6-ketoprostaglandin-f1-alpha and benoxaprofen

Two chemically similar nonsteroidal anti-inflammatory drugs, orpanoxin and F-1067, had almost identical potencies and efficacies as anti-inflammatory (rat paw edema) and analgesic (mouse writhing) agents, but differed markedly in gastrotoxicity. Orpanoxin alone aggravated stomach lesions in rats subjected to pylorus ligation and failed to protect stomachs of rats challenged with indomethacin. The compounds did not differ in their in vitro enzyme inhibition effects, both failing to inhibit 5- and 15-lipoxygenase and both inhibiting prostaglandin synthetase. Extraction of prostaglandins from the gastric mucosa of pylorus-ligated rats revealed, however, that the safer F-1067 depleted prostaglandin 6-keto-F1 alpha less and increased prostaglandin E2 much more than did orpanoxin. A possible causality is suggested.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors; Dinoprostone; Female; Furans; Gastric Mucosa; Indomethacin; Inflammation; Lipoxygenase Inhibitors; Male; Plants; Propionates; Rats; Rats, Sprague-Dawley; Rats, Wistar; Seminal Vesicles; Sheep; Stomach; Structure-Activity Relationship

There is continued debate over any renal sparing effects of sulindac (S): such a property would be of benefit and be unique among nonsteroidal anti-inflammatory drugs (NSAIDS). S undergoes a distinct metabolism whereby the active drug (sulindac sulfide (SS)) does not appear in the urine. Accordingly, we tested the effect of a plasma concentration of SS in the therapeutic range on renal blood flow (RBF), glomerular filtration rate (GFR), and renal prostaglandin (PG) concentrations during sudden renal ischemic stress. The ischemic stress was produced by a 15 to 20% reduction in arterial pressure by arterial hemorrhage (H) in four separate groups of anesthetized dogs: control, SS (0.4 mg/kg i.v. bolus followed by 0.03 mg/kg/min constant infusion), indomethacin (I, 10 mg/kg), and benoxaprofen (B, 75 mg/kg). A plasma concentration of 3.69 micrograms/ml of SS was achieved by the infusion, and no SS appeared in the urine. H reduced GFR (by 46%) and RBF (by 38%) in control dogs; in SS-treated dogs, a 60% decline in GFR and a 73% decrease in RGF occurred. These decreases in renal hemodynamics in the SS group during H were significantly greater than in the control group. Further, these decrements in GFR and RBF were similar to those observed in the I- and B-treated dogs. Finally, SS reduced baseline arterial and renal PG concentrations, and prevented any increase in renal PG release during H. Thus, we conclude that a concentration of SS in the therapeutic range, which does not appear in the urine, is capable of enhancing the decline in GFR and RBF during a sudden ischemic stress such as H.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Dogs; Glomerular Filtration Rate; Hemodynamics; Hemorrhage; Indenes; Indomethacin; Ischemia; Kidney; Kidney Diseases; Propionates; Renal Circulation; Sulindac

The effects of BW755C, benoxaprofen, indomethacin and piroxicam were studied on intravascular platelet aggregation using continuous platelet counting. Plasma levels of thromboxane B2 (TxB2) and 6-keto prostaglandin F1 (6-keto PGF1 alpha) were measured by radioimmunoassay. BW755C, a dual inhibitor of arachidonic acid metabolism, potentiated or inhibited aggregation depending on dose. BW755C increased TxB2 and 6-keto PGF1 alpha plasma levels at low doses. At higher doses BW755C inhibited aggregation and reduced TxB2 plasma levels. At 16 mg/kg BW755C, 6-keto PGF1 alpha was detected. Benoxaprofen also potentiated collagen-induced aggregation. 8 mg/kg indomethacin was shown to have a short lasting increased inhibitory action on collagen-induced aggregation when compared with the more specific cyclooxygenase inhibitor, piroxicam. 6-keto PGF1 alpha was detected in plasma from rats treated with indomethacin and piroxicam. The results obtained using low doses of BW755C suggest that the lipoxygenase pathway is involved in platelet aggregation. Interpretation of the results obtained using higher doses of drugs also suggests this involvement though some nonspecific actions of the drugs must be taken into consideration. Further work is required to detail the role of lipoxygenase products in collagen-induced intravascular platelet aggregation.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Chromatography, Thin Layer; Collagen; Indomethacin; Piroxicam; Platelet Aggregation; Propionates; Pyrazoles; Radioimmunoassay; Rats; Thiazines; Thromboxane B2