Gastric damage in the rat with nitrogen-containing bisphosphonates depends on pH.

BACKGROUND: The use of nitrogen-containing bisphosphonates (N-BPs) has been reported to be associated with gastrointestinal intolerance. The fasted, indomethacin-treated rat provides a model for assessing the gastrointestinal effects of these compounds. AIMS: The aims of this study were to elucidate the effect of pH on N-BP-induced gastric damage, and to evaluate the structure-activity relationship between N-BP anti-resorptive and gastric effects. METHODS: Fasted rats were dosed concomitantly with indomethacin (40 mg/kg, subcutaneously) and an N-BP (pamidronate, alendronate, or risedronate at 150 or 300 mg/kg, orally), with the N-BP dosing solutions adjusted to pH 2, 4 or 7. The aminopentane and aminohexane N-BPs (150, 225 or 300 mg/kg, orally) were only tested at pH 4 only. RESULTS: Nitrogen-containing bisphosphonate-induced gastric damage was pH-dependent, with increased damage at increasing pH. CONCLUSIONS: Gastric damage potential did not correlate with bone anti-resorptive effects, and the more potent anti-resorptive N-BPs were not necessarily more damaging to the stomach.

Musk xylene induces and inhibits mouse hepatic cytochrome P-450 2B enzymes.

The purpose of this work was to characterize the effects of musk xylene on mouse hepatic microsomal enzyme activities. Male B6C3F1 mice were dosed for 7 days at 0 or 200 mg musk xylene/kg after which microsomes were prepared. Musk xylene treatment increased liver weight by 40%, caused hepatocellular hypertrophy and increased total cytochrome P-450 2-fold over control. Microsomes from musk xylene-treated mice showed increased activity for the dealkylation of ethoxy- and methoxyresorufin, results consistent with increased CYP1A1 and 1A2 protein levels determined by Western blotting. No increase in pentoxyresorufin-O-dealkylation activity was seen, but musk xylene treatment markedly increased CYP2B protein levels. Preliminary in vitro studies showed that musk xylene inhibited mouse CYP2B enzymes (IC50 approximately 1 microM), but did not affect the activities of CYP1A1 or 1A2. This inhibition was not NADPH-dependent. These results indicate that, in mice, musk xylene causes generalized hepatic changes similar to classical CYP2B inducers. However, musk xylene is also a potent inhibitor of the CYP2B enzymes.

Effect of bleeding site on clinical laboratory testing of rats: orbital venous plexus versus posterior vena cava.

We sought to determine if there were any differences in the results of clinical laboratory tests between blood samples collected from the orbital venous plexus and the posterior vena cava of adult male rats. Thirty healthy adult male Sprague Dawley rats were anesthetized by ether inhalation, and blood samples were collected successively from the orbital venous plexus (OVP) and the posterior vena cava (PVC) for hematologic (n = 10), serum chemistry (n = 10), and coagulation (n = 10) analyses. The prothrombin and partial thromboplastin times of samples from the OVP were prolonged (17% and 288%, respectively) when compared with samples from the PVC. Respective hematologic biases were as follows: red blood cell count (7%), hemoglobin (6%), hematocrit (5%), mean corpuscular volume (-3%), mean corpuscular hemoglobin (-1%), mean corpuscular hemoglobin content (1%), white blood cell count (13%), and platelet count (-7%). Respective serum chemistry biases were as follows: sorbitol dehydrogenase (-7%), glucose (-7%), blood urea nitrogen (-10%), creatinine (-2%), total protein (4%), albumin (2%), globulin (9%), alkaline phosphatase (5%), lactate dehydrogenase (-6%), aspartate aminotransferase (-5%), alanine aminotransferase (-2%), total bilirubin (0%), direct bilirubin (0%), magnesium (-17%), sodium (4%), potassium (0), chloride (4%), calcium (-2%), phosphorous (-17%), cholesterol (3%), triglycerides (24%), creatinine kinase (-8%), 5'nucleotidase (0%), and total bile acids (4%). For hematologic testing, there were no biologically significant differences between samples collected from the OVP and PVC. The coagulation times and serum Mg and P showed biologically significant differences between samples collected from the OVP and PVC.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of nitrofurantoin on the primary and secondary reproductive organs of female B6C3F1 mice.

The National Toxicology Program (NTP) has reported female mice fed high doses of Nitrofurantoin (NFT) were found to have ovarian atrophy as diagnosed histologically and increased benign ovarian tumors after 24 months of exposure (30). This result contrasts with 4 other recent carcinogenicity assays in rodents with NFT, all with no evidence of an ovarian effect. An extensive database documents benign tubular adenomas develop secondary to ovarian atrophy in many mouse strains, including B6C3F1. The present study was initiated to confirm this mechanism could be responsible for the ovarian tumors in the NTP study and to investigate the time course of ovarian changes seen in female B6C3F1 mice. Mice were provided diet containing NFT at doses of 350 and 500 mg/kg body weight/day and examined after 4, 8, 13, 17, 43 and 64 weeks. A dose-related decrease in feed consumption, feed efficiency and body weight gain was seen and persisted throughout the study. Sexual maturity was delayed in a dose-related fashion, compatible with previously reported effects of reduced food consumption in rodents (12, 16). All groups of mice eventually did have normal estrous cycles, but cycle lengths were increased in a dose-related fashion. Both doses of NFT resulted in histological evidence of senile ovarian atrophy by week 43. Based on the reported association between sterility and ovarian tumors, we conclude the benign tubular adenomas seen at 2 yr in the NTP carcinogenicity study with NFT were secondary to the ovarian atrophy induced in this strain of mouse and not an indication NFT, itself, is a carcinogen.

A two-generation reproductive and developmental toxicity study of sucrose polyester.

Sucrose polyester (SPE) is a mixture of hexa-, hepta- and octa-esters of fatty acids with sucrose, and has physical and organoleptic properties similar to those of conventional dietary fats. Because SPE is neither absorbed nor metabolized it forms a bulk lipid phase in the small intestine, resulting in effects on the absorption and enterohepatic circulation of lipid-soluble materials, such as cholesterol and fat-soluble vitamins. Such effects could potentially alter the physiology of animals to the extent of interfering with reproduction and/or the normal development of the embryo/foetus. To determine the likelihood of such phenomena, Sprague-Dawley rats were continuously fed SPE at dietary levels of 1, 5 or 10% along with controlled levels of vitamins A and E for two generations, with a reproductive and a teratogenic phase in each generation. Body-weight gain of rats fed SPE was comparable to that of the controls throughout the study, but feed consumption increased with increasing levels of SPE. Pregnancy or lactation had no effect on these growth patterns. Throughout the study, SPE had no deleterious effect on mating, conception, embryonic development, foetal or post-natal viability, or on post-natal growth. Nor was there any treatment-related histopathology. Thus, it is concluded that SPE would not represent a reproductive or teratogenic hazard to human consumers of products containing SPE.