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- Author or Editor: Arthur L Craigmill x
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Abstract
Objective—To compare the in vitro imMunosuppressive effects of cyclosporine and 4 novel immunosuppressive drugs on lymphocytes in whole blood collected from healthy cats.
Sample Population—Whole blood samples collected from 10 healthy adult domestic shorthair cats.
Procedure—Mitogen-stimulated lymphocyte proliferation in whole blood incubated with and without various concentrations of cyclosporine, tacrolimus, sirolimus, mycophenolic acid (MPA), or A771726 was measured by use of [3H]thymidine incorporation. Drug concentrations that resulted in a 50% inhibition of mitogen-induced proliferation (IC50) were calculated. Lymphocyte viability was determined by use of the trypan blue dye exclusion method.
Results—An obvious dose-response relationship for the antiproliferative effects of each drug was detected. Mean IC50 determined with concanavalin A was 46 nMfor cyclosporine, 9 nMfor tacrolimus, 12 nM for sirolimus, 16 nM for MPA, and 30 mM for A771726, whereas with pokeweed mitogen, mean IC50 was 33 nM for cyclosporine, 5 nMfor tacrolimus, 15 nM for sirolimus, 14 nM for mycophenolic acid, and 25 mM for A771726. Mitogen-stimulated and nonstimulated lymphocytes remained viable, regardless of drug evaluated.
Conclusions and Clinical Relevance—Tacrolimus, sirolimus, MPA, and A771726 inhibited in vitro mitogen- stimulated proliferation of feline lymphocytes in a dose-dependent manner. These novel immunosuppressive drugs may be useful for management of immune-mediated inflamMatory diseases and prevention and treatment of rejection in cats that undergo organ transplantation. (Am J Vet Res 2000;61: 906–909)
Abstract
Objective—To compare the results of regulatory screening and confirmation assays with those of highperformance liquid chromatography (HPLC) in the detection of ceftiofur metabolites in the tissues of culled dairy cattle.
Animals—17 lactating Holstein dairy cows.
Procedure—Daily IM injections of ceftiofur sodium were administered at a dose of 2.2 mg of ceftiofur equivalents/kg (n = 6) or 1.0 mg of ceftiofur equivalents/kg (10) for 5 days. Following withdrawal times of 12 hours (high-dose ceftiofur) and either 5 or 10 days (low-dose ceftiofur), cows were slaughtered and liver, kidney, and diaphragmatic muscle specimens were harvested and analyzed by HPLC and standard regulatory methods that included the following assays: the swab test on premises, the fast antimicrobial screen test, the calf antibiotic and sulfa test, and the 7-plate bioassay confirmation test.
Results—In all tissue specimens, residues of ceftiofur and desfuroylceftiofur-related metabolites, as measured by HPLC, were less than regulatory tolerance, as defined by the FDA. False-positive screening assay results were more likely for tissue specimens that had been frozen for shipment to a federal laboratory, compared with fresh tissue specimens that were assayed at the slaughter establishment (23% vs 3% false-positive results, respectively).
Conclusions and Clinical Relevance—The observation that fresh tissues had negative results on screening assays, whereas subsets of the same tissue specimens had false-positive results on screening assays following freezing, suggests that freezing and thawing interferes with microbial inhibition-based regulatory screening assays. (Am J Vet Res 2004;65:1730–1733)
Abstract
Objective—To develop a flow-limited, physiologicbased pharmacokinetic model for use in estimating concentrations of sulfamethazine after IV administration to swine.
Sample Population—4 published studies provided physiologic values for organ weights, blood flows, clearance, and tissue-to-blood partition coefficients, and 3 published studies provided data on plasma and other tissue compartments for model validation.
Procedure—For the parent compound, the model included compartments for blood, adipose, muscle, liver, and kidney tissue with an extra compartment representing the remaining carcass. Compartments for the N-acetyl metabolite included the liver and the remaining body. The model was created and optimized by use of computer software. Sensitivity analysis was completed to evaluate the importance of each constant on the whole model. The model was validated and used to estimate a withhold interval after an IV injection at a dose of 50 mg/kg. The withhold interval was compared to the interval estimated by the Food Animal Residue Avoidance Databank (FARAD).
Results—Specific tissue correlations for plasma, adipose, muscle, kidney, and liver tissue compartments were 0.93, 0.86, 0.99, 0.94, and 0.98, respectively. The model typically overpredicted concentrations at early time points but had excellent accuracy at later time points. The withhold interval estimated by use of the model was 120 hours, compared with 100 hours estimated by FARAD.
Conclusions and Clinical Relevance—Use of this model enabled accurate prediction of sulfamethazine pharmacokinetics in swine and has applications for food safety and prediction of drug residues in edible tissues. (Am J Vet Res 2005;66:1686–1693)
Abstract
Objective—To investigate the feasibility of using multivariate cluster analysis to meta-analyze pharmacokinetic data obtained from studies of pharmacokinetics of ampicillin trihydrate in cattle and identify factors that could account for variability in pharmacokinetic parameters among studies.
Sample Population—Data from original studies of the pharmacokinetics of ampicillin trihydrate in cattle in the database of the Food Animal Residue Avoidance Databank.
Procedure—Mean plasma or serum ampicillin concentration versus time data and potential factors that may have affected the pharmacokinetics of ampicillin trihydrate were obtained from each study. Noncompartmental pharmacokinetic analyses were performed, and values of pharmacokinetic parameters were clustered by use of multivariate cluster analysis. Practical importance of the clusters was evaluated by comparing the frequency of factors that may have affected the pharmacokinetics of ampicillin trihydrate among clusters.
Results—A single cluster with lower mean values for clearance and volume of distribution of ampicillin trihydrate administered PO, compared with other clusters, was identified. This cluster included studies that used preruminant calves in which feeding was withheld overnight and calves to which probenecid had been administered concurrently.
Conclusions and Clinical Relevance—Meta-analysis was successful in detecting a potential subpopulation of cattle for which factors that explained differences in pharmacokinetic parameters could be identified. Accurate estimates of pharmacokinetic parameters are important for the calculation of dosages and extended withdrawal intervals after extralabel drug administration. (Am J Vet Res 2005;66:108–112)
Abstract
Objective—To determine the pharmacokinetics of butorphanol tartrate after IV and IM single-dose administration in red-tailed hawks (RTHs) and great horned owls (GHOs).
Animals—6 adult RTHs and 6 adult GHOs.
Procedures—Each bird received an injection of butorphanol (0.5 mg/kg) into either the right jugular vein (IVj) or the pectoral muscles in a crossover study (1-week interval between treatments). The GHOs also later received butorphanol (0.5 mg/kg) via injection into a medial metatarsal vein (IVm). During each 24-hour postinjection period, blood samples were collected from each bird; plasma butorphanol concentrations were determined via liquid chromatography-mass spectrometry.
Results—2- and 1-compartment models best fit the IV and IM pharmacokinetic data, respectively, in both species. Terminal half-lives of butorphanol were 0.94 ± 0.30 hours (IVj) and 0.94 ± 0.26 hours (IM) for RTHs and 1.79 ± 1.36 hours (IVj), 1.84 ± 1.56 hours (IM), and 1.19 ± 0.34 hours (IVm) for GHOs. In GHOs, area under the curve (0 to infinity) for butorphanol after IVj or IM administration exceeded values in RTHs; GHO values after IM and IVm administration were less than those after IVj administration. Plasma butorphanol clearance was significantly more rapid in the RTHs. Bioavailability of butorphanol administered IM was 97.6 ± 33.2% (RTHs) and 88.8 ± 4.8% (GHOs).
Conclusions and Clinical Relevance—In RTHs and GHOs, butorphanol was rapidly absorbed and distributed via all routes of administration; the drug's rapid terminal half-life indicated that published dosing intervals for birds may be inadequate in RTHs and GHOs.
Abstract
Objective—To determine the pharmacokinetics of ceftiofur sodium after IM and SC administration in green iguanas.
Animals—6 male and 4 female adult green iguanas.
Procedure—In a crossover design, 5 iguanas received a single dose of ceftiofur sodium (5 mg/kg) IM, and 5 iguanas received the same dose SC. Blood samples were taken at 0, 20, and 40 minutes and 1, 2, 4, 8, 24, 48, and 72 hours after administration. After a 10-week washout period, each iguana was given the same dose via the reciprocal administration route, and blood was collected in the same fashion. Ceftiofur free-acid equivalents were measured via high-performance liquid chromatography.
Results—The first phase intercepts were significantly different between the 2 administration routes. Mean maximum plasma concentration was significantly higher with the IM (28.6 ± 8.0 µg/mL) than the SC (18.6 ± 8.3 µg/mL) administration route. There were no significant differences between terminal halflives (harmonic mean via IM route, 15.7 ± 4.7 hours; harmonic mean via SC route, 19.7 ± 6.7 hours) and mean areas under the curve measured to the last time point (IM route, 11,722 ± 7,907 µg·h/mL; SC route, 12,143 ± 9,633 µg·h/mL). Ceftiofur free-acid equivalent concentrations were maintained ≥ 2 µg/mL for > 24 hours via both routes.
Conclusions and Clinical Relevance—A suggested dosing schedule for ceftiofur sodium in green iguanas for microbes susceptible at > 2 µg/mL would be 5 mg/kg, IM or SC, every 24 hours. (Am J Vet Res 2003;64:1278–1282)
Abstract
Objective—To describe pharmacokinetics of multidose oral administration of tacrolimus in healthy cats and evaluate the efficacy of tacrolimus in the prevention of allograft rejection in cats with renal transplants.
Animals—6 healthy research cats.
Procedure—Cats received tacrolimus (0.375 mg/kg, PO, q 12 h) for 14 days. Blood tacrolimus concentrations were measured by a high performance liquid chromatography-mass spectrometry assay. Each cat received an immunogenically mismatched renal allograft and native kidney nephrectomy. Tacrolimus dosage was modified to maintain a target blood concentration of 5 to 10 ng/mL. Cats were euthanatized if plasma creatinine concentration exceeded 7 mg/dL, body weight loss exceeded 20%, or on day 50 after surgery. Kaplan-Meier survival curves were plotted for 6 cats treated with tacrolimus and for 8 cats with renal transplants that did not receive immunosuppressive treatment.
Results—Mean (± SD) values of elimination half-life, time to maximum concentration, maximum blood concentration, and area under the concentration versus time curve from the last dose of tacrolimus to 12 hours later were 20.5 ± 9.8 hours, 0.77 ± 0.37 hours, 27.5 ± 31.8 ng/mL, and 161 ± 168 hours × ng/mL, respectively. Tacrolimus treated cats survived longer (median, 44 days; range, 24 to 52 days) than untreated cats (median, 23 days; range, 8 to 34 days). On histologic evaluation, 3 cats had evidence of acute-active rejection, 1 cat had necrotizing vasculitis, and 2 cats euthanatized at study termination had normal appearing allografts.
Conclusions and Clinical Relevance—Tacrolimus may be an effective immunosuppressive agent for renal transplantation in cats. (Am J Vet Res 2003;64:926–934)