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Modifiers of arachidonic acid metabolism

Many effects of prostaglandins, thromboxanes and leukotrienes are adverse in certain circumstances. Available drugs can be Inhibitors of their synthesis or antagonists of their effects.

Diet modifications

The metabolism of eicosanoids can be modified by drugs but also by changes in the diet.

Replacement of arachidonic acid, present in meats, by omega-3 fatty acids such as eicosapentaenoic acid present in the fish oil, leads to an increased synthesis of PGI3 and thromboxane A3. PGI3 has an important activity whereas TXA3 is not very active. Thus, eicosapentaenoic acid has a PGI3-like effect, similar to that of PGI2.

Enrichment of the diet by fish oil has a favorable effect for the prevention of vascular diseases and could perhaps attenuate certain depressive states and reduce the importance of certain rheumatic symptoms. Interesting results were obtained in the treatment of the rheumatoid arthritis by gamma-linoleic acid intake which is metabolized into di-homo-gamma-linoleic, leading to a preferential synthesis of PGE. The enrichment of the diet in unsaturated fatty acids seems to reduce inflammatory reactions and rejection of grafts. One can consequently wonder whether this modification of the intake of fatty acids if it becomes excessive could not reduce also certain mechanisms of defense of the body.

Recent studies, in animals, show that modifications of the intake of certain fatty acids can slow the growth of certain tumors but it is difficult to extrapolate these results to human beings.

There are a lot of preparations rich in n3 polyunsaturated fatty acids.

A2 phospholipase inhibitors

The Inhibitors of A2 phospholipase currently used are glucocorticoids which act indirectly via lipocortin (See “Glucocorticoids”). There are other peptides inhibiting A2 phospholipase called antiflammins.

Studies are ongoing to obtain specific nonpeptidic orally active Inhibitors of A2 phospholipase.

Thromboxane synthase inhibitors

Instead of inhibiting cyclooxygenase which decreases at the same time the synthesis of prostaglandins and prostacyclin considered as beneficial, and of thromboxanes regarded as harmful, it appears better to selectively inhibit thromboxane synthase, enzyme responsible for the synthesis of thromboxane A2. At present, there is no drug inhibiting selectively thromboxane synthase, but their marketing during the next few years is probable.

Lipoxygenase inhibitors

As the effects of leukotrienes are, at least at first sight, harmful, the inhibition of their synthesis is desirable. Many lipoxygenase Inhibitors are currently under trials.

Zileuton is an inhibitor of 5-lipoxygenase which, by inhibiting the synthesis of the corresponding leukotrienes, could be of interest in the treatment of asthma. Its action is short because of its rapid metabolism. Its principal adverse effect seems to be a rise of transaminases with the risk of hepatitis.

Esculetin coumarinic, derivative of Aesculus hippocastanum extract, inhibits the activity of the 12-lipoxygenase and shows antiproliferative effects on certain experimental tumors.

Cyclooxygenase inhibitors, NSAID

Inhibitors of cyclo-oxygenases have antiinflammatory properties and include nonsteroidal antiinflammatory drugs or NSAID to which one can attach acetaminophen and mesalazine. The majority of NSAID were discovered and used in therapeutics long before their mechanism of action was known.

One can distinguish mixed COX-1 and COX-2 Inhibitors or conventional NSAID because they were the first to be marketed, COX- Inhibitors 2 , called coxibs, and the preferential COX-3 inhibitor, acetaminophen.

See the complete chapter on Cyclooxygenase inhibitors, NSAID.

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