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Biomedical subjects

L Shargel

Publications and source records attributed to L Shargel.

29 records · Page 2Linked to original sources
PubMed1975

Cardiovascular effects and blood concentrations of ajmaline and its 17-monochloroacetate ester in cats.

The antiarrhythmic drugs ajmaline and its 17-monochloroacetate ester (MCAA; Rtimos-Elle) were studied in cats. MCAA was less than half as toxic as ajmaline. Non-lethal doses of MCAA decreased blood pressure before heart rate, whereas ajmaline initially decreased heart rate. Both drugs prolonged the PR, QRS and QT intervals of the EKG. Recovery of these effects was within one hr. MCAA (10 mg/kg) and ajmaline (4.05 mg/kg) were studied separately by a one and 10 min infusion in the same cat. The dose of MCAA was ten times the usual dose in man and that of ajmaline four times the usual clinical dose. More marked effects were observed with the one min infusion. Arrhythmias were usually observed with ajmaline, but not with MCAA, even though it was rapidly converted to ajmaline. Maximal cardiovascular effects of MCAA and ajmaline were observed within 3 min of the end of infusion, which was also the time of peak blood levels. The elimination of MCAA resembled the kinetics of a multi-compartment system after a one min infusion. Peak blood levels declined by one-half in 3 min. Ajmaline blood levels declined linearly, with a half-life of 100 min, after a one min infusion. The peak blood level of MCAA after an intraduodenal dose of 25 mg/kg occurred at 20 min, whereas the peak blood level of the ajmaline formed occurred at 4 hr. In conclusion, MCAA has some different pharmacological properties and different kinetics of elimination than ajmaline.

Acetates↗
PubMedDate not supplied

Effect of cimetidine or ranitidine pretreatment on hepatic mixed function oxidase activity in the rat.

This study compared the effect of single equimolar oral doses of cimetidine (100 mg/kg) or ranitidine (139 mg/kg) on rat hepatic mixed function oxidases. Cimetidine significantly (p less than 0.05) increased hexobarbital sleeping time and prolonged aminopyrine and theophylline elimination. In contrast, ranitidine did not significantly affect hexobarbital sleeping time and theophylline elimination but significantly (p less than 0.025) increased aminopyrine elimination. Aminopyrine N-demethylase activity in vitro was significantly (p less than 0.05) inhibited by cimetidine pretreatment but significantly (p less than 0.025) increased by ranitidine pretreatment. The direct addition of cimetidine or SKF 525A to the 10,000g supernatant fraction from controlled liver homogenates decreased aminopyrine N-demethylase activity, whereas the direct addition of ranitidine tended to increase aminopyrine N-demethylase activity. A significant correlation (r = 0.65, p less than or equal to 0.005) was observed between hexobarbital sleeping time in vivo and aminopyrine N-demethylase activity in vitro in the same rat. The results of this study showed that cimetidine inhibited mixed function oxidases, whereas ranitidine had no effect or tended to stimulate mixed function oxidases.

Aminopyrine↗
PubMedDate not supplied

Physiological disposition and metabolism of N-t-butylarterenol and its di-p-toluate ester (bitolterol) in the rat.

The metabolism and disposition of the bronchodilator, N-t-butylarterenol (tBA) and its di-p-toluate ester (bitolterol) were compared in the rat. Radioactivity was preferentially retained in lungs of rats compared with heart and blood after iv medication with tritium-labeled bitolterol, but was not retained in tissues after iv medication with [3H]tBA. After oral and iv medication with [3H]bitolterol, fecal radioactivity accounted for 24% of the dose and 65 and 79% of the radioactivity, respectively, was excreted in urine (0-72 hr). In comparison, urine radioactivity after oral and iv medication with [3H]tBA was 43 and 83% of the dose, respectively, and fecal radioactivity accounted for 43 or 23% of the dose, respectively (0-72 hr). Bitolterol was hydrolyzed in vitro to tBA by esterases found in various tissues including small intestine, liver, and plasma. Moreover, tBA was a substrate for catecholamine O-methyltransferase but not for monoamine oxidase. Similar metabolites were observed in urine samples of rats given either [3H]tBA or [3H]bitolterol. Urine metabolites were identified as free and conjugated forms of both tBA and 3-O-methyl-tBA.

Animals↗
PubMedDate not supplied

Physiological disposition and metabolism of (3H)bitolterol in man and dog.

The metabolism and disposition of bitolterol, the di-p-toluate ester of N-t-butylarterenol (tBA) was studied in man after a single oral dose and in dog after intraduodenal, iv, or oral administration. The mean (+/- SE) peak plasma radioactivity in man (dose, 70 mug/kg) was 180 +/- 18 ng equivalents of [3H]bitolterol per ml or approximately 11% of the dose, whereas peak plasma radioactivity in dog (dose, 200 mug/kg) was 144 +/- 23 ng equivalents per ml or approximately 4% of the dose. For both man and dog, the time for maximum plasma level of radioactivity varied from 0.5 to 2 hr. In man, only 1% of the plasma radioactivity represented intact [3H]bitolterol 1.0 hr after medication. In the dog, radioactivity was concentrated in lung tissue after iv administration of [3H]bitolterol. Recovery of intact [3H]bitolterol in lung at 4.5 hr ranged from 26 to 46% of total tissue radioactivity after iv dosage and from 4 to 14% total tissue radioactivity after intraduodenal administration. Radioactivity recovered in human urine and feces (0-72 hr) accounted for 86 and 8.1% of the dose, respectively. Recovery of radioactivity in dog urine and feces accounted for 58 and 23% of the dose, respectively, in the same time period. Radiochromatograms of urine samples from man and dog revealed similar patterns of metabolites including free and conjugated forms of both tBA and the 3-O-methyl metabolite, N-t-butylmetarterenol. The major radioactive components of the feces were bitolterol and tBA. The results indicate that bitolterol is absorbed orally and retained as the intact ester in lung. The prolonged bronchodilator activity of bitolterol is due to the slow release of the ester from lung and hydrolysis to tBA, an active beta2-adrenoceptor agonist. Pharmacological activity is terminated by metabolism of tBA via conjugation or 3-O-methylation.

Animals↗