A review of nonclinical toxicology studies of becaplermin (rhPDGF-BB).

Becaplermin (recombinant human platelet-derived growth factor-BB [BB homodimer, rhPDGF-BB]) has demonstrated a favorable safety profile in a series of nonclinical studies designed to assess its systemic toxicity, sensitization, local irritation, and genotoxic potential. No significant local or systemic toxicity directly attributable to becaplermin was observed following single and multiple intravenous or subcutaneous administration at doses up to 3 mg/kg in monkeys. Administration of single large intravenous doses (up to 100 mg/kg) and repeated dosing at 1 or 3 mg/kg in mice resulted in rapidly reversible vasodilation and central nervous system depression. In a bone-toxicity study, becaplermin produced histomorphologic changes suggestive of accelerated bone remodeling, which were judged to be potentially reversible. Similar findings have not been observed in humans. Although becaplermin was not considered a dermal or ocular irritant, some skin-sensitizing effects were observed in animals; this finding was not unexpected for a recombinant human-derived protein. Becaplermin was not genotoxic in a variety of in vitro assays and in one in vivo assay.

Preclinical toxicity evaluation of tepoxalin, a dual inhibitor of cyclooxygenase and 5-lipoxygenase, in Sprague-Dawley rats and beagle dogs.

Tepoxalin [5- (4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole -3-propanamide] is an orally active anti-inflammatory agent, which inhibits both cyclooxygenase and 5-lipoxygenase activities. The oral toxicity of tepoxalin was evaluated in 1- and 6-month rat (up to 50 mg/kg/day) and dog (up to 150 mg/kg bid) studies. In rats, increased liver weight, centrilobular hypertrophy, and hepatic necrosis were observed at dosages >/=20 mg/kg/day. Renal changes indicative of analgesic nephropathy syndrome (i.e., papillary edema or necrosis, cortical tubular dilatation) were seen at >/=15 mg/kg. In rats treated for 1 month, these hepatic and renal effects were largely reversible after a 1-month recovery period. Gastrointestinal erosions and ulcers were seen in female rats given 40 mg/kg/day for 6 months. Changes in clinical pathology parameters included decreases in red blood cell count, hemoglobin, and hematocrit mean values; elevation in platelet counts; and an increase in prothrombin and activated partial thromboplastin times. Mild increases in alanine aminotransferase, aspartate aminotransferase, and cholesterol were also noted in rats. Decreased erythrocyte parameters, increased leukocyte counts, and decreased total protein, albumin, and/or calcium were noted in some dogs in the 300 mg/kg/day group following 6 months of dosing. Small pyloric ulcerations were seen at 100 and 300 mg/kg/day dosages for up to 6 months. In both rats and dogs, no accumulation of tepoxalin or its carboxylic acid metabolite was detected in plasma following multiple dosing over a range of 5 to 50 mg/kg/day for rats and 20 to 300 mg/kg/day for dogs. Plasma concentrations of the carboxylic acid metabolite were severalfold higher than those of the parent compound. The no-effect dosages in rats (5 mg/kg/day) and dogs (20 mg/kg/day) were approximately one and six times the ED50 (3.5 mg/kg), respectively, for inhibition of inflammatory effects in the adjuvant arthritic rat without gastric mucosal damage. In terms of severity, the relative lack of gastrointestinal side effects, within the estimated therapeutic dose range, distinguishes tepoxalin from most marketed anti-inflammatory drugs.

Effects of beta-carotene and retinyl palmitate on corn oil-induced superoxide dismutase and catalase in rats.

The present study was undertaken to determine the effects of beta-carotene on corn oil-induced superoxide dismutase and catalase. Six groups of male Buffalo rats were fed the following diets for 6 wk: a control diet containing recommended levels of beta-carotene and retinyl palmitate, a retinol diet containing 10 times the recommended level of retinyl palmitate, and a beta-carotene diet containing 10 times the recommended levels of beta-carotene and adequate levels of retinyl palmitate. Each vitamin combination was fed with either 5% (wt/wt) corn oil (low fat) or 20% corn oil (high fat). Plasma total beta-carotene levels were highest in the beta-carotene groups. Levels varied inversely with the level of fat in the control group and directly with fat in the beta-carotene group. Transport of beta-carotene appeared to parallel that of cholesterol in that 36 and 35%, respectively, were associated with the low density lipoprotein fraction. Accumulation of beta-carotene in the liver was apparent from the observation that levels in liver were much higher than those in plasma. Superoxide dismutase activity was much lower in the beta-carotene groups than in the retinol groups, irrespective of level of fat, and catalase activity was also lower in the beta-carotene group, but it was in proportion to the level of fat. These findings suggest that beta-carotene functions as an antioxidant in vivo.

Differences in the in vivo and in vitro effects of the carbamate insecticide, carbaryl on rat hepatic monooxygenases.

The effects of one of the most widely used insecticides, carbaryl, on the hepatic cytochrome P-450-dependent monooxygenases were determined. Addition of carbaryl to liver microsomes from untreated or phenobarbital (PB)-pretreated rats resulted in a weak Type I binding spectrum. A much stronger spectral Type I interaction was observed when microsomes from 3-methylcholanthrene(3-MC)-treated rats were used. In vitro, carbaryl caused marked inhibition of ethylmorphine and benzphetamine N-demethylases, benzo(a)pyrene hydroxylase, 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylase in liver microsomes. Kinetic studies demonstrated that carbaryl was a competitive inhibitor of ethylmorphine N-demethylase activity. Daily administration of carbaryl for 4 days by gavage or intraperitoneally resulted in no significant alterations in hepatic cytochrome P-450 levels, ethylmorphine N-demethylase or benzo(a)-pyrene hydroxylase activities. The lack of effect of carbaryl in vivo may be due to the rapid metabolism of the insecticide, such that the insecticide may not be present in the liver endoplasmic reticulum to cause the inhibitory effects observed in vitro.