Effects of long-term oral administration of ketoprofen in clinically healthy beagle dogs

To investigate the adverse effects of long-term administration of ketoprofen in dogs, ketoprofen (1 mg/kg) was administered to five clinically healthy beagle dogs (ketoprofen group) and gelatin capsules (control group) were administered to four clinically healthy beagle dogs for 30 days. We monitored the dogs through periodic physical examination, blood analyses, endoscopic examinations, fecal occult blood tests, renal function tests, urinalysis, urinary enzyme indices and cuticle bleeding time analysis. The lesions in the stomach, especially in the pyloric antrum, and fecal occult blood progressively worsened in the ketoprofen group. However, the differences between the ketoprofen group and the control group were not statistically significant. One dog in the ketoprofen group temporarily exhibited a decrease in renal plasma flow and two dogs exhibited enzymuria. However, these changes did not persist and the other examinations showed no significant difference between premedication and postmedication in the ketoprofen group. Therefore, the adverse effects of long-term administration of ketoprofen observed in this study were not clinically important in healthy dogs. Nevertheless, further investigation of adverse renal effects from long-term administration of ketoprofen is necessary in the dogs with subclinical renal disease.     

Additive effects of a sodium chloride restricted diet and furosemide administration in healthy dogs.

OBJECTIVE: To determine the effects of a low or high sodium (Na) diet with or without furosemide administration on plasma electrolyte concentrations and the renin-angiotensin-aldosterone system in healthy dogs. ANIMALS: 20 healthy adult dogs. PROCEDURE: Dogs were randomly allotted to 4 groups of 5 dogs each as follows: dogs fed a low Na diet (0.08% Na and 0.8% chloride [CI] on a dry matter [DM] basis); dogs fed a low Na diet with added NaCl (1.0% Na and 2.2% Cl on a DM basis); dogs fed a low Na diet and treated with furosemide (2 mg/kg of body weight, PO, q 12 h); and dogs fed a low Na diet with added NaCl and treated with furosemide. Plasma electrolyte concentrations were measured on days 0, 21, and 35. Plasma renin activity and aldosterone concentration were analyzed by use of radioimmunoassays on days 0, 21, 35, and 53. RESULTS: Furosemide treatment significantly decreased plasma Cl concentration and significantly increased plasma renin activity and aldosterone concentration. Dogs fed a low Na diet had significantly higher plasma renin activities and plasma aldosterone concentrations. A significant interaction between a low Na diet and furosemide administration resulted in the lowest plasma Cl concentrations, highest plasma renin activities, and highest plasma aldosterone concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: In healthy dogs, feeding a low Na diet and administering furosemide resulted in an additive effect on plasma Cl concentration, renin activity, and aldosterone concentration, which may be an important consideration for treating dogs with cardiac disease.     

Pharmacokinetics of carvedilol after intravenous and oral administration in conscious healthy dogs

OBJECTIVE: To determine the pharmacokinetics of carvedilol administered IV and orally and determine the dose of carvedilol required to maintain plasma concentrations associated with anticipated therapeutic efficacy when administered orally to dogs. ANIMALS: 8 healthy dogs. PROCEDURES: Blood samples were collected for 24 hours after single doses of carvedilol were administered IV (175 microg/kg) or PO (1.5 mg/kg) by use of a crossover nonrandomized design. Carvedilol concentrations were detected in plasma by use of high-performance liquid chromatography. Plasma drug concentration versus time curves were subjected to noncompartmental pharmacokinetic analysis. RESULTS: The median peak concentration (extrapolated) of carvedilol after IV administration was 476 ng/mL (range, 203 to 1,920 ng/mL), elimination half-life (t(1/2)) was 282 minutes (range, 19 to 1,021 minutes), and mean residence time (MRT) was 360 minutes (range, 19 to 819 minutes). Volume of distribution at steady state was 2.0 L/kg (range, 0.7 to 4.3 L/kg). After oral administration of carvedilol, the median peak concentration was 24 microg/mL (range, 9 to 173 microg/mL), time to maximum concentration was 90 minutes (range, 60 to 180 minutes), t(1/2) was 82 minutes (range, 64 to 138 minutes), and MRT was 182 minutes (range, 112 to 254 minutes). Median bioavailability after oral administration of carvedilol was 2.1% (range, 0.4% to 54%). CONCLUSIONS AND CLINICAL RELEVANCE: Although results suggested a 3-hour dosing interval on the basis of MRT, pharmacodynamic studies investigating the duration of beta-adrenoreceptor blockade provide a more accurate basis for determining the dosing interval of carvedilol.     

Safety of reduced-dosage ketoprofen for long-term oral administration in healthy dogs

OBJECTIVE: To evaluate the safety of reduced-dosage ketoprofen (RDKET) for long-term oral administration in healthy dogs. ANIMALS: 14 healthy Beagles. PROCEDURES: Racemic ketoprofen (0.25 mg/kg, PO) and gelatin capsules, as a drug-free placebo, were each administered to 7 dogs for 30 days. Dogs were periodically monitored via physical examination, blood analyses, endoscopic examinations, fecal occult blood tests (tetramethylbenzidine and guaiac methods), renal function tests (effective renal plasma flow and glomerular filtration rate), urinalyses, urinary enzyme indices (N-acetyl-beta-D-glucosaminidase and gamma-glutamyl-transferase), and hemostatic function tests (buccal mucosa bleeding time, cuticle bleeding time, prothrombin time, activated partial thromboplastin time, and fibrinogen concentration). RESULTS: Pyloric antrum lesion grade was significantly higher in the RDKET group on day 28, compared with the pretreatment and control group grades. Fecal occult blood grade measured by use of the tetramethylbenzidine method was significantly higher in the RDKET group on day 30, compared with the pretreatment grade. No other significant differences were detected between treatment groups. CONCLUSIONS AND CLINICAL RELEVANCE: RDKET induced mild to moderate gastric mucosal injuries especially in the pyloric antrum in healthy Beagles, whereas no adverse effects were observed in renal function or hemostasis. Fecal occult blood tests may be useful as screening tests for adverse gastrointestinal effects induced by RDKET in dogs.     

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.     

Pharmacokinetics of ibafloxacin following intravenous and oral administration to healthy Beagle dogs

The pharmacokinetics of ibafloxacin, a new veterinary fluoroquinolone antimicrobial agent, was studied following intravenous (i.v.) and oral administration to healthy dogs. The mean absolute bioavailability of ibafloxacin after oral doses of 7.5, 15 and 30 mg/kg ranged from 69 to 81%, indicating that ibafloxacin was well absorbed by dogs. Ibafloxacin was also absorbed rapidly [time of maximum concentration (t(max)) 1.5 h], reaching a mean maximum concentration (C(max)) of 6 microg/mL at 15 mg/kg, well distributed in the body [large volume of distribution at steady state (V(ss)) and V(area) of 1.1 L/kg and 4 L/kg, respectively], and exhibited an elimination half-life of 5.2 h and a low total body clearance (8.7 mL/min/kg). Both C(max) and area under the concentration-time curve (AUC) showed dose proportionality over the dose range tested (7.5-30 mg/kg). The pharmacokinetics of ibafloxacin was similar following single and repeated dosage regimens, implying no significant accumulation in plasma. Food promoted the absorption of ibafloxacin by increasing C(max) and AUC, but did not change t(max). High amounts of the metabolites, mainly 8-hydroxy- and, 7-hydroxy-ibafloxacin were excreted in urine and faeces, either unchanged or as glucuronide conjugates. Following oral administration of 15 mg ibafloxacin/kg, the total recovery of ibafloxacin, its metabolites and conjugates in urine and faeces was 61.9-99.9% of the dose within 48 h.     

Plasma profile and pharmacokinetics of dextromethorphan after intravenous and oral administration in healthy dogs

Dextromethorphan is an N-methyl-D-aspartate (NMDA) noncompetitive antagonist which has been used as an antitussive, analgesic adjunct, probe drug, experimentally to attenuate acute opiate and ethanol withdrawal, and as an anticonvulsant. A metabolite of dextromethorphan, dextrorphan, has been shown to behave pharmacodynamically in a similar manner to dextromethorphan. The pharmacokinetics of dextromethorphan were examined in six healthy dogs following intravenous (2.2 mg/kg) and oral (5 mg/kg) administration in a randomized crossover design. Dextromethorphan behaved in a similar manner to other NMDA antagonists upon injection causing muscle rigidity, ataxia to recumbency, sedation, urination, and ptyalism which resolved within 90 min. One dog repeatedly vomited upon oral administration and was excluded from oral analysis. Mean +/- SD values for half-life, apparent volume of distribution, and clearance after i.v. administration were 2.0 +/-0.6 h, 5.1 +/- 2.6 L/kg, and 33.8 +/- 16.5 mL/min/kg. Oral bioavailability was 11% as calculated from naive pooled data. Free dextrorphan was not detected in any plasma sample, however enzymatic treatment of plasma with glucuronidase released both dextromethorphan and dextrorphan indicating that conjugation is a metabolic route. The short half-life, rapid clearance, and poor bioavailability of dextromethorphan limit its potential use as a chronic orally administered therapeutic.     

Investigation of pharmacokinetic interaction between ivermectin and praziquantel after oral administration in healthy dogs

The purpose of this study was to determine the pharmacokinetic interaction between ivermectin (0.4 mg/kg) and praziquantel (10 mg/kg) administered either alone or co‐administered to dogs after oral treatment. Twelve healthy cross‐bred dogs (weighing 18–21 kg, aged 1–3 years) were allocated randomly into two groups of six dogs (four females, two males) each. In first group, the tablet forms of praziquantel and ivermectin were administered using a crossover design with a 15‐day washout period, respectively. Second group received tablet form of ivermectin plus praziquantel. The plasma concentrations of ivermectin and praziquantel were determined by high‐performance liquid chromatography using a fluorescence and ultraviolet detector, respectively. The pharmacokinetic parameters of ivermectin following oral alone‐administration were as follows: elimination half‐life (t_1/2λz) 110 ± 11.06 hr, area under the plasma concentration–time curve (AUC_0–∞) 7,805 ± 1,768 hr^.ng/ml, maximum concentration (C_max) 137 ± 48.09 ng/ml, and time to reach C_max (T_max) 14.0 ± 4.90 hr. The pharmacokinetic parameters of praziquantel following oral alone‐administration were as follows: t_1/2λz 7.39 ± 3.86 hr, AUC_0–∞ 4,301 ± 1,253 hr^.ng/ml, C_max 897 ± 245 ng/ml, and T_max 5.33 ± 0.82 hr. The pharmacokinetics of ivermectin and praziquantel were not changed, except T_max of praziquantel in the combined group. In conclusion, the combined formulation of ivermectin and praziquantel can be preferred in the treatment and prevention of diseases caused by susceptible parasites in dogs because no pharmacokinetic interaction was determined between them.     

Effects of dexamethasone administration on serum trypsin-like immunoreactivity in healthy dogs

OBJECTIVE: To determine whether administration of dexamethasone altered serum trypsin-like immunoreactivity (TLI) in healthy dogs. ANIMALS: 12 healthy dogs. PROCEDURE: Dexamethasone (0.25 mg/kg, p.o., q 24 h) was administered for 7 days. Serum TLI, alpha-amylase and alanine aminotransferase (ALT) activities, and urea and creatinine concentrations were determined on days 0, 7, 14, and 21 of the study. RESULTS: Serum TLI and ALT activities were significantly increased, and serum alpha-amylase activity was significantly decreased after administration of dexamethasone for 7 days. However, values obtained on days 14 and 21 were not significantly different from baseline values. Dexamethasone administration was not associated with any significant changes in serum creatinine or urea concentrations. Serum TLI and alpha-amylase activities were significantly correlated prior to dexamethasone administration. Dogs did not develop clinical signs of pancreatitis. CONCLUSIONS AND CLINICAL RELEVANCE: Dexamethasone administration was associated with an increase in serum TLI. However, values returned to baseline 7 days after dexamethasone administration was discontinued. Serum TLI may be falsely high in dogs that have been treated with dexamethasone in the week preceding analysis.     

Pharmacokinetics and pharmacodynamics of furosemide after oral administration to horses

Furosemide is the most common diuretic drug used in horses. Furosemide is routinely administered as IV or IM bolus doses 3-4 times a day. Administration PO is often suggested as an alternative, even though documentation of absorption and efficacy in horses is lacking. This study was carried out in a randomized, crossover design and compared 8-hour urine volume among control horses that received placebo, horses that received furosemide at 1 mg/kg PO, and horses that received furosemide at 1 mg/kg IV. Blood samples for analysis of plasma furosemide concentrations, PCV, and total solids were obtained at specific time points from treated horses. Furosemide concentrations were determined by reversed-phase high-performance liquid chromatography with fluorescent detection. Systemic availability of furosemide PO was poor, erratic, and variable among horses. Median systemic bioavailability was 5.4% (25th percentile, 75th percentile: 3.5, 9.6). Horses that received furosemide IV produced 7.4 L (7.1, 7.7) of urine over the 8-hour period. The maximum plasma concentration of 0.03 microg/mL after administration PO was not sufficient to increase urine volume compared with control horses (1.2 L [1.0, 1.4] PO versus 1.2 L [1.0, 1.4] control). There was a mild decrease in urine specific gravity within 1-2 hours after administration of furosemide PO, and urine specific gravity was significantly lower in horses treated with furosemide PO compared with control horses at the 2-hour time point. Systemic availability of furosemide PO was poor and variable. Furosemide at 1 mg/kg PO did not induce diuresis in horses.     

Serum digoxin concentrations in dogs before and during concomitant administration of furosemide

Healthy dogs were treated once a day for 16 days with a liquid, oral dosage form of digoxin (0.022 mg/kg). From day 9 to 16 they were also injected intramuscularly with furosemide (4.4 mg/kg). Serum digoxin was measured by a radioimmunoassay technique. Eight hours after the eighth dose of digoxin had been administered, serum digoxin concentration was in the accepted therapeutic range. After 8 days of concomitant administration of digoxin and furosemide, serum digoxin concentration was found to be in the accepted moderate-to-severe toxic range. Clinical signs of digitalis toxicosis were consistently observed during the combined digoxin-plus-furosemide treatment period. There was no significant ( P >0.05) change in the serum concentrations of potassium, sodium, or in osmolality during digoxin treatment alone. Serum creatinine concentrations remained within the accepted normal range for dogs. Serum sodium concentration was significantly ( P <0.05) lower during combined digoxin-plus-furosemide treatment when compared to digoxin treatment only.
Results indicate that an interaction between digoxin and furosemide occurred which led to significantly ( P <0.05) higher concentrations of serum digoxin during combined digoxin and furosemide treatment.     

Effect of sampling time on urinary electrolytes following oral furosemide administration in dogs with myxomatous mitral valve disease

Introduction/ObjectivesUrine chemistry has received growing attention to estimate the diuretic response in dogs with cardiac disease.The aim of the study was to evaluate the impact of time elapsed between the oral furosemide administration and sample collection on urine chemistry in dogs with myxomatous mitral valve disease (MMVD) receiving diuretic therapy in American College of Veterinary Internal Medicine (ACVIM) stage C.Materials and methodsSeventy-three dogs with MMVD ACVIM stage C and 106 healthy dogs were prospectively included. Dogs with MMVD were divided, based on the time of sampling, in morning group (MMVD-MG) of one to 6 h and an evening group (MMVD-EG) over 6 h from oral furosemide administration. Analogously, healthy dogs sampled between 9 a.m. and 1 p.m. and between 2 and 7 p.m. were divided in a morning group (H-MG) and an evening group (H-EG), respectively. Urine chemistry, including fractional excretion of electrolytes, was evaluated and compared among groups.ResultsHigher excretion of sodium and chloride and higher urine sodium to urine potassium ratio (uNa⁺:uK⁺) were detected in MMVD-MG than MMVD-EG (P = 0.021, P = 0.038, and P = 0.016, respectively). Natriuresis, chloriuresis, and uNa⁺:uK+ were higher in MMVD-MG than H-MG, while no differences were found in the comparison between H-MG and H-EG and between MMVD-EG and H-EG.ConclusionsUrinary electrolyte excretion is significantly increased within 6 h from furosemide administration in MMVD ACVIM stage C dogs. Time of sampling from furosemide administration significantly affects urine chemistry in MMVD dogs and should be considered in clinical practice and the research field.     

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

Norfloxacin, a 4-quinolone antibiotic, was administered orally to 4 healthy dogs at dosages of 11 and 22 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) norfloxacin concentrations were measured at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after the first and seventh dose of each dosing regimen. When administered at a dosage of 11 mg/kg, the mean peak serum concentration (Cmax) was 1.0 microgram/ml at 1 hour, the time of mean peak concentration (Tmax) after the first dose. After the seventh dose, the Cmax was 1.4 micrograms/ml at Tmax of 1.5 hours. The Tmax for the TCF concentration was 5 hours, with Cmax of 0.3 microgram/ml and 0.7 microgram/ml after the first and seventh dose, respectively. When administered at a dosage of 22 mg/kg, the serum Tmax was 2 hours after the first dose, with Cmax of 2.8 micrograms/ml. After the seventh dose, the serum Tmax was 1.5 hours, with Cmax of 2.8 micrograms/ml. The Tmax for the TCF concentration was 5 hours after the first and seventh doses, with Cmax of 1.2 micrograms/ml and 1.6 micrograms/ml, respectively. After the seventh dose, the serum elimination half-life was 6.3 hours for a dosage of 11 mg/kg and was 6.7 hours for a dosage of 22 mg/kg. For serum concentration, the area under the curve from 0 to 12 hours (AUC0----12) was 8.77 micrograms.h/ml and 18.27 micrograms.h/ml for dosages of 11 mg/kg and 22 mg/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hydroxyzine and cetirizine pharmacokinetics and pharmacodynamics after oral and intravenous administration of hydroxyzine to healthy dogs

Pharmacokinetic parameters of hydroxyzine and its active metabolite cetirizine were determined after oral and intravenous administration of 2 mg kg(-1) of hydroxyzine to six healthy dogs. Plasma drug levels were determined with high-pressure liquid chromatography. Pharmacodynamic studies evaluated the suppressive effect on histamine and anticanine IgE-mediated cutaneous wheal formation. Pharmacokinetic and pharmacodynamic correlations were determined with computer modelling. The mean systemic availability of oral hydroxyzine was 72%. Hydroxyzine was rapidly converted to cetirizine regardless of the route of administration. The mean area-under-the-curve was eight and ten times higher for cetirizine than hydroxyzine after intravenous and oral dosing, respectively. After oral administration of hydroxyzine, the mean peak concentration of cetirizine was approximately 2.2 microg mL(-1) and that of hydroxyzine 0.16 microg mL(-1). The terminal half-life for cetirizine varied between 10 and 11 h after intravenous and oral administration of hydroxyzine. A sigmoidal relationship was fit to the data comparing cetirizine plasma concentration to wheal suppression. Maximum inhibition (82% and 69% for histamine and anticanine IgE-mediated skin reactions, respectively) was observed during the first 8 h, which correlated with a plasma concentration of cetirizine greater than 1.5 microg mL(-1). Pharmacological modelling suggested that increasing either hydroxyzine dosages or frequencies of administration would not result in histamine inhibition superior to that obtained with twice daily hydroxyzine at 2 mg kg(-1). In conclusion, there was rapid conversion of hydroxyzine to cetirizine. The reduction of wheal formation appeared almost entirely due to cetirizine. Pharmacodynamic modelling predicted that maximal antihistamine effect would occur with twice daily oral administration of hydroxyzine at 2 mg kg(-1).     

Prolonged-release hydroxypropyl methylcellulose matrix tablets of furosemide for administration to dogs

Furosemide is a problematic drug in a prolonged-release product because its absorption is site specific, taking place mainly in the upper parts of the alimentary tract. The aim of the study reported here was to develop prolonged-release furosemide formulations for dogs. The type of preparation selected was a hydroxypropyl methylcellulose (HPMC) matrix tablet. Evaluation was based on dissolution studies, on in vivo disintegration studies in the canine stomach and on bioavailability studies in Beagle dogs. The variables tested were the viscosity grade of the polymer, the amount of polymer and presence or absence of an alkaline compound (potassium carbonate) in the formulation. When potassium carbonate was included, furosemide was absorbed so slowly that drug administration once daily would give plateau drug plasma concentrations, even though the elimination half-life of furosemide is only about one hour.     

The pharmacokinetics of pimobendan enantiomers after oral and intravenous administration of racemate pimobendan formulations in healthy dogs

Pimobendan is a benzimidazole‐pyridazinone derivative, marketed as a racemic mixture for the management of canine heart failure. Pharmacokinetics of the enantiomers of pimobendan and its oral bioavailability have not been described in dogs. The aim of this study was to describe pharmacokinetics of three formulations of pimobendan in healthy dogs: the licensed capsule product, and novel liquid and intravenous formulations. A three‐period, nested randomized two‐treatment crossover design was used. Pimobendan was administered p.o. at 0.25 and i.v. at 0.125 mg/kg. Blood and plasma samples were analysed by liquid chromatography–mass spectrometry. Noncompartmental modelling was used to describe the pharmacokinetics. Parameters were compared between formulations using a general linear model. Bioequivalence of the oral formulations was tested using CI90 for AUC_(0–∞) and C_max. Bioavailability of pimobendan after oral dosing was 70%. Liquid and capsule formulations were bioequivalent only for AUC. The positive enantiomer of pimobendan (PE) had a larger volume of distribution than the negative enantiomer (NE) (281 ± 48 vs. 215 ± 68 mL/kg; P = 0.003) and a shorter half‐life (21.7 vs. 29.9 min; P = 0.004). The NE was distributed more quickly than the PE into blood cells. Enantiomers of pimobendan have differing absorption, distribution and elimination. The pharmacokinetics of pimobendan in healthy dogs was described.