Synthesis and biological evaluation of omega-homologues of prostaglandin E1.

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.

Effects of food and antacid on oral absorption of misoprostol, a synthetic prostaglandin E1 analog.

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.

Metabolism of actisomide in the dog, monkey and man: a novel rearrangement of N-dealkylated metabolites.

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.

Simultaneous determination of ventricular function and systemic hemodynamics in the conscious rat.

This study describes a method that utilizes a combination of the Millar transducer and Columbus thermistor in the conscious, spontaneously hypertensive rat and that permits simultaneous evaluation of the effects of cardiovascular agents on ventricular performance and systemic hemodynamics. Left ventricular end diastolic pressure (LVEDP, mmHg) and LV dp/dt (mmHg/sec) were measured with a Millar transducer inserted into the left ventricle of spontaneously hypertensive rats under ether anesthesia. Cardiac output (CO, ml/min) was measured by thermodilution (Columbus Instruments) with a thermocouple in the thoracic aorta via the femoral artery. Mean arterial pressure (MAP, mmHg) was measured via a catheter in the other femoral artery. All cardiovascular parameters measured were shown to attain a steady state within 3 hr after cessation of ether administration. Infusion of the beta adrenergic receptor agonist isoproterenol increased LV max dP/dt, heart rate (HR), and CO, and decreased arterial blood pressure and peripheral resistance. Administration of propranolol resulted in decreased HR, LV dP/dt and CO. The results show that this model was stable over an extended period of time and was responsive to standard inotropic agents. Thus, the combined use of the Millar transducer and the Columbus thermistor appears suitable for the assessment of acute pharmacological interventions on cardiovascular function in the conscious rat.

Pharmacokinetics of a novel antiarrhythmic drug, actisomide.

The pharmacokinetics of a novel antiarrhythmic drug, actisomide, were examined in the rat, dog, monkey, and human. The terminal half-life of actisomide was similar (1.15-1.89 hr) across species, regardless of dose. The total plasma clearance was higher in the monkey (13.5-16.4 mL/min/kg) than in the dog (9.01-9.32 mL/min/kg), rat (8.6-9.8 mL/min/kg), or human (6.79 +/- 1.07 mL/min/kg). Excretion of the parent drug was higher in urine than in feces in the dog and rat, whereas in the monkey and human, urinary and fecal excretions of actisomide were similar. In humans, atypical plasma concentration-time curves with double peak concentrations were observed following oral doses. Systemic availability of actisomide was higher in the dog than in the rat, monkey, and human. Further, the systemic availability appeared to increase with dose in the rat and monkey. The species-dependent systemic availability appeared to be due primarily to species-dependent absorption of actisomide, and not to species-dependent first-pass metabolism, biliary excretion, and/or renal elimination. The absorption of actisomide in the rat and its in vitro uptake in CaCo-2 cells were pH dependent. The higher systemic availability of actisomide observed in the dog may be due partly to the higher pH in the gastrointestinal (GI) tract of the dog. However, the pH differences in the GI tract of the different species alone did not appear to be enough to explain the difference in systemic availability of actisomide.