Design of carcinogenicity studies, dose selection, route, blood levels, transformation.

The results of subacute toxicity tests are the information most commonly used for setting doses for carcinogenicity studies. However, since diet composition is important in regard to tumor incidence, knowledge of the effect of various doses of the compound on the nutritional composition and quality of the diet of the animals on test is also important. It is also important to determine if any of the doses administered in the study exceed the ability of the species under study to excrete it in a manner which is approximately the same as that seen at lower doses.

Effectiveness of allopurinol against Leishmania braziliensis panamensis in Aotus trivirgatus.

Orally administered allopurinol at 50 mg/kg for 21 days showed pronounced antileishmanial activity against experimentally induced lesions of Leishmania braziliensis panamensis on the nose of Panamanian Aotus trivirgatus monkeys, with complete healing in 4 of 5, although parasitologic cure was achieved in only 2 of 5. The same total daily dose of drug, given in a divided dose twice daily, resulted in complete healing in all 5, and parasitologic cure in 4 of 5 animals. Standard treatment controls receiving 40 mg/kg of antimony stibogluconate intramuscularly for 15 days showed healing in 4 of 5 monkeys.

Rat liver microsomal metabolism of propyl halides.

The in vitro metabolism of 1-propyl halides (chloride, bromide, and iodide) by hepatic microsomes from phenobarbital-induced rats was examined. The following metabolites were detected: propene, 1,2-epoxypropane, 1,2-propanediol, propionic acid, and undefined species bound to protein (for propyl chloride). The addition of exogenous glutathione to the incubation mixture led to the production of S-(1'-propyl)glutathione and S-(2'-hydroxy-1'-propyl)glutathione.

The efficacy of a novel compound, (e)-1-(4'-bromo-4-biphenylyl)-1-(4-chlorophenyl)-3-dimethylaminoprop-1-ene against Trypanosoma cruzi in mice.

The biological properties of a novel compound 353C with high activity against Trypanosoma cruzi, are described. The compound was about 10 times and 20 times more effective than either benznidazole or nifurtimox respectively, in producing radical cure in mice. 353C has a long half-life and showed anti-trypanosomal properties when given to mice at weekly intervals.

Inhibition of rat liver cytochrome P-450 by benzyl hydrodisulfide.

The inhibition of rat liver microsomal cytochrome P-450 by benzyl hydrodisulfide has been examined as a model system for the inactivation of cytochrome P-450 seen during the microsomal metabolism of thiono-sulfur-containing compounds. Benzyl hydrodisulfide decreased enzymatic activity toward benzphetamine when incubated with hepatic microsomes prior to the assay for monooxygenase activity. In addition, incubation of microsomes with the hydrodisulfide caused a decrease in the level of cytochrome P-450 detectable as its carbon monoxide complex as well as a decrease in heme detectable as its pyridine-hemochromogen.

Dinitrophenol poisoning: a diagnosis to consider in undiagnosed fever.

A 32-year-old farmer had signs and symptoms of dinitrophenol poisoning after crop spraying with a herbicide containing derivatives of 2,4-dinitrophenol. Dinitrophenol causes toxicity by the uncoupling of oxidative phosphorylation in the mitochondria of cells throughout the body. In man the classic syndrome consists of lassitude, malaise, headache, increased perspiration, thirst, and dyspnea which may progress to hyperpyrexia, profound weight loss, respiratory failure, and death.

Toxicology of thiono-sulfur compounds.

Thiono-sulfur-containing compounds cause a wide variety of toxic effects in mammals. These toxic effects of thiono-sulfur-containing compounds appear to be at least partially the result of their metabolism to reactive intermediates by the cytochrome P-450-containing monooxygenase enzyme systems. Covalent binding of (atomic) sulfur released in the cytochrome P-450 monooxygenase catalyzed metabolism of certain thiono-sulfur compounds appears to be responsible for the inhibition of monooxygenase activity and the loss of cytochrome P-450 seen on administration of these thiono-sulfur compounds in vivo or incubation with cytochrome P-450 monooxygenase enzymes in vitro.

Identification of the major protein adduct formed in rat liver after thioacetamide administration.

The in vivo covalent binding of the hepatocarcinogen thioacetamide to rat liver protein has been examined. Following administration of 3H- or 14C-labeled thioacetamide, the modified amino acids present in the hepatic cytosolic proteins were isolated by enzymatic digestion and ion-exchange chromatography. Approximately 70% of the radioactivity covalently bound to cytosolic protein was recovered in a compound which upon acid hydrolysis yielded lysine and radiolabeled acetate.