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Biomedical subjects

C R Short

Publications and source records attributed to C R Short.

At least 37 records · Page 2Linked to original sources
PubMed1989

Isolation of drug residues from tissues by solid phase dispersion.

A new method based on solid phase dispersion of tissue for the subsequent isolation of drugs is reported. By blending tissues with a polymeric phase bound to a solid support one obtains a semi-dry material which can be used as a column packing material from which one can isolate drugs in a stepwise fashion based on the solubility characteristics of the drugs in this matrix. The applicability of this approach for multidrug residue extraction from a single sample is demonstrated for compounds representing the organophosphate, benzimidazole anthelmintic and beta-lactam antibiotic drug classes.

Animals↗
PubMed1989

The in vivo oxidative metabolism of 2,4- and 2,6-dimethylaniline in the dog and rat.

The xylidine 2,4-dimethylaniline (2,4-DMA) produces hepatic cholangiofibrosis, bile duct proliferation, and foci of cellular hyperplasia and degeneration in the rat. The same compound is relatively innocuous in the dog. 2,6-Dimethylaniline (2,6-DMA) does not produce hepatic lesions in the rat, except at high doses but is a potent inducer of fatty degeneration in the dog. The purpose of the present study was to examine pathways of in vivo metabolism of both isomers in the rat and dog. The major urinary metabolite of 2,4-DMA in the rat was N-acetyl-4-amino-3-methylbenzoic acid (AAMBA) while in the dog it was 6-hydroxy-2,4-dimethylaniline (6-HDMA). The dog also produced a smaller amount of unacetylated 4-amino-3-methylbenzoic acid (4-AMBA) and its glycine conjugate. 2,6-DMA was metabolized principally to 4-hydroxy-2,6-dimethylaniline (4-HDMA) in both species, but the dog also produced significant quantities of 2-amino-3-methylbenzoic acid (2-AMBA), along with trace amounts of the glycine conjugate of the latter and 2,6-dimethylnitrosobenzene. Trace levels of an unknown postulated to be 3,5-dimethyl-4-imino-quinone were also found in urine of dogs. In rats, repeated administration of either xylidine for 10 days failed to increase the appearance of metabolites, but 3-methylcholanthrene (3-MC) did increase the urinary concentration of AAMBA in 2,4-DMA dosed rats. The divergent pathways of metabolism in the 2 species could be responsible for species specific pathologies produced by these 2 xylidines.

Aniline Compounds↗
PubMed1989

Covalent binding of [14C]-2,6-dimethylaniline to DNA of rat liver and ethmoid turbinate.

The xylidide 2,6-dimethylaniline (2,6-DMA) has produced carcinomas and papillary adenomas in the nasal cavity of rats at high dietary doses (3000 ppm) in a 2-yr bioassay. The objective of the present study was to measure the covalent binding of 2,6-DMA to DNA of rat ethmoid turbinate tissues and, for comparison, to DNA of rat liver. The potent hepatocarcinogen 2-acetylaminofluorene (AAF) was studied as a positive control for adduct formation and covalent binding index (CBI) calculation. Both 2,6-DMA and AAF were administered as 14C-(ring)-labeled agents to naive rats and to rats pretreated for 9 d with unlabeled 2,6-DMA or AAF. The CBI value for 2,6-DMA adduct formation with ethmoid turbinate DNA was below the assay's sensitivity limit in nonpretreated rats, but increased to 41.9 in rats pretreated with unlabeled 2,6-DMA. It also increased from 0.6 in nonpretreated to 7.9 in liver of pretreated rats. The opposite pattern, however, was observed for AAF. In nonpretreated rats considerable adduct formation was observed in liver (CBI = 271.5) and modest values (CBI = 39.3) were calculated for ethmoid turbinate tissues. Pretreatment with unlabeled AAF caused a significant decrease in CBI values, to 18.3 for liver and less than 0.5 for ethmoid turbinate. The results suggest that there may be value in conducting DNA covalent binding assays in both naive animals and animals pretreated with the test article.

Aniline Compounds↗
PubMed1989

Characterization of a soft-tissue infection model in the horse and its response to intravenous cephapirin administration.

A soft-tissue infection model was created in eight horses by infecting subcutaneous tissue chambers with Streptococcus zooepidemicus organisms. Responses of the horses to the infections were determined by monitoring changes in the complete blood count and body temperature and by following changes in the cytology and protein content of the tissue chambers. Systemic reactions to the infections included a mild neutrophilia, mild pyrexia and mild anemia. There was a marked influx of neutrophils and protein into the chambers after they were seeded with bacteria and chamber neutrophil viability decreased markedly at the height of the infection. Subsequent to establishing tissue chamber infections four of the horses were treated with intravenous cephapirin t.d. at a dosage of 20 mg/kg for 5 days. Quantitative culturing of tissue chamber fluid was performed to analyze the efficacy of cephapirin therapy. Cephapirin therapy was accompanied by decreases in the systemic neutrophilia, pyrexia, anemia, and chamber bacterial counts. However, cephapirin did not eliminate the infection in any of the chambers. Chamber neutrophil viability was markedly increased during the cephapirin therapy period.

Animals↗
PubMed1989

Subcutaneously implanted tissue chambers--a pharmacokinetic study.

The purpose of this study was to characterize the pharmacokinetics of a subcutaneously implanted tissue-chamber model. Thermoplastic tissue chambers were implanted in the paralumbar fossae of six steers. Starting 30 days after implantation, the distribution of intravenously administered antipyrine and phenylbutazone into the tissue chambers was studied. These pharmacokinetic experiments were repeated 10 days later to determine the effect of time after implantation on tissue-chamber distribution. Fifty days after implantation, tissue chambers were drained of transudate, refilled with sterile saline and the rate of influx of endogenous urea, creatinine and albumin was measured. Delayed diffusion of antipyrine and phenylbutazone into tissue chambers was well described using a compartmental model in which tissue-chamber fluid represented the third of three compartments arranged in series. The distribution of antipyrine into tissue chambers was greater than that of phenylbutazone; an observation which is well correlated with the high degree of protein binding of phenylbutazone. There was no effect of time on the penetration of the two agents. Rapid diffusion of urea and creatinine and extremely slow influx of albumin into chambers showed that these chambers formed true interstitial compartments.

Animals↗
PubMed1989

Subcutaneously implanted tissue chambers: a pathophysiological study.

Tissue and fluid changes occurring within tissue chambers were characterised as a function of time after subcutaneous implantation in cattle. Cytological and chemical investigation revealed that the composition of fluid within chambers approached the theoretical composition of true interstitial fluid as time after implantation progressed. Erythrocyte and leucocyte numbers decreased sharply immediately after implantation and had reached stable numbers by 40 days after implantation. At this stage, chamber fluid samples had lower total protein and albumin concentrations, higher K+ and Cl- concentrations and lower pH than corresponding blood samples. Despite an ongoing low-grade chronic inflammatory reaction resulting in fibrous encapsulation of chambers, the vascularity of chamber tissue did not diminish with time after implantation. By 40 days after implantation, the cellular and chemical constituents had stabilised enough to allow use of the model to study drug distribution.

Albumins↗
PubMed1989

Effect of Pasteurella haemolytica infection on the distribution of sulfadiazine and trimethoprim into tissue chambers implanted subcutaneously in cattle.

A study was designed to determine the effect of Pasteurella haemolytica infection on the rate and extent of penetration of sulfadiazine and trimethoprim into tissue chambers implanted SC in cattle. Thermoplastic tissue chambers were implanted SC in 6 calves. At 35 days after implantation, sulfadiazine (25 mg/kg of body weight) and trimethoprim (5 mg/kg) were administered IV to 5 of the calves. Chamber fluid and blood samples were collected from each animal at various time intervals for 24 hours after administration. Ten days later, all chambers were inoculated with P haemolytica serotype 1. At 36 hours after inoculation, a second pharmacokinetic study was conducted, using sulfadiazine and trimethoprim. Drug doses and sampling schedules were identical to those used prior to inoculation. A histologic study of infected chamber tissue was conducted, using the calf not included in the pharmacokinetic studies. Disposition curves of antimicrobials in serum and chamber fluid were well described by 2-compartment and 1-compartment pharmacokinetic models, respectively. Inoculation of P haemolytica into tissue chambers was accompanied by marked changes in the composition of chamber fluid. Increased total protein and albumin concentrations, decreased pH, and disruption of chamber tissue vasculature were associated with a significant increase in the penetration of sulfadiazine and trimethoprim into infected tissue chambers, compared with that in noninfected chambers. This increased penetration was accompanied by increases in the apparent volume of distribution for sulfadiazine and trimethoprim.

Animals↗
PubMed1989

Interaction between Pasteurella haemolytica, sulfadiazine/trimethoprim, and bovine viral diarrhea virus.

A study was designed to develop and define a sc tissue chamber as a suitable device for establishing a soft-tissue infection model in cattle and to use this model to study the interaction between Pasteurella haemolytica, sulfadiazine/trimethoprim, and bovine viral diarrhea virus (BVDV). Thermoplastic tissue chambers were implanted in the paralumbar fossae of 20 calves. At 35 days after implantation, calves were allotted to 4 groups of equal size and the calves in 2 groups were inoculated intratracheally with a New York-1 strain of BVDV. At 45 days after implantation, all chambers were inoculated with a 6-hour culture of P haemolytica serotype 1. Starting 36 hours after bacterial inoculation, sulfadiazine/trimethoprim was administered IV once a day to half of the virus-inoculated calves and to half of those calves that had not been exposed to virus. Inoculation of P haemolytica into tissue chambers resulted in the establishment of a localized soft-tissue infection, characteristic of pneumonic pasteurellosis. Despite the maintenance of chamber antimicrobial concentrations that exceeded minimal bactericidal concentrations established in vitro, the infections were not sterilized. This lack of efficacy was associated with decreased pH and increased protein concentrations in chamber fluids after inoculation. Infection with BVDV, which is thought to depress host defenses, had no effect on the response of P haemolytica to sulfadiazine/trimethoprim administration. Observation of responsive antibody titers, bacterial phagocytosis, and high leukocyte viability within P haemolytica-infected chambers documented functional host defenses within tissue chambers.

Animals↗
PubMed1988

Comparison of hepatic drug metabolizing enzyme activities in several agricultural species.

1. Several pathways of drug metabolizing enzyme activity were measured in hepatic fractions of cattle, sheep, goats, chickens, turkeys, ducks, rabbits and rats. The pathways examined included the O-demethylation of p-nitrophenol, microsomal ester hydrolysis of procaine and glucuronidation of p-nitrophenol, and the cytosolic acetylation of sulfamethazine and sulfation of 2-naphthol. 2. For most enzymatic pathways measured, goats were more similar to sheep (wether) than to cattle (steers). The exception was UDP-glucuronyltransferase activity, which was significantly higher for the goat than for any other species studied. 3. Within the avian subset, the chicken and turkey were usually the most similar species. 4. The activities of arylsulfotransferase isozymes III and IV were particularly low for the duck compared to the chicken and turkey. 5. N-acetyltransferase activity was very high for rabbits and very low for sheep and goats.

Animals↗
PubMed1988

Hepatic drug metabolizing enzyme activity in the channel catfish, Ictalurus punctatus.

1. Several pathways of drug metabolizing enzymic activity were measured in hepatic fractions of the channel catfish and rat using model substrates. The pathways examined included the O-demethylation of p-nitroanisole, microsomal ester hydrolysis of procaine and glucuronidation of p-nitrophenol, and the cytosolic acetylation of sulfamethazine and sulfation of 2-naphthol. Catfish liver preparations were incubated at both 25 degrees C and 37 degrees C. 2. The oxidative metabolism of p-nitrophenol was only one-eighth that of the rat at 37 degrees C and one-twelfth that of the rat at 25 degrees C. 3. Procaine ester hydrolysis was negligible in catfish microsomal preparations. 4. At 37 degrees C, p-nitrophenol glucuronidation was equivalent in catfish and rat microsomes. 5. Catfish cytosolic preparations exhibited N-acetyltransferase and arylsulfotransferase nearly comparable to those of the rat. 6. Rates of glucuronidation and sulfation were higher at 37 degrees C than at 25 degrees C in hepatic fractions of catfish.

Animals↗
PubMed1988

The oxidative metabolism of fenbendazole: a comparative study.

The oxidative metabolism of fenbendazole (FBZ) was studied in hepatic fractions prepared from livers of cattle, sheep, goats, chickens, ducks, turkeys, rats, rabbits and catfish. All species produced the sulfoxide metabolite (oxfendazole; FBZ-SO), and p-hydroxyfenbendazole (FBZ-OH) was produced by all species except sheep. The product of demethoxycarbonylation, fenbendazole amine (FBZ-NH2), was not produced by liver preparations of any species. A fourth metabolite, resulting from the further oxidation of oxfendazole, fenbendazole sulfone (FBZ-SO2), was formed in all species but at highly varying rates. The chicken exhibited the highest overall rate of FBZ metabolism, followed by the duck, goat, sheep, steer, catfish, rat, rabbit, and turkey. Considerable variation was evident among avian species, the duck and turkey produced substantially less of the FBZ-OH and FBZ-SO2 metabolites than the chicken. Catfish liver preparations formed equivalent amounts of metabolite at 25 degrees C and 37 degrees C incubation temperatures. The formation of the sulfone metabolite (FBZ-SO2), however, was practically nonexistent in catfish.

Animals↗
PubMed1988

Comparative drug metabolism and disposition in minor species.

The disposition of fenbendazole (FBZ) was studied in vivo in cattle (steers), goats, chickens, ducks, turkeys and rabbits, and in vitro in hepatic enzyme preparations from cattle, sheep, goats, rabbits, rats, chickens, ducks, turkeys and catfish. The major excretory metabolite when FBZ was administered either iv or po (5 mg/kg) was p-hydroxyfenbendazole (FBZ-OH). The sulfoxide (FBZ-SO) and sulfone (FBZ-SO2) appeared in plasma but were recovered in only trace amounts in urine or feces, and the amine (FBZ-NH2) was a minor metabolite appearing only occasionally in plasma. The greatest species differences were seen among the avian species, and differences in metabolite excretion correlated well with the ability of the species to metabolize the drug (especially to FBZ-OH) in vitro. Other in vitro studies measured the rate of oxidative, hydrolytic, and conjugative (glucuronide, acetate, sulfate) pathways in liver preparations.

Acetylation↗
PubMed1988

Disposition of fenbendazole in the rabbit.

The disposition of fenbendazole was studied in rabbits following either oral or intravenous administration. The major metabolites appearing in plasma were fenbendazole sulphoxide (oxfendazole) and fenbendazole sulphone. Calculation of the total urinary and faecal elimination of the drug and of its known metabolites showed that only 40 per cent of the dose was recovered after oral dosing; 29.7 per cent after an intravenous dose. The sulphoxide and sulphone were minor elimination products. The major excretory metabolite was p-hydroxyfenbendazole.

Administration, Oral↗
PubMed1987

Qualitative and quantitative analysis of the anthelmintic fenbendazole and its metabolites in biological matrices by direct exposure probe mass spectrometry.

Methodology for the qualitative and quantitative analysis of the anthelmintic fenbendazole and its metabolites in goat feces using electron impact (EI)/direct exposure probe (DEP)/mass spectrometric (MS) and tandem mass spectrometric (MS/MS) techniques is presented. Analyses were conducted on extracts from spiked feces and feces from animals treated per os with 5 mg fenbendazole/kg, with samples being collected at zero time and at twelve hour intervals for 144 h. The results of the EI/DEP/MS quantitation of these samples are compared to those for the same samples analysed by high pressure liquid chromatography (HPLC). Mass spectral data for fenbendazole and its metabolites are presented and the advantages of the use of EI/DEP/MS and/or DEP/MS/MS over HPLC are discussed. This methodology may be used as a confirmatory method for the HPLC analysis of fenbendazole and its metabolites or may be used as a method in its own right for the rapid qualitative and quantitative analysis of these compounds.

Animals↗
PubMed1987

Pharmacologic considerations in drug therapy in foals.

Rational drug therapy in the foal requires a sound knowledge of the pharmacodynamics and pharmacokinetics of various drugs as well as a thorough understanding of the physiologic differences that exist between the neonate and the adult and that may serve to alter drug disposition and, therefore, drug response. A summary of these physiologic factors with emphasis on the foal is presented and is followed by recommendations regarding the applied therapeutics of various antimicrobial agents.

Administration, Oral↗
PubMed1987

Distribution of cephapirin into a tissue chamber implanted subcutaneously in horses.

The pharmacokinetics of cephapirin sodium and its distribution into a tissue chamber implanted subcutaneously in the neck of mature horses are described. Cephapirin was administered as an intravenous bolus dose of 20 mg/kg. The serum concentration vs time curve was best described by a two-compartment open model. Cephapirin disappeared from serum rapidly (t1/2 beta = 18.8 min), and had only a modest volume of distribution (Vd(area) approximately equal to 346 mg/kg, Vd(ss) approximately equal to 204 ml/kg). Total clearance was also rapid (approximately equal to 13 ml/min.kg). Concentrations of the antibiotic in tissue chamber fluid, however, were quite constant from 30 min to 3 h post-injection, and did not decay in parallel with either the concentration of the drug in serum or the estimated concentration of drug in the peripheral compartment. The ratio of area under the curve (AUC0-3 h) for serum: chamber fluid was 13.8 : 1, while that for peripheral compartment : chamber fluid was 11 : 1. The slow rate of cephapirin transport into, and out of, the chamber may be related to its hydrophilic nature. The lack of parallelism between the chamber fluid decay curve and that of serum is characteristic of drugs with a very short half-life.

Animals↗