Misoprostol, a synthetic PGE1 analog with mucosal protective and antisecretory properties, is rapidly and essentially completely metabolized to its active metabolite, misoprostol acid. Relative to fasting conditions administration of misoprostol with antacid resulted in reduced bioavailability, as manifested by lower AUC(0-4) values from (mean +/- SD; n = 12) 417 +/- 135 to 349 +/- 108 pg.hr/ml (P less than 0.05), without significant changes in the rate of absorption (tmax = 14 +/- 8 [fasting] vs. 20 +/- 14 min [with antacid]). The observed Cmax values were also reduced (from 811 +/- 317 to 689 +/- 315 pg/ml), however, the difference was not statistically significant. Drug administration with a high-fat content meal resulted in a marked slowing in the absorption rate without a substantial decrease in the extent. Relative to fasting conditions food decreased misoprostol acid Cmax from 811 +/- 317 to 303 +/- 176 pg/ml (P less than 0.05) and increased tmax from 14 +/- 8 to 64 +/- 79 min (P less than 0.05): the AUC changes remained statistically insignificant from 417 +/- 135 to 373 +/- 111 pg.hr/ml. Administration of misoprostol with food could potentially decrease the incidence of systemic side effects by reducing the early high peak plasma concentrations of misoprostol acid.

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A series of 2-arylamino-l-azacycloalkenes (3) was synthesized and evaluated for antihypertensive activity. The compds were generally prepared by treating the cyclic imidoyl chlorides (6 and 7) with primary aromatic amines and, in one case, by the Beckmann rearrangement of cyclopentanone oxime with PhSOiCl in the presence of 2,6-dichloroaniline. A discussion of the structure-activity relationships in this series is presented.

The synthesis and biological activities of some compounds with novel modifications of the omega side chain of prostaglandin E1 (PGE1) are described. The preparation of (+/-)-omega-Me-PGE1 (3) (+/-)-omega-Pr-PGE1 (5), and (+/-)-omega-Bu-PGE1 (6) is outlined. The compounds were evaluated for in vitro smooth muscle stimulating activity on isolated gerbil colon preparations, for hypotensive action in anesthetized rats, and for gastric antisecretory effects in histamine-stimulated Heidenhain pouch dogs. Structural changes in the omega position of the noncarboxyl side chain of PGE1 influenced the biological potency of the resulting compound when compared to the reference standard PGE1 (2). The homologues demonstrated interesting separation of biological activities; for example, 4 showed potent hypotensive activity (84% of PGE1, it showed very low smooth muscle stimulating activity. Compound 3 possessed the same order of potency as 2 in the gastric antisecretory assay.

The metabolism of actisomide, a novel antiarrhythmic agent, was studied in the dog, monkey and man and was found to be more extensive in the monkey than in the dog or man. The major metabolites identified were a piperidinyl hydroxylated metabolite, the mono-N-dealkylated, cyclized and piperidine hydroxylated metabolite, and the cyclized and mono-N-dealkylated metabolite. Excretion of the parent drug was higher in urine than in feces in the dog, but in the monkey and man, urinary and fecal excretion of actisomide was similar. In all species the metabolites were primarily excreted in feces.