Pharmacokinetic disposition of an immediate-release aminophylline and a sustained-release theophylline formulation in the horse

The pharmacokinetic disposition of theophylline was determined by high-performance liquid chromatographic analysis of plasma samples from six healthy, adult horses following the administration of intravenous aminophylline (dosed at 9.94 mg/kg as theophylline), immediate-release aminophylline tablets (dosed at 9.94 mg/kg as theophylline), and sustained-release theophylline tablets (dosed at 20 mg/kg). The elimination rate constant (lambda z), apparent volume of distribution (Vz), and clearance (Cl) determined by compartmental analysis of the intravenous data were 0.07 +/- 0.01 h-1, 0.80 +/- 0.06 l/kg, and 0.06 +/- 0.01 l/kg/h (mean +/- SD), respectively. Mean residence time determined by statistical moment theory of the oral data was different (P less than 0.05) for the immediate-release aminophylline (13.8 +/- 2.8 h) and sustained-release theophylline (18.2 +/- 2.3 h) formulation. Immediate-release aminophylline tablets quickly achieved peak theophylline plasma concentration of 11.51 +/- 1.4 micrograms/ml at 1.6 +/- 0.6 h while the sustained-release theophylline tablets were more slowly absorbed and achieved peak theophylline concentrations of 17.20 +/- 1.3 micrograms/ml at 7.3 +/- 1.0 h. Absolute bioavailability was 87% for the immediate-release and 97% for the sustained-release formulation. Using the principle of superposition, a loading dose of 20 mg/kg of the sustained-release formulation followed by maintenance doses of 15 mg/kg every 24 h was predicted to achieve trough-peak theophylline plasma concentrations between 6 and 17 micrograms/ml.     

Clenbuterol plasma concentrations after repeated oral administration and its effects on cardio-respiratory and blood lactate responses to exercise in healthy Standardbred horses

To evaluate the effects of clenbuterol on cardio-respiratory parameters and blood lactate relation to exercise tolerance, experimental horses performed standardized exercise tests on a high-speed treadmill before and after administration of the drug. Clenbuterol was administered in feed to six healthy Standardbreds at a dose rate of 0.8 micrograms/kg b.wt twice daily for 5.5 days. Each horse was tested twice, without and with a respiratory mask, during two consecutive days. One week elapsed between the baseline tests without drug and the tests with clenbuterol treatment (each horse served as its own control). The results show an unchanged heart rate response to exercise 2 h after the last clenbuterol administration. The blood lactate response and the arterial oxygen tension during exercise did not differ before and after drug treatment. The oxygen uptake as well as pulmonary ventilation relative to the work load performed was essentially unaffected. The arterial pH during exercise was significantly increased (P less than 0.05) following clenbuterol treatment. Plasma levels of clenbuterol were maximal 2 h post-administration with values between 0.45 and 0.75 ng/ml. The plasma half-life of elimination was 10.4 h (+/- 2.25 SD). In conclusion, clenbuterol did not cause any major effects on the cardio-respiratory and blood lactate parameters studied in healthy horses performing submaximal exercise tolerance tests.     

Pharmacokinetics of norfloxacin in dogs after single intravenous and single and multiple oral administrations of the drug

Norfloxacin was given to 6 healthy dogs at a dosage of 5 mg/kg of body weight IV and orally in a complete crossover study, and orally at dosages of 5, 10, and 20 mg/kg to 6 healthy dogs in a 3-way crossover study. For 24 hours, serum concentration was monitored serially after each administration. Another 6 dogs were given 5 mg of norfloxacin/kg orally every 12 hours for 14 days, and serum concentration was determined serially for 12 hours after the first and last administration of the drug. Complete blood count and serum biochemical analysis were performed before and after 14 days of oral norfloxacin administration, and clinical signs of drug toxicosis were monitored twice daily during norfloxacin administration. Urine concentration of norfloxacin was determined periodically during serum acquisition periods. Norfloxacin concentration was determined, using high-performance liquid chromatography with a limit of detection of 25 ng of norfloxacin/ml of serum or urine. Serum norfloxacin pharmacokinetic values after single IV dosing in dogs were best modeled, using a 2-compartment open model, with distribution and elimination half-lives of 0.467 and 3.56 hours (harmonic means), respectively. Area-derived volume of distribution (Vd area) was 1.77 +/- 0.69 L/kg (arithmetic mean +/- SD), and serum clearance (Cls) was 0.332 +/- 0.115 L/h/kg. Mean residence time was 4.32 +/- 0.98 hour. Comparison of the area under the curve (AUC; derived, using model-independent calculations) after iv administration (5 mg/kg) with AUC after oral administration (5 mg/kg) in the same dogs indicated bioavailability of 35.0 +/- 46.1%, with a mean residence time after oral administration of 5.71 +/-2.24 hours. Urine concentration was 33.8 +/- 15.3 micrograms/ml at 4 hours after a single dose of 5 mg/kg given orally, whereas concentration after 20 mg/kg was given orally was 56.8 +/- 18.0 micrograms/ml at 6 hours after dosing. Twelve hours after drug administration, urine concentration was 47.4 +/- 20.6 micrograms/ml after the 5-mg/kg dose and 80.6 +/- 37.7 micrograms/ml after the 20/mg/kg dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioavailability of four slow-release theophylline formulations in the Beagle dog

Theophylline was administered to six Beagles intravenously (Aminophyllin Injectable, Searle Laboratories) and orally as four sustained-release formulations (Choledyl -SA Tablets, Parke-Davis; Theo-Dur Tablets, Key Pharmaceuticals; Theo-24 Capsules, Searle Laboratories, and Slo-bid Gyrocaps, William H. Rorer, Inc.). Values were determined for mean residence time, mean absorption time, absolute bioavailability, time to peak plasma concentration, and peak plasma concentration normalized to a theophylline dose of 20 mg/kg. In this order the values found for each formulation were: Choledyl (10.2 +/- 1.8 h, 2.8 +/- 2.2 h, 63 +/- 10%, 3.9 +/- 1.0 h, 10 +/- 1.1 micrograms/ml), Theo-Dur (12.1 +/- 5.2 h, 4.9 +/- 5.3 h, 76 +/- 18% 4.7 +/- 3.1 h, 12 +/- 3.7 micrograms/ml), Theo-24 (15.6 +/- 8.9 h, 8.1 +/- 8.4 h, 30 +/- 16%, 3.6 +/- 1.7 h, 3.5 +/- 1.3 micrograms/ml), and Slo-bid (11.9 +/- 1.9 h, 4.4 +/- 1.3 h, 60 +/- 9%, 4 +/- 1.1 h, 8.6 +/- 0.8 micrograms/ml). Choledyl, Theo-Dur and Slo-bid appear to have absorption characteristics which, if given twice daily, would maintain therapeutic plasma concentrations of theophylline between 10 and 20 micrograms/ml in the dog. Of these, Theo-Dur was predicted to provide the least peak:trough fluctuation in theophylline plasma concentrations.     

Evaluation of the bioavailability and pharmacokinetics of two extended-release theophylline formulations in dogs

OBJECTIVE: To evaluate the bioavailability and pharmacokinetic characteristics of 2 commercially available extended-release theophylline formulations in dogs. DESIGN: Randomized 3-way crossover study. ANIMALS: 6 healthy adult dogs. PROCEDURE: A single dose of aminophylline (11 mg x kg(-1) 15 mg x lb(-1)], i.v., equivalent to 8.6 mg of theophylline/kg 13.9 mg x lb(-1) or extended-release theophylline tablets (mean dose, 15.5 mg x kg(-1) [7.04 mg x lb9-1), PO) or capsules (mean dose, 15.45 mg x kg(-1) [7.02 mg x lb(-1)], PO) was administered to all dogs. Blood samples were obtained at various times for 36 hours after dosing; plasma was separated and immediately frozen. Plasma samples were analyzed by use of fluorescence polarization immunoassay. RESULTS: Administration of theophylline i.v. best fit a 2-compartment model with rapid distribution followed by slow elimination. Administration of extended-release theophylline tablets and capsules best fit a 1-compartment model with an absorption phase. Mean values for plasma terminal half-life, volume of distribution, and systemic clearance were 8.4 hours, 0.546 L x kg(-1), and 0.780 mL x kg(-1) x min(1), respectively, after i.v. administration of theophylline. Systemic availability was > 80% for both oral formulations. Computer simulations predicted that extended-release theophylline tablets or capsules administered at a dosage of 10 mg x kg(-1) (4.5 mg x lb(-1)), PO, every 12 hours would maintain plasma concentrations within the desired therapeutic range of 10 to 20 microg x mL(-10. CONCLUSIONS AND CLINICAL RELEVANCE: Results of these single-dose studies indicated that administration of the specific brand of extended-release theophylline tablets or capsules used in this study at a dosage of 10 mg x kg(-1), PO, every 12 hours would maintain plasma concentrations within the desired therapeutic range (10 to 20 microg x mL(-1)) in healthy dogs.     

Pharmacokinetics and Pharmacodynamics of Dexamethasone after Intravenous Administration in Camels: Effect of Dose

The pharmacokinetics and pharmacodynamics of dexamethasone were evaluated in healthy camels after single intravenous bolus doses of 0.05, 0.1 and 0.2 mg/kg body weight. Dexamethasone showed dose-independent pharmacokinetics. The pharmacokinetic parameters of the two-compartment pharmacokinetic model for the lowest intravenous dose (mean+/-SD) were as follows: terminal elimination half-life 8.17 +/- 1.79 h; total body clearance 100.7 +/- 52.1 (ml/h)/kg; volume of distribution at steady state 0.95 +/- 0.23 L/kg; and volume of the central compartment 0.22 +/- 0.07 L/kg. The extent of plasma protein binding was linear over the concentration range 5-100 ng/ml and averaged 75% +/- 2%. Pharmacodynamic effects were evaluated by measuring endogenous plasma cortisol concentrations, numbers of circulating lymphocytes and neutrophils and plasma glucose concentrations and were analysed using indirect pharmacokinetic/pharmacodynamic models. The cumulative systemic effect increased with dose for markers of pharmacodynamic activity. The estimated IC50 of dexamethasone for cortisol and lymphocytes for the lowest dose were 3.74 +/- 2.44 and 5.58 +/- 8.37 ng/ml, respectively and the EC50 values for neutrophils and glucose were 45.8 +/- 36.9 and 1.17 +/- 0.71 ng/ml, respectively.     

Serum and skin concentrations after multiple-dose oral administration of trimethoprim-sulfadiazine in dogs.

Six healthy adult mixed breed dogs were each given 5 oral doses of trimethoprim (TMP)/sulfadiazine (SDZ) at 2 dosage regimens: 5 mg of TMP/kg of body weight and 25 mg of SDZ/kg every 24 hours (experiment 1) and every 12 hours (experiment 2). Serum and skin concentrations of each drug were measured serially throughout each experiment and mean serum concentrations of TMP and SDZ were determined for each drug for 24 hours (experiment 1) and 12 hours (experiment 2) after the last dose was given. In experiment 1, mean serum TMP concentration was 0.67 +/- 0.02 micrograms/ml, and mean skin TMP concentration was 1.54 +/- 0.40 micrograms/g. Mean serum SDZ concentration was 51.1 +/- 12.2 micrograms/ml and mean skin SDZ concentration was 59.3 +/- 9.8 micrograms/g. In experiment 2, mean serum TMP concentration was 1.24 +/- 0.35 micrograms/ml and mean skin TMP concentration was 3.03 +/- 0.54 micrograms/g. Mean serum SDZ concentration was 51.6 +/- 9.3 micrograms/ml and mean skin SDZ concentration was 71.1 +/- 8.2 micrograms/g. After the 5th oral dose in both experiments, mean concentration of TMP and SDZ in serum and skin exceeded reported minimal inhibitory concentrations of TMP/SDZ (less than or equal to 0.25/4.75 micrograms/ml) for coagulase-positive Staphylococcus sp. It was concluded that therapeutically effective concentrations in serum and skin were achieved and maintained when using the manufacturer's recommended dosage of 30 mg of TMP/SDZ/kg (5 mg of TMP/kg and 25 mg of SDZ/kg) every 24 hours.     

Distribution of orally administered trimethoprim and sulfadiazine into noninfected subcutaneous tissue chambers in adult ponies

The distribution of trimethoprim (TMP) and sulfadiazine (SDZ) into subcutaneously implanted noninfected tissue chambers was studied in healthy adult ponies. Six ponies were given an oral TMP/SDZ paste formulation at a dose of 5 mg/kg TMP and 25 mg/kg SDZ at 12 h intervals for 2 days in order to reach steady-state concentrations. Plasma concentrations and tissue chamber fluid (TCF) concentrations of both drugs were measured at regular intervals during a period commencing 24 h after the last oral administration. The peak concentration of TMP (mean +/- SD) was 2.92 +/- 0.86 microg/mL for plasma and 1.09 +/- 0.25 microg/mL for TCF. For SDZ, the mean peak concentration was 40.20 +/- 14.74 microg/mL for plasma and 23.48 +/- 5.84 microg/mL for TCF. TMP peak concentrations in plasma were reached at 3.17 +/- 03.48 h and those in TCF at 7.33 +/- 03.72 h. SDZ peak concentrations in plasma were reached at 1.83 +/- 02.04 h and those in TCF at 8.00 +/- 03.10 h. Concentrations of TMP and SDZ in TCF remained above the generally accepted breakpoint for susceptibility (0.5/9.5 for the TMP/SDZ combination) for 12 h. Therefore, in ponies oral administration of TMP/SDZ at a dose rate of 30 mg/kg given twice daily in the form of a paste should be appropriate for effective treatment of infections caused by susceptible bacteria.     

Dose-dependent plasma elimination of subcutaneously administered calcium heparin in horses

Pharmacokinetic parameters for subcutaneous low dose heparin in horses have been determined. Four groups of five and one group of eleven mature, healthy horses of various breeds were given single subcutaneous injections of 60, 80, 100, 125, and 150 units of calcium heparin/kg of body weight (U/kg) in the pectoral region. Jugular blood samples were collected prior to, and at hourly intervals for 12 h after injection. Heparin plasma concentrations were measured using a commercially available amidolytic assay. Peak concentrations 4 h after administration were 0.021 +/- 0.016 (mean +/- SD) units of heparin/ml of plasma (U/ml) after 60 U/kg, 0.035 +/- 0.025 U/ml after 80 U/kg, 0.023 +/- 0.004 U/ml after 100 U/kg, 0.034 +/- 0.019 U/ml after 125 U/kg, and 0.053 +/- 0.019 U/ml after 150 U/kg. Data from groups given 60 and 100 U/kg could not be used for kinetic calculations. Elimination constant (l/h), elimination half-life (h), and elimination time (h) calculated to reach base-line values after 80 U/kg were 0.182 +/- 0.041 l/h, 3.8 +/- 0.9 h, and 9.7 +/- 2.2 h. After 125 U/kg, corresponding values were 0.211 +/- 0.019 l/h, 3.3 +/- 0.3 h, 13.4 +/- 1.2 h, and after 150 U/kg 0.098 +/- 0.015 l/h, 7.1 +/- 1.1 h, and 20.6 +/- 3.2 h. Calculated heparin concentrations 12 h after administration of 80, 125, and 150 U/kg were 0.011 +/- 0.002, 0.010 +/- 0.001, and 0.027 +/- 0.004 U/ml.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical pharmacology and pharmacokinetics of flumequine after intravenous, intramuscular and oral administration in pigeons (Columba livid)

The in-vitro activity of flumequine against 157 strains of bacteria isolated from birds was determined. The minimum inhibitory concentration (MIC) of 96.3% of the Enterobacteriaceae, Proteus spp. and Yersinia pseudotuberculosis studied (n = 135) was less than or equal to 1 microgram/ml. Pharmacokinetics of flumequine in pigeons (Columba livia) was investigated after intravenous, intramuscular and oral administration. From the blood disappearance curves after i.v. bolus injection (10 mg/kg body weight) clearance rate, blood half-time and distribution volume were calculated. The recovery of unchanged flumequine from the droppings in 24 h was 37 +/- 10% of the administered dose. Flumequine was also given i.m. at two dose levels, 10 and 60 mg/kg body weight. The availability of flumequine as intact drug was 22 and 23%, respectively, in 24 h. Therapeutic blood levels were maintained for 4 and 10 h, respectively. After an oral dose of flumequine (60 mg/kg body weight) an availability of 6.7 +/- 2.5% and a peak blood concentration of 2.68 +/- 0.92 microgram/ml at 2 h after administration were found. The recovery of unchanged flumequine from the droppings in 24 h was 1.55 +/- 0.79% of the administered dose. With the exception of the i.m. dose of 10 mg/kg, all flumequine administrations made the pigeons vomit. It appears that blood concentrations below 3 micrograms/ml will not induce vomiting. On the basis of the present data, a dosage regimen for flumequine in pigeons of a priming dose of 30 mg/kg i.m., followed after 8 h by oral administration of 30 mg/kg, this dose being repeated every 8-12 h, would be expected to give blood concentrations between 1.44 and 2.88 micrograms/ml.     

Single- and multiple-dose pharmacokinetics of intravenously administered vancomycin in dogs

Vancomycin was administered IV to healthy adult female dogs at a dosage of 15 mg/kg of body weight every 12 hours for 10 days. Pharmacokinetic values were determined after the first and last doses. The disposition of vancomycin was not altered by multiple dosing, and little accumulation attributable to multiple dosing was observed. Serum vancomycin concentration after the first and last dose were described, using a 2-compartment open model with first-order elimination. The distribution and elimination half-lives after the single dose were 15.4 +/- 2.7 minutes and 137 +/- 21.8 minutes (geometric mean +/- pseudo-SD), respectively; whereas the distribution and elimination half-lives after the last dose were 11.3 +/- 2.61 minutes and 104 +/- 11.2 minutes, respectively. The mean (+/- SD) area-derived volume of distribution was 396 +/- 156 ml/kg and 382 +/- 160 ml/kg after the first and last dose, respectively. Serum vancomycin clearance was 2.13 +/- 0.35 ml/min/kg and 2.49 +/- 0.79 ml/min/kg after the first and last dose, respectively, and 25 to 49% of the total dose of vancomycin was recovered in the urine in the first 24 hours after the single dose administered IV. Mean serum vancomycin concentration reached 101.8 +/- 30.6 micrograms/ml and 99.7 +/- 28.0 micrograms/ml at 5 minutes after a single dose and the last of the multiple doses, respectively, and decreased to 0.94 +/- 0.58 microgram/ml and 1.51 +/- 1.44 micrograms/ml, respectively, at 12 hours after administration. The side effects that accompany vancomycin treatment in human beings were not observed in the dogs; all remained healthy through the end of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics, metabolism and renal clearance of flumequine in veal calves

The pharmacokinetics of flumequine was studied in 1-, 5- and 18-week-old veal calves. A two-compartment model was used to fit the plasma concentration-time curve of flumequine after the intravenous injection of 10 mg/kg of a 10% solution. The elimination half-life (t1/2 beta) of the drug ranged from 6 to 7 h. The Vd beta and ClB of 1-week-old calves (1.07 l/kg, 1.78 ml/min/kg) were significantly lower than those of 5-week-old (1.89 l/kg, 3.23 ml/min/kg) and 18-week-old calves (1.57 l/kg, 3.10 ml/min/kg). After the oral administration of 10 mg/kg of a 2% flumequine formulation mixed with milk replacer, the Cmax was highest in 1-week-old (9.27 micrograms/ml) and lowest in 18-week-old calves (4.47 micrograms/ml). The absorption was rapid (Tmax of approximately 3 h) and complete. When flumequine itself and a formulation containing 2% flumequine and 20 X 10(6) iu of colistin sulphate were mixed with milk replacer and administered at the same dose rate, absorption was incomplete and Cmax was lower. The main urinary metabolite of flumequine was the glucuronide conjugate (approximately 40% recovery within 48 h of intravenous injection) and the second most important metabolite was 7-hydroxy-flumequine (approximately 3% recovery within 12 h of intravenous injection). Only 3.2-6.5% was excreted in the urine unchanged. After oral administration a 'first-pass' effect was observed, with a significant increase in the excretion of conjugated drug. For 1-week-old calves it is recommended that the 2% formulation should be administered at a dose rate of 8 mg/kg every 24 h or 4 mg/kg every 12 h; for calves over 6 weeks old, the dose should be increased to 15 mg/kg every 24 h or 7.5 mg/kg every 12 h. The formulation containing colistin sulphate should be administered to 1-week-old calves at a flumequine dose of 12 mg/kg every 24 h or 6 mg/kg every 12 h.     

Pharmacokinetics of fluconazole following intravenous and oral administration and body fluid concentrations of fluconazole following repeated oral dosing in horses

OBJECTIVE: To determine the pharmacokinetics of fluconazole in horses. ANIMALS: 6 clinically normal adult horses. PROCEDURE: Fluconazole (10 mg/kg of body weight) was administered intravenously or orally with 2 weeks between treatments. Plasma fluconazole concentrations were determined prior to and 10, 20, 30, 40, and 60 minutes and 2, 4, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after administration. A long-term oral dosing regimen was designed in which all horses received a loading dose of fluconazole (14 mg/kg) followed by 5 mg/kg every 24 hours for 10 days. Fluconazole concentrations were determined in aqueous humor, plasma, CSF, synovial fluid, and urine after administration of the final dose. RESULTS: Mean (+/- SD) apparent volume of distribution of fluconazole at steady state was 1.21+/-0.01 L/kg. Systemic availability and time to maximum plasma concentration following oral administration were 101.24+/-27.50% and 1.97+/-1.68 hours, respectively. Maximum plasma concentrations and terminal half-lives after IV and oral administration were similar. Plasma, CSF, synovial fluid, aqueous humor, and urine concentrations of fluconazole after long-term oral administration of fluconazole were 30.50+/-23.88, 14.99+/-1.86, 14.19+/-5.07, 11.39+/-2.83, and 56.99+/-32.87 microg/ml, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Bioavailability of fluconazole was high after oral administration to horses. Long-term oral administration maintained plasma and body fluid concentrations of fluconazole above the mean inhibitory concentration (8.0 mg/ml) reported for fungal pathogens in horses. Fluconazole may be an appropriate agent for treatment of fungal infections in horses.     

Plasma profiles of ivermectin in horses following oral or intramuscular administration

A study was undertaken in order to evaluate and compare ivermectin's (IVM) plasma disposition kinetic parameters after oral or intramuscular (IM) administration in horses. Ten clinically healthy adult horses, weighing 380-496 kg body weight (BW), were allocated to two experimental groups of five horses. Group I, was treated with an oral paste formulation of IVM at the manufacturer's recommended dose of 0.2 mg/kg BW. Group II, was treated IM with an injectable 1% formulation of IVM at a dose of 0.2 mg/kg BW. Blood samples were collected by jugular puncture at different times between 0.5 h and 75 days post-treatment. After plasma extraction and derivatization, samples were analysed by high-performance liquid chromatography with fluorescence detection. A computerized kinetic analysis was performed, and data were compared using the Wilcoxon signed rank test. The parent molecule was detected in plasma between 30 min and either 20 (oral) or 40 (IM) days post-treatment. Significant differences were found for the time corresponding to peak plasma concentrations (tmax) and for absorption half-life. Peak plasma concentrations (Cmax) of 51.3 +/- 16.1 ng/ml (mean +/- SD) were obtained after oral administration and of 31.4 +/- 6.0 ng/ml for the IM route. The values for area under concentration-time curve were 137.1 +/- 35.9 ng day/ml for the group treated orally, and 303.2 +/- 4.3 ng day/ml for the IM treated group. The mean plasma residence times were 4.2 +/- 0.4 and 8.9 +/- 0.7 days for oral and IM-treated groups, respectively. The results of this study show that the route of administration considerably affects the disposition of IVM. A significant difference in bioavailabilty and half-life of elimination of IVM was observed after IM administration compared with oral administration. A close relationship between pharmacokinetic profiles and the clinical efficacy of IVM was established.     

Serum and tissue cage fluid concentrations of ciprofloxacin after oral administration of the drug to healthy dogs

Ciprofloxacin, a fluoroquinolone antimicrobial agent, was administered orally to 4 healthy dogs at dosage of approximately 11 and 23 mg/kg of body weight, every 12 hours for 4 days, with a 4-week interval between dosing regimens. Serum and tissue cage fluid (TCF) concentrations of ciprofloxacin were measured after the first and seventh dose of each dosing regimen. The peak concentration was greatest in the serum after multiple doses of 23 mg/kg (mean +/- SEM; 5.68 +/- 0.54 micrograms/ml) and least in the TCF after a single dose of 11 mg/kg (0.43 +/- 0.54 micrograms/ml). The time to peak concentration was not influenced by multiple dosing or drug dose, but was longer for TCF (6.41 +/- 0.52 hour) than for serum (1.53 +/- 0.52 hour). Accumulation of ciprofloxacin was reflected by the area under the concentration curve from 0 to 12 hours after administration (AUC0----12). The AUC0----12 was greatest in the serum after multiple doses of 23 mg/kg (31.95 +/- 1.90 micrograms.h/ml) and least in the TCF after a single dose of 11 mg/kg (3.87 +/- 1.90 micrograms.h/ml). The elimination half-life was not influenced by multiple dosing or dose concentration, but was greater for TCF (14.59 +/- 1.91 hours) than for serum (5.14 +/- 1.91 hours). The percentage of TCF penetration (AUCTCF/AUCserum) was greater after multiple doses (95.76 +/- 6.79%) than after a single dose (55.55 +/- 6.79%) and was not different between doses of 11 and 23 mg/kg. Both dosing regimens of ciprofloxacin resulted in continuous serum and TCF concentrations greater than 90% of the minimal inhibitory concentration for the aerobic and facultative anaerobic clinical isolates tested, including Pseudomonas aeruginosa.     

Effect of hypertonic vs isotonic saline solution on responses to sublethal Escherichia coli endotoxemia in horses

Cardiovascular responses to sublethal endotoxin infusion (Escherichia coli, 50 micrograms/ml in lactated Ringer solution at 100 ml/h until pulmonary arterial pressure increased by 10 mm of Hg) were measured 2 times in 5 standing horses. In a 2-period crossover experimental design, horses were either administered hypertonic (2,400 mosm/kg of body weight, IV) or isotonic (300 mosm/kg, IV) NaCl solution after endotoxin challenges. Each solution was administered at a dose of 5 ml/kg (infusion rate, 80 ml/min). Complete data sets (mean arterial, central venous, and pulmonary arterial pressures, pulmonary arterial blood temperature, cardiac output, total peripheral vascular resistance, heart rate, plasma osmolality, plasma concentration of Na, K, Cl, and total protein, blood lactate concentration, and PCV) were collected at 0 (baseline, before endotoxin infusion), 0.25, 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after initiation of the endotoxin infusion. Blood constituents alone were measured at 0.5 hour and cardiovascular variables alone were evaluated at 0.75 hour. By 0.25 hour, endotoxin infusion was completed, a data set was collected, and saline infusion was initiated. By 0.75 hour, saline solutions had been completely administered. Mean (+/- SEM) cardiac output decreased (99.76 +/- 3.66 to 72.7 +/- 2.35 ml/min/kg) and total peripheral resistance (1.0 +/- 0.047 to 1.37 +/- 0.049 mm of Hg/ml/min/kg) and pulmonary arterial pressure (33.4 +/- 0.86 to 58.3 +/- 1.18 mm of Hg) increased for both trials by 0.25 hour after initiation of the endotoxin infusion and prior to fluid administration. For the remainder of the protocol, cardiac output was increased and total peripheral resistance was decreased during the hypertonic, compared with the isotonic, saline trial.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of marbofloxacin in blue and gold macaws (Ara ararauna)

OBJECTIVE: To determine the pharmacokinetics of marbofloxacin after single IV and orally administered doses in blue and gold macaws. ANIMALS: 10 healthy blue and gold macaws. PROCEDURES: In a crossover study, marbofloxacin (2.5 mg/kg) was administered orally (via crop gavage) to 5 birds and IV to 5 birds. Blood samples were obtained at 0, 0.5, 1, 3, 6, 12, 24, 48, 72, and 96 hours after marbofloxacin administration. After a 4-week washout period, the study was repeated, with the first 5 birds receiving the dose IV and the second 5 birds receiving the dose orally. Serum marbofloxacin concentrations were quantitated by use of a validated liquid chromatography-mass spectrometry assay. RESULTS: After oral administration, mean +/- SD area under the curve was 7.94 +/- 2.08 microg.h/mL, maximum plasma concentration was 1.08 +/- 0.316 microg/mL, and bioavailability was 90.0 +/- 31%. After IV administration of marbofloxacin, the apparent volume of distribution was 1.3 +/- 0.32 L/kg, plasma clearance was 0.29 +/- 0.078 L/h/kg, area under the curve was 9.41 +/- 2.84 microg.h/mL, and the harmonic mean terminal half-life was 4.3 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Single IV and orally administered doses of marbofloxacin were well tolerated by blue and gold macaws. The orally administered dose was well absorbed. Administration of marbofloxacin at a dosage of 2.5 mg/kg, PO, every 24 hours may be appropriate to control bacterial infections susceptible to marbofloxacin in this species.     

Pharmacokinetics of enrofloxacin administered intravenously and orally to foals

OBJECTIVE: To determine the pharmacokinetics of enrofloxacin administered IV and orally to foals. ANIMALS: 5 clinically normal foals. PROCEDURE: A 2-dose cross-over trial with IV and oral administration was performed. Enrofloxacin was administered once IV (5 mg/kg of body weight) to 1-week-old foals, followed by 1 oral administration (10 mg/kg) after a 7-day washout period. Blood samples were collected for 48 hours after the single dose IV and oral administrations and analyzed for plasma enrofloxacin and ciprofloxacin concentrations by use of high-performance liquid chromatography. RESULTS: For IV administration, mean +/- SD total area under the curve (AUC0-infinity) was 48.54 +/- 10.46 microg x h/ml, clearance was 103.72 +/- 0.06 ml/kg/h, half-life (t1/2beta) was 17.10 +/- 0.09 hours, and apparent volume of distribution was 2.49 +/- 0.43 L/kg. For oral administration, AUC0-infinity was 58.47 +/- 16.37 microg x h/ml, t1/2beta was 18.39 +/- 0.06 hours, maximum concentration (Cmax) was 2.12 +/- 00.51 microg/ml, time to Cmax was 2.20 +/- 2.17 hours, mean absorption time was 2.09 +/- 0.51 hours, and bioavailability was 42 +/- 0.42%. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with adult horses given 5 mg of enrofloxacin/kg IV, foals have higher AUC0-infinity, longer t1/2beta, and lower clearance. Concentration of ciprofloxacin was negligible. Using a target Cmax to minimum inhibitory concentration ratio of 1:8 to 1:10, computer modeling suggests that 2.5 to 10 mg of enrofloxacin/kg administered every 24 hours would be effective in foals, depending on minimum inhibitory concentration of the pathogen.     

Study of intragastric administration of doxycycline: pharmacokinetics including body fluid, endometrial and minimum inhibitory concentrations

The objectives of this study were to determine the pharmacokinetics and tissue concentrations of doxycycline after repeated intragastric administration, and to determine the minimum inhibitory concentrations (MIC) for equine pathogenic bacteria. In experiment 1, 2 mares received a single intragastric dose of doxycycline hyclate (3 mg/kg bwt). Mean peak serum concentration was 0.22 microg/ml 1 h postadministration. In experiment 2, 5 doses of doxycycline hyclate (10 mg/kg bwt), dissolved in water, were administered to each of 6 mares via nasogastric tube at 12 h intervals. The mean +/- s.e. peak serum doxycycline concentration was 0.32+/-0.16 microg/ml 1 h after the first dose and 0.42+/-0.05 microg/ml 2 h after the fifth dose. The mean trough serum concentrations were > 0.16 microg/ml. Highest mean synovial concentration was 0.46+/-0.13 microg/ml and highest mean peritoneal concentration was 0.43+/-0.07 microg/ml, both 2 h after the fifth dose. Highest urine concentration was mean +/- s.e. 145+/-25.4 microg/ml 2 h after the last dose. Highest endometrial concentration was mean +/- s.e. 1.30+/-0.36 microg/ml 3 h after the fifth dose. Doxycycline was not detected in any of the CSF samples. Mean +/- s.e. Vd(area) was 25.3+/-5.0 l/kg and mean t1/2 was 8.7+/-1.6 h. In experiment 3, minimum inhibitory concentrations of doxycycline were determined for 168 equine bacterial culture specimens. The MIC90 was < or = 1.0 microg/ml for Streptococcus zooepidemicus and 0.25 microg/ml for Staphylococcus aureus. Based on drug concentrations achieved in the serum, synovial and peritoneal fluids and endometrial tissues and MIC values determined in the present study, doxycycline at a dose of 10 mg/kg bwt per os every 12 h may be appropriate for the treatment of infections caused by susceptible (MIC < 0.25 microg/ml) gram-positive organisms in horses.     

Disposition of clorazepate in dogs after single- and multiple-dose oral administration

Clorazepate dipotassium was administered orally to 8 healthy dogs at a dosage of 2 mg/kg of body weight, q 12 h, for 21 days. Serum disposition of nordiazepam, the principle metabolite of clorazepate, was determined after the first and last dose of clorazepate. Disposition variables were analyzed by use of model-independent pharmacokinetics by the predictive equations method and the trapezoidal rule method. Complete blood counts, serum chemical analyses, and urinalyses were performed before administration of clorazepate and at 10 and 21 days after administration of clorazepate. Maximal nordiazepam concentrations ranged from 446 to 1,542 ng/ml (814 +/- 334 ng/ml), at 59 to 180 minutes (97.9 +/- 42.0 minutes) after a single oral dose of clorazepate. Maximal nordiazepam concentrations ranged from 927 to 1,460 ng/ml (1,308 +/- 187.6 ng/ml), at 120 to 239 minutes (153 +/- 57.9 minutes) after multiple oral doses of clorazepate. Serum disposition was significantly altered after multiple doses of clorazepate. Using data determined by the predictive equations method, the mean residence time after multiple doses (712 +/- 214 minutes) was longer (P less than 0.05) than after a single dose (527 +/- 95.8 minutes). Oral volume of distribution after multiple doses of clorazepate (1.76 +/- 0.647 L/kg) was smaller (P less than 0.02) than after a single dose (3.18 +/- 1.52 L/kg). Oral clearance after multiple doses of clorazepate (3.09 +/- 0.726 ml/min/kg) was less (P less than 0.001) than after a single dose (6.54 +/- 2.15 ml/min/kg). Absorption half-life after multiple doses (72 minutes) was longer (P less than 0.01) than after a single dose (33 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)