6-ketoprostaglandin-f1-alpha and tiaprofenic-acid

Both analgesic and ulcerogenic activities of d-2-[4-(3-methyl-2-thienyl)phenyl] propionic acid (M-5011), a novel non-steroidal anti-inflammatory drug (NSAID), were compared with those of indomethacin (IND), ketoprofen (KP), diclofenac sodium (DIF), zaltoprofen (ZLT) and tiaprofenic acid (TIA) in mice. All orally administered NSAIDs including M-5011 inhibited kaolin-induced writhing in a dose-dependent manner. M-5011 had an effective antinociceptive activity (ED50 value) of 0.63 mg/kg, being more potent than ZLT (16.80 mg/kg) and TIA (4.78 mg/kg), equipotent to DIF (0.68 mg/kg), and less potent than IND (0.21 mg/kg) and KP (0.28 mg/kg). All drugs tested significantly reduced peritoneal 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) levels at the peak kaolin-induced writhing time (7.5 min post-kaolin injection) without affecting peritoneal bradykinin (BK) levels. Antinociceptive effects of all drugs were closely correlated with inhibition of peritoneal 6-keto-PGF1 alpha levels. Ulcerogenic activities (UD50 value) of M-5011 in the stomach and small intestines were 88.23 and 46.09 mg/kg, respectively. UD50 values of other drugs in the stomach and small intestines were as follows: 8.96 and 4.78 mg/kg, 20.04 and 10.75 mg/kg, 4.19 and 2.24 mg/kg, 62.86 and 46.55 mg/kg, and 110.92 and 54.78 mg/kg for IND, KP, DIF, TIA, and ZLT, respectively. Thus, the safety indexes (UD50/ED50) of the stomach (or small intestine) for M-5011, IND, KP, DIF, TIA and ZLT were 140.05 (73.16), 42.67 (22.76), 71.57 (38.39), 6.16 (3.29), 13.15 (9.74) and 6.60 (3.26), respectively. These findings suggest that M-5011 is a useful NSAID that shows potent antinociceptive effects with low ulcerogenic activities.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Bradykinin; Dose-Response Relationship, Drug; Gastric Mucosa; Indomethacin; Intestinal Mucosa; Kaolin; Ketoprofen; Linear Models; Male; Mice; Mice, Inbred ICR; Pain Measurement; Phenylpropionates; Propionates

The effects of infusion of the non-steroidal anti-inflammatory drugs (NSAID), tiaprofenic acid (2.2 micrograms/min or 10.0 micrograms/min) and indomethacin (1.0 microgram/min) on the release of leukotriene (LT) C4-like immunoreactivity, thromboxane (TX) B2 and 6-keto-prostaglandin (PG) F1 alpha from isolated perfused anaphylactic guinea-pig hearts were investigated. Tiaprofenic acid at both concentrations used significantly inhibited anaphylactic release of TXB2 and 6-keto-PGF1 alpha as did indomethacin (1.0 microgram/min) which was, however, about ten times more potent in this respect. Release of immunoreactive LTC4-like material was not influenced by the lower concentration of tiaprofenic acid used (2.2 micrograms/min), but significantly enhanced by the higher concentration (10.0 micrograms/min). Thus, the effect of tiaprofenic acid on eicosanoid release by the anaphylactic heart is very similar to that of indomethacin without any differential inhibition of TXB2 or 6-keto-PGF1 alpha formation.

Topics: 6-Ketoprostaglandin F1 alpha; Anaphylaxis; Animals; Anti-Inflammatory Agents; Eicosanoic Acids; Guinea Pigs; In Vitro Techniques; Indomethacin; Male; Myocardium; Propionates; SRS-A; Thromboxane B2

Tiaprofenic acid (Surgam, Cassenne) was administered intravenously to saline-diuretic conscious rats, at doses of 2, 10 and 25 mg kg-1 body weight. Tiaprofenic acid significantly reduced urinary prostaglandin E2 (PGE2) and 6 keto PGF1 alpha excretion, at all three doses employed. The extent of the reduction was similar for both PGE2 and 6 keto PGF1 alpha output; hence no evidence of 'selectivity' (i.e. sparing of PGI2 synthesis) was observed. Tiaprofenic acid was also administered to rats receiving an infusion of 5% dextrose. The dose employed (0.5 or 1 mg kg-1 body weight) was submaximal and elicited reductions in PGE2 output to values still more than 60% of the control period values. In this group of animals, the percentage change in 6 keto PGF1 alpha excretion was again not significantly different from that of PGE2. The maximal extent of reduction in urinary PGE2 excretion with tiaprofenic acid (25 mg kg-1 body weight) was not significantly different from that elicited by indomethacin (10 mg kg-1 body weight), although the time course of the reduction was different.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Depression, Chemical; Dinoprostone; Glucose; Indomethacin; Male; Propionates; Prostaglandins E; Radioimmunoassay; Rats; Rats, Inbred Strains; Time Factors

Two experimental models were used to compare tiaprofenic acid and indomethacin. The first model involved assessing their effect on in vitro prostacyclin synthesis by rat aortic rings and human umbilical endothelial cells. The results showed that the inhibitory effect of the two drugs was similar. The second model involved assessing the effect of these drugs on in vitro thromboxane A2 release by human platelets. Indomethacin was shown to be a more potent inhibitor of TXA2 release than tiaprofenic acid, but this difference was only significant at low concentrations of the drugs; at concentrations equivalent to those achieved during routine treatment, both produced near maximal inhibition of TXA2 release by platelets. It is concluded that the findings do not support the claim that tiaprofenic acid is more 'selective' in its actions on these aspects of prostaglandin synthesis than another non-steroidal anti-inflammatory drug, indomethacin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Platelets; Epoprostenol; Female; Humans; In Vitro Techniques; Indomethacin; Male; Propionates; Radioimmunoassay; Rats; Rats, Inbred Strains; Thromboxane A2; Umbilical Cord

Gastric ulcerogenicity and depletion of endogenous prostaglandins (PGs) content induced by tiaprofenic acid, dicrofenac and indomethacin were examined using the same antiinflammatory effective doses. Male Wistar rats were given each of these drugs intragastrically 24, 18, and 3 hrs before sacrifice in the following doses (mg/kg): indomethacin (0.8, 4 and 20); tiaprofenic acid (1.2, 6 and 30); dicrofenac (0.8, 4 and 20). Endogenous prostacyclin (PGI2) and PGE2 in fundic mucosa were determined by radioimmunoassay. The three compounds produced fundic mucosal lesions in a dose-dependent manner. However, tiaprofenic acid and dicrofenac were both less potent than indomethacin in producing gastric mucosal lesions at similar antiinflammatory doses. Mucosal PGE2 content was abolished by the three compounds in the following doses (mg/kg): indomethacin (4 and 20); tiaprofenic acid (6 and 30); dicrofenac (20). Mucosal PGI2 was maintained around 50% of the control value in rats given tiaprofenic acid in a dose of 6 mg/kg or dicrofenac in a dose of 4 mg/kg, while indomethacin in a dose of 4 mg/kg markedly reduced mucosal PGI2 to 17% of the control value. In larger doses, tiaprofenic acid and dicrofenac were also significantly less potent in reducing mucosal PGI2 than indomethacin. These results suggest that the difference in ulcerogenicity between indomethacin and the other two compounds was closely related to their potency in decreasing PGI2 in the gastric (fundic) mucosa.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Diclofenac; Dinoprostone; Dose-Response Relationship, Drug; Epoprostenol; Gastric Fundus; Gastric Mucosa; Indomethacin; Male; Propionates; Prostaglandins E; Radioimmunoassay; Rats; Rats, Inbred Strains; Structure-Activity Relationship