Juvenile toxicity assessment of open-acid lovastatin in rats.

Background: Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, reduces de novo cholesterol biosynthesis primarily in the liver. Since cholesterol is a major component of brain myelin and peak periods of brain myelination occurs after birth, this study was designed to encompass this period in rats and evaluate the potential neurotoxic effects.

Methods: The pharmacologically active, open-acid form of lovastatin was administered to groups of 50 Sprague-Dawley rats per sex subcutaneously once daily at dose levels of 0 (vehicle), 2.

Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9.

Dipeptidyl peptidase (DPP)-IV inhibitors are a new approach to the treatment of type 2 diabetes. DPP-IV is a member of a family of serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9; DPP-IV is a key regulator of incretin hormones, but the functions of other family members are unknown. To determine the importance of selective DPP-IV inhibition for the treatment of diabetes, we tested selective inhibitors of DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies and in acute dog tolerability studies.

The role of maternal toxicity in lovastatin-induced developmental toxicity.

The role of maternal toxicity in lovastatin-induced developmental toxicity in rats was examined in a series of studies. The first study administered lovastatin at 100, 200, 400, or 800 mg/kg/day (mkd) orally to mated rats from Gestation Day (GD) 6 through 20. Maternal toxicity was observed as transient dose-related body weight losses at the initiation of dosing; there were also deaths and/or morbidity at 400 and 800 mkd.

Evaluation of ubiquinone concentration and mitochondrial function relative to cerivastatin-induced skeletal myopathy in rats.

As a class, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors can potentially cause skeletal myopathy. One statin, cerivastatin, has recently been withdrawn from the market due to an unacceptably high incidence of rhabdomyolysis. The mechanism underlying statin-induced myopathy is unknown.

Developmental toxicity of orally administered thiabendazole in ICR mice.

Thiabendazole (TBZ) is a potent anthelmintic and fungicide used in the treatment of parasitic infections in humans and domestic animals and post-harvest protection of agricultural commodities. TBZ is not teratogenic or selectively foetotoxic in rats or rabbits, in contrast to several other benzimidazole derivatives. However, when administered orally to pregnant (Jcl:ICR) mice at lethal dosages, malformations were observed in treated fetuses.

Reduced immunotoxicity and preservation of antibacterial activity in a releasable side-chain carbapenem antibiotic.

A carbapenem antibiotic, L-786,392, was designed so that the side chain that provides high-affinity binding to the penicillin-binding proteins responsible for bacterial resistance was also the structural basis for ameliorating immunopathology. Expulsion of the side chain upon opening of the beta-lactam ring retained antibacterial activity while safely expelling the immunodominant epitope. L-786,392 was well tolerated in animal safety studies and had significant in vitro and in vivo activities against methicillin- and vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci.

Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice.

A subpopulation of the CF-1 mouse strain contains a spontaneous mutation in the P-glycoprotein (Pgp) mdr1a gene, which leads to a lack of mdr1a expression in the placenta as well as brain and intestine. Individual CF-1 mice can be identified according to their Pgp status by a restriction fragment length polymorphism. Male and female mice selected on the basis of Pgp genotype were mated and the pregnant dams exposed during gestation to the known Pgp substrate, L-652,280, the 8,9 Z photoisomer of the naturally occurring avermectin Bla, which is known to produce cleft palate in mice.

Identification of a P-glycoprotein-deficient subpopulation in the CF-1 mouse strain using a restriction fragment length polymorphism.

There is a subpopulation of the CF-1 mouse strain that is very sensitive to the neurotoxicity induced by the avermectins, a class of natural products widely used in veterinary and human medicine as anti-parasitic agents. This sensitivity results from a lack of P-glycoprotein in the intestine and brain of sensitive animals, allowing increased penetration of these compounds in the blood and brain, respectively. We describe a restriction fragment length polymorphism that is able to predict which animals will be deficient in this protein, confirming at the genetic level a heterogeneous population of this mouse strain.

P-glycoprotein deficiency in a subpopulation of CF-1 mice enhances avermectin-induced neurotoxicity.

A subpopulation of CF-1 mice is unusual in its sensitivity to the avermectins, abamectin and ivermectin, with neurotoxicity occurring at 100-fold lower doses than in other species and mouse strains. We have shown that the sensitive CF-1 mice are deficient in P-glycoprotein in the intestinal epithelium and brain capillary endothelium, tissues forming the principle barriers for penetration into the systemic circulation and central nervous system, respectively. Consistent with the role of P-glycoprotein as a barrier to tissue entry, the plasma and tissue levels of radiolabeled ivermectin in the sensitive mice were markedly higher than in the insensitive mice, particularly in brain, the target organ for toxicity.

Species specificity of 2-aryl carbapenem-induced immune-mediated hemolytic anemia in primates.

L-695,256 is a novel 2-fluorenonyl carbapenem antibiotic with significant antimicrobial activity against strains of methicillin-resistant Staphylococci. This prototype compound was administered intravenously to rhesus monkeys (Macaca mulatta) at does of 50 or 200 mg/kg/day for 2 weeks to assess toxicity and found to induce a hemolytic anemia characterized by extravascular hemolysis and splenomegaly. A subsequent study in this species in which 100 mg/kg/day was administered i.

Development and submission of a nonclinical (pharmacology/toxicology) CANDA.

The experience with the submission of a nonclinical (pharmacology and toxicology) computer-assisted New Drug Application (CANDA) is reviewed. This system consisted of a stand-alone personal computer running several commercial programs in Microsoft Windows to access both text and data. WordPerfect was used as the word processor that contained all the documents and data tables (in read-only format) that were submitted in hard copy, and Andyne GQL was used as a tool to query the data in an Oracle relational database.

Dietary two-generation reproduction study of thiabendazole in Sprague-Dawley rats.

The potential reproductive toxicity of the fungicide and anthelmintic thiabendazole (TBZ) was assessed in Sprague-Dawley rats for two generations. Doses of 10, 30 or 90 mg/kg/day were administered by way of the diet beginning at 8 wk of age for the F0 generation and postnatal wk 4 for the F1 generation and continuing until the animals were killed. Concentrations of TBZ in the diet were adjusted weekly, except during the gestation and lactation intervals when concentrations were held constant.

Toxicokinetic and mechanistic considerations in the interpretation of the rodent bioassay.

When chemicals that are nongenotoxic in conventional assays produce increases in tumor incidence in rodents in chronic bioassays, the determination of the significance of these data for human safety is a challenging task. An important first step in this process is consideration of available data on the mechanism of action and biological properties of the chemical as well as pharmacokinetic and metabolism data in the species showing the response. In recent years, there has been an increase in the understanding of so-called "secondary mechanisms" of carcinogenesis (e.

Developmental toxicity of orally administered thiabendazole in Sprague-Dawley rats and New Zealand white rabbits.

The developmental toxicity of thiabendazole (TBZ) was assessed in studies in New Zealand white rabbits and Sprague-Dawley rats. The doses of TBZ for these studies were based on decreases in maternal weight gain in dose range-finding studies in pregnant females of each species. In rabbits, TBZ was administered orally at doses ranging from 24 to 600 mg/kg body weight/day in two separate studies.

Induction of reversible urothelial cell hyperplasia in rats by clorsulon, a flukicide with weak carbonic anhydrase inhibitory activity.

Clorsulon, a flukicide registered for use in treating Fasciola hepatica infections in cattle, has induced urinary bladder urothelial cell hyperplasia in rats at oral doses of 30 mg/kg/day or more. Despite previous testing at doses above this threshold, this lesion had not been found in subchronic or chronic toxicity studies in rats. After ruling out the presence of a contaminant as the causative factor in producing this lesion, a study was conducted in which clorsulon increased the pH and altered the electrolyte composition of urine, consistent with its weak carbonic anhydrase inhibitory activity.

The toxicity of a fluorinated-biphenyl HMG-CoA reductase inhibitor in beagle dogs.

L-645, 164, a potent inhibitor of hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase, is a structurally unique, synthetic monofluorinated-biphenyl that was administered to beagle dogs at dosages of 2, 10, or 50 mg/kg/day for 14 weeks to evaluate its toxic potential. Previously tested HMG-CoA reductase inhibitors from this laboratory have either been semisynthetic or fermentation-derived products containing a hexahydronaphthalene ring structure (i.e.

Effects of ivermectin on reproduction and neonatal toxicity in rats.

In this study we describe the effects of ivermectin (MK-0933) on the reproduction and neonatal toxicity of several generations of rats. Ivermectin was administered orally at dose levels of 0.05, 0.

Evidence of hepatitis A infection in immature rhesus monkeys.

Forty immature (less than 2 years old) rhesus monkeys (Macaca mulatta) with marked increases in aspartate and alanine aminotransferase activities were examined. Serological and histopathological evaluations were done to determine if affected animals were infected with hepatitis A virus. Although no clinical signs of illness were noted in any of the monkeys, an excellent correlation was found between the increased serum aminotransferase values and seropositivity with the acute phase (IgM) HAVAB-M antibody.

The effects of long-term dietary administration of the rubber accelerator, N-oxydiethylene thiocarbamyl-N-oxydiethylene sulfenamide, to rats.

Continuous administration of diets containing 0, 20, 60, 200, or 600 ppm of N-oxydiethylene thiocarbamyl-N-oxydiethylene sulfenamide to groups of male and female Sprague-Dawley rats (60/sex/group) for over 2 years resulted in oncogenic and toxic effects which generally were limited to the high-dose (600 ppm) group. The most significant findings of this study were in the urinary system of the high-dose males and females. Postmortem examinations revealed a compound-related increase in both benign and malignant urothelial tumors in these animals but not in animals at lower doses.

Spectral dependencies of killing, mutation, and transformation in mammalian cells and their relevance to hazards caused by solar ultraviolet radiation.

Using germicidal lamps and Westinghouse sunlamps with and without filtration, the effectiveness of ultraviolet and near-ultraviolet light in inducing molecular and cellular changes was measured. Cell survival and the induction of resistance to 6-thioguanine or to ouabain were measured with V79 Chinese hamster cells, cell survival and neoplastic transformation were measured with C3H mouse 10 T 1/2 cells, and the induction of pyrimidine dimers containing thymine was measured in both cell lines. The short-wavelength cutoff of the sunlamp emission was shifted from approximately 290 nm (unfiltered) to approximately 300 and approximately 310 nm by appropriate filters.

Enhancement of recovery of chemical carcinogen-induced ouabain-resistant mutants in Chinese hamster cells by the tumor-promoting agent, 12-o-tetradecanoyl-phorbol-13-acetate.

The effects of a tumor-promoting agent on the frequency of mutation to ouabain resistance and survival of Chinese hamster cells treated with a chemical carcinogen have been investigated. 12-O-Tetradecanoyl-phorbol-13-acetate (TPA) significantly enhanced the mutation frequency induced by the carcinogen, methylazoxymethanol acetate (MAM), without having similar effects on cytotoxicity, at concentrations of 2 micrograms/ml or less. The observed degree of enhancement of mutagenesis increased with promoter concentration up to the point where the latter exhibited frank toxicity.

Enhanced near-ultraviolet light sensitivity induced by coal combustor effluents in cultured mammalian cells.

The cytotoxicity of radiation from Westinghouse sun lamps (principal emission 290-340 nm) was enhanced by treatment of cells with nontoxic concentrations of condensate from the gaseous effluent from a pressurized, fluidized-bed coal combustor. The effect was similar to the photoenhanced cell killing induced by nontoxic concentrations of 7,12-dimethylbenz[a]anthracene, a carcinogenic derivative of substances produced by incomplete combusion of fossil fuels. Furthermore, light-dependent cell killing requiring the presence of the condensate was observed even when the sun lamp emission was filtered (principal emission 300-340 nm) to eliminate cell killing due to near-ultraviolet light alone, or when a black light near ultraviolet source (emission maximum, 365 nm) was used.

Effect of cell growth rate and dose fractionation on chemically-induced ouabain-resistant mutations in Chinese hamster V79 cells.

Chinese hamster V79 cells were grown in medium containing either 10% or 2% FCS during the expression time following exposure to MNNG. The lower serum concentration was used to reduce the rate of cell replication, thereby allowing more time for DNA repair prior to "fixation" of the mutagenic lesion. In addition, fractionated and continuous exposures to MNNG and MAM, respectively, were carried out to determine their effect on the number of induced ouabain-resistant mutants.

Effect of alkane tumor-promoting agents on chemically induced mutagenesis in cultured V79 Chinese hamster cells.

Linear alkanes of specific chain length between 6 and 16 carbon atoms, an aryl derivative of dodecane, and a phorbol diester were tested in a cell culture system for relative ability to enhance mutagenesis induced by a chemical carcinogen, methylazoxymethanol acetate (MAM). Mutation frequencies at the ouabain-resistance locus were measured. Results indicated an excellent correlation between the relative activities of the above compounds in enhancing mutagenesis in the in vitro culture system and their tumor-promoting activities in mouse skin.