A series of 2'-deoxy-4'-thioribo purine nucleosides was prepared by trans-N-deoxyribosylase-catalyzed reaction of 2'-deoxy-4'-thiouridine with a variety of purine bases. This synthetic procedure is an improvement over methods previously used to prepare purine 4'-thio nucleosides. The compounds were tested against hepatitis B virus (HBV), human cytomegalovirus (HCMV), herpes simplex virus (HSV-1 and HSV-2), varicella zoster virus (VZV), and human immunodeficiency virus (HIV-1). Cytotoxicity was determined in a number of cell lines. Several compounds were extremely potent against HBV and HCMV and had moderate to severe cytotoxicity in vitro. The lead compound from the series, 2-amino-6-(cyclopropylamino)purine 2'-deoxy-4'-thioriboside, was the most potent and selective agent against HCMV and HBV replication in vitro; however, this analogue was nephrotoxic when tested in vivo.

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Emivirine (EMV), formerly known as MKC-442, is 6-benzyl-1-(ethoxymethyl)-5-isopropyl-uracil, a novel nonnucleoside reverse transcriptase inhibitor that displays potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity in vivo. EMV showed little or no toxicity towards human mitochondria or human bone marrow progenitor cells. Pharmacokinetics were linear for both rats and monkeys, and oral absorption was 68% in rats. Whole-body autoradiography showed widespread distribution in tissue 30 min after rats were given an oral dose of [ 14 C]EMV at 10 mg/kg of body weight. In rats given an oral dose of 250 mg/kg, there were equal levels of EMV in the plasma and the brain. In vitro experiments using liver microsomes demonstrated that the metabolism of EMV by human microsomes is approximately a third of that encountered with rat and monkey microsomes. In 1-month, 3-month, and chronic toxicology experiments (6 months with rats and 1 year with cynomolgus monkeys), toxicity was limited to readily reversible effects on the kidney consisting of vacuolation of kidney tubular epithelial cells and mild increases in blood urea nitrogen. Liver weights increased at the higher doses in rats and monkeys and were attributed to the induction of drug-metabolizing enzymes. EMV tested negative for genotoxic activity, and except for decreased feed consumption at the high dose (160 mg/kg/day), with resultant decreases in maternal and fetal body weights, EMV produced no adverse effects in a complete range of reproductive toxicology experiments performed on rats and rabbits. These results support the clinical development of EMV as a treatment for HIV-1 infection in adult and pediatric patient populations.

Abstract. Ochratoxicosis was induced in young female swine by a diet contaminated with a rice culture of Aspergillus ostiantrs that contained ochratoxin A and by daily oral doses of 2.0 or I .O mg/kg body weight pure ochratoxin A. Mycotoxicosis was characterized early by depression and reduction in feed intake and loss of body weight, followed by diarrhea, polyuria, polydipsia and dehydration. The pigs given pure ochratoxin A were dead or moribund in 5 to 6 days. Packed cell volume, hemoglobin, total plasma protein, and blood urea nitrogen were increased. Progressive leukocytosis, neutrophilia and moderate left shift in the differential count occurred. Concentrations of lactic dehydrogenase, isocitric dehydrogenase and glutamic-oxalacetic transaminase in the serum and urine were increased by the fourth to sixth day, but only the increase in urinary concentrations was significant. Gross findings included dehydration, enteritis, pale tan discoloration of the liver, and edema and hyperemia of the mesenteric and other lymph nodes. Microscopic lesions were most frequent and severe in the kidney and gastrointestinal tract. Necrosis of renal tubular epithelium was most frequent in the convoluted tubules. Many renal tubules were dilated. The intestinal lesions were focal and necrotizing and occurred in most anatomic regions. Fatty change was demonstrated in most of the livers. In lymphoid tissues the changes were edema, hyperemia and focal necrosis of lymphocytes within germinal centers and around follicles.

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