l-745337 and Fever

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.

Topics: Animals; Antineoplastic Agents; Cisplatin; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dexamethasone; Drug Combinations; Ferrets; Fever; Hyperalgesia; Indans; Indomethacin; Leukotriene Antagonists; Leukotrienes; Male; Orchiectomy; Prostaglandins; Vomiting

1. The growing pig provides a useful, nonrodent model for studying mechanisms involved in the febrile response. 2. Indomethacin (IND) has previously been shown to prevent lipopolysaccharide (LPS) fever in prepubertal pigs. 3. This study compared the abilities of IND and L-745,337, a novel cyclooxygenase-2 (cox-2) inhibitor, to counteract the effects a low dose of LPS (20 micrograms/pig IV) on deep body temperature. Effects of IND and L-745,337 on core temperature and plasma cortisol concentrations were also examined in nonfebrile animals. 4. L-745,337 (0.3 mg/kg IV) did not alter the response to LPS, whereas both IND and L-745,337 (1.7 mg/kg) reduced the febrile effects of LPS given 60 min earlier. 5. Neither IND, nor L-745,337 (1.7 mg/kg IV) affected core temperature in nonfebrile animals whereas IND, but not L-745,337, stimulated cortisol release. 6. The results suggest that prostaglandin modulates the febrile effects of LPS in swine and that inhibition of inducible cyclooxygenase (Cox-2) suppresses fever without producing the stressful side-effects that accompany constitutive cyclooxygenase (Cox-1) inhibition, as exemplified by IND (a mixed Cox-1/Cox-2 antagonist).

Topics: Analgesics, Non-Narcotic; Animals; Body Temperature; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Drug Interactions; Fever; Hydrocortisone; Indans; Indomethacin; Isoenzymes; Lipopolysaccharides; Male; Prostaglandin-Endoperoxide Synthases; Swine

Recent studies have shown that there are two isoforms of cyclooxygenases. The constitutive form, cyclooxygenase 1 (COX-1), is believed to be involved in the maintenance of physiological functions. A second isoform, cyclooxygenase 2 (COX-2), has been shown to be induced in inflammation. In the present study, the pharmacology of a selective inhibitor of COX-2, L-745,337 (5-methanesulfonamido-6-(2,4-difluorothiophenyl)-1-indano ne), is described. L-745,337 has IC50 values of 23 +/- 8 nM and > 10 microM for the inhibition of prostaglandin E2 production in whole-cell assays for COX-2 and COX-1, respectively. This compound inhibited carrageenan-induced rat paw edema and rat paw hyperalgesia with ID50 values of 2.00 and 0.37 mg/kg, respectively. In an endotoxin-induced pyresis assay in the rat, L-745,337 significantly reversed the pyretic responses (ID50 = 3.75 mg/kg). L-745,337 did not cause visible gastric lesions in rats at up to 30 mg/kg (4 hr after dosing). In a fecal 51chromium (51Cr) excretion assay to detect gastrointestinal integrity in rats and primates, L-745,337 had no effect at doses up to 100 mg/kg (rat) or after chronic dosing at 20 mg/kg per day for 5 days (primates). In contrast, oral administration of indomethacin, diclofenac or flurbiprofen resulted in substantial increase in fecal 51Cr excretion and/or frank gastric ulceration (rats). L-745,337 significantly inhibited the prostaglandin E2 levels in the inflammatory exudates from the rat pleural cavity after injection with carrageenan but did not inhibit prostaglandin E2 levels in the stomach.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Carrageenan; Chromium Radioisotopes; Cyclooxygenase Inhibitors; Edema; Electron Transport Complex IV; Feces; Fever; Humans; Hyperalgesia; Indans; Isoenzymes; Male; Pleurisy; Rats; Rats, Sprague-Dawley; Saimiri; Stomach Ulcer; Tumor Cells, Cultured