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.     

Effect of sucralfate on oral minocycline absorption in healthy dogs

Sucralfate and minocycline may be administered concurrently to dogs. The relative bioavailability of tetracyclines may be reduced if administered with sucralfate, but studies confirming these interactions in dogs are not available. This study evaluated the pharmacokinetics of oral minocycline in dogs (M), determined the effects of concurrent administration of sucralfate and minocycline (MS) on minocycline pharmacokinetics, determined the effects of delaying sucralfate administration by 2 h (MS+2) on minocycline pharmacokinetics, and established dosing recommendations based on pharmacodynamic indices. Oral minocycline (300 mg) and sucralfate suspension (1 g) were administered to five greyhounds in a randomized crossover design. Minocycline plasma concentrations were evaluated using liquid chromatography with mass spectrometry. The maximum plasma concentration (C_MAX) and area under the curve (AUC) of minocycline were 1.15 μg/mL and 8.0 h* μg/mL, respectively. The C_MAX and AUC were significantly lower (P < 0.05) in the MS group (C_MAX = 0.33 μg/mL, AUC 3.0 h*μg/mL) compared with M or MS+2 (C_MAX = 0.97 μg/mL, AUC 10.3 h*μg/mL). Delaying sucralfate by 2 h did not decrease oral minocycline absorption, but concurrent administration significantly decreased minocycline absorption. A dose of 7.5 mg/kg p.o. q12 h achieves the pharmacodynamic index for a bacterial minimum inhibitory concentration (MIC) of 0.25 μg/mL (AUC:MIC≥33.9).     

Single-dose oral pharmacokinetics of pergolide mesylate in healthy adult mares

This pilot study evaluated protection of an equine autogenous bacterin-toxoid vaccine against Corynebacterium pseudotuberculosis infection. Twenty-four BALB/c mice were inoculated with two doses of bacterin-toxoid vaccine or two injections of a placebo. Clinical, microbiologic, and pathologic outcomes were assessed after intradermal infection with one of two equine-origin C. pseudotuberculosis strains. Mice receiving bacterin-toxoid from fast-growing C. pseudotuberculosis showed significant protection from challenge infection, as evidenced by a higher survival rate, fewer gross and histopathologic lesions, and lower bacterial levels on culture. Successful protection via a vaccine against equine internal abscesses might provide supplementary management options against an important, potentially fatal disease.     

Pharmacokinetics and adverse effects of oral meloxicam tablets in healthy adult horses

The objective of this study was to assess the pharmacokinetic profile and determine whether any adverse effects would occur in seven healthy adult horses following oral meloxicam tablet administration once daily for 14 days at a dose of 0.6 mg/kg·bwt. Horses were evaluated for health using physical examination, complete blood count, serum chemistry, urinalysis, and gastroscopy at the beginning and end of the study. Blood was collected for the quantification of meloxicam concentrations with liquid chromatography and mass spectrometry. The mean terminal half‐life was 4.99 ± 1.11 h. There was no significant difference between the mean C_max, 1.58 ± 0.71 ng/mL at T_max 3.48 ± 3.30 h on day 1, 2.07 ± 0.94 ng/mL at T_max 1.24 ± 1.24 h on day 7, and 1.81 ± 0.76 ng/mL at 1.93 ± 1.30 h on day 14 (P = 0.30). There was a statistically significant difference between the T_max on the sample days (P = 0.04). No statistically significant increase in gastric ulcer score or laboratory analytes was noted. Oral meloxicam tablets were absorbed in adult horses, and adverse effects were not statistically significant in this study. Further studies should evaluate the adverse effects and efficacy of meloxicam tablets in a larger population of horses before routine use can be recommended.     

Determination of oral tramadol pharmacokinetics in horses

The determination of the pharmacokinetic parameters of tramadol in plasma and a better characterization of its metabolites after oral administration to horses is necessary to design dosage regimens to achieve target plasma concentrations that are associated with analgesia. The purpose of this study was to determine the pharmacokinetics and elimination pattern in urine of tramadol and its metabolites after oral administration to horses. Tramadol was administered orally to six horses and its half-life, T_max and C_max in plasma were 10.1, 0.59 h, and 132.7 ng/mL, respectively. The half-life, T_max and C_max for M1 in plasma were 4.0, 0.59 h, and 28.0 ng/mL, respectively. Tramadol and its metabolites were detectable in urine between 1 and 24 h after the administration. In conclusion, the PK data reported in this study provides information for the design of future studies of tramadol in horses.     

Pharmacokinetics and bioequivalence of 2 meloxicam oral dosage formulations in healthy adult horses

Meloxicam, a non-steroidal anti-inflammatory drug, is approved for use in horses in several countries, but an equine formulation is not available in North America. However, meloxicam is being used in an extra-label manner in horses in Canada. The purpose of this study, therefore, was to assess the bioequivalence of an approved oral meloxicam suspension (Metacam 15 mg/mL for horses; Boehringer Ingelheim Vetmedica GmBH, Ingelheim, Germany) from the European Union with human meloxicam tablets (Meloxicam 15 mg tablets; TEVA Canada, Toronto, Ontario) compounded with molasses to improve palatability and administration. The geometric mean ratios (GMR test/reference) and the 90% confidence intervals of the pivotal pharmacokinetic parameters (area under the curve and maximum concentration) were within the defined limits of 80% to 125% generally accepted for products to be considered bioequivalent. Therefore, use of human meloxicam tablets compounded with molasses would be expected to produce a similar clinical response in horses as the approved oral product from the European Union.     

Effects of long-term oral administration of levothyroxine sodium on glucose dynamics in healthy adult horses

OBJECTIVE: To determine the effects of long-term oral administration of levothyroxine sodium (L-T(4)) on glucose dynamics in adult euthyroid horses. ANIMALS: 6 healthy adult mares. PROCEDURES: Horses received L-T(4) (48 mg/d) orally for 48 weeks. Frequently sampled IV glucose tolerance test procedures were performed on 3 occasions (24-hour intervals) before and at 16, 32, and 48 weeks during the treatment period. Data were assessed via minimal model analysis. The repeatability of measurements was evaluated. RESULTS: During treatment, body weight decreased significantly from the pretreatment value; mean +/- SD weight was 49 +/- 14 kg, 43 +/- 7 kg, and 25 +/- 18 kg less than the pretreatment value at weeks 16, 32, and 48, respectively. Compared with pretreatment findings, 1.8-, 2.4-, and 1.9-fold increases in mean insulin sensitivity (SI) were detected at weeks 16, 32, and 48, respectively; SI was negatively correlated with body weight (r = -0.42; P < 0.001). During treatment, glucose effectiveness increased and the acute insulin response to glucose decreased. Overall mean within-horse coefficients of variation were 5% and 29% for plasma glucose and serum insulin concentrations, respectively, and 33%, 26%, and 23% for SI, glucose effectiveness, and the acute insulin response to glucose, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Long-term administration of L-T(4) was associated with weight loss and increased SI in adult euthyroid horses, although other factors may have confounded results. Levothyroxine sodium may be useful for the treatment of obesity and insulin resistance in horses, but further studies are required.     

Plasma pharmacokinetics of ranitidine HCl in adult horses

Plasma pharmacokinetics of ranitidine HCl were investigated after intravenous (i.v.) and oral (p.o.) administration of 2.2 mg/kg drug to six healthy adult horses. Concentrations of ranitidine were determined using normal-phase, high-performance liquid chromatography. Plasma concentrations of ranitidine HCl declined from a mean of 5175 ng/mL at 5 min to 37 ng/mL at 720 min after i.v. administration. A three-exponent equation, C_p= A₁· e^–k1t+ A₂· e^–k2t+ A₃· e^–k3t, best described data for all horses. Mean values for model-independent values calculated from the last quantifiable time point were: apparent volume of distribution (Vd_ss) = 1.07 L/kg; area under the curve ( AUC ) = 231,000 ng · min/mL; area under the moment curve ( AUMC ) = 26,900,000 ng · min²/mL; mean residence time ( MRT ) = 113 min; and clearance (Cl) = 9.8 mL/min.kg. Following p.o. administration, a two-exponent equation, C_p= A₁· e^–k1t+ A₂· e^–k2t, best described the data for five horses; data for the remaining horse were best described by a three-exponent equation. Mean values of pharmacokinetic values from the p.o. study include: AUC = 59,900 ng · min/mL; AUMC = 10,600,000 ng · min²/mL; mean absorption time ( MAT ) = 58.9 min; T _max= 99.2 min; C _max= 237 ng/mL; and F = 27%.     

Disposition of levetiracetam in healthy adult horses

Nine horses received 20 mg/kg of intravenous (LEV_IV ); 30 mg/kg of intragastric, crushed immediate release (LEV_CIR ); and 30 mg/kg of intragastric, crushed extended release (LEV_CER ) levetiracetam, in a three‐way randomized crossover design. Crushed tablets were dissolved in water and administered by nasogastric tube. Serum samples were collected over 48 hr, and levetiracetam concentrations were determined by immunoassay. Mean ± SD peak concentrations for LEV_CIR and LEV_CER were 50.72 ± 10.60 and 53.58 ± 15.94 μg/ml, respectively. The y ‐intercept for IV administration was 64.54 ± 24.99 μg/ml. The terminal half‐life was 6.38 ± 1.97, 7.07 ± 1.93 and 6.22 ± 1.35 hr for LEV_CIR , LEV_{CER ,} and LEV_IV , respectively. Volume of distribution at steady‐state was 630 ± 73.4 ml/kg. Total body clearance after IV administration was 74.40 ± 19.20 ml kg^?1 hr^?1. Bioavailability was 96 ± 10, and 98 ± 13% for LEV_CIR and LEV_CER , respectively. A single dose of Levetiracetam (LEV ) was well tolerated. Based on this study, a recommended dosing regimen of intravenous or oral LEV of 32 mg/kg every 12 hr is likely to achieve and maintain plasma concentrations within the therapeutic range suggested for humans, with optimal kinetics throughout the dosing interval in healthy adult horses. Repeated dosing and pharmacodynamic studies are warranted.     

Effect of feeding increasing quantities of starch on glycaemic and insulinaemic responses in healthy horses

The aim of this study was to investigate the effect of increasing the intake of starch on the glycaemic and insulinaemic responses of horses. A cross-over study design was used in which four horses were fed increasing amounts of a compound feed (0.5–3.5 kg) to provide 0.3, 0.6, 0.8, 1.1, 1.4 and 2 g starch/kg bodyweight (BW)/meal. The glycaemic response increased with starch intake (P < 0.05), while feeding <1.1 g starch/kg BW resulted in a lowered response, compared to when 1.1–2 g starch/kg BW was fed (P < 0.01). The results suggested that insulin responses may be more appropriate to define the effect of feeding different starch levels than glycaemic responses. A starch intake of <1.1 g/kg BW/meal produced only moderate glucose and insulin responses, even though highly processed cereals were used. It is therefore recommended that a starch intake of <1.1 g/kg BW/meal or a meal size of 0.3 kg/100 kg BW (starch content of 30–40%) is used for horses.     

Pharmacokinetics of oral terbinafine in adult horses

The primary study objective was to compare the pharmacokinetics of p.o. terbinafine alone to p.o. terbinafine administered with p.o. cimetidine in healthy adult horses. The second objective was to assess the pharmacokinetics of terbinafine when administered per rectum in two different suspensions at 30 mg/kg to adult horses. Six healthy adult horses were included in this crossover study. Plasma terbinafine concentrations were quantified with liquid chromatography and mass spectrometry. The half‐life (geometric mean) was 8.38 and 10.76 h, for p.o. alone and p.o. with cimetidine, respectively. The mean maximum plasma concentrations were 0.291 μg/mL at 1.54 h and 0.418 μg/mL at 1.28 h for p.o. alone and p.o. with cimetidine, respectively. Terbinafine with cimetidine had an average C_MAX 44% higher and the relative F was 153% compared p.o. terbinafine alone, but was not statistically different (P > 0.05). Terbinafine was infrequently detected when administered per rectum in two different suspensions (water or olive oil). Minor adverse effects included oral irritation, fever, and colic. All resolved spontaneously. More pharmacokinetic studies are indicated assessing drug–drug interactions and using multiple dosing intervals to improve our knowledge of effective oral dosing, the potential for drug accumulation, and systemic adverse effect of terbinafine in horses.     

Effect of multiple oral dosing of fluconazole on the pharmacokinetics of cyclosporine in healthy beagles

Fluconazole (Fcz) is successfully used in human organ transplant patients as an antifungal therapy. However, Fcz can increase the cyclosporine (CsA) trough level and lead to CsA nephrotoxicity. In canine renal transplantation, CsA has been used as a major immunosuppressant, and it is important to control its trough level. However, the interaction of Fcz with CsA has not yet been reported in dogs. In this study, the effect of Fcz treatment on the pharmacokinetics of CsA in four healthy beagles was investigated using a four-period crossover design. The treatments included CsA alone (A), CsA + multiple-dose Fcz 50 mg (B), CsA + multiple-dose Fcz 25 mg (C) and CsA + single-dose Fcz 50 mg (D). Blood CsA concentrations were measured at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hr after CsA administration. The AUC(0-12) and C(max) values for treatment B were significantly higher than those for the other treatments. In particular, the AUC(0-12) of treatment B was about two times higher than that of treatment A. Fcz administration did not significantly prolong the half-life or mean residence time of CsA. The results of our study show that administration of multiple therapeutic doses of Fcz can significantly increase the CsA blood concentration, which might partially depend upon the Fcz blood concentration. When Fcz is used in CsA-based canine renal transplantation, it may be necessary to adjust the CsA trough level by decreasing the dose.     

Total parenteral nutrition in four healthy adult horses

Total parenteral nutrition was accomplished in 4 healthy adult horses. During the 10-day study, the horses were not permitted to ingest food or water. Body weight was maintained at 94% of initial values without clinical evidence of dehydration. Serum urea nitrogen and triacylglycerol concentrations decreased during the study, without other significant hematologic or biochemical changes. Horses adapted without problems to the routine of IV feeding and confinement. All horses were healthy at the conclusion of the study. It was concluded that intravenous feeding with a lipid-glucose-amino acid-electrolyte solution was an acceptable method of maintaining nutrition in the healthy adult horse.     

Reduction in absorption of gallium maltolate in adult horses following oral administration with food: chemistry and pharmacokinetics

Gallium (Ga) is under study for the treatment of osteolytic disorders in equines. Previous studies indicate that oral gallium maltolate (GaM) would provide a higher bioavailability than oral Ga salts. However, oral administration to adult horses of 2 mg/kg of GaM, in the form of a solution mixed with food, did not lead to detectable Ga levels in plasma. Therefore, a study was performed to model the chemical behaviour of GaM in the digestive tract. The equilibrium formation constants for Ga(III) and maltol were calculated by means of UV–visible measurements and validated by ¹H‐NMR measurements at selected pH values. Data indicate that the dissociation of GaM in aqueous solutions is very rapid, while the re‐association is slower. Based on these results, poor Ga absorption seems to be due to the equilibrium dissociation of GaM in the stomach and to its slow formation rate in the intestine. The concomitant presence of high concentrations of phytates (strong charged metal chelating agents, which represent about 1% of dry matter in vegetables) might also explain the low absorption of GaM by the gastrointestinal tract. Methods of optimizing Ga absorption after oral administration of GaM require further investigation.     

Effects of oral administration of lactulose in healthy horses

Lactulose (1-4-galactosidofructose) was administered to seven healthy, mature horses at a dosage of 333 mg/kg, by mouth, three times daily for 11 days. There was a significant (P<0.05) reduction in the concentration of blood ammonia during the period after first administration, with a mean reduction of 3 umol/L. Although fecal pH tended to increase after the administration of lactulose, the change was not statistically significant (P>0.05). There were no substantial changes in the results of physical examinations during the periods before, during and after administration in six horses. One horse developed signs of laminitis on the sixth day of administration, was removed from the study and responded well to treatment for laminitis.     

Comparative pharmacokinetics of two intravenous administration regimens of tiludronate in healthy adult horses and effects on the bone resorption marker CTX-1

Bioavailability and pharmacological effects of tiludronate were compared when administered as an intravenous (i.v.) bolus at a dosage of 0.1 mg/kg body weight (b.w.) once daily for 10 consecutive days (group 1, n  = 6) and as a single constant rate infusion (CRI) at a total dose of 1 mg/kg b.w. (group 2, n  = 6) in healthy adult horses.
Tiludronate and carboxy-terminal cross-linking telopeptide of type I collagen (CTX-1) were measured in plasma and urine.
There was no statistically significant difference in area under the curve ( AUC ) and clearance ( Cl ) between the two groups. Bioavailability of the CRI was 103% (not significantly different) that of the 10 daily i.v. bolus doses. Cumulative urine tiludronate excretion could not be compared between groups because of poor sensitivity of the assay in urine. Plasma and urine CTX-1 levels were not different between groups throughout the study. However, interindividual variations were greater in group 1 than in group 2. A significant decrease in CTX-1 levels was observed in plasma after the first administration in group 1, but not in urine; while in group 2, a significant decrease in CTX-1 concentrations was observed after treatment in both plasma and urine.
In conclusion, both dosage regimens of tiludronate produced similar plasma exposure and pharmacological effects in adult healthy horses.     

Comparison of the pharmacokinetics of two formulations of hydroxyethyl starch in healthy horses

A lower molecular weight and molar substitution formulation (130/0.4) of hydroxyethyl starch solution has been shown to have a more sustained effect on COP and similar hemodynamic effects as a higher molecular weight and molar substitution formulation (600/0.75) in healthy horses. In humans, these pharmacodynamic characteristics are coupled with more rapid clearance and decreased adverse coagulation effects and accumulation. The objective of this study was to determine and compare the pharmacokinetics of these two formulations in horses. Eight healthy horses were given a 10 mL/kg bolus of each formulation (600/0.75 and 130/0.4) of hydroxyethyl starch solution in a randomized crossover design. Blood was collected, and plasma was harvested for plasma levels over 24 h. Pharmacokinetic parameters for each horse were estimated from a noncompartmental analysis. Treatment with 600/0.75 resulted in a higher initial plasma concentration (C₀), systemic half‐life (t_1/2), and overall drug exposure (AUC_0–inf) in addition to decreased elimination rate (β), volume of distribution (Vd), and clearance (CL), compared to treatment with 130/0.4 (P < 0.001). The pharmacokinetic findings combined with previous pharmacodynamics findings suggest that 130/0.4 can provide similar benefits to 600/0.75 with a lower risk of accumulation in the circulation.