Pharmacokinetics of ceftiofur sodium and ceftiofur crystalline free acid in neonatal foals

Ceftiofur, a third generation cephalosporin, demonstrates in vitro efficacy against microorganisms isolated from septicemic neonatal foals. This pharmacokinetic study evaluated the intravenous and subcutaneous administration of ceftiofur sodium (5 mg/kg body weight; n = 6 per group) and subcutaneous administration of ceftiofur crystalline free acid (6.6 mg/kg body weight; n = 6) in healthy foals. Plasma ceftiofur- and desfuroylceftiofur-related metabolite concentrations were measured using high performance liquid chromatography following drug administration. Mean (±SD) noncompartmental pharmacokinetic parameters for i.v. and s.c. ceftiofur sodium were: AUC(0→∝) (86.4 ± 8.5 and 91 ± 22 h·μg/mL for i.v. and s.c., respectively), terminal elimination half-life (5.82 ± 1.00 and 5.55 ± 0.81 h for i.v. and s.c., respectively), C(max(obs)) (13 ± 1.9 μg/mL s.c.), T(max(obs)) (0.75 ± 0.4 h for s.c.). Mean (± SD) noncompartmental pharmacokinetic parameters for s.c. ceftiofur crystalline free acid were: AUC(0→∝) (139.53 ± 22.63 h·μg/mL), terminal elimination half-life (39.7 ± 14.7), C(max(obs)) (2.52 ± 0.35 μg/mL) and t(max(obs)) (11.33 ± 1.63 h). No adverse effects attributed to drug administration were observed in any foal. Ceftiofur- and desfuroylceftiofur-related metabolites reached sufficient plasma concentrations to effectively treat common bacterial pathogens isolated from septicemic foals.     

Comparative pharmacokinetics of minocycline in foals and adult horses

The objective of this study was to compare the pharmacokinetics of minocycline in foals vs. adult horses. Minocycline was administered to six healthy 6‐ to 9‐week‐old foals and six adult horses at a dose of 4 mg/kg intragastrically (IG) and 2 mg/kg intravenously (i.v.) in a cross‐over design. Five additional oral doses were administered at 12‐h intervals in foals. A microbiologic assay was used to measure minocycline concentration in plasma, urine, synovial fluid, and cerebrospinal fluid (CSF). Liquid chromatography–tandem mass spectrometry was used to measure minocycline concentrations in pulmonary epithelial lining fluid (PELF) and bronchoalveolar (BAL) cells. After i.v. administration to foals, minocycline had a mean (±SD) elimination half‐life of 8.5 ± 2.1 h, a systemic clearance of 113.3 ± 26.1 mL/h/kg, and an apparent volume of distribution of 1.24 ± 0.19 L/kg. Pharmacokinetic variables determined after i.v. administration to adult horses were not significantly different from those determined in foals. Bioavailability was significantly higher in foals (57.8 ± 19.3%) than in adult horses (32.0 ± 18.0%). Minocycline concentrations in PELF were higher than in other body fluids. Oral minocycline dosed at 4 mg/kg every 12 h might be adequate for the treatment of susceptible bacterial infections in foals.     

Plasma salicylate concentrations in immature dogs following aspirin administration: comparison with adult dogs

Aspirin disposition in immature and adult dogs, assessed by plasma salicylate concentrations following single doses of aspirin given orally (p.o.) and intravenously (i.v.), was compared. Using a cross-over design, four immature (12–16-weeks-old) and eight adult (1– 2-years-old) dogs were given a single dose of aspirin at 17.5 mg/kg body weight i.v. and a single dose of buffered aspirin at 35 mg/kg body weight p.o. Blood was collected from the jugular vein for 24 h following each dose. A fluorescence polarization immunoassay was used for determination of salicylate in plasma. Significant differences in aspirin disposition were identified between the two groups. Immature dogs had significantly shorter salicylate half-life, lower mean residence time, and more rapid salicylate clearance than adult dogs. The difference in volume of distribution between the two groups was not significantly different. Immature dogs had lower mean (± SD) peak plasma salicylate concentrations (64.5 ± 2.38 mg/L) than adult dogs (95.9 ± 12.2 mg/L) following a single oral dose of buffered aspirin at 35 mg/kg body weight. Predicted plasma salicylate concentration-time curves were constructed for various aspirin dosage regimens. This analysis showed that the previously recommended buffered aspirin dose for adult dogs of 25 mg/kg body weight p.o. every 8 h would be ineffective in maintaining plasma salicylate concentrations > 50 mg/L in immature dogs.     

Warfarin in the dog: pharmacokinetics as related to clinical response

Warfarin was administered intravenously (i.v.) as a single dose of 1.5 mg/kg to healthy dogs and the pharmacokinetic parameters were investigated. Elimination could be described by a one-compartment open model. Values for the elimination half-life and apparent specific volume of distribution were 14.5 ± 4.1 h and 0.22 ± 0.04 litre/kg, respectively. Oral maintenance doses were calculated from the data collected following i.v. administration and administered every 12 h for a total of five doses after an initial i.v. loading dose of 1.5 mg/kg. Prothrombin times increased from a control value of 8.6 ± 0.3 sec to 55.2 ± 5.2 sec over a period of 96 h. Prothrombin time returned to control values by 62 h after withdrawal of the drug. We propose a dosage regimen of warfarin for anticoagulant therapy in the dog of 0.22 mg/kg to be given orally every 12 h. Prothrombin time should be monitored during therapy and the dose of warfarin modified according to the degree of suppression of coagulation factors desired.     

Pharmacokinetics of gentamicin in mares in late pregnancy and early lactation

The disposition of drugs may differ between pregnant and nonpregnant animals, necessitating a change in dosage. We hypothesized that volume of distribution or clearance may be different for aminoglycoside antibiotics in pregnant mares vs. nonpregnant lactating mares. To examine this hypothesis, we administered gentamicin sulfate to seven Thoroughbred and Quarterhorse mares on two occasions, followed by plasma drug gentamicin assay and pharmacokinetic analysis. The first dose was administered 1-4 weeks before parturition (mean weight 578 kg) and the second dose was administered in the period 1-4 weeks after parturition (mean weight 518 kg). The dose administered at each time was approximately 6.6 mg/kg, intravenously (i.v.). Plasma gentamicin concentrations were determined using fluorescence polarization immunoassay and pharmacokinetic analysis was performed using a two-compartment open model. The plasma concentration vs. time profiles and total area-under-the-curve were almost identical for mares at late gestation vs. early lactation. Mean volume of distribution at steady-state was 0.15 (+/-0.02) and 0.16 (+/-0.03) L/kg, systemic clearance was 1.06 (+/-0.17) and 1.11 (+/-0.17) mL/kg/min, and mean (harmonic) elimination half-life was 2.2 and 2.1 h, for pregnant and nonpregnant mares, respectively. We concluded that there were no differences in drug distribution and clearance between pregnant and nonpregnant lactating mares. Gentamicin was also assayed in plasma of newborn foals after an injection of 6.6 mg/kg to three of the mares within 60 min of parturition. Gentamicin was undetectable in plasma samples from these foals and, therefore, apparently does not cross the placenta of mares at term.     

Pharmacokinetics and Safety of Oral Administration of Meloxicam to Foals

Background

The pharmacokinetics, efficacy, and safety of meloxicam have been evaluated in adult horses, but not foals. Physiologic differences between neonates and adults might alter drug pharmacokinetics and therapeutic index.

Hypotheses

The pharmacokinetics of meloxicam will be different in foals compared with adult horses, and foals could be at increased risk for adverse drug effects.

Animals

Twenty lightbreed foals less than 6 weeks of age at commencement of the study.

Methods

Single and repeated oral dose pharmacokinetics were determined for meloxicam (0.6 mg/kg) in 10 foals. The safety of the drug was further evaluated in a 2nd group of 10 foals in a randomized blinded prospective study.

Results

Plasma concentrations after a single oral dose of meloxicam (0.6 mg/kg) and time to maximum plasma concentration were similar to adult horses. However, drug clearance was much more rapid in foals (elimination half‐life 2.48 ± 0.25 hours). Administration of 0.6 mg/kg every 12 hours was well tolerated by foals for up to 3 weeks, with no evidence of drug accumulation in plasma. Adverse effects observed in adult horses at higher dose rates were not observed in foals given 1.8 mg/kg twice daily for 7 days.

Conclusions and clinical importance

Meloxicam at an oral dose rate of 0.6 mg/kg every 12 hours provided plasma concentrations likely to be therapeutic. In contrast to findings for other NSAIDs, foals appeared more resilient to the adverse effects of this drug than was observed in adult horses.     

Effect of antidotal N-acetylcysteine on the pharmacokinetics of acetaminophen in dogs

The effects of N-acetylcysteine (NAC) on the pharmacokinetic parameters of acetaminophen (AP) in adult female beagles were studied. Each of eight dogs received a single i.v. injection of 150 mg/kg of AP as a 5% solution in a vehicle of 40% aqueous propylene glycol at 0 h. Each of four AP-treated dogs (Group I) received an oral dose of 140 mg/kg NAC as a 20% aqueous solution at 0 h, and 70 mg/kg at 30 min and 1 h post-AP administration. Four dogs (Group II) served as controls and received isotonic saline orally. Mild signs of AP toxicosis seen in both groups within 2-3 h of AP administration including depression, weakness, recumbency and methaemoglobinaemia. Relative to Group II, treatment with NAC (Group I) enhanced the elimination of AP from the body as indicated by the decreased plasma half-life (t1/2 = 1.06 h for Group I v. 1.78 h for Group II) and a higher elimination rate constant (beta = 0.67/h for Group I v. 0.40/h for Group II). Changes in the area under plasma concentration curve data (AUC = 0.39 mg.h/ml for Group I v. 0.65 mg.h/ml for Group II) were associated with a 61% increase in total body clearance of AP in Group I. The apparent volume of drug distribution Vdarea was not affected.     

Plasma and pulmonary disposition of ceftiofur and its metabolites after intramuscular administration of ceftiofur crystalline free acid in weanling foals

The objectives of this study were to determine the plasma and pulmonary disposition of ceftiofur crystalline free acid (CCFA) in weanling foals and to compare the plasma pharmacokinetic profile of weanling foals to that of adult horses. A single dose of CCFA was administered intramuscularly to six weanling foals and six adult horses at a dose of 6.6 mg/kg of body weight. Concentrations of desfuroylceftiofur acetamide (DCA) were determined in the plasma of all animals, and in pulmonary epithelial lining fluid (PELF) and bronchoalveolar lavage (BAL) cells of foals. After intramuscular (IM) administration to foals, median time to maximum plasma and PELF concentrations was 24 h (12-48 h). Mean (± SD) peak DCA concentration in plasma (1.44 ± 0.46 μg/mL) was significantly higher than that in PELF (0.46 ± 0.03 μg/mL) and BAL cells (0.024 ± 0.011 μg/mL). Time above the therapeutic target of 0.2 μg/mL was significantly longer in plasma (185 ± 20 h) than in PELF (107 ± 31 h). The concentration of DCA in BAL cells did not reach the therapeutic level. Adult horses had significantly lower peak plasma concentrations and area under the curve compared to foals. Based on the results of this study, CCFA administered IM at 6.6 mg/kg in weanling foals provided plasma and PELF concentrations above the therapeutic target of 0.2 μg/mL for at least 4 days and would be expected to be an effective treatment for pneumonia caused by Streptococcus equi subsp. zooepidemicus at doses similar to the adult label.     

Acute-phase Response Alters the Disposition Kinetics of Cefepime following Intravenous Administration to Rabbits

The effect of experimentally induced fever on the pharmacokinetics of cefepime administered intravenously at a dose of 75 mg/kg bw was studied in six healthy rabbits. The study was conducted in two consecutive phases, separated by a washout period of 2 weeks. Infection was induced by the intravenous inoculation of 5 × 10⁸ cfu of Escherichia coli 24 h before the pharmacokinetic investigation was carried out. Serial blood samples for cefepime concentration determination were obtained for 48 h following drug administration. The concentrations of cefepime in the plasma were determined by a quantitative microbiological assay using an agar-gel diffusion method employing Bacillus subtilis ATCC 6633 as the test organism, with a level of detectability of approximately 0.10 μg/ml. Cefepime plasma concentrations versus time were evaluated by non-compartmental methods using WinNonLin. Cefepime was well tolerated and no serious adverse events were observed. Rectal temperature increased 1^°C 24 h post injection in infected animals. Highly significant differences in the blood plasma concentrations of cefepime were observed between febrile and healthy animals at all the sampling times. This could explain the greater area under the plasma level–time curve of the drug in febrile compared with healthy animals. The results from pharmacokinetic calculations showed that both the distribution volume at steady state (V _dss) and body clearance (CL_tot) were affected in febrile as compared to healthy animals. The mean values of V _dss and CL_tot of cefepime in healthy rabbits were 1.168 L/kg and 0.303 L/kg/h, respectively. As compared with healthy animals, the mean estimates of V _dss (0.917 L/kg) and CL_tot (0.205 L/kg per h) of cefepime were significantly lower, whereas t _1/2λ, MRT and AUMC were significantly higher in febrile rabbits. It is concluded that, although experimental infection had an effect on the disposition kinetics of cefepime in healthy and febrile rabbits, this was not sufficiently pronounced to require alteration of the dosage during disease.     

Comparative disposition kinetics and plasma protein binding of gentamicin sulphate in three juvenile animal species

The pharmacokinetics of gentamicin was studied in lambs, calves and foals, respectively after single intravenous (i.v.) injections of 5 mg kg(-1) body weight. The plasma concentration-time curves of gentamicin sulphate were best fitted to follow a two-compartment open model in calves and foals and a three-compartment open model in lambs. Gentamicin showed high plasma level at 5 min post-injection. Then its concentration decreased gradually until its minimum detectable level at 10 and 12 h post-injection in foals and calves, respectively, was reached. In contrast, the plasma concentrations were much higher in lambs and persisted up to 48 h from the onset of injection. Values of pharmacokinetic parameters for gentamicin sulphate in different animals after i.v. injections were calculated. Pharmacokinetic data in lambs demonstrated a triphasic decline in plasma gentamicin concentration with slow terminal elimination phase (washout phase) with (t(1/2y)) of 7.7 h. Gentamicin showed a small volume of distribution Vd(ss) (80.3 ml kg(-1)) in lambs indicating that the drug is slightly distributed in extra-vascular tissues. The overall rate of total body clearance ClB in lambs was (0.46 ml kg(-1)) slower than in calves (1.5 ml kg(-1)) and foals (2.7 ml kg(-1)). In vitro protein binding per cent of gentamicin sulphate in plasma were 16.80, 11.03 and 7.98% in lambs, calves and foals. The results of this study emphasize the importance of determining the pharmacokinetics of gentamicin in each species of young animals separately.     

Disposition of oral clarithromycin in foals

Clarithromycin offers numerous advantages over erythromycin and thus, is an attractive alternative for the treatment of Rhodococcus equi infections in foals. The disposition of clarithromycin was investigated in 6 foals after intragastric administration at a dose of 10 mg/kg body weight. Detectable serum concentrations of clarithromycin were found in 3 of 6 foals at 10 minutes and in all foals by 20 minutes post-administration. Time to peak serum concentration (Tmax) was 1.5 hours and peak serum concentration (Cmax) was 0.92+/-0.17 microg/ml. Mean serum concentrations decreased to 0.03 microg/ml at 24 h. No adverse reactions were noted during or after IG administration in any of the foals. Based on the pharmacokinetic parameters, the MIC90 of R. equi isolates, and predicted steady state concentrations, an oral dose of 7.5 mg/kg given every 12 hours would appear appropriate for the treatment of R. equi infections in foals.     

The disposition of five therapeutically important antimicrobial agents in llamas

The disposition of five therapeutic antimicrobial agents was studied in llamas ( Lama glama ) following intravenous bolus administration. Six llamas were each given ampicillin, tobramycin, trimethoprim, sulfamethoxazole, enrofloxacin and ceftiofur at a dose of 12 mg/kg, 1 mg/kg, 3 mg/kg, 15 mg/kg, 5 mg/kg, and 2.2 mg/kg of body weight, respectively, with a wash out period of at least 3 days between treatments. Plasma concentrations of these antimicrobial agents over 12 h following i.v. bolus dosing were determined by reverse phase HPLC. Disposition of the five antimicrobial agents was described by a two compartment open model with elimination from the central compartment, and also by non-compartmental methods. From compartmental analysis, the elimination rate constant, half-life, and apparent volume of distribution in the central compartment were determined. Statistical moment theory was used to determine noncompartmental pharmacokinetic parameters of mean residence time, clearance, and volume of distribution at stead state. Based on the disposition parameters determined, and stated assumptions of likely effective minimum inhibitory concentrations (MIC) a dose and dosing interval for each of five antimicrobial agents were suggested as 6 mg/kg every 12 h for ampicillin; 4 mg/kg once a day or 0.75 mg/kg every 8 h for tobramycin; 3.0 mg/kg/15 mg/kg every 12 h for trimethoprim/sulfamethoxazole; 5 mg/kg every 12 h for enrofloxacin; and 2.2 mg/kg every 12 h for ceftiofur sodium for llamas. Steady-state peak and trough plasma concentrations were also predicted for the drugs in this study for llamas.     

Pharmacokinetics of sparfloxacin in broiler chicken

1. The pharmacokinetics of sparfloxacin in broiler chicken was investigated following a single intravenous dose of 10 mg/kg and a single oral dose of 20 mg/kg. The pharmacokinetic parameters (AUC(0-24) or C(max)) were integrated with the pharmacodynamic parameter (MIC(90)) to optimize sparfloxacin dosage in chicken. 2. The apparent volume of distribution, total body clearance, mean residence time and elimination half-life following oral administration were 2.411/kg, 4.55 ml/min per kg, 10.54 and 5.94 h, respectively. Oral bioavailability was 61.7%. 3. Sparfloxacin was found to possess clinically useful pharmacokinetic properties. Based on pharmacokinetic/pharmacodynamic integration an oral dose of 20 mg/kg sparfloxacin for every 24 h might be recommended for a successful clinical effect in chickens.     

Pharmacokinetics of intravenously and intramuscularly administered ticarcillin and clavulanic acid in foals

Serum concentrations of ticarcillin and clavulanic acid were measured in healthy foals (2 to 6 months old) given the drugs in combination by intravenous and intramuscular routes of administration. Five foals were administered 50 mg of ticarcillin/kg of body weight and 1.67 mg of clavulanic acid/kg, IV. Five foals were administered 100 mg of ticarcillin/kg and 3.33 mg of clavulanic acid/kg, IV, and 4 of those 5 were given the same combined dose IM. The elimination half-life of ticarcillin for intravenous administration was 0.83 hour for the low dosage and 0.96 hour for the high dosage. After intramuscular administration, the half-life of elimination was 2.9 hours, with bioavailability of 54.6%. For IV administered clavulanic acid, the elimination half-life was 0.65 hour for the low dosage and 0.74 hour for the high dosage. After intramuscular administration, the elimination half-life was 0.92 hour, and bioavailability was 68.1%. A combined dosage, 50 mg of ticarcillin/kg and 1.67 mg of clavulanic acid/kg, given every 6 hours is recommended.     

Pharmacokinetics and pharmacodynamics of A77 1726 and leflunomide in domestic cats

The pharmacokinetics and pharmacodynamics of A77 1726 and leflunomide after intravenous (i.v.) and oral (p.o.) administration were evaluated in adult cats. Three treatments were administered: a single i.v. dose of A77 1726 (4 mg/kg), a single oral dose of leflunomide (4 mg/kg), and multiple oral doses of leflunomide (2 mg/kg). Mean pharmacokinetic parameter values after a single i.v. dose of A77 1726 were distribution (A) and elimination (B) intercepts (15.2 μg/mL and 34.5 μg/mL, respectively), distribution and elimination half-lives (1.5 and 71.8 h, respectively), area under the curve (AUC(0 → ∞); 3723 μg*h/mL), mean residence time (MRT; 93 h), clearance (Cl(obs); 1.1 mL/kg/h), and volume of distribution at steady state (Vd(ss); 97 mL/kg). Mean pharmacokinetic parameter values after a single oral dose of leflunomide were absorption and elimination rate constants (0.3 1/h and 0.01 1/h, respectively), absorption and elimination half-lives (2.3 and 59.1 h, respectively), AUC(0 → ∞) (3966 μg*h/mL), and maximum observed plasma concentration (C(max); 38 μg/mL). The bioavailability after a single oral dose of leflunomide was 100%. The mean ± SD A77 1726 concentration that inhibited 50% lymphocytes (EC(50) ) was 16 ± 13.5 μg/mL. The mean ± SD maximum A77 1726 concentration (EC(max)) was 61.0 ± 23.9 μg/mL.     

Pharmacokinetics of cefepime administered by i.v. and i.m. routes to ewes

The pharmacokinetics of cefepime were studied following i.v. and i.m. administration of 20 mg/kg in 10 ewes. Following i.v. administration of a single dose, the plasma concentration-time curves of cefepime were best fitted using a two-compartment open model. The elimination half-life (t(1/2beta)) was 1.76 +/- 0.07 h, volume of distribution at steady-state [V(d(ss))] was 0.32 +/- 0.01 L/kg and total body clearance (Cl(B)) was 2.37 +/- 0.05 mL/min.kg. Following i.m. administration, the drug was rapidly absorbed with an absorption half-life (t(1/2ab)) of 0.49 +/- 0.05 h, maximum plasma concentration (Cmax) of 31.9 +/- 1.5 mug/mL was attained at (tmax) 1.1 +/- 0.2 h and the drug was eliminated with an elimination half-life (t(1/2el)) of 2.06 +/- 0.11 h. The systemic bioavailability (F) after i.m. administration of cefepime was 86.8 +/- 7.5%. The extent of plasma protein binding measured in vitro was 14.8 +/- 0.54%. The drug was detected in urine for 36 h postadministration by both routes.     

Pharmacokinetics of an orally administered methylcellulose formulation of gallium maltolate in neonatal foals

Chaffin, M. K., Fajt, V., Martens, R. J., Arnold, C. E., Cohen, N. D., O’Conor, M., Taylor, R. J., Bernstein, L. R. Pharmacokinetics of an orally administered methylcellulose formulation of gallium maltolate in neonatal foals. J. vet. Pharmacol. Therap. doi: 10.1111/j.1365‐2885.2009.01150.x. Gallium is a trivalent semi‐metal with anti‐microbial effects because of its incorporation into crucial iron‐dependent reproductive enzyme systems. Gallium maltolate (GaM) provides significant gallium bioavailability to people and mice following oral administration and to neonatal foals following intragastric administration. To study the prophylactic and therapeutic effects of GaM against Rhodococcus equi pneumonia in foals, we developed a methylcellulose formulation of GaM (GaM‐MCF) for oral administration to neonatal foals. Normal neonatal foals were studied. Six foals received 20 mg/kg and another six foals received 40 mg/kg of GaM‐MCF orally. Serial serum samples were collected and serum gallium concentrations were determined using inductively coupled plasma mass spectroscopy. Gallium was rapidly absorbed (T_max of 4 h), and a mean C_max of 0.90 or 1.8 μg/mL was achieved in foals receiving 20 or 40 mg/kg respectively. Marked variability existed in C_max among foals: only half of the foals receiving 20 mg/kg attained serum concentrations of >0.7 μg/mL, a level suggested to be therapeutic against R. equi by previous studies. Mean elimination half‐life was 32.8 or 32.4 h for foals receiving 20 or 40 mg/kg respectively. The results of this study suggest that at least 30 mg/kg orally every 24 h should be considered in future pharmacodynamic and efficacy studies.     

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.     

Activity of closantel in the prevention of Gasterophilus and Strongylus vulgaris larval infections in equine foals and yearlings

Two controlled tests were conducted in equine foals and yearlings to determine the optimal oral dosage and the duration of activity of closantel for the prevention of Gasterophilus spp larval infections. Additional data were collected on the activity of closantel against Strongylus vulgaris larval infections. In experiment 1, 12 foals and 12 yearlings were equally allocated to 4 experimental groups, and were given oral treatments with closantel at dosages of 0 (nontreated controls), 2, 5, or 8 mg/kg of body weight every 2 months during bot season. The foals and yearlings were allowed to graze on open pasture throughout the experiment to provide a natural source for bot and helminth infections. All animals were euthanatized and necropsied 6 weeks after the final treatment. Closantel was highly effective (98.6% to 100%) at all doses in preventing Gasterophilus spp larval infections in the foals, but only the 8 mg/kg dose had significant (P less than 0.05) activity (99.7%) in the yearlings. This dose also significantly reduced the numbers of 4th-stage and immature adult S vulgaris (86.0%) in the mesenteric arteries as compared with nontreated controls. In experiment 2, 9 foals and 9 yearlings received a single oral treatment of 8 mg of closantel/kg of body weight; 3 foals and 3 yearlings were kept as nontreated controls. Groups of 6 treated (3 foals, 3 yearlings) and 2 control (1 foal, 1 yearling) animals were euthanatized and necropsied 1, 2, and 3 months after treatment. Closantel remained effective for 2 months in preventing infections of G intestinalis larvae in these foals and yearlings. Clinical signs of toxicosis were not observed in the treated animals of either study.     

Pharmacokinetic properties of toceranib phosphate (Palladia™, SU11654), a novel tyrosine kinase inhibitor,in laboratory dogs and dogs with mast cell tumors

Yancey, M. F., Merritt, D. A., Lesman, S. P., Boucher, J. F., Michels, G. M. Pharmacokinetic properties of toceranib phosphate (Palladia?, SU11654), a novel tyrosine kinase inhibitor, in laboratory dogs and dogs with mast cell tumors. J. vet. Pharmacol. Therap. 33 , 162–171. Toceranib phosphate (Palladia?, SU11654), an oral tyrosine‐kinase inhibitor, is under investigation for the treatment of mast cell tumors in dogs. The pharmacokinetics of toceranib phosphate has been characterized in dogs. Means of the following pharmacokinetic parameters were estimated following a 1.0 mg/kg i.v. dose to laboratory beagles: plasma clearance of 1.45 L/kg/h, volume of distribution of 29.7 L/kg, and terminal half‐life of 17.7 h. Following single oral doses of 3.25 mg/kg administered to laboratory beagles, mean C_max estimates ranged from 68.6 ng/mL to 112 ng/mL with t_max ranging from 5.3 h and 9.3 h postdose. Terminal half‐life was estimated at 31 h. Oral bioavailability was 76.9%. There were no statistically significant (P > 0.05) differences with any pharmacokinetic parameter due to fed/fasted state or with time during 13 weeks of every‐other‐day dosing at 3.25 mg/kg. Toceranib concentrations were proportional with dose over the range of 2.0 to 6.0 mg/kg. The pharmacokinetics of toceranib in client‐owned dogs of a variety of pure and mixed breeds with mast cell tumors was similar to that in healthy laboratory dogs. In summary, toceranib phosphate exhibited moderate clearance, a high volume of distribution, and a moderate elimination half‐life. After a single oral dose at 3.25 mg/kg, the concentration vs. time curve showed broad, sustained exposure with measurable concentrations for more than 48 h. These pharmacokinetic parameters support every‐other‐day administration of toceranib phosphate at an initial dose of 3.25 mg/kg for the treatment of mast cell tumors in dogs.