Showing papers in "Journal of Veterinary Pharmacology and Therapeutics in 2008"

Serotonin: a review.

Abstract: 5-Hydroxytryptamine, or serotonin, is a biogenic amine most noted for its role as a neurotransmitter. Manipulation of serotonin in animal models was used as a tool for studying its role in humans. Through such research serotonin has been shown to modulate gastrointestinal motility, peripheral vascular tone, cerebral vascular tone, and platelet function and has been implicated in the pathophysiology of mood disorders, emesis, migraine, irritable bowel syndrome (IBS), and pulmonary and systemic hypertension. The knowledge gained is being directly applied back to animals in research on drugs that manipulate the serotonergic system in dogs and cats. Increasing use and availability of drugs that manipulate the serotonergic system has created a circumstance through which a novel toxicity was discovered in both humans and animals. Serotonin Syndrome describes the clinical picture seen in humans and animals with serotonin toxicity. This paper provides a review the physiology of serotonin and its involvement in the pathophysiologic mechanisms of various conditions, including the Serotonin Syndrome.

Pharmacokinetics of eight anticoagulant rodenticides in mice after single oral administration

Abstract: The first aim of the study was to investigate the pharmacokinetics of eight anticoagulant rodenticides (brodifacoum, bromadiolone, chlorophacinone, coumatetralyl, difenacoum, difethialone, flocoumafen and warfarin) in plasma and liver of the mouse after single oral administration Eight groups of mice dosed orally with a different anticoagulant rodenticide in a dose equal to one-half the lethal dose 50 (LD(50)), were killed at various times up to 21 days after administration The eight anticoagulant rodenticides were assayed in plasma and liver by an LC-ESI-MS/MS method Depending on the compound, the limit of quantification was set at 1 or 5 ng/mL in plasma In liver, the limit of quantification was set at 250 ng/g for coumatetralyl and warfarin and at 100 ng/g for the other compounds The elimination half-lives in plasma for first-generation rodenticides were shorter than those for second-generation rodenticides Coumatetralyl, a first-generation product, had a plasma elimination half-life of 052 days Brodifacoum, a second-generation product, showed a plasma elimination half-life of 917 days The elimination half-lives in liver varied from 158 days for coumatetralyl to 3074 days for brodifacoum The second aim of the study was to illustrate the applicability of the developed method in a clinical case of a dog suspected of rodenticide poisoning

The pharmacokinetics and pharmacodynamics of alfaxalone in cats after single and multiple intravenous administration of Alfaxan® at clinical and supraclinical doses

Abstract: This study aimed to determine the pharmacokinetic parameters and pharmacodynamics of alfaxalone in a 2-hydroxypropyl-beta-cyclodextrin alfaxalone formulation (Alfaxan), Jurox Pty Ltd, Rutherford, NSW, Australia) in cats after single administration at clinical and supraclinical dose rates and as multiple maintenance doses First, a prospective two-period cross-over study was conducted at single clinical and supraclinical doses Second, a single group multiple dose study evaluated the effect of maintenance doses Eight (five female and three male) domestic cats completed the cross-over experiment and six female cats completed the multiple dose study In the first experiment, alfaxalone was administered intravenously (IV) at 5 or 25 mg/kg with a washout period of 14 days In the second experiment, alfaxalone was administered IV at 5 mg/kg followed by four doses each of 2 mg/kg, administered at onset of responsiveness to a noxious stimulus Blood was collected at prescribed intervals and analysed by LCMS for plasma alfaxalone concentration Noncompartmental pharmacokinetics were used to analyse the plasma alfaxalone data The plasma clearance of alfaxalone at 5 and 25 mg/kg differed statistically at 251 and 148 mL/kg/min respectively The elimination half lives were 452 and 766 min respectively Alfaxalone has nonlinear pharmacokinetics in the cat Nevertheless, for cats dosed with sequential maintenance doses, a regression line through their peak plasma concentrations indicated that there was no clinically relevant pharmacokinetic accumulation The duration of nonresponsiveness after each maintenance dose was similar at approximately 6 min, indicating a lack of accumulation of pharmacodynamic effect The cardiovascular and respiratory parameters measured in cats after administration of the labelled doses of Alfaxan were stable In conclusion, the pharmacokinetics of alfaxalone in cats are nonlinear At clinical dose rates, however, neither alfaxalone nor its effects accumulated to a clinically relevant extent Further, in the un-premedicated cat the induction and maintenance of surgical anaesthesia was free of untoward events after a dose of 5 mg alfaxalone/kg body weight followed by four sequential doses of 2 mg/kg as needed (ie, approximately 7 to 8 mg/kg/h)

Safety, pharmacokinetics and use of the novel NK-1 receptor antagonist maropitant (CereniaTM) for the prevention of emesis and motion sickness in cats

Abstract: The present study characterizes the safety, pharmacokinetics, and anti-emetic effects of the selective NK-1 receptor antagonist maropitant in the cat. Safety of maropitant was determined following 15 days of subcutaneous (SC) administration at 0.5-5 mg/kg. Maropitant was well tolerated in cats at doses that exceeded the efficacious anti-emetic dose range of the drug by at least a factor of 10 and adverse clinical signs or pathological safety findings were not noted at any dose.The pharmacokinetics of maropitant in cats were determined following single dose oral (PO), intravenous (IV) and SC administration. Maropitant had a terminal half-life of 13-17 h and a bioavailability of 50 and 117% when administered PO and SC, respectively. Efficacy was determined against emesis induced either by xylazine or by motion. A dosage of 1 mg/kg maropitant administered IV, SC or PO prevented emesis elicited by xylazine. The compound had good oral antiemetic activity and a long (24 h) duration of action. Maropitant (1.0 mg/kg) was highly effective in preventing motion-induced emesis in cats. These studies indicate that the NK-1 receptor antagonist maropitant is well tolerated, safe and has excellent anti-emetic properties in cats.

The pharmacokinetics of meloxicam in vultures

Abstract: Vulture populations across the Asian subcontinent have declined dramatically in the last 15 years and are now on the verge of extinction. Although the cause of the population decline was initially unknown, the decrease has recently been conclusively linked to the use of the nonsteroidal anti-inflammatory drug diclofenac in cattle that inadvertently ended up in the vulture food chain. With the vulture numbers continuing to decline by up to 48% a year, the Indian, Nepali and Pakistan governments have recently banned the manufacture and importation of veterinary diclofenac. They have also suggested meloxicam as an alternate anti-inflammatory for use in cattle. This recommendation was based on extensive acute safety studies in the African White-backed vulture (Gyps africanus), which evaluated worst case scenarios of maximum intake based on a once in three day feeding pattern. However, the possible cumulative pharmacokinetic and pharmacodynamic effects in vultures receiving multiple daily doses of meloxicam over time were not assessed. At present very little pharmacokinetic or pharmacodynamic information is available to add further support for the safety of meloxicam in this animal species. This article discusses the oral and intramuscular pharmacokinetics of meloxicam in Cape Griffon vultures (Gyps coprotheres). Therapeutic drug monitoring was also undertaken in White-backed, Egyptian (Neophron pernopterus) and one Lappet Faced vulture (Torgos tracheliotos). In all these species, meloxicam was characterized by a short half-life of elimination. The rapid metabolism of meloxicam in combination with a short duration of effect in the studied species Gyps vultures shown in this study makes it unlikely that the drug could accumulate. This confirms the safety of repeated exposure to meloxicam in vultures of this genus.

Thermal antinociception after dexmedetomidine administration in cats: a dose-finding study.

Abstract: The optimum dose of dexmedetomidine for antinociception to a thermal stimulus was determined in a crossover study of 12 cats. In five treatment groups (n = 10 per group), dexmedetomidine was administered intramuscularly (i.m.) at 2, 5, 10, 20 and 40 microg/kg; positive and negative controls were administered buprenorphine (20 microg/kg, i.m.) and 0.9% saline (0.006 mL/kg, i.m.) respectively. Baseline thermal thresholds and visual analogue scale (VAS) sedation scores were obtained prior to drug treatment and then at regular intervals until 24 h after administration. The summary measures of overall mean thresholds and overall mean VAS scores were investigated using a univariate general linear model for multiple factors with post hoc Tukey's tests (P < 0.05). Only dexmedetomidine at 40 microg/kg displayed an analgesic effect (less than that of buprenorphine). The VAS for sedation did not significantly affect the thresholds obtained and treatment was the only significant factor to influence VAS. Dexmedetomidine resulted in higher VAS for sedation than saline and buprenorphine. Dexmedetomidine at 40 microg/kg significantly increased nociceptive thresholds compared with saline control, but less than buprenorphine. Dexmedetomidine produced dose-dependent sedation, but only the highest dose produced analgesia, suggesting that induction of analgesia requires the highest dose (or an additional analgesic) in the clinical setting.

Pharmacokinetics and bioavailability of cefquinome in healthy piglets.

Abstract: A study on bioavailability and pharmacokinetics of cefquinome in piglets was conducted after intravenous (i.v.) and intramuscular (i.m.) administrations of 2.0 mg/kg of body weight, respectively. Plasma concentrations were measured by high-performance liquid chromatography assay with UV detector at 268-nm wavelength. Plasma concentration-time data after i.v. administration were best fit by a two-compartment model. The pharmacokinetic values were distribution half-life 0.27 +/- 0.21 h, elimination half-life 1.85 +/- 1.11 h, total body clearance 0.26 +/- 0.08 L/kg.h, area under curve 8.07 +/- 1.91 microg x h/mL and volume of distribution at steady state 0.46 +/- 0.10 L/kg. Plasma concentration-time data after i.m. administration were also best fit by a two-compartment model. The pharmacokinetic parameters were distribution half-life 0.88 +/- 0.42 h, elimination half-life 4.36 +/- 2.35 h, peak concentration 4.01 +/- 0.57 microg/mL and bioavailability 95.13 +/- 9.93%.

Single-dose pharmacokinetics of detomidine in the horse and cow.

Abstract: The pharmacokinetics of detomidine, a novel analgesic sedative, was studied in the major target species after high (80 micrograms/kg) i.v. and i.m. doses. In addition, drug residues in some organs were determined. Concentrations were measured using a sensitive, detomidine-specific radio-immunoassay method. Rapid absorption following i.m. dosing occurred. Absorption half-lives were 0.15 h (horse) and 0.08 h (cattle). The mean peak concentration in the horse (51.3 ng/ml) was achieved in 0.5 h and in the cow (65.8 ng/ml) in 0.26 h. The areas under the concentration curve after i.m. dosing were 66% (horse) and 85% (cow) of the corresponding i.v. values. Distribution was rapid with half-lives of 0.15 h (horse, i.v.) and 0.24 h (cow, i.v.). The apparent volume of distribution was higher after the i.m. dosing (horse 1.56 l/kg, cow 1.89 l/kg) than after i.v. dosing (horse 0.74 l/kg, cow 0.73 l/kg). Elimination half-lives were 1.19 h (horse) and 1.32 h (cow) for the i.v. dose and 1.78 h (horse) and 2.56 h (cow) for the i.m. dose. Total clearances ranged from 6.7 (horse, i.v.) to 12.3 (cow, i.m.) ml/min/kg. Renal clearances were less than 1% of the total clearances showing negligible excretion of the drug in urine and suggesting elimination by metabolism. A cross-reacting metabolite in urine corresponded to less than 1.5% of the detomidine dose's immunoreactivity. High-dose detomidine increased urine flow significantly. Excretion of detomidine in milk in cattle was extremely low. No detectable amounts were present 23 h after dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative efficacy of maropitant and selected drugs in preventing emesis induced by centrally or peripherally acting emetogens in dogs

Abstract: Maropitant (Cerenia; a novel, selective neurokinin(1) receptor antagonist), chlorpromazine, metoclopramide and ondansetron were compared in two randomized, placebo-controlled studies for efficacy in preventing emesis induced by emetogens acting centrally (apomorphine; Study 1) or peripherally (syrup of ipecac; Study 2) in dogs. In each study, ten male and ten female beagles were treated in a five-treatment, five-period crossover design. The five treatments were 0.9% saline (0.1 mL/kg), maropitant (1 mg/kg), metoclopramide (0.5 mg/kg), or chlorpromazine (0.5 mg/kg) all administered subcutaneously, or ondansetron (0.5 mg/kg) administered intravenously. One hour posttreatment dogs were challenged with apomorphine at 0.1 mg/kg intravenously (Study 1) or syrup of ipecac at 0.5 mL/kg orally (Study 2). Following emetogen challenge, dogs were observed for 30 min (Study 1) or 1 h (Study 2) for emesis. No clinical signs, other than those related to emesis, were observed. Efficacy of maropitant in preventing emesis induced centrally by apomorphine was not different (P > 0.05) from metoclopramide or chlorpromazine but was superior (P 0.05) from ondansetron but was superior (P

The pharmacogenomics of P‐glycoprotein and its role in veterinary medicine

Abstract: Despite advancements in pharmacogenetics in human medicine, the incorporation of pharmacogenetics into veterinary medicine is still in its early stages of development. To date, efforts to understand the pharmacologic impact of genetic variation in veterinary species have largely focused on genes encoding for the membrane transporter, P-glycoprotein (P-gp). The emphasis on the role of P-gp is largely because of safety concerns associated with the use of some macrocyclic lactones in dogs. Because of the body of information available on this topic, we use P-gp as a platform for understanding the importance of population diversity in veterinary medicine. The impact of P-gp on drug pharmacokinetics and pharmacodynamics is considered, along with endogenous and exogenous factors that can modulate P-gp activity. The review includes discussion of how population diversity in P-gp activity can lead to susceptibility to certain diseases or alter patient response to environmental stress or pharmaceutical intervention. In addition, phenotypic diversity also needs to be considered, as demonstrated by the impact of P-gp up-regulation and drug resistance. The aim of this review was to set the stage for further exploration into the impact of genetic and phenotypic variability on drug pharmacokinetics, disease propensity, product formulation and drug response in both companion and food-producing animals.

Glargine and protamine zinc insulin have a longer duration of action and result in lower mean daily glucose concentrations than lente insulin in healthy cats

Abstract: The pharmacological effects of glargine, protamine zinc (PZI), and lente insulins were evaluated in nine healthy cats. A 3-way crossover study was performed and plasma concentrations of insulin and glucose were determined for 24 h after a single subcutaneous injection of each insulin at 3-day intervals. Time to onset of action did not differ between insulins. Mean time to first nadir glucose was longer for glargine (14 h) relative to PZI (4 h) and lente (5 h). PZI was biphasic in action with nadirs at 4 and 14 h with the second nadir occurring at a similar time to glargine. Nadir glucose did not differ significantly between insulin types. The duration of action was similar for glargine and PZI and was longer than that for lente insulin. Mean daily glucose after glargine and PZI were also similar and were lower than after lente insulin. Time to reach peak insulin did not differ between insulin types. Time to return to baseline insulin level for PZI was longer than glargine but did not differ significantly from lente. In conclusion, healthy cats injected subcutaneously with glargine, compared to those injected with lente insulin, have a later glucose nadir and longer duration of action. Glargine and PZI had similar durations of action in study cats but a larger study is required to obtain precise comparisons of duration of action.

Pharmacokinetics and pharmacodynamics of meloxicam in piglets.

Abstract: The pharmacokinetics and pharmacodynamics of meloxicam in piglets (16-23 days old) were studied using a stratified parallel group design. One group (n = 13) received 0.4 mg/kg meloxicam intravenously, while the other group (n = 12) received physiological saline solution. A carrageenan-sponge model of acute inflammation was used to evaluate the effects of meloxicam. The plasma clearance was low (0.061 L/kg/h), the volume of distribution was low (0.19 L/kg) and the elimination half-life was short (2.7 h). At most time points, the mean concentration of meloxicam in plasma exceeded the concentrations in exudate indicating a limited accumulation of the drug at the site of the inflammation. There were significant differences between the groups in the exudate prostaglandin E2 (PGE2) concentration, but the inhibition of PGE2 in the meloxicam group was limited. The inhibition of thromboxane B(2) (TXB2) production in serum in the meloxicam group was extensive, but of shorter duration than the PGE2 inhibition in exudate.

Pharmacokinetics of valacyclovir in the adult horse.

Abstract: Recent outbreaks of equine herpes virus type-1 infections have stimulated renewed interest in the use of effective antiherpetic drugs in horses. The purpose of this study was to investigate the pharmacokinetics of valacyclovir (VCV), the prodrug of acyclovir (ACV), in horses. Six adult horses were used in a randomized cross-over design. Treatments consisted of 10 mg/kg ACV infused intravenously, 5 g (7.7-11.7 mg/kg) VCV delivered intragastrically (IG) and 15 g (22.7-34.1 mg/kg) VCV administered IG. Serum samples were obtained at predetermined times for acyclovir assay using high-performance liquid chromatography. Following the administration of 5 g VCV, the mean observed maximum serum ACV concentration (C(max)) was 1.45 +/- 0.38 (SD) microg/mL, at 0.74 +/- 0.43 h. At a dose of 15 g VCV, the mean C(max) was 5.26 +/- 2.82 microg/mL, at 1 +/- 0.27 h. The mean bioavailability of ACV from oral VCV was 60 +/- 12% after 5 g of VCV and 48 +/- 12% after 15 g VCV, and did not differ significantly between dose rates (P > 0.05). Superposition suggested that a loading dose of 27 mg/kg VCV every 8 h for 2 days, followed by a maintenance dose of 18 mg/kg every 12 h, will maintain effective serum ACV concentrations.

Safety and efficacy of injectable and oral maropitant, a selective neurokinin 1 receptor antagonist, in a randomized clinical trial for treatment of vomiting in dogs.

Abstract: Maropitant (Cerenia), a selective neurokinin(1) receptor antagonist, was evaluated for safety and efficacy in treatment and prevention of acute vomiting due to various etiologies in dogs in a randomized clinical trial. Two-hundred seventy-eight dogs were enrolled from 29 veterinary hospitals. Two-hundred fifty-two were evaluable for efficacy, while 275 were evaluable for safety. A randomized block design was utilized (three maropitant- and one placebo-treated dog per block). Initial treatment was maropitant at 1 mg/kg body weight (0.45 mg/lb) or an equivalent volume of saline (placebo) administered subcutaneously. On the subsequent 1 to 4 days, maropitant or placebo (dependent on allocation) was administered subcutaneously or orally at approximate 24-h intervals as needed. Oral doses were administered as maropitant tablets using unit dosing to deliver a minimum dose of 2 mg/kg body weight (0.9 mg/lb) or equivalent numbers of similar placebo tablets. Dogs and housing were observed twice daily for evidence of vomiting. Emesis was significantly (P

An experimental study of hemolysis induced by onion (Allium cepa) poisoning in dogs.

Abstract: The mechanism of hemolysis induced by onion poisoning in dogs was studied. Six adult, clinically normal Pekingese dogs were fed cooked onions at 30 g/kg body weight/day for 2 days. Blood samples were collected on days 1, 3, 5, 8, 12, 18 and 24 after onion administration, and urine was collected the day after bleeding. Red blood cell counts, hemoglobin and hematocrit were decreased from day 1, and significantly so on day 5 (P < 0.01), contrary to the results of white blood cell counts. So the plasma bilirubin levels and urobilinogen were increased on day 3 (P < 0.01) and day 4 (P < 0.01), respectively. The Heinz body counts were increased dramatically from day 1 (P < 0.01), peaking on day 3 (P < 0.01). Reticulocyte counts were increased from day 1 and the highest value was on day 8 (P < 0.01). Besides anemia, the following erythrocyte parameters were altered: erythrocyte glucose-6-phosphate dehydrogenase was reduced from day 1 and reached the lowest value on day 5 (P < 0.01); the reduced form of nicotinamide adenine dinucleotide phosphate was decreased on day 1 (P < 0.01); reduced glutathione was decreased from day 1 (P < 0.01) and the lowest value was on day 3 (P < 0.01); glutathione-peroxidase was increased on day 1, but decreased significantly on day 3 (P < 0.01); hydrogen peroxide was increased on day 1 (P < 0.01), then went down on days 3-12 (the undermost value on day 5, P < 0.01); catalase was risen dramatically on day 5 (the peak value, P < 0.01); malondialdehyde (MDA) was increased on days 1-8, (P < 0.01), and reached the peak value on day 5 (P < 0.01). Deformity of the erythrocyte membrane was decreased on days 1-12 and fluorescence polarization (rho) and microviscosity (eta) of the erythrocyte membrane were increased on days 1-12 (P < 0.01). There were positive correlations between MDA and rho as well as eta, with correlation coefficients of 0.908 and 0.922, respectively (P < 0.01), but there was a negative correlation between MDA and deformity index, with a correlation coefficient of -0.887 (P < 0.05). This study confirmed that onion poisoning in dogs causes hemolytic anemia.

Pharmacokinetics and physiological effects of intravenous hydromorphone in conscious dogs.

Abstract: This study evaluated the pharmacokinetics, the sedative and anti-nociceptive effects of intravenous hydromorphone in dogs. Five adult dogs were administered hydromorphone (0.1 mg/kg and 0.2 mg/kg) and morphine (0.5 mg/kg and 1 mg/kg) at weekly intervals. Blood samples were drawn before and at 1, 2, 5, 15, 30, 60 and 120 min after drug administration. Plasma hydromorphone only was measured by high pressure liquid chromatography (HPLC) with electrochemical detection and pharmacokinetic parameters calculated. Anti-nociceptive and sedation scores were submitted to Kruskal-Wallis one-way anova on ranks and post-hoc Bonferroni test with 5% significance level. The data fitted a two-compartment model with a fast distribution (<1 min for both doses) and slower elimination rate. Mean elimination half-life was 80 +/- 52.7 and 57.7 +/- 30.4 min for the high and low dose, respectively. The apparent mean volumes of distribution at steady-state were 7.2 +/- 3 and 4.5 +/- 2.4 L/kg, while the clearance was 74.7 +/- 19 and 68.1 +/- 20 mL/kg/min for the high and low doses, respectively. Compared to saline, hydromorphone and morphine produced significant anti-nociception and sedation of similar magnitude for 120 min. In conclusion, intravenous hydromorphone has a large volume of distribution, and high clearance rate that exceeds hepatic blood flow. In dogs, it produced mechanical anti-nociception and sedation of a magnitude similar to morphine.

Evaluation of the interaction between ivermectin and albendazole following their combined use in lambs.

Abstract: Mixtures of drugs from different chemical families have been proposed as a valid strategy to delay the development of anthelmintic resistance. The current work summarizes the outcome of the evaluation of the plasma disposition kinetics of albendazole (ABZ) and ivermectin (IVM) administered either alone or co-administered to lambs infected with gastrointestinal (GI) nematodes resistant to both anthelmintic molecules. Thirty six (36) Corriedale lambs naturally infected with multiple resistant GI nematodes were allocated into six treatment groups: (a) ABZ intravenous (ABZ(IV)); (b) IVM(IV); (c) ABZ(IV) + IVM(IV); (d) ABZ intraruminal (IR); (e) IVM subcutaneous (SC) and (f) ABZ(IR) + IVM(SC). Plasma samples were collected over 15 days post-treatment and analysed by HPLC. The estimated pharmacokinetic (PK) parameters were statistically compared using parametric and non-parametric statistical tests. The presence of IVM did not affect the plasma disposition kinetics of ABZ and its metabolites after the i.v. administration. However, the ABZ sulphoxide (ABZSO) area under the concentration vs. time curve (AUC) was significantly lower (P < 0.01) after the intraruminal (i.r.) administration of ABZ alone compared to that obtained for the combined treatment with IVM [subcutaneous (s.c.) injection]. The IVM plasma AUC obtained after its i.v. co-administration with ABZ was 88% higher (P < 0.05) compared to the treatment with IVM alone. Any marked difference on IVM PK parameters was observed between the treatments ABZ + IVM and IVM alone injected subcutaneously. The data obtained here indicate that the co-administration of ABZ and IVM does not induce an adverse kinetic interaction. This type of pharmacology-based evaluation of drug interactions is becoming highly relevant as drug combinations are now widely used as an alternative to control resistant helminth parasites in livestock.

Efficacy of metaphylactic florfenicol therapy during natural outbreaks of bovine respiratory disease.

Abstract: The efficacy of an injectable formulation of florfenicol (300 mg/mL) as metaphylactic control of naturally occurring bovine respiratory disease (BRD) was evaluated in two double-blind randomly controlled field studies on two Dutch veal calf herds (A and B). Cattle aged not older than 3 months and in the direct presence of calves with clinical respiratory disease were randomly allocated to treatment with 40 mg/kg florfenicol subcutaneously (s.c.) a positive control treatment (12.5 mg/kg tilmicosin p.o. twice daily for five consecutive days in herd A, and 12.5 mg/kg doxycycline p.o. twice daily for five consecutive days in herd B), or a negative control (one placebo saline s.c. administration on D0). The predominant respiratory pathogens present in pretreatment respiratory samples from affected animals were Mycoplasma bovis and Pasteurella multocida in outbreaks A and B, respectively. Metaphylactic administration of florfenicol resulted in a statistically significant weight gain, decreased rectal temperature for five consecutive days after treatment and decreased metaphylactic failure percentages compared with both positive and negative control groups. In summary, these studies demonstrated that a single s.c. injection of florfenicol is effective and practical for control of the bacterial component of BRD in veal calves.

Intramuscular, intravenous and oral levetiracetam in dogs: safety and pharmacokinetics

Abstract: Intravenous (IV) levetiracetam (LEV) is available for humans for bridge therapy when the oral route is unavailable. We investigated the safety and pharmacokinetics of LEV administered intramuscularly (IM), IV, and orally to dogs. Six Hound dogs received 19.5-22.6 mg/kg of LEV IM, IV and orally with a wash-out period in between. All dogs received 500 mg LEV orally and 5 mL of 100 mg/mL LEV IM. Three dogs received 500 mg of LEV IV and three dogs received 250 mg LEV IV with 250 mg given perivascularly to approximate extravasation. Safety was assessed using a pain scale at time of IM administration and histopathological examination 24 h to 5 days after injection. Intravenous LEV half-life was 180 +/- 18 min. Bioavailability of IM LEV was 100%. Mean time to T(max) after IM was 40 +/- 16 min. The mean C(max) IM was 30.3 +/- 3 mug/mL compared to the C(0) of 37 +/- 5 mug/mL for IV. Mean inflammation score (0-4 scale) for IM LEV was 0.28 and for saline 0.62. Extravasation did not cause tissue damage. Parenteral LEV is well tolerated and appears safe following IM and IV injections in dogs. Parenteral LEV should be evaluated for use in dogs with epilepsy.

Ocular toxicity and distribution of subconjunctival and intravitreal rapamycin in horses

Abstract: In vitro photosensitivity of rapamycin (RAPA) and ocular toxicity and distribution of intravitreal and subconjunctival RAPA was evaluated in normal horses. RAPA (2.5 mg, 5 mg, and 10 mg) was placed in 10 mL of PBS and maintained in a water bath at 37 degrees C, kept in the dark or subjected to room light, and sampled for up to 3 months for RAPA levels. Six normal adult horses received either 5 mg (n = 2) or 10 mg (n = 2) of RAPA intravitreally or 10 mg (n = 2) subconjunctivally. Ophthalmic exams and electroretinography (ERG) were performed prior to injection and on days 1, 7, 14, and 21 post-injection. Eyes were enucleated and samples were collected for RAPA concentrations and histopathology. No difference in light vs. dark RAPA concentrations was observed, suggesting a lack of RAPA phototoxicity. No evidence of ocular toxicity was noted on ophthalmic examination or histopathology. RAPA was not detected intraocularly 7 days post-injection in eyes receiving subconjunctival RAPA, but was detected in the vitreous at 21 days post-injection. Drug could be detected in both the aqueous and vitreous humor after intravitreal injection. Further study is needed to determine the efficacy of intravitreal RAPA.

Efficacy and safety of maropitant, a selective neurokinin 1 receptor antagonist, in two randomized clinical trials for prevention of vomiting due to motion sickness in dogs.

Abstract: Maropitant (Cerenia), a selective neurokinin(1) receptor antagonist, was evaluated for efficacy and safety in prevention of vomiting due to motion sickness in dogs in two randomized clinical trials. One-hundred eighty-nine dogs with a history of motion sickness were enrolled at 26 veterinary clinics (across 12 US states) across the two trials; of these, 163 were fully evaluable, 19 were evaluable only for safety, and seven were not evaluable. Each trial used a two-period crossover design. Each dog was treated orally with placebo or maropitant (minimum dose of 8 mg/kg body weight using unit dosing) tablets at approximately 2 h (Trial 1) or 10 h (Trial 2) before an automobile ride of approximately 60 min, during which dogs were observed for signs of motion sickness. Following a 10-14-day washout period, each dog was administered the opposite treatment and taken for another journey (same route, driver and vehicle). Maropitant reduced the occurrence of vomiting compared to placebo by 86.1% or 76.5% when given approximately 2 or 10 h prior to travel, respectively. No significant clinical signs were observed after maropitant treatment. Maropitant was safe and effective in preventing vomiting due to motion sickness in dogs when administered at a minimum dose of 8 mg/kg body weight as oral tablets 2 or 10 h prior to travel.

Pharmacokinetics of gabapentin in horses.

Abstract: *Department of Veterinary Biosciences, University of Illinois, College of Veterinary Medicine, Urbana, IL; Department of Biomedical Sciences, College of Veterinary Medicine, Nursing and Allied Health, Tuskegee University, Tuskegee, AL; Livestock Disease and Diagnostic Center, College of Agriculture, University of Kentucky, Lexington, KY; Department of Large Animal Clinics, College of Veterinary Medicine, Nursing and Allied Health, Tuskegee University, Tuskegee, AL; 128C Maxwell Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY, USA

Impact of antimicrobial drug usage measures on the identification of heavy users, patterns of usage of the different antimicrobial classes and time-trends evolution.

Abstract: Several measurement units are available to quantify antimicrobial usage in veterinary medicine, to obtain diverse measures such as the weight of active substance used, the live weight (LW) treated, the fraction of animals exposed, the number of treatments recorded or the cost represented. These measures can be applied to study practices variability between farms, to characterize patterns of usage of the different antimicrobial classes or to follow evolution of antimicrobial usage with time. An investigation was carried out to specifically explore the influence of measurement units on the conclusions obtained from such studies. Antimicrobial exposure was explored in a sample of turkey and chicken broiler flocks, using six different units [kg of active compound, treatments, days of administration, kg of LW treated, animal daily dose to treat 1 kg of LW (ADD(kg)) and euros] to compare flocks usage variability and patterns of use of the different antimicrobial classes. Time-trends evolutions of macrolides usage in turkey broilers, characterized by percentage of flocks exposed and LW treated, were also compared. In all analyses, the measure gave different results without equivalences, highlighting the necessity for care in choosing the measurement unit and caution in interpreting the figures obtained.

Pharmacokinetics of lidocaine following the application of 5% lidocaine patches to cats.

Abstract: Lidocaine patches have been used to provide local analgesia in dogs and cats. We conducted this study to assess the systemic and local absorption of lidocaine from topical patches in cats. Eight 2-year-old cats received either intravenous lidocaine at 2 mg/kg or one 700 mg lidocaine patch placed on the lateral thorax for 72 h, in a cross-over randomized repeated measures design. Plasma was collected at specific times and the skin was biopsied at the time of patch removal for the quantitative analysis of lidocaine and its major metabolite, monoethylglycinexylidide (MEGX), by gas chromatography with mass spectrometry. Percent absorption time plots for systemic lidocaine appearance were constructed using the Loo-Riegelman method. Approximately, constant rate absorption was observed from 12-72 h after patch application at a mean +/- SD rate of 109 +/- 49 microg/kg/h, resulting in steady-state lidocaine plasma concentrations of 0.083 +/- 0.032 microg/mL and MEGX concentrations of 0.012 +/- 0.009 microg/mL. Overall bioavailability of transdermal lidocaine was 6.3 +/- 2.7%, and only 56 +/- 29% of the total lidocaine dose delivered by the patch reached systemic circulation. Skin lidocaine concentrations were much higher than plasma concentrations, at 211 +/- 113 microg/g in the thoracic skin beneath the patch and 2.2 +/- 0.6 microg/g in the contralateral thoracic skin without the patch. As both lidocaine and MEGX were recovered from contralateral skin, it is likely that lidocaine accumulated in the skin from low systemic concentrations of circulating lidocaine over the 72-h period of patch application. Plasma lidocaine concentrations remained well below systemically toxic concentrations, and no obvious clinical side effects were observed in any of the cats. The low systemic absorption rate coupled with high local lidocaine concentrations on the skin support the safe use of lidocaine patches in cats.

Prediction of xenobiotic clearance in avian species using mammalian or avian data: how accurate is the prediction?

Abstract: *Elanco Animal Health, A Division of Eli Lilly and Company, Greenfield, IN, USA; Office of Blood Review & Research (OBRR), Center forBiologic Evaluation and Research, Food and Drug Administration, Rockville, MD, USA; Division of Therapeutic Drugs for Food Animals (HFV-130), Office of New Animal Drug Evaluation, Center for Veterinary Medicine, Food & Drug Administration, Rockville, MD, USA

Pharmacokinetics of zonisamide and drug interaction with phenobarbital in dogs

Abstract: The purposes of the present study were to elucidate the pharmacokinetics of zonisamide, determine the presence of a drug interaction with phenobarbital, and evaluate how long any interaction lasted after discontinuation of phenobarbital in dogs. Five dogs received zonisamide (5 mg/kg, p.o. and i.v.) before and during repeated oral administration of phenobarbital (5 mg/kg, bid, for 30-35 days). Zonisamide (5 mg/kg, p.o.) was also administered 8, 10, and 12 weeks after discontinuation of phenobarbital. Blood was sampled until 24 h after each zonisamide administration and serum concentrations of zonisamide were determined. Repeated phenobarbital decreased the maximum serum concentration, area under the serum concentration vs. time curve, apparent elimination half-life, and bioavailability of zonisamide. Total clearance increased. Time to maximum serum concentration and volume distribution were not changed. The maximum serum concentration and area under the serum concentration vs. time curve of zonisamide continued to be low until 10 weeks after the discontinuation of phenobarbital. They were restored to the same serum concentration as before phenobarbital administration 12 weeks after the discontinuation of phenobarbital. These data suggested that repeated administration of a clinical dose of phenobarbital enhanced the clearance of zonisamide and the enhanced clearance lasted at least 10 weeks after the discontinuation of phenobarbital. Caution may be necessary when zonisamide is given with phenobarbital and when antiepileptic therapy is changed from phenobarbital to zonisamide.

Disposition and safety of zonisamide after intravenous and oral single dose and oral multiple dosing in normal hound dogs

Abstract: The purpose of this study was to determine an oral dosing regimen of zonisamide in healthy dogs such that therapeutic concentrations would be safely reached and maintained at steady-state. Adult hound dogs (n = 8) received a single IV (6.9) and an oral (PO) dose (10.3 mg/kg) using a randomized cross-over design. Zonisamide was then administered at 10.3 mg/kg PO every 12 h for 8 weeks. Zonisamide was quantitated in blood compartments or urine by HPLC and data were subjected to noncompartmental pharmacokinetic analysis. Comparisons were made among blood compartments (one-way anova; P

Pharmacokinetics of pradofloxacin and doxycycline in serum, saliva, and tear fluid of cats after oral administration.

Abstract: The pharmacokinetic properties of pradofloxacin and doxycycline were investigated in serum, saliva, and tear fluid of cats. In a crossover study design, six cats were treated orally with a single dose of pradofloxacin (Veraflox Oral Suspension 2.5%) and doxycycline (Ronaxan 100 mg) at 5 mg/kg body weight. Following administration, samples of serum, saliva, and tear fluid were taken in regular intervals over a period of 24 h and analysed by turbulent flow chromatography/tandem mass spectrometry. All values are given as mean +/- SD. Pradofloxacin reached a mean maximum serum concentration (C(max)) of 1.1 +/- 0.5 microg/mL after 1.8 +/- 1.3 h (t(max)). In saliva and tear fluid, mean C(max) was 6.3 +/- 7.0 and 13.4 +/- 20.9 microg/mL, respectively, and mean t(max) was 0.5 +/- 0 and 0.8 +/- 0.3 h, respectively. Doxycycline reached a mean C(max) in serum of 4.0 +/- 0.8 microg/mL after 4.3 +/- 3.2 h. Whilst only at two time-points doxycycline concentrations close to the limit of quantification were determined in tear fluid, no detectable levels were found in saliva. The high concentrations of pradofloxacin in saliva and tear fluid are promising to apply pradofloxacin for the treatment of conjunctivitis and upper respiratory tract infections in cats. As doxycycline is barely secreted into these fluids after oral application the mechanisms of its clinical efficacy remain unclear.

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

Abstract: 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.