|February 1999||Bruce H. Woolley, Pharm.D., Editor||Vol. 6, No.2|
|Kenneth J. Hunt, Associate Editor|
COX-2 INHIBITORS: A SYNOPSIS OF TECHNOLOGY
During the 1980s, it was thought that the formation of prostaglandins was controlled by availability of the precursor compound arachidonic acid. This concept was based on the observation that the cyclooxygenase known at that time was identified as a constitutive enzyme. That is, an enzyme that is widely distributed throughout the body and has a constant production within most cells.
Upon further evaluation, Needleman and his colleagues have observed that the cyclooxygenase located in inflamed tissue is inducible. That is, its production can be increased by specific agents and conditions. Agents known to increase production include: cytokines, endothelin-1, growth factors, and certain invasive bacteria. These observations have confirmed that there are two isoforms of cyclooxygenase. One that is constitutive (COX-1) and one that is inducible (COX-2).
Even though these two isoforms are encoded by separate chromosomes, they have a 60% homology (similarity in structure) and their enzymatic action on arachidonic acid is very similar. However, due to their differences in expression, they differ in their physiologic roles.
Since the discovery of COX-2 in the early 1990s, pharmaceutical companies have been vigorously trying to develop agents that will specifically inhibit this enzyme while leaving the important physiologic functions of COX-1 unaltered. (The term "specific" denotes an agent that inhibits only one of the enzymes, sparing the other.) COX-1 catalyzes production of prostaglandins that protect the stomach and kidneys. COX-2 catalyzes production of prostaglandins that are involved in the inflammatory process. Thus, COX-2 inhibitors are correctly described as specific at therapeutic doses; while sparing COX-1. Currently available nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit actions of both enzymes. Since COX-1 is involved in the formation of prostaglandins that protect gastric mucosa, diminishing them may produce side effects such as peptic ulcers and GI bleeds.
The anticipated promise of COX-2 specific inhibitors is equivalent activity and efficacy with NSAIDs in pain and inflammation management without similar side effects. Structure-activity relationship studies have determined the importance of a three-ring structure for COX-2 selectivity. It has also been observed that the addition of a sulfonamide group increases in vitro inhibition of COX-2.
The identification of the COX-2 isoform and the resulting development of compounds which specifically inhibit this enzyme has potentially provided clinical applications for all of the disorders for which NSAIDs are currently used. Key potential applications will be arthritis (and related inflammatory pathophysiology) and pain management while maintaining the protective effects of COX-1 on the gastric mucosa, platelet activity, and renal function. Thus, these compounds may provide a realistic option for patients who cannot tolerate the side effects of currently available NSAIDs and opiates.
Thanks to: Needleman P, Isakson PC. The discovery and function of COX-2. J Rheumatol. 1997; 24(suppl 49): 6-8
SPOTLIGHT ON HERBS: GINKGO BILOBA
Among the medicinal herbs and plants that appear to be relevant to rehabilitation, ancient Chinese remedies comprise a wealth of candidates that have been used for millennia. Ginkgo biloba is a tree leaf that has been used in Chinese medicine for more than 5000 years to improve blood flow and cognitive performance. It has recently received attention in western medicine as of late, especially in health food stores and herb manufacturers.
Ginkgo biloba is currently one of the most widely prescribed medications in Germany due to an abundance of positive research in recent years. In a placebo-controlled, double-blinded study of 50 subarachnoid hemorrhage patients, only ginkgo treated subjects showed significant improvements in attention and short-term memory. An additional study demonstrated modest cognitive and behavioral improvements in Alzheimers and multi-infarct dimentia patients taking Ginkgo biloba.
In addition to its positive effects on memory, Ginkgo has been used in treating Raynauds disease, cerebral insufficiency, anxiety and stress, tinnitus, dementias, circulatory disorders, and asthma. It is also purported as useful in combatting diseases associated with free radical generation. Severe side effects with ginkgo are extremely rare. Possible effects include headache, dizziness, heart palpitations and GI and dermatologic reactions. Ginkgo pollen can be strongly allergenic. Contact with the fleshy fruit pulp causes allergic dermatitis, similar to that caused by poison ivy.
The safety of Ginkgo has been widely studied. In 44 double-blind studies involving 9,772 patients taking Ginkgo biloba extract, the number of side effects reported was extremely small. The most common side effect, gastrointestinal discomfort, occurred in only 21 cases, followed by headache (seven cases) and dizziness (six cases). Interactions with aspirin and other anticoagulants have been noted  and include subdural hematoma and one case of retinol hemorrhage in association with ginkgo and aspirin. The usefulness of the herb is now under close scientific scrutiny. There are several ongoing trials on the benefits of ginkgo biloba extract against the above mentioned conditions. Once the extent and magnitude of the effects are known and products are standardized in the United States, ginkgo may be a useful medicinal aid.
 Kanowski S, et al. Proof of efficacy of the ginkgo biloba special extract EGB 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia (Reprinted from Pharmacopsychiatry vol. 29, pp 47-56, 1996). Phytomedicine. 4(1):3-13, 1997 Mar.
 Rowin-J; Lewis-SL Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion.
Neurology 1996 Jun; 46(6):1775-6.
VITAMIN A FUNCTION IN THE CNS DOPAMINERGIC SYSTEM
Retinoic acids play an important role in the development of the central nervous system (CNS). Vitamin A, which is ingested as retinol, is attached to retinol binding protein (RBP) in the circulation and converted to retinal in the microvasculature of the brain. It was recently discovered that an enzyme converts retinal to retinoic acid in mice; retinoic acid is then concentrated in the forebrain, specifically in dopaminergic neurons. This led researchers to the hypothesis that retinoic acid is involved in dopamine signaling in the brain.
Dopamine is a signaling molecule in the CNS that controls coordinated movements. It is also involved in the synthesis of pituitary hormone. A defect in the dopaminergic system is the major cause of Parkinsons disease. Dopamine functions by binding to and activating specific membrane receptors. In mice which lack one of the dopamine receptors, dopamine receptor 2 (D2R), pituitary tumors develop and Parkinson-like motor defects are evident.1
Samad et al. investigated the transcriptional factors operating on the D2R, revealing a Retinoic Acid Response Element (RARE) as part of the promoter region of the D2R gene. The researchers were further able to demonstrate that D2R is activated by retinoic acid. To test this in vivo, they used mice who had been genetically altered to lack RARE. The results were dramatic reductions (up to 70%) in D2R activity, and mice which displayed defects in motor skills similar to those seen in Parkinsons disease.2
It appears that the presence of retinoic acids is necessary for the expression of D2R and that, therefore, retinoic acids play a key role in adult CNS function. This led Samad, et al. to conclude that Parkinsons disease may be connected to defective expression of the dopamine receptor. From a nutritional standpoint, these findings are further evidence of the importance of dietary Vitamin A. The current RDA for Vitamin A is 1000 µg retinol equivalents for adults. The best sources of Vitamin A are the carotenoids in carrots and leafy green vegetables. Animal liver is also rich in Vitamin A.
 Krezel W, Ghyselnick N, Samad TA, et al. Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science 1998; 279:863-7.
 Samad TA, Krezel W, Chambon P, et al. Regulation of dopaminergic pathways by retenoids: activation of the D2 receptor promotor by members of the retinoic acid receptor-retinoic X receptor family. Proc Natl Acad Sci USA 1997; 94:14349-54.
FDA DIETARY SUPPLEMENT LABELING REVIEW RULED UNCONSTITUTIONAL
According to Facts and Comparisons, the US Court of Appeals has ruled that the regime for the FDA review for dietary supplement labeling is unconstitutional, arbitrary, and capricious. The agency has been held in violation of the Administrative Procedure Act and the court instructed the FDA to: define the term "significant scientific agreement" for health claims on dietary supplement labels; and to allow the use of disclaimers on labels. The Court also ruled that four of the FDAs Final Rules that prohibit nutrietn-disease relationship claims are invalid under the First Amendment to the Constitution. The case has been remanded to the US District Court.
HIGH FIBER DIET PROTECTIVE AGAINST COLORECTAL CANCER?
The January 21, 1999 issue of New England Journal of Medicine contained a study where the authors reported their data showing that the relative risk of developing colorectal cancer and adenoma was not significantly different between women whose fiber intake was considered high and those whose fiber intake was considered low. The authors also found that some vegetable fiber may increase the risk of cancer in women.
LABORATORY CREATED ANTIBODIES
In the January-March issue of Emerging Infectious Diseases, Johns Hopkins University scientists describe new advances in biotechnology with monoclonal antibodies. The authors state that new antibiodies created in the laboratory can be produced in common field crops, such as corn and soy, and provide protection against diarrheal diseases, respiratory ailments and STDs. The scientists feel that these developments have enormous implications in the public health arena because of the relatively recent identification of new anatomical areas for the fight against invading organisms. Specifically the areas of emphasis are the respiratory, GI and genital/urinary tracts, where most pathogens are initially transmitted.
ORLISTAT FOUND TO REDUCE OBESITY-RELATED RISK FACTORS
study in the Jan 19, 1999 JAMA indicates that orlistat (Xenical®/Roche) improves obesity-related risk factors such as heart disease and diabetes. Both blood pressure and blood cholesterol levels declined significantly as did blood glucose and insulin levels.
FDA NEW DRUG APPROVALS
Celecoxib (Celebrex®/Searle & Pfizer) [approved Dec 31, 1998] for the relief of the signs and symptoms of osteoarthritis and adult rheumatoid arthritis.
Atovaquone (Mepron®/GlaxoWellcome) [new indication] for the prevention of Pneumocystis carinii pneumonia. It was previously approved for acute oral treatment of mild-to-moderate PCP in patients who are intolerant to trimethoprim-sulfamethoxazole.
Enoxaparin sodium (Lovenox®/Rhone-Poulenc Rorer) [new indication] for the inpatient treatment of acute deep-vein thrombosis with and without pulmonary embolism and for outpatient treatment of acute deep-vein thrombosis without pulmonary embolism. Both indications are for coadministration with warfarin.
Cilostazol (Pletal®/Otsuka) [approved Jan 15, 1999] for the reduction of symptoms of intermittent claudication. The drug is contraindicated in patients with any degree of severity of CHF.
The information and opinions expressed in the Therapeutics Letter do not necessarily reflect the official policy of the sponsoring organizations.