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- Author or Editor: Cyril R. Clarke x
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Abstract
Objective—To determine the pharmacokinetics of acetazolamide administered IV and orally to horses.
Animals—6 clinically normal adult horses.
Procedure—Horses received 2 doses of acetazolamide (4 mg/kg of body weight, IV; 8 mg/kg, PO), and blood samples were collected at regular intervals before and after administration. Samples were assayed for acetazolamide concentration by high-performance liquid chromatography, and concentrationtime data were analyzed.
Results—After IV administration of acetazolamide, data analysis revealed a median mean residence time of 1.71 ± 0.90 hours and median total body clearance of 263 ± 38 ml/kg/h. Median steady-state volume of distribution was 433 ± 218 ml/kg. After oral administration, mean peak plasma concentration was 1.90 ± 1.09 µg/ml. Mean time to peak plasma concentration was 1.61 ± 1.24 hours. Median oral bioavailability was 25 ± 6%.
Conclusions and Clinical Relevance—Oral pharmacokinetic disposition of acetazolamide in horses was characterized by rapid absorption, low bioavailability, and slower elimination than observed initially after IV administration. Pharmacokinetic data generated by this study should facilitate estimation of appropriate dosages for acetazolamide use in horses with hyperkalemic periodic paralysis. (Am J Vet Res 2000;61:965–968)
Abstract
Objective—To use force plate analysis to evaluate the analgesic efficacies of flunixin meglumine and phenylbutazone administered IV at typical clinical doses in horses with navicular syndrome.
Animals—12 horses with navicular syndrome that were otherwise clinically normal.
Procedure—Horses received flunixin (1.1 mg/kg), phenylbutazone (4.4 mg/kg), or physiologic saline (0.9% NaCl; 1 mL/45 kg) solution administered IV once daily for 4 days with a 14-day washout period between treatments (3 treatments/horse). Before beginning treatment (baseline) and 6, 12, 24, and 30 hours after the fourth dose of each treatment, horses were evaluated by use of the American Association of Equine Practitioners lameness scoring system (half scores permitted) and peak vertical force of the forelimbs was measured via a force plate.
Results—At 6, 12, and 24 hours after the fourth treatment, subjective lameness evaluations and force plate data indicated significant improvement in lameness from baseline values in horses treated with flunixin or phenylbutazone, compared with control horses; at those time points, the assessed variables in flunixin- or phenylbutazone-treated horses were not significantly different.
Conclusions and Clinical Relevance—In horses with navicular syndrome treated once daily for 4 days, typical clinical doses of flunixin and phenylbutazone resulted in similar significant improvement in lameness at 6, 12, and 24 hours after the final dose, compared with findings in horses treated with saline solution. The effect of flunixin or phenylbutazone was maintained for at least 24 hours. Flunixin meglumine and phenylbutazone appear to have similar analgesic effects in horses with navicular syndrome. (Am J Vet Res 2005;66:284–288)
SUMMARY
To investigate the effect of chloramphenicol, a cytochrome P-450 inhibitor, on the pharmacokinetics of propofol, either chloramphenicol (50 mg/kg of body weight, iv) or saline solution was administered iv to 5 Greyhounds in randomized manner, with at least 2 weeks between trials. Thirty minutes after either chloramphenicol or saline treatment, a bolus dose of propofol (10 mg/kg, iv) was administered, followed by a 2-hour infusion of propofol (0.4 mg/kg/min, iv). Samples for determination of blood propofol concentration were collected sequentially over a 6-hour period during each trial. After termination of propofol infusion, the time to spontaneous head lift, extubation, sternal recumbency, and standing was recorded. Blood propofol concentration was determined by use of high-performance liquid chromatography. Concentration-time data were fitted to a two-compartment open pharmacokinetic model and pharmacokinetic variables were determined, using a microcomputer program for modeling and simulation of concentration-time data. The effect of chloramphenicol on the pharmacokinetics of propofol and recovery time were evaluated, using paired t-tests and Wilcoxon's test for parameters that are not normally distributed (t½(β), Vd(ss), ClB). Significant (P < 0.05) effects of chloramphenicol pretreatment included increased t1/2(β) (by 209%), and decreased ClB (by 45%), and prolonged recovery indices (by 768 to 946%). These results indicate that cytochrome P-450 metabolic pathways have an important role in propofol clearance and propofol anesthetic recovery in Greyhounds.
Summary
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 × 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.
Summary
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 (> 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.
Abstract
Objective
To determine whether characteristic changes in neutrophil morphology caused in vitro by Pasteurella haemolytica leukotoxin (LKT) can be observed in vivo by electron microscopic examination of infected tissue chamber fluids and pneumonic lungs.
Animals
7 mixed-breed beef calves.
Procedure
Tissue chambers were implanted subcutaneously in 3 calves and were inoculated with P haemolytica or phosphate-buffered saline solution. Chamber fluid samples, obtained at 8 and 32 hours after inoculation, were examined, using electron microscopy. Experimental pneumonia was induced in an additional 4 calves by transthoracic inoculation with P haemolytica. These calves were euthanatized at 6, 12, 24, and 36 hours after inoculation and lung sections were examined, using transmission electron microscopy.
Results
On examination, using transmission electron microscopy, neutrophils in lung sections and tissue chamber fluids had cytoplasmic and nuclear changes indicative of irreversible cell injury, including cell swelling, loss of plasma membrane ruffling, mitochondrial swelling, autolytic vacuolation, disruption of plasma membrane, nuclear pyknosis, karyolysis, and karyorrhexis. On examination, using scanning electron microscopy, leukocytes obtained from tissue chambers did not have their typical convoluted surfaces, but appeared rounded and swollen or shrunken with pitted surfaces.
Conclusions
Pasteurella haemolytica-induced changes in neutrophil morphology in vivo were similar to those previously induced by in vitro exposure of neutrophils to LKT. Changes were suggestive of injury initiated by damage to the plasma membrane, which is consistent with the mechanism of action of pore-forming cytolysins.
Clinical Relevance
Pasteurella haemolytica LKT appears to be an important virulence factor in vivo; a fact that should be addressed in the development of vaccines. (Am J Vet Res 1998;59:588–592)
Abstract
Objective—To develop and validate an ex vivo model for study of adherence of Mannheimia haemolytica (formerly Pasteurella haemolytica) to respiratory tract mucosa of cattle and to use this model to confirm adherence of M haemolytica serovar 1 (Mh1) to several relevant respiratory mucosal surfaces.
Sample Population—Excised nasal, nasopharyngeal, turbinate, and tonsillar mucosal tissue from the bovine upper respiratory tract.
Procedure—Mh1 was radiolabeled by use of tritiated leucine. Various concentrations of labeled bacteria were incubated with bovine upper respiratory tract tissues for various times. Tissue was washed to remove nonadherent bacteria, and percentage of bacteria adhered (percentage of adherence) was estimated using radioactivity. Using an optimal inoculum concentration and incubation time, percentage of Mh1 adherence was compared on nasal, nasopharyngeal, turbinate, and tonsillar mucosal tissue, and adherence to nasopharyngeal tissue was confirmed by scanning and transmission electron microscopy.
Results—The optimal Mh1 inoculum concentration was 1 × 107 colony forming units/ml and incubation time was 3 hours. Percentage of adherence of Mh1 to nasopharyngeal tissue was greater than adherence to other tissue types.
Conclusions and Clinical Relevance—The ex vivo model maintained the functional and structural integrity of bovine upper respiratory tract mucosa, as confirmed by light and electron microscopy. Electron microscopy revealed participation of epithelial cell cilia and surface mucus in adherence of Mh1 to nasopharyngeal tissue. Adherence of Mh1 was confirmed in repeated assays, indicating that this organism adheres to upper respiratory tract mucosa of cattle. (Am J Vet Res 2001;62:805–811)
Abstract
Objective
To determine pharmacokinetics of IV, IM, and oral administration of cefepime in horses and to compare pharmacokinetics of IM administration of cefepime with those of ceftiofur sodium.
Animals
6 clinically normal adult horses.
Procedure
Horses received 3 doses of cefepime (11 mg/kg of body weight, PO; 2.2 mg/kg, IV; and 2.2 mg/kg, IM) and 1 dose of ceftiofur (2.2 mg/kg, IM). Two horses also received l-arginine, PO and IV, at doses identical to those contained in the cefepime dihydrochloride-l-arginine preparations previously administered. Blood samples were collected for 24 hours after administration of cefepime or ceftiofur and were assayed for cefepime and ceftiofur concentrations.
Results
Pharmacokinetic analysis of disposition data indicated that IV administration data were best described by a 2-compartment open model, whereas IM administration data were best described by a 1-compartment absorption model. Median elimination half-life and volume of distribution after IV administration of cefepime were 125.7 minutes and 225 ml/kg, respectively. After IM administration of cefepime, mean maximal plasma concentration of (8.13 μg/ml) was reached at a mean time of 80 minutes. Absorption of cefepime after IM administration was complete, with a median bioavailability of 1.11. Intramuscular administration of ceftiofur resulted in similar mean maximal plasma concentration (7.98 μg/ml) and mean time to this concentration (82 minutes). Cefepime was not detected in samples collected after oral administration. Adverse effects consisting principally of gastrointestinal disturbances were observed after oral and IM administration of cefepime and after 1 IM administration of ceftiofur.
Conclusions and Clinical Relevance
Cefepime, administered IV or IM at a dosage of 2.2 mg/kg, every 8 hours is likely to provide effective antibacterial therapy for cefepime-sensitive organisms in horses. Further studies are needed to evaluate adverse effects on the gastrointestinal tract. (Am J Vet Res 1998;59:458–463)
Abstract
Objective—To investigate the concentration-dependent effects of Mannheimia haemolytica (formerly Pasteurella haemolytica) leukotoxin (LKT) on apoptosis and oncosis in bovine neutrophils and to examine the role of calcium ions (Ca2+) in LKT-induced apoptosis.
Sample Population—Neutrophils isolated from blood samples obtained from healthy calves.
Procedure—Neutrophil suspensions were exposed to lytic or sublytic dilutions of LKT and then examined by use of transmission electron microscopy (TEM) or gel electrophoresis. Contribution of extracellular Ca2+ to LKT-induced apoptosis was investigated by incubating neutrophils with LKT or control solutions in buffer containing 1 mM CaCl2 or in Ca2+-free buffer containing 1 mM ethylene glycol-bis (b-aminoethyl ether)- N,N-tetraacetic acid (EGTA) prior to diphenyl amine analysis.
Results—Examination by TEM revealed that bovine neutrophils exposed to lytic dilutions of LKT had changes consistent with oncosis, whereas neutrophils exposed to sublytic dilutions of LKT and staurosporin, an inducer of apoptosis, had changes consistent with apoptosis. Effects of sublytic dilutions of LKT on apoptosis were confirmed by gel electrophoresis. Replacement of extracellular Ca2+ with EGTA, a Ca2+ chelator, reduced apoptosis attributable to the calcium ionophore A23187, but it did not have significant effects on apoptosis induced by LKT or staurosporin.
Conclusions and Clinical Relevance—The ability of LKT to cause apoptosis instead of oncosis is concentration- dependent, suggesting that both processes of cell death contribute to an ineffective host-defense response, depending on the LKT concentration in pneumonic lesions. Furthermore, although Ca2+ promotes A23187-induced apoptosis, it is apparently not an essential second messenger for LKT-induced apoptosis. ( Am J Vet Res 2001;62:136–141)
Abstract
Objective—To characterize ultrastructural changes of bovine lymphocytes exposed to Pasteurella haemolytica leukotoxin (LKT).
Sample Population—Partially purified LKT from a wild type P haemolytica A1 strain and inactive pro-LKT from an isogeneic mutant P haemolytica strain. Isolated bovine lymphocytes were obtained from 2 healthy calves.
Procedure—Isolated bovine lymphocytes were incubated with various concentrations of LKT and pro-LKT for 3 hours at 37 C and examined by use of transmission electron microscopy. A cytochemical Klenow DNA fragmentation assay was used to examine lymphocytes for DNA fragmentation.
Results—Lymphocytes incubated with LKT at a high concentration (1.0 toxic U/ml) had ultrastructural evidence of cytoplasmic and nuclear membrane rupture and swelling or lysis of mitochondria. Low concentrations of leukotoxin (0.1 toxic U/ml) induced DNA fragmentation in 80% of lymphocytes. Ultrastructurally, these cells had nuclear membrane blebbing, cytoplasmic vaculation, chromatin condensation, nuclear fragmentation, and membrane-bound apoptotic bodies. Incubation of lymphocytes with LKT at extremely low concentrations (0.001 toxic U/ml) or with pro-LKT did not alter their ultrastructure. Inclusion of 0.5 mM ZnCl2 in the medium blocked leukotoxin-induced ultrastructural changes in bovine lymphocytes.
Conclusions and Clinical Relevance—Low concentrations of LKT induce apoptosis and high concentrations induce oncotic cell lysis in bovine lymphocytes. The ability of low LKT concentrations to induce apoptosis in host leukocytes may allow bacteria to escape host immune surveillance and colonize the host. (Am J Vet Res 2000;61:51–56)
