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

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 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.     

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.     

Anti-emetic drug maropitant induces intestinal motility disorder but not anti-inflammatory action in mice

Maropitant is a neurokinin 1 receptor (NK1R) antagonist that is clinically used as a new anti-emetic drug for dogs. Substance P (SP) and its receptor NK1R are considered to modulate gastrointestinal peristalsis. In addition, SP works as an inflammatory mediator in gastrointestinal diseases. Aim of this study is to clarify the effects of maropitant on intestinal motility and inflammation in mice. Ex vivo examination of luminal pressure-induced intestinal motility of whole intestine revealed that maropitant (0.1–10 µM) increased frequency of contraction, decreased amplitude of contraction and totally inhibited motility index in a concentration-dependent manner. We measured intestinal transit in vivo by measuring transportation of orally administered luminal content labeled with phenol red. Our results demonstrated that maropitant (10 mg/kg, SC) delayed intestinal transit. Geometric center value was significantly decreased in maropitant-treated mice. Anti-inflammatory effects of maropitant against leukocytes infiltration into the intestinal smooth muscle layer in post-operative ileus (POI) model mice were measured by immunohistochemistry. In POI model mice, a great number of CD68-positive macrophages or MPO-stained neutrophils infiltrated into the inflamed muscle region of the intestine. However, in the maropitant treated mice, the infiltration of leukocytes was not inhibited. The results indicated that maropitant has ability to induce disorder of intestinal motility in mice, but has no anti-inflammatory action in the mouse of a POI model. In conclusion, in mice, maropitant induces disorder of intestinal motility in vivo.     

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 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.     

Neurokinin‐1 receptor expression and antagonism by the NK‐1R antagonist maropitant in canine melanoma cell lines and primary tumour tissues

We interrogated the neurokinin‐1 receptor (NK‐1R)/substance P (SP) pathway in canine melanoma tumour tissues and cell lines. NK‐1R messenger RNA (mRNA) and protein expression were observed in the majority of tumour tissues. Immunohistochemical assessment of archived tissue sections revealed NK‐1R immunoreactivity in 11 of 15 tumours, which may have diagnostic, prognostic and therapeutic utility. However, we were unable to identify a preclinical in vitro cell line or in vivo xenograft model that recapitulates NK‐1R mRNA and protein expression documented in primary tumours. While maropitant inhibited proliferation and enhanced apoptosis in cell lines, in the absence of documented NK‐1R expression, this may represent off‐target effects. Furthermore, maropitant failed to suppress tumour growth in a canine mouse xenograft model derived from a cell line expressing mRNA but not protein. While NK‐1R represents a novel target, in the absence of preclinical models, in‐species clinical trials will be necessary to investigate the therapeutic potential for antagonists such as maropitant.     

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.     

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.     

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.     

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.     

Effect of epidural and intravenous use of the neurokinin-1 (NK-1) receptor antagonist maropitant on the sevoflurane minimum alveolar concentration (MAC) in dogs

ObjectiveTo determine the effect of maropitant, an NK-1 receptor antagonist on the minimum alveolar concentration (MAC) of sevoflurane after intravenous and epidural administration to dogs.Study designProspective experimental study.AnimalsSeven, adult, spayed-female dogs (24.8 ± 1.9 kg).MethodsEach dog was anesthetized twice with sevoflurane in oxygen, with at least 10 days separating the anesthetic events. The minimum alveolar concentration (MAC) of sevoflurane was determined using the tail-clamp technique. During the first anesthetic event, the MAC of sevoflurane was determined initially and again after intravenous administration of maropitant (5 mg kg^?1) and an infusion (150 μg kg^?1 hour^?1). During the second anesthetic event, an epidural catheter was advanced to the 4th lumbar vertebra and MAC was determined after administration of saline and maropitant (1 mg kg^?1) epidurally. All MAC determinations were done in duplicate. The MAC values were adjusted to sea level and compared using student's t-test.ResultsThe baseline MAC for sevoflurane was 2.08 ± 0.25%. Intravenous maropitant decreased (p < 0.05) MAC by 16% (1.74 ± 0.17%). In contrast, epidural administration of either saline or maropitant did not change (p > 0.05) the MAC (2.17 ± 0.34% and 1.92 ± 0.12%, respectively).Conclusion and clinical relevanceMaropitant decreased the MAC of sevoflurane when administered intravenously to dogs but not after epidural administration.     

Kinetic gait and subjective analysis of the effects of a tachykinin receptor antagonist in dogs with sodium urate-induced synovitis

OBJECTIVE: To examine the ability of preemptive administration of a proprietary neurokinin-1 (NK(1)) receptor antagonist to attenuate limb dysfunction associated with monosodium urate-induced synovitis in the stifle joints of dogs. ANIMALS: 16 clinically normal adult mixed-breed dogs (8 males and 8 females). PROCEDURES: A crossover study was conducted in 2 phases. Dogs were assigned to 2 groups (8 dogs/group) and orally administered an NK(1) receptor antagonist (3 mg/kg) or a control substance once daily for 4 days. Synovitis was then induced in the left stifle joint by intra-articular injection of monosodium urate. Investigators were not aware of treatment group assignments. Dogs were evaluated by use of subjective lameness scores during standing, walking, and trotting and by use of ground reaction force data 3, 6, 9, 12, and 24 hours after urate injection. After a 21-day washout period, the experiment was repeated with each dog administered the other treatment and injected with monosodium urate in the contralateral stifle joint. RESULTS: No significant differences were detected between the NK(1) receptor antagonist and control treatments with regard to peak vertical force, vertical impulse area, or subjective evaluations of lameness during standing, walking, or trotting, except during walking 24 hours after monosodium urate injection. CONCLUSIONS AND CLINICAL RELEVANCE: Preemptive administration of an NK(1) receptor antagonist failed to significantly improve subjective or objective outcome measures in dogs with monosodium urate-induced synovitis.     

Comparative efficacy of metoclopramide,ondansetron and maropitant in preventing parvoviral enteritis‐induced emesis in dogs

The aim of the study was to evaluate the efficiencies of selected anti‐emetic drugs (metoclopramide, ondansetron and maropitant) in preventing vomiting in the treatment of canine parvoviral enteritis. We designed a randomized, prospective clinical study. PVE quick ELISA test‐positive dogs between 4 and 12 months of age were included in the study. Each of metoclopramide, ondansetron, maropitant and control group had 8 dogs. Metoclopramide and ondansetron were administered as 0.5 mg/kg doses three times a day via intravenous route, and maropitant was administered as 1 mg/kg doses once a day subcutaneously. The number and severity of daily vomitings were recorded. All dogs were treated and monitored for five days; treatments were continued until all animals healed. Metoclopramide, ondansetron and maropitant decreased the severity of vomiting from the first day and the vomiting numbers from the third day in PVE treatment. Obtained results showed that maropitant can be used successfully such as metoclopramide and ondansetron, which are frequently used for PVE treatment. At the same time, it was discovered that metoclopramide, ondansetron and maropitant were equally effective in reducing the frequency and severity of vomiting.     

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.     

Characterisation of the response of equine digital arteries and veins to substance P

Substance P (SP), a potent vasodilator, has been detected in equine digital sensory-motor nerves. The aim of the study was to characterise the functional responses of equine digital blood vessels to exogenous SP. Pre-constricted equine digital arteries (EDA) and veins (EDV) vasodilated in a biphasic, endothelium- and concentration-dependent manner to SP. A nitric oxide (NO) synthase inhibitor Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME; 300 microm) inhibited both phases of the relaxation response curve of EDAs to SP by >70%. In EDVs, the first relaxant phase to SP was largely L-NAME-resistant, whereas the second phase was inhibited by 60%. Both L-NAME and a cyclo-oxygenase inhibitor (ibuprofen; 10 microm) were required to inhibit EDV relaxation to SP by > or =80%. Experiments determining the receptor mediated responses to physiological concentrations of SP (1 nm) revealed that the relaxant responses of both EDA and EDV were inhibited by a neurokinin-1 (NK1) receptor antagonist (CP-96 345; 10 nm). In conclusion, SP is an endothelium-dependent vasodilator of both EDA and EDV. NO is the predominant pathway activated in EDA, whereas both prostacyclin and NO pathways are involved in EDVs. NK1 receptors appear to mediate responses to low concentrations of SP.     

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.     

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.     

Food intake and rumen motility in dwarf goats. Effects of some serotonin receptor agonists and antagonists

The serotonergic regulation of feeding behaviour has not so far been studied in ruminants. Therefore, the effects of some serotonin (5-HT) receptor agonists and antagonists on food intake and forestomach motility were studied in dwarf goats.Goats ate less food when treated intravenously (IV) with the 5-HT precursor 5-HTP (25 µg, 50 µg or 100 µg kg^–1 min^–1 over 15 min) than when they were treated with 5-HT (which does not pass the blood-brain barrier) or with saline. Accordingly, IV dexfenfluramine infusions (50 µg or 100 µg kg^–1 min^–1 over 15 min), which induces release of brain 5-HT, also led to dose-related reductions in food intake. In contrast, no anorectic effects were observed after IV infusions with the selective 5-HT reuptake inhibitor fluoxetine (100 µg kg^–1 min^–1 over 15 min), the selective 5-HT1A agonist 8-OH-DPAT (0.5 µg kg^–1 min^–1 over 15 min), or eltoprazine (4 or 8 µg kg^–1 min^–1 over 15 min), a mixed 5-HT1A/5HT1B receptor agonist. None of the 5-HT antagonists tested gave any increase in food consumption in this model. Interestingly, the non-selective 5-HT receptor antagonist methysergide (360 µg/kg IV) reduced food intake. This effect was most noticeable at 3 h after injection. The 5-HT3 receptor antagonist ondansetron (IV 10 µg kg^–1 min^–1 over 15 min) and the peripheral 5-HT2 receptor antagonist xylamidine (IV 100 µg kg^–1 min^–1 over 10 min) failed to modify food intake. These results provide evidence for central serotonergic involvement in the control of feeding. However, this control system differs markedly in goats and rodents.Dexfenfluramine, 5-HTP and eltoprazine administered at similar dose rates to those used in the food intake experiments induced some clinical signs including inhibition of forestomach contractions. These results, together with our earlierin vivo andin vitro observations, suggest that the inhibitory effects of serotonin receptor agonists on forestomach contractions are due to interactions with both peripheral and central serotonergic receptors. The change in smooth muscle tension, which leads to a change in the signals transmitted via vagal afferents to the central nervous system, appears not to modify feeding behaviour in dwarf goats.     

Adenosine A2A receptor agonists inhibit lipopolysaccharide-induced production of tumor necrosis factor-alpha by equine monocytes

Adenosine is an endogenous nucleoside that regulates many physiological processes by activating one or more adenosine receptor subtypes, namely A1, A2A, A2B and A3. The results of previous studies indicate that adenosine analogues inhibit lipopolysaccharide (LPS)-induced production of reactive oxygen species (ROS) by equine neutrophils primarily through activation of A2A receptors. Because peripheral blood monocytes produce cytokines that are responsible for many of the deleterious effects of LPS, the current study was performed to evaluate the effects of an array of novel adenosine receptor agonists on LPS-induced production of tumor necrosis factor-alpha (TNF-alpha), and to assess the selectively of these agonists for equine adenosine A2A over the A1 receptor. Radioligand binding studies performed with equine tissues expressing adenosine A1 and A2A receptor subtypes yielded a rank order of affinity for the equine A2A receptor of ATL307>ATL309 approximately ATL310 approximately ATL313>ATL202 approximately ATL361 approximately ATL376>ATL372>CGS21680>NECA. Co-incubation of equine peripheral blood monocytes with LPS and these agonists resulted in inhibition of TNF-alpha production with a rank order of potency that strongly correlated with their binding affinities for equine adenosine A2A receptors. Results of experiments performed with one of the adenosine receptor agonists (ATL313) and selective adenosine receptor antagonists confirmed that inhibition of LPS-induced production of TNF-alpha occurred via stimulation of A2A receptors. Although incubation of monocytes with IB-MECA, a compound purported to act as an adenosine A3 receptor agonist, reduced LPS-induced TNF-alpha production, this effect of IB-MECA was inhibited by the A2A selective antagonist ZM241385 but not by the A3 receptor antagonist MRS1220. These results indicate that the adenosine receptor subtype responsible for regulation of LPS-induced cytokine production by equine monocytes is the A2A receptor. To address the signal transduction mechanism responsible for the anti-inflammatory effects of ATL313 in equine monocytes, production of cAMP was compared in the presence and absence of either the adenosine A2A receptor antagonist ZM241385 or the adenosine A2B receptor antagonist MRS1706. In the absence of the antagonists, ATL313 increased production of cAMP; ZM241385 inhibited this effect of ATL313, whereas MRS1706 did not. Furthermore, incubation of monocytes with either the stable analogue of cAMP, dibutyryl cAMP, or forskolin, an activator of adenylyl cyclase, also inhibited LPS-induced production of TNF-alpha production by equine monocytes. Collectively, the results of the current study indicate that adenosine analogues inhibit LPS-induced production of TNF-alpha by equine monocytes primarily via activation of adenosine A2A receptors and do so in a cAMP-dependent manner. The results of this study indicate that stable adenosine analogues that are selective for adenosine A2A receptors may be suitable for development as anti-inflammatory drugs in horses.