Pharmacological properties of MDL 19,301: A novel, nonsteroidal, anti-inflammatory agent

Autor: Thomas H. Beaver, Lawrence E. Roebel, Gerald L. Westrich, Miller Francis P, Niall S. Doherty
Rok vydání: 1989
Předmět:
Zdroj: Drug Development Research. 16:31-44
ISSN: 1098-2299
0272-4391
DOI: 10.1002/ddr.430160105
Popis: Oral administration of MDL 19,301 (N-(1,3-dithiolan-2-ylidene)-4-hexyl-benzenamine) inhibited rat paw edema induced by carrageenan (ED30 4.8 mg/kg) or an Arthus reaction (ED30 8.2 mg/kg p.o.). The oral dose which induced gastric ulceration in 50% of fasted rats (UD50) was greater than 1,000 mg/kg, demonstrating a more favorable therapeutic ratio than conventional nonsteroidal anti-inflammatory agents. Its major metabolite ((MDL16,861, 4[1,3-dithiolan-2-yliden)amino]-benzeneacetic acid) was also a potent inhibitor of carrageenan paw edema (ED50 5.5 mg/kg p.o.), although it was more ulcerogenic (UD50 52 mg/kg p.o.). The anti-inflammatory activity of MDL 19,301, but not that of MDL 16,861, was attenuated by co-administration of an inhibitor of drug metabolism (SKF inhibition of arachidonic-acid-induced, but not prostaglandin-E2-induced, diarrhea in mice; and inhibition of ex vivo arachidonic-acid-induced, but not adenosine-diphosphate-induced, rat platelet aggregation. MDL 19,301 and MDL 16,861 were unexpectedly weak antipyretic agents in rats. In summary, MDL 19,301 is an anti-inflammatory, analgesic prodrug which, unlike conventional agents, is devoid of ulcerogenic activity at therapeutic doses.
Databáze: OpenAIRE
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