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.     

Effect of maropitant,a neurokinin‐1 receptor antagonist,on the minimum alveolar concentration of sevoflurane during stimulation of the ovarian ligament in cats

ObjectiveDetermine if maropitant decreases the minimum alveolar concentration (MAC) of sevoflurane during stimulation of the ovarian ligament in cats.Study designProspective study.AnimalsFifteen, female cats weighing 2.5 ± 0.6kg (mean ± SD).MethodsAnesthesia was induced and maintained with sevoflurane. The right ovary was accessed via laparoscopy. A suture around the ovary and ovarian ligament was exteriorized through the abdominal wall for stimulation. A stimulus–response curve was created to identify the optimal force for MAC comparisons. In 10 cats, MAC was determined with only sevoflurane (baseline) then after 1 and 5 mg kg^?1 intravenous maropitant administration. The stimulation tension force used was 4.9 N. Repeated measures anova was used to compare the groups. MAC was defined as the average of the cross‐over concentrations and reported MAC is adjusted to sea‐level and depicted as mean ± SD.ResultsThe stimulus‐response curve was hyperbolic and plateaued at 4.3 ± 3 N. The optimal tension force chosen to compare MAC was 4.9 N. The baseline sevoflurane MAC was 2.96 ± 0.3%. Maropitant, 1 mg kg^?1, decreased the MAC to 2.51 ± 0.3% (15%, p < 0.01). The higher maropitant dose of 5 mg kg^?1 did not change MAC further when compared to the low dose (2.46 ± 0.4%, p = 0.33).Conclusion and clinical relevanceThe ovarian ligament stimulation model is suitable to determine MAC during visceral stimulation in cats. Maropitant decreased the anesthetic requirements during visceral ovarian and ovarian ligament stimulation in cats. Maropitant (1 mg kg^?1) decreases MAC by 15%; a higher dose had no additional effect.     

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.     

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.     

Distribution of the neurokinin-1 receptor in equine intestinal smooth muscle

REASON FOR PERFORMING STUDY: Tachykinins have profound effects on equine intestinal motility, but the distribution of the neurokinin receptors (NKRs) through which they act is unknown. This study reports the distribution of one of these receptors, the neurokinin-1 receptor (NK1R), in smooth muscle throughout the equine intestinal tract. OBJECTIVES: To quantify the distribution of the NK1R, based upon mRNA expression, in smooth muscle of different regions of the equine intestinal tract. METHODS: Nine regions of the intestinal tract were sampled in 5 mature horses. Total RNA was isolated from smooth muscle and reverse transcribed; NK1R mRNA was then quantified using real-time PCR. RESULTS: NK1R mRNA was found at all levels of the sampled intestinal tract. The smooth muscle of the proximal small intestine and the ventral colon exhibited the highest level of NK1R mRNA expression in the equine intestinal tract. CONCLUSIONS: Tachykinins probably affect intestinal contractility and propulsion in the proximal small intestine and in the ventral colon.     

Time-dependent changes in inhibitory action of lipopolysaccharide on intestinal motility in rat

Endotoxin causes gastrointestinal motility disorder. Aim of this study is to clarify inhibitory mechanisms of lipopolysaccharide (LPS) on smooth muscle contraction in rat ileum. Ileal tissues were isolated from control rat or from LPS-induced peritonitis model rat. Treatment with LPS inhibited carbachol (CCh)-mediated contraction in a time-dependent manner. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) genes were also upregulated, but iNOS expression was preceded by a rising of COX-2. All subtypes of prostaglandin E₂ (PGE₂) receptors (EP1-EP4) were expressed in ileum, and PGE₂ and selective EP2 or EP4 agonist inhibited CCh-mediated contraction. Selective iNOS inhibitor did not reverse LPS-induced inhibition of contraction by CCh at 1 and 2 hr, but reduced the inhibitory action at 4 hr after the LPS treatment. COX-2 inhibitor reversed the inhibitory action by LPS in all exposure time. Finally, in ileal tissues isolated from peritonitis model rat, iNOS expression was upregulated only at 4 hr after LPS administration, resulting in enhanced inhibitory action of LPS against CCh-induced contraction. In conclusion, LPS induces COX-2 to produce PGE₂, which initially activates EP2 and/or EP4 on smooth muscle cells to inhibit the contractility in early phase of LPS exposure. Moreover, in late phase of LPS treatment, iNOS is expressed to produce NO, which in turn inhibited the contraction by CCh. The inhibitory cascade is similar in the ileum isolated from peritonitis model rat, indicating time-dependent changes of inhibitory action by LPS on intestinal motility in peritonitis.     

Polysaccharides from Acanthopanax senticosus enhances intestinal integrity through inhibiting TLR4/NF‐κB signaling pathways in lipopolysaccharide‐challenged mice

To investigate the role of polysaccharide from Acanthopanax senticosus (ASPS) on lipopolysaccharide (LPS)‐induced intestinal injury, mice in three treatments were administrated orally with or without ASPS (300 mg/kg body weight) for 14 days, followed by challenge with LPS or saline. At 4 h post‐injection, blood and intestinal samples of six mice / treatment were collected. The results showed ASPS ameliorated LPS‐induced intestinal morphological deterioration, proven by improved villus height (P < 0.05) and villus height : crypt depth ratio (P < 0.05). ASPS also elevated the mucosal barrier of LPS‐challenged mice, supported by reduced plasma diamine oxidase (DAO) activity (P < 0.05) and L‐lactate (P < 0.05), increased mucosal DAO activity (P < 0.05) as well as enhanced intestinal tight junction proteins expression involving occludin‐1 (P < 0.05) and zonula occludens‐1 (P < 0.05). In addition, ASPS decreased LPS‐induced secretion of inflammatory mediators, including tumor necrosis factor (TNF)‐α (P < 0.05) and prostaglandin E₂ (P < 0.05). Also, ASPS down‐regulated messenger RNA expression of toll‐like receptor 4 (TLR4) and its downstream signals, including myeloid differentiation factor 88 (P < 0.05), TNF‐α receptor‐associated factor 6 (P < 0.05), as well as nuclear factor (NF)‐κB p65 (P < 0.05) and its protein expression. These findings suggest that ASPS improves intestinal integrity under inflammation conditions connected with inhibiting TLR4/NF‐κB signaling pathways.