ABSTRACT
A new, chemically stable analogue of PGE2, 11-deoxy-13,14-didehydro-16(S)-methyl PGE2 methylester (FCE 20700) was studied for the prevention of different gastrointestinal ulcers and for the inhibition of basal gastric acid secretion in the rat. The diarrhoea-inducing activity was also investigated. FCE 20700 was more potent than PGE2 in the prevention of stress-induced gastric ulcers (ED50 = 262 and 787 mcg/kg) and indomethacin-induced intestinal ulcers (ED50 = 557 and 4569 mcg/kg), and showed the same potency as PGE2 in the prevention of ethanol (ED50 = 9.2 and 14.8 mcg/kg) and indomethacin-induced gastric ulcers (ED50 = 37.8 and 22.3 mcg/kg). FCE 20700 weakly affects gastric acid secretion with an ED50 of 2385 mcg/kg, showing clear separation of antisecretory activity and gastric antiulcer potency. FCE 20700 does not induce diarrhoea in rats at doses up to 6.25 mg/kg, 10 to 600 times the effective antiulcer doses.
Subject(s)
Anti-Ulcer Agents , Dinoprostone/analogs & derivatives , Gastric Juice/metabolism , Prostaglandins E, Synthetic/pharmacology , Animals , Diarrhea/chemically induced , Ethanol/antagonists & inhibitors , Indomethacin/antagonists & inhibitors , Intestines , Male , Peptic Ulcer/prevention & control , Rats , Secretory Rate/drug effects , Stomach Ulcer/chemically induced , Stress, Physiological/complicationsABSTRACT
A study was made of the interaction between FCE 20700 (11-deoxy-13,14-didehydro-16(S)-methyl-PGE2 methylester) at a fixed dose of 250 mcg/kg and the ulcerogenic and antiinflammatory effect of indomethacin (I) on rat carrageenin paw edema. The combination tested showed the same antiinflammatory effect as I alone: potency ratio FCE 20700 + I/I was 1.03, demonstrating the lack of interaction between the two compounds. Moreover the gastric lesions in FCE 20700 + I treated rats were markedly reduced, allowing the dosage of I to be increased by about three times without increasing its ulcerogenic effect.
Subject(s)
Dinoprostone/analogs & derivatives , Gastric Mucosa/drug effects , Indomethacin/pharmacology , Prostaglandins E, Synthetic/pharmacology , Animals , Drug Interactions , Indomethacin/toxicity , Male , Rats , Rats, Inbred Strains , Stomach Ulcer/chemically inducedABSTRACT
Carboprostacyclin (dl-9a-deoxy-9a-methylene-PGI2), a new stable PGI2-analogue, has been studied in vitro and in vivo. This analogue relaxes bovine coronary artery (potency ratio to PGI2 = 0.17), inhibits human PRP aggregation induced by ADP (IC50 = 12.5 nM2), deaggregates platelet clumps in cat heparinized blood (ED50 = 10.4 microgram/kg) and raises cAMP content in human PRP, but is less potent than PGI2. It is less potent (about 30 times) than PGI2 in lowering blood pressure in anaesthetized rats, inhibits basal gastric secretion in the rat and is 8 and 6 times less potent than PGE2 in protecting rat gastric mucosa from the lesions induced by stress and ASA, respectively, and about half as potent as PGE2 in protecting intestinal mucosa from damage by indomethacin.
