Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastrointestinal (GI) Adverse Drug Reactions (ADRs) from the NSAIDs are a major cause of morbidity and mortality in arthritic patients taking these drugs. The recent much heralded development of COX-2 selective drugs (celecoxib, rofecoxib), the objective of which has been to spare inhibition of the production of COX-1 derived mucosal protective prostaglandins, may have represented an advance in reducing the risk of serious ADRs--ulcers and bleeding--but does not appear to have reduced the incidence of symptomatic side-effects (nausea, vomiting, epigastric pain/heartburn, abdominal discomfort) which are a major reason for withdrawal from NSAID therapy, especially in the long term. The rationale of COX-2 selectivity from these newer drugs is controversial since there may be pharmacokinetic differences from established carboxylate-NSAIDs that accounts for their apparent lower ulcerogenicity. Moreover, concerns have been recently expressed that as COX-2 is important in ulcer healing, control of prostacyclin production and renal function that they may have adverse reactions from these effects. Indeed, recent reports of enhanced risk of congestive heart failure with rofecoxib are of importance and may relate to impaired prostacyclin production. Moreover, there are other therapeutic strategies that have yielded equally low ulcerogenic NSAIDs (e.g. the prodrug, nabumetone; the established COX-2 inhibitory drug, nimesulide) and even the well-established NSAIDs ibuprofen and diclofenac have relatively low upper GI ulcerogenicity and have been used as benchmark standards in comparative trials of the newer "Oxib" drugs (celecoxib, rofecoxib). Much research interest has centred on the nitric oxide-donating NSAIDs (NO-NSAIDs). The rationale for donating NSAIDs being to counteract the vasoconstriction effects of NSAIDs but this has yet to be fully evaluated. It is not certain that this "antidote" approach will be acceptable as there may also be systemic effects of the nitrobutoxyl--or other NO-donors that may have toxicological consequences. Another strategy is the development of mixed COX-5 lipoxygenase (LOX) inhibitors--the progenitors of which were benoxaprofen and BW-755C. The rationale of reducing the potential for lipoxygenase mediated actions in the stomach (e.g. vasoconstriction, leucocyte accumulation). Clearly, the need to develop newer NSAIDs with lower risks of ulcers and bleeding as well as symptomatic ADRs is still representing a major challenge.
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PMID:The ever-emerging anti-inflammatories. Have there been any real advances? 1159 13

Cisplatin at 5 mg/kg, i.p. induced an acute (day 1) and delayed (days 2 and 3) emetic response in the ferret that was used to investigate the anti-emetic activity of the non-selective cyclooxygenase inhibitor indomethacin (3 - 30 mg/kg, i.p., three times per day) and two cyclooxygenase-2 inhibitors, DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone; 1 - 10 mg/kg, i.p. administered at 40 and 48 h] and L-745,337 [5-methanesulphonamido-6-(2,4-diflurothiophenyl)-1-indanone; 10 mg/kg, i.p., administered at 40 and 48 h]. Only indomethacin potentiated significantly cisplatin-induced retching + vomiting (P<0.05); DFU antagonized delayed emesis (P<0.05) but the action was not dose-related and L-745,337 was inactive (P>0.05). However, indomethacin alone (30 mg/kg) also induced emesis (P<0.05). The leukotriene biosynthesis inhibitor, MK-886 {3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-tert-butylthioindol-2-yl]-2,2-dimethylpropanoic acid; 1 - 10 mg/kg, i.p., three times per day} had no action to modify cisplatin-induced emesis (P>0.05). The combination treatment of indomethacin (10 mg/kg, i.p., three times per day) with MK-886 (10 mg/kg, i.p., three times per day) did not antagonize cisplatin-induced acute delayed retching + vomiting and had a different profile compared to the action of dexamethasone (1 mg/kg, i.p., three times per day; P<0.05). Inhibition of the cyclooxygenase and lipoxygenase pathways does not account for the anti-emetic of dexamethasone.
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PMID:Action of cyclooxygenase inhibitors and a leukotriene biosynthesis inhibitor on cisplatin-induced acute and delayed emesis in the ferret. 1731 74