Effect of temperature on the high-performance liquid chromatographic separation of the anti-HIV agents, didanosine and stavudine.

This paper examines the effect of temperature on the chromatographic separation characteristics of anti-HIV agents, didanosine and stavudine. As a result of lowering the column temperature, an improved resolution between didanosine and stavudine peaks is observed. Thus, lower temperatures may permit the simultaneous monitoring of didanosine and stavudine levels.

Physiological disposition of CGS 16617 in rat, dog, and man.

The disposition and metabolism of CGS 16617 (3-[(5-amino-1-carboxy-1S-pentyl)amino],2,3,4,5-tetrahydro-2-oxo-3S-1H-1 - benzazepine-1-acetic acid), and angiotensin l-converting enzyme inhibitor, were investigated in rats, dogs, and man. In rats, a single oral dose of 10 mg/kg 14C-CGS 16617 afforded peak plasma concentrations of drug between 0.5 and 6 hr of dosing. The AUC was on average 9.6% of that after iv administration of the same dose, indicating low oral absorption of the drug. The apparent volumes of distribution, V1 and Vdss, were 0.45 and 2.5 liters/kg, respectively. Disappearance of the drug from plasma after the iv dose was biphasic, with mean half-lives of 0.5 and 13 hr, respectively, for the lambda 1 and lambda 2 phases. After single iv doses (10 mg/kg) to dogs and rats, 14CGS 16617 was almost exclusively eliminated by the renal route, with urinary recoveries of greater than 90% of dose. The same dose administered orally gave urinary recoveries of less than 10% of the dose in rats and about 15% in the dog. The remainder of the dose was eliminated in the feces. Bile duct-cannulated rats excreted less than 3% of an oral 10 mg/kg dose in the bile, in 24 hr. In man (N = 4), a single oral dose of 100 mg 14C-CGS 16617 resulted in peak plasma concentrations of 0.02-0.07 microgram of drug eq/ml between 4 and 6 hr of dosing. The mean terminal half-life was estimated at 81 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition and metabolism of prinomide in laboratory animals.

The disposition and metabolism of prinomide, the 1:1 triethanolamine salt of 1-methyl-beta-oxo-alpha-(phenylcarbamoyl)-2-pyrrolepropionitrile (CGS 10787B), have been investigated in a number of animal species after single and multiple oral dosing with 14C-labeled and unlabeled drug. After single oral doses of 25 to 50 mg/kg of [14C]prinomide to mice, rats, hamsters, dogs, cynomolgus monkeys, and baboons, radioactivity was excreted primarily in urine, in the form of metabolites. However, in the mouse and monkey, fecal excretion was also significant. In the cynomolgus monkey, a radioactive dose of drug administered after multiple doses of unlabeled drug gave rise to peak plasma concentrations of radioactivity within 1 to 6 hr. Prinomide accounted for approximately 69% of this radioactivity. The terminal plasma half-life of the drug was 24 to 41 hr. Studies in rats with [14C]prinomide indicated that radioactivity was distributed rapidly to all tissues, with the highest levels being observed in blood and well perfused organs and tissues. The lowest levels were detected in fat, eyes, and brain. Tissue levels declined to less than 6% of peak values by 48 hr after dosing, the only exceptions being fat and kidney, which retained 14 and 17% of peak radioactivity, respectively. The metabolism of prinomide was qualitatively similar in all species investigated. Major metabolites identified were the phenyl ring p-hydroxy, M1, and the bicyclic spiro, M2, derivatives of the parent drug. Other common metabolites were M3, the phenyl ring p-hydroxy analog of M2 and a complete rearrangement product in the form of a succinimide derivative, M4.(ABSTRACT TRUNCATED AT 250 WORDS)

Arylmethanol and thiosemicarbazone influence of plasmodial macromolecular synthesis and cell stability.

The influence of mefloquine and additional antimalarial drugs on (3H)adenosine uptake, macromolecular synthesis, and cell stability was determined in rodent red cells parasitized with Plasmodium berghei. High arylmethanol to cell ratios induced lysis, whereas inhibition of macromolecular synthesis occurred at lower drug/cell ratios. A 2-acetylpyridine thiosemicarbazone rapidly suppressed (3H)adenosine uptake, and also blocked macromolecular synthesis by parasitized cells.

Preferential inhibition of ribonucleic acid synthesis by a new thiosemicarbazone possessing antibacterial and antiparasitic properties.

We determined the influence of the azacycloheptane derivative (H) of a 2-acetylpyridine thiosemicarbazone on growth and macromolecular synthesis in Escherichia coli AT-9. Thiosemicarbazone H caused bacteriostasis and a primary inhibition of ribonucleic acid synthesis; secondary effects included inhibition of deoxyribonucleic acid and protein synthesis. Addition of cooper or other transition elements was not necessary for these inhibitions.