the treatment of inflammation and a return to more basic mechanisms.

It is interesting that in the presence of knowledge of possible serious adverse side effects of these wonderful COX-2 inhibitors and the knowledge of other beneficial actions of COX-2 in treating inflammation with the addition of aspirin 5,6,7,8,10 the stampede to the anti-COX-2 inhibitors proceeded. Perhaps it relates to the business need to recoup development costs.

It was found as early as 2002 that there was a family of bioactive products, resolvins, produced from omega-3 fatty acids by aspirin.5 Serhan's group showed that mice treated with Aspirin and docosahexaenoicacid (DHA) produced a family of bioactive 17 R-hydroxy-containing di- and tri-hydroxydocosahexaenoics called resolvins.5 These biosynthetic pathways utilize omega-3 DHA and EPA to produce resolvins.5 They demonstrated that Aspirin (ASA) treatment of human tissues in vitro carrying COX-2 during times of stress produced these resolvins that serve in anti-inflammation signaling.5 The compounds were of interest in the treatment of inflammation since when administered to new animals they sharply reduced PMN (polymorphonuclear leukocytes) infiltration by about 60%.5 The work found that acetaminophen and indomethacin did not share the ability of ASA to produce 17R-HDHA.5 Further evidence of the role of aspirin in triggering the endogenous formation of resolvins and docosatrienes was presented in 2004 and of their potent anti-inflammatory actions.6,7,8 More detail of these mechanisms was discussed in 2005.9 Human resolvin E-1, produced as mentioned above, binds to a G-protein coupled receptor called ChemR23 that is found on leukocytes and inhibits the migration of these cells to sites of inflammation.9 This article speculates that the COX-2 inhibitor drugs, Vioxx®, Bextra®, Celebrex®, etc, could block the synthesis of resolvin E1.9 Thus we see the effect of the Law of Unintended Consequences. Further work is being done on resolvin E1 and attempts to scale up the manufacture of synthetic resolvin E1 will produce it cheaply in bulk for use in well controlled human trials.11

It is likely that commercial synthetic production of human resolvin E1 will occur. However until that time one can take advantage of the knowledge that a diet high in omega-3 fatty acids places one in position to add aspirin to produce this resolvin substance to treat inflammation.12 If there is the background of omega-3 fatty acids in the diet then how much aspirin must be taken to get the desired anti-inflammatory response. The accurate answer is that no one knows.

However the writer of this article utilizes the following routine:
1. Two tablespoons of flax oil or its equivalent in flax oil capsules morning, noon, and night at the time of major meals.
2. One, regular size, enteric coated aspirin three times per day with the two flax oil capsules at these same times. The current result has been that small joints thought to be uncomfortable from arthritis are now just as comfortable as they were with Vioxx®, Bextra®, or Celebrex®.
This is only an uncontrolled , one person result however it is presented for consideration. Aspirin at these dosages can have adverse gastrointestinal side effects and preventive measures against that problem must be taken.

This small saga illustrates that the mechanisms of this machine we live in are very complex and introduction of various chemicals to treat medical conditions can have unintended consequences.

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