Reproductive toxicology profile of emtricitabine in mice and rabbits.

Reproductive and developmental toxicology studies were conducted with emtricitabine, a nucleoside analog in development for treatment of human immunodeficiency virus (HIV) (Phase III) and hepatitis B (HBV) (Phase III) infections. Oral doses up to 1000 mg/kg/day provided daily area under the curve (AUC(0-->24)) exposure to pregnant animals approximately 60- (mice) to 120-fold (rabbits) higher than that in humans at the recommended dose of 200 mg given once per day. In a mouse fertility study, emtricitabine had no effect on fertility, sperm count, or early embryonic development.

Efficacy of topical acyclovir monophosphate, acyclovir, or penciclovir in orofacial HSV-1 infections of mice and genital HSV-2 infections of guinea pigs.

The purpose of these studies was to compare the efficacy of acyclovir monophosphate (ACVMP), acyclovir (ACV), or penciclovir (PCV) against HSV-1 in an orofacial infection of mice and against ACV sensitive and resistant genital HSV-2 infections of guinea pigs. Treatment was initiated 24, 48, or 72 hours post inoculation with 5% ACVMP, 5% ACV (Zovirax) or 1% PCV (Denavir). In all experiments, similar efficacy was obtained for ACVMP and ACV, whereas PCV was considerably less effective.

Screening for potential toxicity of antiviral therapies.

Preclinical screening for the toxicity of antiviral drugs has thus far proven quite successful. Twenty-three antivirals spanning a variety of chemical classes and including a combination product, have been safely developed and are listed in the 1999 Physician's Desk Reference. Several of these antivirals have been administered for many years and in various combinations and we are currently unaware of any being withdrawn for safety-related reasons.

Safety assessment, in vitro and in vivo, and pharmacokinetics of emivirine, a potent and selective nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1.

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.

Preclinical development of antiviral drugs.

The early preclinical development of an antiviral agent is accomplished essentially in two stages. The first stage consists of gathering data to estimate the potential therapeutic index of the agent. This process includes testing for antiviral activity and for cytotoxicity in vitro and performing preliminary pharmacokinetic and toxicology studies in vivo.

Synthesis and antiviral activity of 2'-deoxy-4'-thio purine nucleosides.

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).

Inactivators of herpes simplex virus ribonucleotide reductase: hematological profiles and in vivo potentiation of the antiviral activity of acyclovir.

A1110U (BW 1110U81) is an inactivator of herpesvirus ribonucleotide reductases and a potentiator of the antiviral activity of acyclovir (ACV) (T. Spector, J. A.

Neurotoxic effects of the anti-varicella zoster virus agent 2'-valeryl-6-methoxypurine arabinoside in monkeys and rats dosed orally for 90 days.

The 2'-valerate ester of 6-methoxypurine arabinoside (170U88), a nucleoside analog with anti-varicella zoster virus (VZV) activity, was given to monkeys and rats. In subchronic preclinical toxicity studies, dosing was by gavage to monkeys (distilled water vehicle) and rats (0.5% methylcellulose vehicle) for 90 days.

Nail loss and footpad erosions in beagle dogs given BW 134U, a nucleoside analog.

The oral administration of BW 134U to Beagle dogs in a 1-month study was associated with lameness, footpad erosions, and nail loss. Groups of dogs received 60, 120, and 240 mg/kg/day. Compound-related effects were observed in the high dose group and only during the postdose period.

Preclinical toxicology studies with acyclovir: carcinogenicity bioassays and chronic toxicity tests.

Acyclovir (ACV), a nucleoside analog that is a new herpes-specific antiviral drug, was given by gavage at 50, 150 and 450 mg/kg/day to Sprague Dawley rats and Swiss mice for most of their lifetime to assess chronic toxicity and carcinogenicity. Treatment with ACV did not shorten the lifespan of either rats or mice. In fact, female mice given 150 and 450 mg/kg/day had significantly longer mean durations of survival than control female mice when analyzed by the life table technique.

Preclinical toxicology studies with acyclovir: acute and subchronic tests.

Acyclovir (ACV), a new antiherpes drug, was evaluated for toxicity in a series of acute and subchronic toxicity tests. Oral LD50 values were greater than 10 000 mg/kg in male ICR mice and greater than 20 000 mg/kg in male Long Evans rats. When ACV was given iv, the LD50 was 405 mg/kg for male mice and greater than 600 mg/kg for male rats.

Preclinical toxicology studies with acyclovir: ophthalmic and cutaneous tests.

Topical formulations of acyclovir (ACV) were tested in animals to define potential for tissue irritation and systemic toxicity. Acyclovir ointments (5 and 10% concentrations in polyethylene glycol vehicle) produced no sign of dermal irritation or systemic toxicity when applied to shaved abraded and intact skin of guinea pigs for 24 consecutive days. Solutions (0.

Preclinical toxicology studies with acyclovir: teratologic, reproductive and neonatal tests.

Five studies were done to define the potential of Acyclovir (ACV), a new nucleoside analog for antiviral chemotherapy, to produce adverse effects on reproduction and development in laboratory animals. ACV produced no adverse effects when given by gavage to F0 generation mice at 50, 150 and 450 mg/kg/day in a two generation reproduction/fertility study. Some mice were evaluated for teratologic effects and others for postnatal development, including behavior, with negative results.

Postnatal behavioral effects of ochratoxin A in offspring of treated mice.

Ochratoxin A is a toxic isocoumarin derivative produced by Aspergillus ochraceus and several Penicillium species, which are storage fungi. Many kinds of agricultural commodities can be contaminated with ochratoxin A, which has been reported in both animal and human foods. Pure crystalline ochratoxin A was dissolved in 0.

Dose selection as it pertains to testing a prodrug in carcinogenicity bioassays.

Toxicologists need more information than is usually available in the early stages of development of a drug in order to choose proper dose levels for testing in the bioassays. The approach most likely to result in successful bioassays involves an early multidisciplinary effort in which there is pharmacokinetic characterization of the test material in both rats and mice. Preliminary 3 month studies are desirable.

Prenatal effects of 2,4,5-T, 2,4,5-trichlorophenol, and phenoxyacetic acid in mice.

The herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and two structurally related compounds, phenoxyacetic acid and 2,4,5-trichlorophenol, were suspended in a 1:1 solution of honey:water and administered by gavage to pregnant mice on one of gestation days 8-15 (copulation plug day = day 1) or on three consecutive days (7-9, 10-12, or 13-15). Doses were 800-900 mg/kg for single and 250-300 mg/kg/day for multiple treatments. With the exception of 2,4,5-trichlorophenol treatment on day 14, only 2,4,5-T treatment significantly increased prenatal mortality, and only 2,4,5-T was associated with decreased fetal weight when comparisons were made with the solvent controls.

Effects in mice of simultaneous prenatal exposure to ochratoxin A and T-2 toxin.

Aspergillus ochraceus and Fusarium tricinctum are food contaminating molds whose toxic metabolites, ochratoxin A and T-2 toxin, are known mammalian teratogens. In order to determine the possible effects of simultaneous exposure to such environmental agents, ochratoxin A (2 or 4 mg/kg) and T-2 toxin (0.5 mg/kg) were injected ip, either together or individually, in CD-1 mice on gestation days 8 or 10.

Preclinical safety evaluation of 15[S]15-methyl prostaglandin F2alpha : reproduction and teratology.

The abortifacient 15[S]15-methyl prostaglandin F2alpha, designated PGF2alpha (M), was tested in pregnant rats and rabbits for purposes of preclinical safety evaluation. The material tested was the tromethamine salt of PGF2alpha with the generic name, carboprost tromethamine. Doses of 0.