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

Maropitant (Cerenia^?; a novel, selective neurokinin₁ 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 < 0.0001) to ondansetron. Efficacy of maropitant in preventing emesis induced by syrup of ipecac was not different (P > 0.05) from ondansetron but was superior (P ≤ 0.0102) to metoclopramide or chlorpromazine. Maropitant was effective (P < 0.0001 relative to control) in preventing vomiting caused by stimulation of either central or peripheral emetic pathways, whereas the other drugs examined prevented vomiting caused by central (metoclopramide and chlorpromazine; P < 0.0001) or peripheral (ondansetron; P < 0.0001) stimulation but not both.     

The anti-emetic efficacy of maropitant (Cerenia) in the treatment of ongoing emesis caused by a wide range of underlying clinical aetiologies in canine patients in Europe

OBJECTIVES: The efficacy of maropitant (Cerenia; Pfizer Inc.) as an anti-emetic for use in dogs with ongoing emesis was evaluated in a two-phase multi-centric study conducted at veterinary clinics in France, Italy, Slovakia and the UK. METHODS: In phase I, dogs with ongoing emesis were randomised in a 1:1 ratio to either maropitant (32 dogs) or metoclopramide (34 dogs). In phase II, dogs were randomised in a 2:1 ratio to maropitant (77 dogs) or metoclopramide (40 dogs). Maropitant was administered subcutaneously at 1 mg/kg/day for up to five days. Metoclopramide was administered as recommended on the product labels as licensed at 0.5 to 1 mg/kg/day subcutaneously or orally with the daily dose divided over two to three administrations per day for up to three to five days. RESULTS: In phase I, 97 per cent of dogs treated with maropitant and 71 per cent of dogs treated with metoclopramide did not vomit after treatment (P<0.01). The mean number of emetic events after maropitant treatment was significantly reduced compared with that after metoclopramide treatment (P=0.01). In phase II, the occurrence of emesis was lower for maropitant during the first 24 hours (P<0.0001) and for each day thereafter. CLINICAL SIGNIFICANCE: A single daily dose of maropitant was more effective than metoclopramide administered two or three times daily in the treatment of emesis caused by various aetiologies in dogs.     

Safety and efficacy of injectable and oral maropitant,a selective neurokinin1 receptor antagonist,in a randomized clinical trial for treatment of vomiting in dogs

Maropitant (Cerenia?), a selective neurokinin₁ 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 ≤ 0.0012) reduced in maropitant‐treated dogs as 50% (32/64) of placebo‐treated dogs continued to vomit compared to only 21.8% (41/188) of maropitant‐treated dogs. Post‐treatment clinical signs were consistent with clinical diagnoses and judged not to be treatment related. In this clinical trial, maropitant was safe and effective in reducing emesis due to various etiologies in dogs.     

Pharmacokinetics of single doses of maropitant citrate in adult horses

The neurokinin‐1 (NK) receptor antagonist, maropitant citrate, mitigates nausea and vomiting in dogs and cats. Nausea is poorly understood and likely under‐recognized in horses. Use of NK‐1 receptor antagonists in horses has not been reported. The purpose of this study was to determine the pharmacokinetic profile of maropitant in seven adult horses after single intravenous (IV; 1 mg/kg) and intragastric (IG; 2 mg/kg) doses. A randomized, crossover design was performed. Serial blood samples were collected after dosing; maropitant concentrations were measured using LC‐MS/MS. Pharmacokinetic parameters were determined using noncompartmental analysis. The mean plasma maropitant concentration 3 min after IV administration was 800 ± 140 ng/ml, elimination half‐life was 10.37 ± 2.07 h, and volume of distribution was 6.54 ± 1.84 L/kg. The maximum concentration following IG administration was 80 ± 40 ng/ml, and elimination half‐life was 9.64 ± 1.27 hr. Oral bioavailability was variable at 13.3 ± 5.3%. Maropitant concentrations achieved after IG administration were comparable to those in small animals. Concentrations after IV administration were lower than in dogs and cats. Elimination half‐life was longer than in dogs and shorter than in cats. This study is the basis for further investigations into using maropitant in horses.     

Efficacy of maropitant in the prevention of delayed vomiting associated with administration of doxorubicin to dogs

Background: Vomiting, nausea, inappetence, and diarrhea are common delayed adverse effects of doxorubicin. Maropitant, a neurokinin‐1 receptor antagonist, is known to prevent acute vomiting in dogs receiving cisplatin. Objective: To evaluate the efficacy of maropitant in preventing delayed vomiting after administration of doxorubicin to dogs. Animals: Fifty‐nine dogs with cancer. Methods: This randomized, double‐blind, placebo‐controlled study used a cross‐over design. Dogs were randomized into 1 of 2 treatment groups. Group A received maropitant after the 1st doxorubicin, and placebo after the 2nd. Group B received placebo first, and maropitant second. Maropitant (2 mg/kg) or placebo tablets were administered PO for 5 days after doxorubicin treatment. Owners completed visual analog scales based on Veterinary Cooperative Oncology Group‐Common Terminology Criteria for Adverse Events to grade their pet's clinical signs during the week after administration of doxorubicin. Statistical differences in gastrointestinal toxicosis and myelosuppression between maropitant and placebo treatments were evaluated. Results: Significantly fewer dogs had vomiting (P= .001) or diarrhea (P= .041), and the severity of vomiting (P < .001) and diarrhea (P= .024) was less the week after doxorubicin when receiving maropitant compared with placebo. No differences were found between maropitant and placebo for other gastrointestinal and bone marrow toxicoses. Conclusions and Clinical Importance: Maropitant is effective in preventing delayed vomiting induced by doxorubicin. Its prophylactic use might improve quality of life and decrease the need for dose reductions in certain dogs.     

Efficacy and safety of maropitant,a selective neurokinin1 receptor antagonist,in two randomized clinical trials for prevention of vomiting due to motion sickness in dogs

Maropitant (Cerenia^TM), a selective neurokinin₁ 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 maropitant citrate after oral administration of multiple doses in adult horses

The neurokinin-1 (NK-1) receptor antagonist, maropitant citrate, mitigates nausea and vomiting in dogs and cats. Nausea is poorly understood in horses, and clinical use of NK-1 receptor antagonists has not been reported. This study aimed to determine the pharmacokinetics and safety of maropitant after administration of multiple doses. We hypothesized that maropitant concentrations would be similar at steady state to those reported in dogs, with minimal adverse effects. Maropitant was administered at 4 mg/kg orally, once daily for 5 days in seven adult horses. Serial plasma maropitant concentrations were measured by liquid chromatography-mass spectrometry. Noncompartmental pharmacokinetic parameters were determined. The maximum, minimum, and average concentrations of maropitant achieved at steady state were 375.5 ± 200, 16.8 ± 7.7, and 73.5 ± 45.1 ng/ml, respectively. The terminal elimination half-life was 11.6 ± 1.4 hr, and the accumulation index was 1.3 ± 0.07. Heart rate decreased between Day 1 and Day 5 (p = .005), with three horses having heart rates of 20 beats per minute and atrioventricular block on Day 5. Pharmacokinetics of repeated maropitant administration suggests the drug could be considered for use in healthy horses. Further investigation on the clinical relevancy of its cardiac effects is warranted.     

The pharmacokinetics of maropitant citrate dosed orally to dogs at 2 mg/kg and 8 mg/kg once daily for 14 days consecutive days

The pharmacokinetics of maropitant were evaluated in beagle dogs dosed orally with Cerenia^® tablets (Pfizer Animal Health) once daily for 14 consecutive days at either 2 mg/kg or 8 mg/kg bodyweight. Noncompartmental pharmacokinetic analysis was performed on the plasma concentration data to measure the AUC_0–24 (after first and last doses), C_t (trough concentration—measured 24 h after each dose), C_max (after first and last doses), t_max (after first and last doses), λ_z (terminal disposition rate constant; after last dose), t_1/2 (after last dose), and CL/F (oral clearance; after last dose). Maropitant accumulation in plasma was substantially greater after fourteen daily 8 mg/kg doses than after fourteen daily 2 mg/kg doses as reflected in the AUC_0–24 accumulation ratio of 4.81 at 8 mg/kg and 2.46 at 2 mg/kg. This is most likely due to previously identified nonlinear pharmacokinetics of maropitant in which high doses (8 mg/kg) saturate the metabolic clearance mechanisms and delay drug elimination. To determine the time to reach steady‐state maropitant plasma levels, a nonlinear model was fit to the least squares (LS) means maropitant C_t values for each treatment group. Based on this model, 90% of steady‐state was determined to occur at approximately four doses for daily 2 mg/kg oral dosing and eight doses for daily 8 mg/kg oral dosing.     

Evaluation of adverse events in small‐breed dogs treated with maropitant and a single dose of doxorubicin

BackgroundThe recommended doxorubicin (DOX) dose for small dogs is 1 mg/kg. Recent data suggest that DOX‐induced gastrointestinal (GI) toxicosis can be reduced with maropitant treatment.ObjectivesTo investigate the incidence of adverse events (AEs) in small‐breed dogs administered a single 25 mg/m² DOX followed by administration of maropitant (DOX25). The primary aim was to assess myelo‐ and GI toxicoses for 2 weeks after DOX administration. The secondary aim was to compare the incidence and grades of AEs found in the DOX25 group with a historical control group (DOX 1 mg/kg without administration of antiemetic or antidiarrheal medications).AnimalsNineteen small‐breed tumor‐bearing dogs.MethodsA prospective, observational study of tumor‐bearing dogs, weighing 5 to 10 kg, administered a single 25 mg/m² dose of DOX IV, followed by administration of maropitant for the next 5 days.ResultsInappetence, vomiting, and diarrhea were found in 7/19, 2/19, and 6/19 of the DOX25 dogs, respectively. Neutropenia and thrombocytopenia was 12/19 and 3/19, respectively. Most AEs were grades 1 and 2, except for grades 3 and 4 inappetence and neutropenia in 3 and 4 dogs, respectively. Furthermore, febrile neutropenia occurred in 3/19 dogs in the DOX25 group. All AEs between the DOX25 and historical control groups were not significantly different.Conclusions and Clinical ImportanceVomiting and diarrhea were deemed acceptable with 25 mg/m² DOX followed by maropitant treatment in 5 to 10 kg dogs; however, additional supportive care might be needed for dogs with inappetence and neutropenia.     

Evaluation of metoclopramide hydrochloride as an aid for passage of a flexible endoscope into the duodenum of dogs.

The purposes of this study were to evaluate the efficacy of metoclopramide to aid passage of a flexible endoscope into the duodenum of dogs, and to determine whether the effect of metoclopramide is dependent on dose. In a randomized, blinded, complete-block design, 6 healthy dogs were anesthetized, then each was given saline solution or 1 of 4 doses of metoclopramide on different days. The ease of passage of a flexible, fiberoptic gastroscope through the pylorus was assessed independently by 3 endoscopists. Administration of metoclopramide hydrochloride at a dosage of 0.4 mg/kg of body weight, iv, made passage of a flexible endoscope into the duodenum significantly (P = 0.009) more difficult than when saline solution was administered; however, dosages of 0.1, 0.2 and 0.8 mg of metoclopramide/kg did not (P = 0.489, 0.842, and 0.092 respectively). It was concluded that metoclopramide did not facilitate, and at one dosage hindered, successful passage of a flexible endoscope into the duodenum of healthy dogs under the conditions of the study. Metoclopramide, therefore, cannot be recommended as an aid for passage of a flexible endoscope into the duodenum of dogs.     

Efficacy of maropitant for treatment and prevention of emesis caused by intravenous infusion of cisplatin in dogs

OBJECTIVE: To evaluate the efficacy of maropitant, a novel neurokinin-1 receptor antagonist, to treat and prevent emesis caused by IV infusion of a chemotherapeutic dose of cisplatin (70 mg/m(2)) in dogs. ANIMALS: 64 healthy 6-month-old Beagles (32 males and 32 females). PROCEDURES: To evaluate the effect of maropitant on ongoing emesis, 24 dogs were randomized to 2 treatment groups (12 dogs each). Saline (0.9% NaCl) solution or maropitant (1 mg/kg) was administered once by SC injection immediately following the first emetic event after cisplatin infusion. Dogs were assessed for emesis for 6 hours after initiation of cisplatin infusion. To evaluate the use of maropitant for the prevention of emesis, 40 dogs were randomized to 4 treatment groups (10 dogs each). Placebo or maropitant (1, 2, or 3 mg/kg) was administered PO as a tablet. Cisplatin infusion was initiated at 19 hours after treatment, and dogs were assessed for emesis for 6 hours. RESULTS: No treatment-related adverse events were observed in either study. For the treatment of ongoing emesis, significantly fewer emetic events were observed for maropitant-treated dogs, compared with placebo-treated dogs (mean, 5.2 vs 15.8), and the mean time to cessation of emesis was significantly shorter (0.65 vs 1.65 hours). In the prevention of emesis, maropitant-treated dogs had significantly fewer emetic events (means, 2.7, 1.1, and 0.5 for maropitant at 1, 2, and 3 mg/kg, respectively), compared with placebo-treated dogs (mean, 20.3). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that maropitant is safe and effective in the treatment and prevention of cisplatin-induced emesis in dogs.     

Pharmacokinetic comparison of oral tablet and suspension formulations of grapiprant,a novel therapeutic for the pain and inflammation of osteoarthritis in dogs

A new anti‐inflammatory drug for pain (grapiprant) was recently shown to have minimal side effects following chronic (9‐month) daily oral dose of 6 or 50 mg/kg suspension. The current study compares the pharmacokinetics of the formulation used in the chronic safety study to those of the tablet formulation that will be marketed upon FDA approval. Sixteen Beagle dogs were randomized to receive single doses of either 6 or 50 mg/kg grapiprant as both suspension and table formulations within a cross‐over design with a 15‐day washout. Clinical observations were vomiting in one high‐dose suspension dog and loose stools in two dogs, one in each 6 mg/kg formulation group. For both formulations, grapiprant reached a maximum concentration within two hours. The tablet formulation had better bioavailability, with AUC_last values 34% higher at 6 mg/kg and 64% higher at 50 mg/kg compared to the suspension. Results on Day 0 were similar to those reported on Day 15, suggesting little to no accumulation. Using conversion factors of 1.34 and 1.64, these findings suggest that the 6 and 50 mg/kg suspension doses are equivalent to 4.5 and 30 mg/kg tableted doses, respectively. Combining these findings with the 9‐month safety study demonstrates that safety was evaluated at doses approximately 15‐fold above the demonstrated therapeutic dose of 2 mg/kg and 10‐fold over the ‘safety dose’, defined as the maximum dose a dog of any body weight could receive when dosed at 2 mg/kg with whole or half‐tablets.     

The pharmacokinetics of maropitant, a novel neurokinin type-1 receptor antagonist, in dogs

Maropitant is the first NK1 receptor antagonist developed to treat and prevent emesis in dogs; it is administered by subcutaneous (s.c.) injection at 1 mg/kg, or orally (p.o.), in tablet form, at either 2 or 8 mg/kg depending on indication. The absolute bioavailability of maropitant was markedly higher (90.7%) following s.c. injection than after oral administration (23.7% at the 2 mg/kg dose and 37.0% at the 8 mg/kg dose). First-pass metabolism contributes to the low bioavailability of maropitant following oral administration. The difference in bioavailability between the two oral doses reflects the nonlinear kinetics characterizing the disposition of maropitant within the 2-8 mg/kg dose range. Systemic clearance of maropitant following intravenous (i.v.) administration was 970, 995 and 533 mL/h.kg at doses of 1, 2 and 8 mg/kg, respectively. Nonproportional kinetics were observed for p.o. administered maropitant at doses ranging from 2 to 16 mg/kg but dose proportionality was demonstrated at higher doses (20-50 mg/kg). Linearity was also demonstrated following s.c. administration at 0.5, 1 and 2 mg/kg. Maximum plasma drug concentration (Cmax) occurred 0.75 h (tmax) after s.c. administration at 1 mg/kg, and at 1.7 and 1.9 h after oral administration of 8 and 2 mg/kg doses, respectively. The apparent terminal half-life of maropitant was 7.75, 4.03 and 5.46 h after dosing at 1 mg/kg (s.c.), 2 mg/kg (p.o.) and 8 mg/kg (p.o.), respectively. Feeding status had no effect on oral bioavailability. Limited accumulation occurred following once-daily administration of maropitant for five consecutive days at 1 mg/kg (s.c.) or 2 mg/kg (p.o.). At the dose of 8 mg/kg (p.o.) once daily for two consecutive days, the mean AUC(0-24h) (second dose) was 218% that of the first dose value. Urinary recovery of maropitant and its main metabolite was minimal (<1%), thus supporting the evidence that maropitant clearance is primarily hepatic.     

Efficacy of injectable maropitant (Cerenia™) in a randomized clinical trial for prevention and treatment of cisplatin-induced emesis in dogs presented as veterinary patients

Chemotherapy‐induced nausea and vomiting (CINV) is a common side‐effect of cisplatin therapy. Maropitant (Cerenia?), a novel neurokinin‐1 receptor antagonist, was evaluated for prevention and treatment of cisplatin‐induced emesis in tumour‐bearing dogs. Dogs (n= 122) were randomly allocated to three treatment groups: T01, placebo before and after cisplatin; T02, placebo before and maropitant after cisplatin; or T03, maropitant before and placebo after cisplatin. Maropitant treatment (T02) following a cisplatin‐induced‐emetic event resulted in significantly fewer subsequent emetic events (P= 0.0005) than in placebo‐treated dogs (T01). In placebo‐treated (T01) dogs, 56.4% were withdrawn from the study because of treatment failure compared with 5.3% in group T02. When maropitant was administered prior to cisplatin treatment (T03) in a prevention regime, 94.9% did not vomit compared with only 4.9% of placebo‐treated dogs, and significantly fewer emetic events (P < 0.0001) were observed in those dogs that did vomit. In summary, maropitant was safe and highly effective in reducing or completely preventing cisplatin‐induced emesis.     

Safety evaluation of orally administered afoxolaner and milbemycin oxime in eight‐week‐old dogs

The safety profile of afoxolaner (an isoxazoline molecule) when combined with milbemycin oxime (a macrocyclic lactone) was evaluated according to the regulatory requirements when administered six times orally in a soft chewable formulation at a dose of at least 1×, 3×, or 5× the maximum exposure dose in 8‐week‐old Beagle dogs. Thirty‐two healthy puppies (16 males and 16 females) were enrolled and allocated randomly to one of four treatment groups. Three doses were administered at 28‐day intervals (Days 0, 28, and 56), followed by three additional doses administered with 14‐day intervals (Days 84, 98, and 112). The study ended on Day 126. Treatment groups were as follows: Group 1: untreated, sham‐dosed control; Group 2: afoxolaner/milbemycin oxime chews administered at a dose of at least 5 and 1 mg/kg, respectively (1×); Group 3: afoxolaner/milbemycin oxime chews administered at a dose of at least 15 and 3 mg/kg, respectively (3); and Group 4: afoxolaner/milbemycin oxime chews administered at a dose of at least 25 and 5 mg/kg, respectively (5×). All dogs were examined for general health twice a day beginning on Day ‐14. Physical examinations, and blood collections for clinical pathology analysis and afoxolaner and milbemycin oxime plasma concentrations, were performed throughout the study. No afoxolaner/milbemycin oxime treatment‐related changes were observed in growth, physical variables, clinical pathology variables, or tissues examined histologically. No clinically relevant or statistically significant health abnormalities related to the administration of afoxolaner/milbemycin oxime were observed. No signs of macrocyclic lactone sensitivity were observed at any time during the study. Vomiting and diarrhea were observed sporadically across all groups including the controls. Based upon the results of this study, afoxolaner/milbemycin oxime soft chewables were shown to be safe when administered repeatedly at up to 5× the maximum exposure dose in dogs as young as 8 weeks of age.     

Pharmacokinetic modeling and Monte Carlo simulation of ondansetron following oral administration in dogs

Ondansetron is a potent antiemetic drug that has been commonly used to treat acute and chemotherapy‐induced nausea and vomiting (CINV) in dogs. The aim of this study was to perform a pharmacokinetic analysis of ondansetron in dogs following oral administration of a single dose. A single 8‐mg oral dose of ondansetron (Zofran^®) was administered to beagles (n = 18), and the plasma concentrations of ondansetron were measured by liquid chromatography‐tandem mass spectrometry. The data were analyzed by modeling approaches using ADAPT5, and model discrimination was determined by the likelihood‐ratio test. The peak plasma concentration (C_max) was 11.5 ± 10.0 ng/mL at 1.1 ± 0.8 h. The area under the plasma concentration vs. time curve from time zero to the last measurable concentration was 15.9 ± 14.7 ng·h/mL, and the half‐life calculated from the terminal phase was 1.3 ± 0.7 h. The interindividual variability of the pharmacokinetic parameters was high (coefficient of variation > 44.1%), and the one‐compartment model described the pharmacokinetics of ondansetron well. The estimated plasma concentration range of the usual empirical dose from the Monte Carlo simulation was 0.1–13.2 ng/mL. These findings will facilitate determination of the optimal dose regimen for dogs with CINV.     

Metoclopramide modifies oral cephalexin pharmacokinetics in dogs

The purpose of this study was to investigate whether previous administration of metoclopramide affects cephalexin pharmacokinetics after its oral administration in dogs as well as whether these changes impair its predicted clinical efficacy. Six healthy beagle dogs were included in this study. Oral 25 mg/kg cephalexin monohydrate and intravenous 0.5 mg/kg metoclopramide HCl single doses were administered. Each dog received cephalexin or cephalexin following metoclopramide, with a 2-week washout period. Plasma concentrations of cephalexin were determined by microbiological assay. Cephalexin peak plasma concentration and area under the curve from 0 to infinity significantly increased from 18.77+/-2.8 microg/mL and 82.65+/-10.4 microg.h/mL to 21.88+/-0.8 microg/mL and 113.10+/-20.9 microg.h/mL, respectively, after pretreatment with metoclopramide. No differences between treatments were found for other pharmacokinetic parameters. Pharmacokinetic/pharmacodynamic indices calculated for highly susceptible staphylococci were similar for both experiences. Metoclopramide pretreatment may have increased cephalexin absorption by affecting its delivery to the intestine, and/or enhancing intestinal transporter PEPT1 function. Neither difference in the efficacy of cephalexin nor an increase in toxicity is expected as a result of this modification. Consequently, no dose adjustment is required in cephalexin-treated patients pretreated with metoclopramide.     

Effect of combinations of morphine,dexmedetomidine and maropitant on the electroencephalogram in response to acute electrical stimulation in anaesthetized dogs

This study was conducted to compare the efficacy of combinations of morphine, dexmedetomidine and maropitant in preventing the changes in electroencephalographic (EEG) indices of nociception in anaesthetized dogs subjected to a noxious electrical stimulus. In a crossover study, eight healthy adult dogs were randomly allocated to four groups: Mor: morphine 0.6 mg/kg; Dex + Mor: morphine 0.3 mg/kg + dexmedetomidine 5 μg/kg; Maro + Mor: morphine 0.3 mg/kg + maropitant 1 mg/kg; and Dex + Maro + Mor: morphine 0.2 mg/kg + dexmedetomidine 3 μg/kg + maropitant 0.7 mg/kg. Following intramuscular administration of test drugs in a minimal anaesthesia model, a supramaximal electrical stimulus (50 V at 50 Hz for 2 s) was applied and the EEG data were recorded. There were significant increases (p < .05) in the poststimulus median frequency (F50) only in groups Mor and Maro + Mor. Dex + Mor group had a significantly lower change in F50 and F95 compared to all other treatment groups. There was no correlation of the changes in EEG frequencies with blood plasma concentration of the drugs during and after noxious stimulation. Combination of dexmedetomidine and morphine was most effective in abolishing the changes in EEG indices in response to a noxious stimulus indicating a supra-additive interaction between these two drugs.     

Pharmacokinetics of morphine in combination with dexmedetomidine and maropitant following intramuscular injection in dogs anaesthetized with halothane

The purpose of this study was to evaluate the pharmacokinetics of morphine in combination with dexmedetomidine and maropitant injected intramuscularly in dogs under general anaesthesia. Eight healthy dogs weighing 25.76 ± 3.16 kg and 3.87 ± 1.64 years of age were used in a crossover study. Dogs were randomly allocated to four groups: (1) morphine 0.6 mg/kg; (2) morphine 0.3 mg/kg + dexmedetomidine 5 μg/kg; (3) morphine 0.3 mg/kg + maropitant 1 mg/kg; (4) morphine 0.2 mg/kg + dexmedetomidine 3 μg/kg + maropitant 0.7 mg/kg. Blood samples were collected before, 15 and 30 min, and 1, 2, 3 4, 6 and 8 hr after injection of the test drugs. Plasma concentration of the drugs was determined by liquid chromatography-mass spectrometry. The elimination half-life (T_1/2) of morphine was higher and the clearance rate (CL) was lower when combined with dexmedetomidine (T_1/2 = 77.72 ± 20.27 min, CL = 119.41 ± 23.34 ml kg⁻¹ min⁻¹) compared to maropitant (T_1/2 = 52.73 min ± 13.823 ml kg⁻¹ min⁻¹, CL = 178.57 ± 70.55) or morphine alone at higher doses (T_1/2 = 50.53 ± 12.55 min, CL = 187.24 ± 34.45 ml kg⁻¹ min⁻¹). Combining morphine with dexmedetomidine may increase the dosing interval of morphine and may have a clinical advantage.     

Oral,subcutaneous, and intravenous pharmacokinetics of ondansetron in healthy cats

Ondansetron is a 5‐HT₃ receptor antagonist that is an effective anti‐emetic in cats. The purpose of this study was to evaluate the pharmacokinetics of ondansetron in healthy cats. Six cats with normal complete blood count, serum biochemistry, and urinalysis received 2 mg oral (mean 0.43 mg/kg), subcutaneous (mean 0.4 mg/kg), and intravenous (mean 0.4 mg/kg) ondansetron in a cross‐over manner with a 5‐day wash out. Serum was collected prior to, and at 0.25, 0.5, 1, 2, 4, 8, 12, 18, and 24 h after administration of ondansetron. Ondansetron concentrations were measured using liquid chromatography coupled to tandem mass spectrometry. Noncompartmental pharmacokinetic modeling and dose interval modeling were performed. Repeated measures anova was used to compare parameters between administration routes. Bioavailability of ondansetron was 32% (oral) and 75% (subcutaneous). Calculated elimination half‐life of ondansetron was 1.84 ± 0.58 h (intravenous), 1.18 ± 0.27 h (oral) and 3.17 ± 0.53 h (subcutaneous). The calculated elimination half‐life of subcutaneous ondansetron was significantly longer (P < 0.05) than oral or intravenous administration. Subcutaneous administration of ondansetron to healthy cats is more bioavailable and results in a more prolonged exposure than oral administration. This information will aid management of emesis in feline patients.