Date of Award

1998

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Veterinary Physiology, Pharmacology, and Toxicology (Veterinary Medical Sciences)

First Advisor

Charles R. Short

Second Advisor

Michael J. Myers

Abstract

Efficacy studies are often done on diseased animals while pharmacokinetic studies are done on healthy animals. Disease models are inherently difficult to standardize because of the many variables associated with measuring pharmacokinetic parameters in abnormal animals. Information derived from pharmacokinetic studies with diseased animals could be useful to determine if therapeutic doses of a drug or antimicrobial becomes less effective or toxic due to changes in distribution and clearance. The objectives of this study were to: characterize a pulmonary infection model in swine using Actinobacillus pleuropneumoniae; evaluate the pharmacokinetic changes associated with the pulmonary infection model and dexamethasone after the infusion of enrofloxacin and urine enrofloxacin and ciprofloxacin concentrations; and the comparison endotoxin administration and dexamethasone to the pharmacokinetic changes of the infection model. In the infection study, infected pigs became ill within two hours of inoculation and had microscopic lesions of necrotizing, fibrinopurulent pneumonia consistent with Actinobacillus pleuropneumoniae infection; plasma interleukin-6 was slightly elevated in the infected pigs and not the dexamethasone pigs; clearance of enrofloxacin was increased in the dexamethasone treated pigs; volume of distribution of the elimination phase and at steady state were decreased in the infection; and the urine enrofloxacin/creatinine ratios were decreased in the dexamethasone treated pigs. In the endotoxin study, the endotoxin treated pigs exhibited toxic signs within 30 minutes; the plasma interleukin-6 concentrations were markedly elevated in the endotoxin treated pigs; the dexamethasone treated pigs showed an increased clearance of enrofloxacin; volumes of distribution was increased in the dexamethasone treated pigs; the urine enrofloxacin/creatinine ratios were elevated in the endotoxin group compared to control, dexamethasone and endotoxin-dexamethasone groups while the ciprofloxacin/creatinine ratios in the endotoxin group was elevated and the dexamethasone treated pigs had elevated urine ciprofloxacin/creatinine ratio at 24 h but decreased at 48 and 72 h. These results show that the infection model was reliable, infection had no effect on enrofloxacin distribution and clearance, dexamethasone concurrent administration with enrofloxacin may reduce efficacy because of increased clearance and the comparison of the endotoxin model compared to the infection model gave incongruous results.

ISBN

9780591904888

Pages

276

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