Prostaglandin synthase inhibitors

Pharmacotherapy. Acute relief of inflammatory symptoms can be achieved by prostaglandin synthase inhibitors nonsteroidal anti-inflammatory drugs, or NSAlDs, such as diclofenac, indomethacin, piroxicam, p. 200), and glucocorticoids (p. 248). The inevitably chronic use of NSAlDs is likely to cause adverse effects. Neither NSAlDs nor glucocorticoids can halt the progressive destruction of joints. 

The prostaglandin synthase inhibitor rofe-coxib (Vioxx , now withdrawn from the market) was reported to inhibit P450 8A1 [1868]. 

In addition to aconitases, nitric oxide is an inhibitor of many other enzymes such as ribonucleotide reductase [71], glutathione peroxidase [72,73], cytochrome c oxidase [74], NADPH oxidase [75], xanthine oxidase [76], and lipoxygenase [77] but not prostaglandin synthase [78]. (Mechanism of lipoxygenase inhibition by nitric oxide is considered in Chapter... 

Gossypol has been isolated from the roots, stems, and seeds of the cotton plant and reported as a COX inhibitor based on in vitro assay in neutrophils [165] and an inhibitor of LOX and prostaglandin synthase from rat basophilic leukemia cells [166]. Gossypol showed as a potent inhibitor of leukotrienes B4 and D4 production and also reduced PTF-induced contraction of guinea-pig lung parenchyma [167]. 

Figure 17.32. (a) Inactivation of prostaglandin H2 synthase by aspirin, and (b) inhibitors cocrystallized with prostaglandin synthase. 

Inhibitors of prostaglandin synthase (aspirin, indomethacin) may delay onset of labour and, in the fetus, cause closure of the ductus arteriosus, patency of which is dependent on prostaglandins. It is probable that drug allergy in the mother can also occur in the fetus and it is possible that the fetus may be sensitised where the mother shows no effect, e.g. neonatal thrombocytopenia from thiazide diuretics. 

The role of xenobiotic metabolism in the cytotoxicity of an ecotoxicant to fish cell lines has been best studied with BaP, but even with this PAH the story is incomplete (Table 3). Two types of cytotoxic responses to BaP have been documented. One has been a transitory decline in metabolism, but not in cell viability, after BaP exposures of 24-48 h. This was observed in the rainbow trout liver cell lines, RTL-W1 and Rl174. Metabolism appeared necessary for this effect as the response was blocked in RTL-W1 and Rl by, respectively, the CYP1A inhibitor, a-naphthoflavone (ANF) and the prostaglandin-H-synthase inhibitor, indomethacin. BaP quinones were thought to be the BaP metabolites responsible for this effect. 

Finally, the investigational use of new pharmacotherapeutics such as thromboxane synthase inhibitors, vasodilator prostaglandin infusions, antioxidants, and P-receptor agonists in the treatment of microvascular permeability edema is well covered in several reviews (Demling, 1982 McMillan and Boyd, 1982 Persson et al., 1982). 

Naphthoresorcinol NSC 115890. Inhibitor of prostaglandin synthase. Used to assay sugars, oils and glucuronic acid in urine. White leaflets mp = 123.5° Xm = 214, 236, 287, 336 nm (MeOH) slightly soluble in Me2CO, CeHe, ligroin, soluble in H2O, EtOH, Et20, AcOH. 

Kalf and associates (1989) have investigated the action of prostaglandin H synthase in benzene toxicity and prevention of benzene-induced myelo- and genotoxic-ity by nonsteroidal anti-inflammatory drugs (NSAIDs). Indomethacin, a prostaglandin H synthase inhibitor prevented the dose- dependent bone marrow depression and increase in... 

As well as the apparent pathological role that thromboxane A2 plays in unstable angina, it also seems to be involved in the transient ischaemic attacks that occur in stroke patients. Aspirin is recommended by the FDA for treating these patients. The evaluation of thromboxane synthase inhibitors and prostaglandin endoperoxide-thromboxane A2 receptor antagonists in the clinical setting will doubtless reveal pathological roles for thromboxane A2 in other human diseases. 

Figure 6.1 Proposed mechanisms of action of thromboxane synthase inhibitors on platelet activity. Thromboxane synthase inhibition prevents the conversion of prostaglandin endoperoxides (PGH2) to thromboxane A2 (1). Prostaglandin endoperoxides are proaggregatory (2) and are metabolized by endothelium to platelet-inhibitory prostacyclin (3)...

Figure 6.5 Percent change in thromboxane A2 and prostacyclin biosynthesis, measured as excretion of their urinary metabolites, 2,3-dinor-thromboxane (Tx) 82 and 2,3-dinor-6-keto-prostaglandin (PG) respectively, in response to a thromboxane A2/prostaglandin endoperoxide receptor antagonist (L636,499) alone and in combination with a thromboxane synthase inhibitor (U63,557A) in the chronic canine model of coronary thrombosis. (Note that occlusion did not occur in dogs treated with the combination therapy)...

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