Biomedical subjects

R J Clay

Publications and source records attributed to R J Clay.

9 recordsLinked to original sources

PubMed2001

BMS-189453, a novel retinoid receptor antagonist, is a potent testicular toxin.

BMS-189453 is a synthetic retinoid that acts as an antagonist at retinoic acid receptors alpha, beta, and gamma. In Sprague Dawley rats at daily oral doses of 15, 60, or 240 mg/kg for 1 month, BMS-189453 produced increases in leukocyte counts, alkaline phosphatase and alanine aminotransferase levels, and marked testicular degeneration and atrophy at all doses. Significant overt signs of toxicity and deaths occurred at 240 mg/kg, whereas body-weight and food-consumption decreases occurred at 60 and 240 mg/kg. When BMS-189453 was administered to male rats at daily doses ranging from 12.5 to 100 mg/kg for 1 week, only minimal testicular changes occurred at all doses, shortly after the dosing period. However, after a 1-month drug-free observation period, marked testicular atrophy was evident at all doses. BMS-189453 was then administered at doses of 2, 10, or 50 mg/kg to male rats for 1, 3, or 7 consecutive days. Dose- and duration-dependent testicular toxicity that occurred after a 1-month observation period did not recover, and, in some cases, was more severe 4 months after the last dose. In rabbits administered BMS-189453 at oral doses of 2, 10, or 50 mg/kg for 1 week, testicular degeneration and atrophy were evident in the high-dose group at 1 month following treatment. These studies indicate that retinoid antagonists can selectively produce progressive and prolonged testicular toxicity after single or repeated oral doses that are otherwise well tolerated.

Alanine Transaminase↗

PubMed1996

Pulmonary activation and toxicity of cyclopentadienyl manganese tricarbonyl.

Cyclopentadienyl manganese tricarbonyl (CMT) produces acute pulmonary injury following cytochrome P450 mixed-function oxidase (CYP450) activation. The current studies were designed to characterize the role of hepatic and/or pulmonary CMT activation and the subsequent pneumotoxicity of this compound following subcutaneous injection in the male Sprague-Dawley rat. Both pulmonary and hepatic tissues were capable of CYP450-dependent CMT metabolism in vitro. Phenobarbital pretreatment, which induced hepatic but not pulmonary CMT metabolism, protected against CMT-depended pneumotoxicity suggesting escape of an active CMT metabolite from the liver is not responsible for the pneumotoxic response. Animals were also pretreated with either m-xylene or 3-methylindole, each of which reduce CMT metabolism in the lung but not in the liver. These pretreatments also reduced CMT-dependent pulmonary damage. Protection against toxicity by two compounds that inhibit pulmonary but not hepatic CMT metabolism provides strong evidence that CMT-induced pneumotoxicity is due to the activation of CMT within the lungs. Histopathological studies revealed that CMT induced an alveolar injury without apparent damage to the bronchiolar airways. Based on this pattern of injury, studies were performed with freshly isolate alveolar type II (ATII) cells as these cells are thought to contain significant CYP450 activity. However, CMT metabolism was not detectable in ATII cells in vitro. Although CMT was cytotoxic to ATII cells in vitro, this response was not inhibited by metyrapone indicating CYP450 activation was not involved in the in vitro phenomenon. Together these data suggest in situ activation of CMT is necessary for the alveolar toxicity of this compound; however, activation does not occur in ATII cells.

Animals↗

PubMed1991

Deposition of dibasic esters in the upper respiratory tract of the male and female Sprague-Dawley rat.

Inhalation exposure of the male and female rat to high concentrations of a mixture of the dibasic esters dimethyl succinate (DMS), dimethyl glutarate (DMG), and dimethyl adipate (DMA) results in mild olfactory toxicity. This response is thought to be due to the in situ formation of acidic metabolites via nasal carboxylesterases. The current study was designed to provide inhalation dosimetric information for these vapors. Deposition of DMS, DMG, and DMA was measured in the surgically isolated upper respiratory tracts (URT) of ketamine-xylazine-anesthetized male and female rats under constant velocity flow conditions at a flow rate of 100 ml/min. Deposition of acetone was measured in both genders for comparative purposes. URT deposition efficiencies in excess of 98.3% were observed for DMS, DMG, and DMA in animals exposed to each vapor individually. No gender differences in deposition efficiency were observed for these vapors or for acetone. Deposition of DMS, DMG, and DMA was also measured in animals exposed to all three vapors simultaneously. Deposition efficiency under simultaneous exposure conditions ranged between 97.3 and 98.5%. These values were slightly lower (about 1%) than those obtained under individual exposure conditions (p less than 0.0001). The reduced deposition efficiency may have resulted from competitive inhibition of nasal metabolism due to the simultaneous presence of all three carboxylesterase substrate vapors in nasal tissues. If so, inhalation of dibasic ester vapors would be expected to inhibit the uptake of other carboxylesterase substrate vapors without influencing uptake of vapors which are not substrates for this enzyme. Such was observed in studies using DMS, ethyl acetate (the substrate vapor), and isoamyl alcohol (the nonsubstrate vapor). Specifically, simultaneous exposure to DMS markedly inhibited uptake of ethyl acetate without altering uptake of isoamyl alcohol. Gender differences were not observed in URT deposition of any of the six vapors used in the current study, DMS, DMG, DMA, ethyl acetate, isoamyl alcohol, or acetone, suggesting that gender differences in URT deposition may not be widespread among vapors. The high URT deposition efficiencies of the dibasic esters are consistent with the olfactory toxicity resulting from inhalation exposure to these vapors.

Acetates↗

PubMed1989

Comparative pneumotoxicity of cyclopentadienyl manganese tricarbonyl and methylcyclopentadienyl manganese tricarbonyl.

The acute pneumotoxic effects of cyclopentadienyl manganese tricarbonyl (CMT) and methylcyclopentadienyl manganese tricarbonyl (MMT) were compared to delineate the role of the methyl side chain in the toxicity of these organomanganese compounds and to further our understanding of the mechanisms by which these compounds act. Specifically, lung manganese (Mn) burdens and the pneumotoxic response, as measured by bronchoalveolar lavage parameters, were determined in male Sprague-Dawley rats 24 hr after sc administration of 0.5, 1.0, or 2.5 mg Mn/kg as CMT or MMT. The pneumotoxic response to either compound was characterized by large increases in lavage albumin and protein content with smaller increases in lactate dehydrogenase levels. CMT was approximately twice as potent as MMT. This difference in potency may be due to methyl side chain oxidation, a metabolic detoxification pathway unavailable to CMT. Lung Mn content was significantly elevated after treatment with either CMT or MMT. Heptane extraction studies revealed that Mn was accumulated in a nonlipid soluble form, suggesting the accumulation of metabolites rather than heptane soluble parent MMT or CMT. A strong correlation between pulmonary Mn content and toxicity was observed, suggesting a causal relationship between the accumulation of CMT or MMT metabolites and toxicity. Piperonyl butoxide diminished both the pneumotoxicity and Mn accumulation resulting from CMT or MMT, suggesting both phenomena are due to monooxygenase metabolites. Pulmonary nonprotein sulfhydryl (NPSH) levels were increased twofold 24 hr after administration of either CMT or MMT. Depletion of NPSH was not observed 1.5 or 6 hr after administration. The mechanisms of this response are unclear but may be due to the metabolism of CMT or MMT to unstable compounds which release inorganic Mn within pulmonary cells.

Albumins↗

PubMed1989

Further characterization of serum alkaline phosphatase from male and female beagle dogs.

Alkaline phosphatase (AP) from the sera of both male and female beagle dogs was partially purified and then analyzed for the presence of AP isoenzymes having intestinal or osseous characteristics as detected by bromotetramisole inhibition or wheat germ lectin agarose electrophoresis, respectively. The sera from both sexes were similar in regard to the presence of AP isoenzymes with intestinal (16 vs. 20%) or osseous (19 vs. 23%) characteristics, but serum AP from the male had a greater sialic acid content and only the male serum contained a detectable constitutive acidic (pI = 3.4) AP isoenzyme. This was similar to a serum AP isoenzyme previously found elevated in the sera of dogs afflicted with hyperadrenocorticalism or of dogs treated with certain corticosteroids.

Alkaline Phosphatase↗

PubMed1987

Disposition and toxicity of methylcyclopentadienyl manganese tricarbonyl in the rat.

The disposition and toxicity of methylcyclopentadienyl manganese tricarbonyl (MMT) was studied in Sprague-Dawley rats after subcutaneous administration at a dose of 4 mg/kg. Blood, lung, liver and kidney Mn levels were increased between 1.5 and 96 h after MMT injection, with peak organ levels occurring at 3-6 h. At this time the MMT-derived Mn concentration in lung, liver and kidney averaged 13-, 4- and 4-fold higher, respectively, than in the blood, indicating the accumulation and retention of MMT (or metabolite) in these tissues. Maximal pulmonary toxicity, as assessed by pulmonary lavage protein levels, occurred 24-48 h after injection. Plasma urea and sorbitol dehydrogenase levels were not increased at any time after MMT, suggesting minimal or no hepatic or renal injury. That maximal pulmonary toxicity occurred after peak Mn accumulation, and that the organ-specific toxicity of MMT correlated with its accumulation and retention, suggests a causal relationship between tissue Mn accumulation and MMT-induced toxicity.

Animals↗

PubMed1986

Species differences in upper respiratory tract deposition of acetone and ethanol vapors.

Regional deposition patterns determine the dose of inhaled gaseous toxicant received by various areas of the respiratory tract. To study potential species differences in upper respiratory tract (URT) deposition of acetone and ethanol vapors, and to determine if deposition of these vapors could be described by a ventilation-perfusion (V-P) model, URT deposition efficiencies of these vapors were measured over a 12- to 18-min period at selected flow rates in the surgically isolated URT of urethane-anesthetized Fischer rats and Hartley guinea pigs. For both gases in both species, deposition efficiencies were significantly dependent upon inspiratory flow rate (p less than 0.0005). The V-P model predicts a linear relationship will exist between the ratio of the deposited to the nondeposited fraction and the inverse of the inspiratory flow rate. Such relationships were observed for deposition of acetone (r = 0.93, p less than 0.0005) and ethanol vapors (r = 0.95, p less than 0.0005) in the guinea pig and for deposition of acetone vapor (r = 0.95, p less than 0.0005) in the rat. In contrast, a linear relationship was not observed for ethanol in the rat suggesting that deposition mechanism(s) differ for this vapor in this species. Despite the fact that the surface area of the URT of the guinea pig is greater than that of the rat, URT deposition of these vapors was as much as twice as efficient in the rat as in the guinea pig (p less than 0.0005). This effect was not due to different blood:air partition coefficients as they were identical in both species. In toto, these results suggest there may be important anatomic and/or physiologic differences in the URT of the Hartley guinea pig and Fischer rat. Such differences may have to be considered when comparing the response(s) of these species to toxic gases or when extrapolating data obtained from these species to the human.

Acetone↗

PubMed1982

The desolvation and oxidation of crystals of dialuric acid monohydrate.

Examination of the influence of the solvent of crystallization on the solid-state oxidation of dialuric acid (I) monohydrate to alloxantin (II) is reported. This reaction was investigated at low and high humidities using photomicrography, X-ray crystallography, and IR and mass spectrometry. Crystals of dialuric acid desolvated somewhat anisotropically; this behavior was consistent with crystal packing. The desolvated crystals of dialuric acid monohydrate had approximately the same crystal structure as the monohydrate and were stable in air at room temperature at low humidities. At high humidity, these crystals rehydrated and rapidly oxidized to alloxantin. These studies showed for the first time that desolvation was not a necessary prerequisite to solid-state oxidation and that solid-state oxidation reactions could be accelerated by high humidity.

Barbiturates↗

PubMed1979

Criteria for internal auditing.

An effective, inclusive internal auditing endeavor should help assure hospital managements that (1) an adequate system of internal control exists to assure the safeguarding of assets and the reliability of data produced by the financial information system, (2) uneconomic operating practices are detected promptly so they can be remedied, and (3) program results and effectiveness levels are of sufficiently high quality to demonstrate managerial competence.

Accounting↗