Artesunate: developmental toxicity and toxicokinetics in monkeys.

Background: The developmental toxicity, toxicokinetics, and hematological effects of the antimalarial drug, artesunate, were previously studied in rats and rabbits and have now been studied in cynomolgus monkeys.

Methods: Groups of up to 15 pregnant females were dosed on Gestation Days (GD) 20-50 or for 3-7-day intervals.

Results: At 30 mg/kg/day, 6 embryos died between GD30 and GD40.

Effects of food restriction on testis and accessory sex glands in maturing rats.

Reduced food consumption and associated lower body weights may occur in subacute toxicity studies. The short-term effects of food restriction (FR) on body and reproductive organ weights, hormones, and testis histology were assessed in Sprague-Dawley rats fed 20% to 36% less (21 g feed/day) than rats fed ad libitum (AL) starting at six, eight, ten, or twelve weeks of age for two or six weeks. Body weight and relative seminal vesicle, ventral prostate, and/or epididymis weights were reduced in rats FR for two or six weeks.

Interlaboratory evaluation of genomic signatures for predicting carcinogenicity in the rat.

The Critical Path Institute recently established the Predictive Safety Testing Consortium, a collaboration between several companies and the U.S. Food and Drug Administration, aimed at evaluating and qualifying biomarkers for a variety of toxicological endpoints.

Identification of drug-induced hyper- or hypoprolactinemia in the female rat based on general and reproductive toxicity study parameters.

Observations associated with drug-induced hyper- or hypoprolactinemia in rat toxicology studies may be similar and include increased ovarian weight due to increased presence of corpora lutea. Hyperprolactinemia may be distinguished if mammary gland hyperplasia with secretion and/or vaginal mucification is observed. Reproductive toxicity study endpoints can differentiate hyper- from hypoprolactinemia based on their differential effects on estrous cycles, mating, and fertility.

Histologic changes in ovary, uterus, vagina, and mammary gland of mature beagle dogs treated with the SERM idoxifene.

Background: Idoxifene is a selective estrogen receptor modulator similar to tamoxifen but is no longer in pharmaceutical development due to adverse genitourinary effects in the clinic. Histologic observations of the reproductive system and mammary glands are presented from female dogs treated with idoxifene for up to 12 months.

Methods: Studies were conducted as part of regulatory requirements to support clinical development.

SB-236057: Critical window of sensitivity study and embryopathy of a potent musculoskeletal teratogen.

Background: SB-236057 is a potent skeletal teratogen in rodents and rabbits. The study objective was to identify the critical developmental window of compound sensitivity and to characterize the early onset of SB-236057 embryopathy.

Methods: SB-236057 was orally administered to Sprague Dawley dams at 100 mg/kg/day on days 6-7, 8-11, 12-14, or 15-17 postcoitus (pc).

Evidence for a molecular mechanism of teratogenicity of SB-236057, a 5-HT1B receptor inverse agonist that alters axial formation.

Background: SB-236057 is a potent skeletal teratogen in rodents and rabbits, producing axial and posterior somite malformations in cultured rat embryos. The compound shares some structural similarity to cyclopamine.

Methods: M13 phage display was used to identify amino acid motifs with binding affinity to SB-236057.

Preclinical safety of recombinant human interleukin-18.

Recombinant human interleukin-18 (rHuIL-18) is currently in clinical trials for treatment of cancer. This report presents results of preclinical toxicity studies with rHuIL-18 in cynomolgus monkeys and recombinant murine IL-18 (rMuIL-18) in mice. The rHuIL-18 was administered intravenously in 1 or 2 different 5-day cycles at doses 0.