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Biomedical subjects

C R Clarke

Publications and source records attributed to C R Clarke.

At least 37 records · Page 2Linked to original sources
PubMed1995

The effects of Artemisia filifolia and Helenium flexuosum on disposition of antipyrine in rabbits.

The objectives of the present experiment were to determine the effects of Artemisia filifolia or Helenium flexuosum ingestion on antipyrine disposition as an indirect index of mixed function oxidase (MFO) activity and to evaluate the rabbit as an animal model for assessing the impact of xenobiotics in food. Twelve adult male New Zealand white rabbits were acclimated and maintained on commercial rabbit pellets for 1 w before treatment commenced. On day 1, all rabbits were given 25 mg antipyrine/kg iv. Beginning on day 14, 6 of the rabbits were fed A filifolia and the other 6 were fed H flexuosum at 250 mg/kg daily for 5 d. Antipyrine injection was repeated in all rabbits on day 19. Serial blood samples were taken following each antipyrine administration and serum concentrations determined and subjected to pharmacokinetic analysis. Administration of H flexuosum significantly increased antipyrine half-life elimination from 99.5 +/- 15 min to 215.5 +/- 28 min, typical of an inhibitory-type effect on MFO. Administration of A filifolia was not accompanied by a significant change in antipyrine disposition. Rabbits appear to be appropriate animal models for evaluating the effect of plant ingestion on hepatic biotransformation.

Animal Feed↗
PubMed1994

Pasteurella haemolytica leukotoxin-induced synthesis of eicosanoids by bovine neutrophils in vitro.

Exposure of isolated bovine neutrophils to partially purified Pasteurella haemolytica leukotoxin caused increased synthesis of leukotriene B4 (LTB4) but not thromboxane B2 (TXB2) from endogenous arachidonic acid. Synthesis of LTB4 was closely correlated with leukotoxin-induced neutrophil lysis. At low toxin concentrations, LTB4 production lagged behind leukotoxin-induced neutrophil lysis over a 3-h period. The neutralizing monoclonal antileukotoxin antibody MM601 neutralized both leukotoxin-induced neutrophil lysis and LTB4 synthesis. Both leukotoxin-induced neutrophil lysis and LTB4 synthesis were Ca(2+)-dependent. When leukotoxin-induced LTB4 synthesis from exogenous arachidonic acid was examined, significant LTB4 synthesis occurred at 5 min of leukotoxin exposure, which was before leukotoxin-induced lysis developed. Leukotoxin-induced LTB4 synthesis from endogenous arachidonic acid appears to require leukotoxin-induced plasma membrane damage (occurring during neutrophil lysis), whereas LTB4 synthesis from exogenous arachidonic acid is initiated rapidly and occurs in the absence of plasma membrane damage.

Animals↗
PubMed1994

Effect of Pasteurella haemolytica infection on alpha 1-acid glycoprotein and albumin concentrations in serum and subcutaneous tissue chamber fluid of calves.

Thermoplastic tissue chambers were implanted subcutaneously in the paralumbar fossae of 10 calves. Concentrations of alpha 1-acid glycoprotein (AAG) and albumin in serum and subcutaneous tissue chamber fluid were measured before and after inoculation of Pasteurella haemolytica into tissue chambers. Two months after implantation, serum and tissue chamber fluid samples were collected and all tissue chambers were then inoculated with P haemolytica. Additional serum and chamber fluid samples were collected two, four, six and 10 days after inoculation. The concentrations of AAG and albumin in the samples were measured by radial immunodiffusion assay and the bromcresol method, respectively. P haemolytica inoculation resulted in an increase in the serum and chamber fluid AAG concentrations and an increase in chamber fluid albumin concentrations, suggesting that the proportion of drugs bound to serum and interstitial proteins may be affected by P haemolytica infection.

Animals↗
PubMed1994

Effects of phenylbutazone on thiamylal disposition and anaesthesia in ponies.

Phenylbutazone given during the perisurgical period has been reported to increase the intensity and duration of thiamylal anaesthesia in horses. A possible mechanism of competitive plasma protein binding has been suggested. The purpose of the present study was to experimentally reproduce the phenomenon of increased intensity and/or duration of thiamylal anaesthesia and to determine if there is competitive displacement of plasma protein bound thiamylal by phenylbutazone. Six ponies each received one of three treatments, 11 mg/kg intravenous (i.v.) thiamylal; 8.8 mg/kg i.v. phenylbutazone; and 11 mg/kg i.v. thiamylal with 8.8 mg/kg i.v. phenylbutazone given 9 min later. Thirteen blood samples were collected from 0 time through 600 min following drug administration and plasma drug concentrations quantified by high performance liquid chromatography. The pharmacokinetics of thiamylal and phenylbutazone were best described by three- and two-compartment models, respectively. There were no significant differences in pharmacokinetic parameters for thiamylal in the presence of phenylbutazone. However, there were differences in phenylbutazone pharmacokinetics when preceded by thiamylal administration. Unbound phenylbutazone concentrations were increased at 171, 231 and 351 min when given with thiamylal, accompanied by decreases in per cent bound phenylbutazone (P < 0.05). There were also significant (P < 0.05) changes in per cent plasma protein binding of thiamylal and phenylbutazone between 120 and 360 min, when in combination. No changes in intensity or duration of anaesthesia were observed.

Anesthesia↗
PubMed1994

The role of eicosanoids in the chemotactic response to Pasteurella haemolytica infection.

The chemotactic role of eicosanoids in the pathogenesis of Pasteurella haemolytica infection was studied, using a tissue chamber infection model and pharmacological inhibitors of eicosanoid synthesis. Tissue chambers were implanted subcutaneously in 12 calves allotted to three treatment groups of equal size. At 45 days after implantation, calves received saline, dexamethasone, or phenylbutazone treatments, and tissue chambers in all animals were then inoculated with P. haemolytica. Chamber fluid samples were collected before inoculation and at 2, 6, 18, 40, and 90 h after inoculation. Bacterial counts, total leukocyte counts, pH and albumin concentrations in chamber fluids were determined using standard bacteriological and clinical pathological methods. Concentrations of eicosanoids and activity of interleukin-1 (IL-1) were measured by radioimmunoassay and a helper T cell bioassay, respectively. Concentrations of leukotriene B4 (LTB4), thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (PGF1 alpha) and prostaglandin E2 (PGE2) increased markedly after inoculation. An inhibitory effect of dexamethasone on both LTB4 production and neutrophil influx, together with the temporal relationship between these two events, suggested that LTB4 served as a chemo-attractant. Activity-time profiles for IL-1 in chamber fluids were similar to those of the eicosanoids. Phenylbutazone and dexamethasone reduced the severity of the inflammatory responses as measured by lower concentrations of albumin and higher pH in treated versus control chamber fluids. The results of this study suggest that eicosanoid inflammatory mediators play an important chemotactic role in the pathogenesis of P. haemolytica infection.

Animals↗
PubMed1994

Effects of localized Pasteurella haemolytica infection on erythromycin-binding properties of bovine alpha-1-acid glycoprotein, albumin, serum, and tissue chamber fluids.

The in vitro erythromycin-binding properties of bovine alpha-1-acid glycoprotein (AAG) and albumin were studied by using equilibrium dialysis. In addition, the proportions of free erythromycin in bovine serum and tissue chamber fluid before and 4 days after inoculation of subcutaneous tissue chambers with Pasteurella haemolytica were measured. At a concentration of 5 micrograms/ml, erythromycin was moderately bound to AAG (39% +/- 4% free) and was only slightly bound to albumin (86% +/- 2% free). Scatchard analysis of the data describing binding to pure bovine AAG indicated that erythromycin was bound to a single high-affinity (6.45 x 10(4) M-1) site on the protein. At lower total concentrations of erythromycin, the free concentrations of the antibiotic were lower in serum samples collected after infection (49% +/- 3% at 5 micrograms of erythromycin per ml) than in those collected before inoculation (55% +/- 3% at 5 micrograms of erythromycin per ml). Inoculation had no effect on binding to macromolecules in chamber fluids. Inoculated tissue chambers served as a convenient model for studying the effect of infection on drug-macromolecule interactions in interstitial fluid.

Animals↗
PubMed1994

Effect of dietary obesity on naloxone disposition in sheep.

Naloxone is an opioid antagonist used frequently in studies of appetite regulation in lean and obese animals and humans. Body condition may affect plasma and tissue distribution of injected naloxone and thus confound interpretation of responses to naloxone in lean compared with obese subjects. The objective of this experiment was to determine the effect of dietary obesity per se on the pharmacokinetic behavior of iv-injected naloxone (3 mg/kg) in lean (46 kg body weight) and dietary obese (77 kg body weight) sheep that were maintained at equilibrium weight. To this end, an HPLC procedure combined with electrochemical detection was developed for measuring naloxone in sheep plasma. Naloxone disappearance from plasma followed an apparent first-order process, the kinetics of which were described best using a two-compartment open model. Components of the biexponential equations describing the plasma concentration (C)-time (t) curves for naloxone disappearance in lean (Ct = 1814e(-0.190t) + 413e(-0.017t)) and obese (Ct = 2282e(-0.282t) + 573e(-0.018t)) sheep were similar (p > 0.05). Mean (+/- SE) elimination half-lives for naloxone in lean (42.7 +/- 4.6 min) and obese (44.3 +/- 10.2 min) sheep were similar (p > 0.05). Volume of distribution of naloxone (Vd) was extensive but also similar (p > 0.05) in lean (5.6 +/- 0.9 L/kg) and obese (4.1 +/- 0.6 L/kg) sheep. Naloxone was distributed extensively throughout the body fluids and trapped or stored in significant amount in extravascular tissues because the naloxone Vd greatly exceeded 100% of body weight in both lean (557 +/- 86 mL/100 g) and obese (413 +/- 58 mL/100 g) sheep.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Distribution of intramuscularly administered erythromycin into subcutaneous tissue chambers before and after inoculation with Pasteurella haemolytica.

Distribution of erythromycin into subcutaneous tissue chambers was characterised pharmacokinetically and the effect of Pasteurella haemolytica infection on the extent of penetration was studied. Thermoplastic tissue chambers were implanted subcutaneously in the paralumbar fossae of six calves. Thirty-five days after implantation, the tissue chamber distribution of intramuscularly administered erythromycin (30 mg kg-1) was studied. Chambers were then inoculated with P haemolytica and the tissue chamber pharmacokinetics of erythromycin were again studied. Diffusion of erythromycin into tissue chambers was best described using a two-compartment model with tissue chambers representing a relatively inaccessible compartment. Despite changes in chamber fluid pH, the extent of erythromycin penetration into chambers was not affected by P haemolytica inoculation. Comparison of computer simulated concentration-time curves resulting from different routes of administration revealed that penetration of erythromycin into less accessible sites was more likely to be higher after intravenous administration than after intramuscular administration.

Animals↗
PubMed1992

High-performance liquid chromatographic determination of BRB-I-28, a novel antiarrhythmic agent, in dog plasma and urine.

A sensitive reversed-phase high-performance liquid chromatographic (HPLC) technique with ultraviolet detection has been developed to determine the concentration of BRB-I-28 (I), a novel antiarrhythmic agent, in dog plasma and urine. The mobile phase was acetonitrile-methanol-37.5 mM phosphate buffer, pH 6.8-triethylamine (50:50:75:0.1, v/v). The compound was extracted from dog plasma and urine with chloroform after alkalinization with sodium hydroxide. The extraction recovery was 83% from plasma and 84% from urine. Good linearity (r > 0.996) was observed throughout the ranges 0.1-12.0 micrograms/ml (plasma) and 0.1-8.0 micrograms/ml (urine). Intra- and inter-assay variabilities were less than 4%. The lower limit of quantitation was 0.08 microgram/ml in either plasma or urine. HPLC analysis of plasma and urine samples from a dog treated with I has demonstrated that the method was accurate and reproducible.

Animals↗
PubMed1992

Pharmacokinetics of intravenously and orally administered pyrimethamine in horses.

Single-dose pharmacokinetic variables of pyrimethamine were studied in horses. Pyrimethamine (1 mg/kg of body weight) was administered IV and orally to 6 adult horses, and plasma samples were obtained at frequent intervals thereafter. Plasma pyrimethamine concentration was assayed by gas chromatography, and concentration-time data were analyzed, using a pharmacokinetic computer program. The IV and oral administration data were best described by 3-compartment and 1-compartment models, respectively. The median volume of distribution at steady state after IV administration was 1,521 ml/kg and the median elimination half-time was 12.06 hours. Mean plasma concentration after oral administration fluctuated between a maximal concentration of 0.18 microgram/ml and 0.09 microgram/ml (24 hours after dosing). Bioavailability after oral administration was 56%.

Administration, Oral↗
PubMed1992

Pharmacokinetics, penetration into cerebrospinal fluid, and hematologic effects after multiple oral administrations of pyrimethamine to horses.

Pharmacokinetics, CSF penetration, and hematologic effects of oral administration of pyrimethamine were studied after multiple dosing. Pyrimethamine (1 mg/kg of body weight) was administered orally once a day for 10 days to 5 adult horses, and blood samples were collected frequently after the first, fifth, and tenth doses. The CSF samples were obtained by cisternal puncture 4 to 6 hours after administration of the first, third, seventh, and tenth doses. Pyrimethamine concentration in plasma and CSF was quantified by gas chromatography, and plasma concentration-time data were analyzed, using a pharmacokinetic computer program. Repeated daily dosing resulted in accumulation of pyrimethamine in plasma, with steady state being achieved within 5 days, when the mean peak plasma concentration was more than twice that measured after the first dose. Pyrimethamine concentration in CSF was 25 to 50% of corresponding plasma concentration and did not appear to accumulate with successive administration of doses. Blood samples collected during and after the dosing regimen were submitted for hematologic analysis; neutrophil numbers decreased slightly, but remained within normal range for adult horses.

Administration, Oral↗
PubMed1992

Response of Pasteurella haemolytica to erythromycin and dexamethasone in calves with established infection.

A subcutaneous soft tissue infection model in calves was used to study the in vivo response of Pasteurella haemolytica to erythromycin and dexamethasone. Two tissue chambers were implanted SC in each of 12 calves. At 45 days after implantation, all tissue chambers were inoculated with an erythromycin-sensitive strain of P haemolytica. Starting 24 hours after inoculation, calves were allotted to 4 groups of equal size and a 2 x 2-factorial arrangement of treatments was applied: 3 calves were given erythromycin (30 mg/kg of body weight, IM, for 5 days), 3 calves were given dexamethasone (0.05 mg/kg, IM, for 2 days), 3 calves were given erythromycin and dexamethasone, and the remaining calves served as nontreated controls. Chamber fluids were tested daily, and the response to treatment was measured. Neither erythromycin nor dexamethasone affected viability or growth of bacteria within tissue chambers. Dexamethasone had no effect on the influx of neutrophils into infected chambers. Despite repeated administration of a high dose of erythromycin and attainment of adequate concentration in serum, erythromycin concentration in chamber fluids did not exceed the minimal inhibitory concentration established in vitro. These results indicate that the clinical efficacy of erythromycin against P haemolytica sequestered in consolidated pneumonic lesions may not be well correlated with predictions based on serum pharmacokinetic and in vitro susceptibility data.

Albumins↗
PubMed1992

Comparison of antigens of Pasteurella haemolytica serotype 1 grown in vitro and in vivo.

To determine whether antigenic differences exist in Pasteurella haemolytica serotype 1 grown in different culture conditions, the bacteria was grown on solid enriched medium, in broth culture, and in tissue chambers subcutaneously implanted in the flanks of calves. The organisms obtained by each culture method were comparable with respect to encapsulation and lipopolysaccharide content. In the bacteria grown in vivo, several unique high molecular-mass (greater than 150 kDa) protein antigens were found by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and protein immunoblotting. Bacteria grown in vitro had higher concentrations of a 49- and a 26-kDa protein than the organisms grown in vivo. The concentration of several major proteins (30, 42, 55, 71, and 100 kDa) were similar among the organisms grown by the three cultural conditions. Although the high molecular-mass antigens were unique for the chamber-grown bacteria, they were recognized by serum from a calf that had been vaccinated with formalin-killed, solid medium-grown P haemolytica and were resistant to challenge exposure with the live organism. This recognition of antigens by serum from the P haemolytica-resistant calf that had been vaccinated with solid-medium-grown bacterium, indicates that the high molecular-mass antigens from chamber-grown P haemolytica may be precursors of or share antigenic determinants with other P haemolytica proteins and may not be important for consideration in vaccine formulation.

Animals↗
PubMed1991

Therapy of bovine bacterial pneumonia.

Practical strategies for developing rational therapeutic regimens based on in vitro sensitivity and pharmacokinetic disposition are presented. Special attention is given to Pasteurella haemolytica, which is regarded as the most frequent cause of bovine bacterial pneumonia. Bacterial-dependent and host-dependent causes of therapeutic failure and potentially valuable novel therapies and drug combinations are considered.

Animals↗