Preclinical pharmacokinetics of benznidazole-loaded interpolyelectrolyte complex-based delivery systems.

Benznidazole (BZ), first-line drug for Chagas treatment, is available as immediate-release tablets. High frequency of administration, long-term therapy, and side effects of BZ conspire against treatment adherence, and negatively impact in therapeutic success. We have developed BZ-loaded interpolyelectrolyte complexes (IPECs) composed of polymethacrylates (EE-EL-BZ) or polysaccharides (Ch-AA-BZ) for controlled BZ release. This work aimed to evaluate their preclinical pharmacokinetics compared to Abarax® (reference treatment) and to correlate them with the in vitro BZ release. A randomization schedule with a 3 × 2 cross-over design was used. Each healthy dog received a single oral dose of 100 mg of BZ from EE-EL-BZ, Ch-AA-BZ or Abarax®. BZ quantification was performed in plasma by a validated HPLC-UV method. Moreover, in silico simulations using the pharmacokinetic software PK Solutions 2.0™ were calculated for the multiple-dose administration at two dose regimens: 100 mg of BZ administered every 12 and 24 h. Also, the relationship between in vitro dissolution and in vivo plasma BZ concentration profiles in a single step was model for IVIVC analysis. BZ was rapidly absorbed from all formulations. The Cmax value for Ch-AA-BZ was 32% higher than reference (p < 0.05) and an earlier Tmax (4.2 h) was observed as compared to EE-EL-BZ (6.0 h). For both IPECs, the Tmax values were higher (p < 0.05) and the areas under the curve were 25% greater than those of Abarax® (p < 0.01). Despite these variations in pharmacokinetics parameters, simulations of once or twice daily dosing showed that all formulations reached a steady-state range concentration above of the minimum therapeutic dose while avoiding high BZ concentrations related to increased side effects. A linear level A IVIVC model was established using plasma concentration profiles and dissolved data obtained. Thus, BZ-loaded IPECs prolonged drug release and formulated as capsules showed improved in vivo performance, in terms of bioavailability and Tmax values, which were significantly higher compared to Abarax®. These BZ carrier systems would be useful for oral administration in the treatment of Chagas disease.

A comparison between maropitant and metoclopramide for the prevention of morphine-induced nausea and vomiting in dogs.

Morphine is widely used as a preanesthetic agent in dogs, but it often produces signs of nausea and vomiting. Maropitant (MRP) and metoclopramide (MCP) prevent emesis attributable to the opioid agent apomorphine in dogs. We evaluated the antiemetic efficacy and the discomfort in response to SQ injection of MRP [1 mg/kg body weight (BW)], MCP (0.5 mg/kg BW), and normal saline (SAL; 0.1 mL/kg BW) administered to 63 dogs, 45 minutes prior to morphine (0.5 mg/kg BW) and acepromazine (0.05 mg/kg BW). Dogs were observed for signs of nausea (ptyalism, lip licking, and increased swallowing) and vomiting for 30 minutes after morphine/acepromazine. The incidence of emesis was 0% for MRP, 38% for MCP, and 71% for SAL (P < 0.001). The incidence of signs of nausea was not different between groups. Discomfort due to injection was higher after MRP (48%), than after MCP (9.8%) and SAL (4.8%) (P < 0.001).

Comparaison entre le maropitant et la métoclopramide pour la prévention de nausée et des vomissements induits par la morphine chez les chiens. La morphine est largement utilisée comme agent pré-anesthésique chez les chiens, mais elle produit souvent des symptômes de nausée et de vomissements. Le maropitant (MRP) et la métoclopramide (MCP) préviennent le vomissement causé par l'agent opioïde apomorphine chez les chiens. Nous avons évalué l'efficacité antiémétique et l'inconfort en réponse à une injection SC de MRP [1 mg/kg de poids corporel (PC)], de MCP (0,5 mg/kg PC) et d'une solution saline normale (SAL; 0,1 mL/kg PC) administrée à 63 chiens, 45 minutes avant la morphine (0,5 mg/kg PC) et l'acépromazine (0,05 mg/kg PC). Les chiens ont été observés pour détecter des signes de nausée (ptyalisme, lèchement des lèvres et déglutition accrue) et le vomissement pendant 30 minutes après l'administration de morphine/acépromazine. L'incidence du vomissement était de 0 % pour MRP, de 38 % pour MCP et de 71 % pour SAL (P < 0,001). L'incidence des signes de nausée n'était pas différente entre les groupes. L'inconfort attribuable à l'injection était supérieur après MRP (48 %) par rapport à celui après MCP (9,8 %) et SAL (4,8 %) (P < 0,001).(Traduit par Isabelle Vallières).

Evaluation of the antiemetic efficacy of maropitant in dogs medicated with morphine and acepromazine.

OBJECTIVE: To evaluate whether maropitant (1 mg kg(-1)) injected subcutaneously (SC), administered simultaneously or 30 minutes prior to intramuscular (IM) administration of morphine (0.5 mg kg(-1)) and acepromazine (0.05 mg kg(-1)), reduces the incidence of salivation, retching and emesis in dogs. STUDY DESIGN: Randomized, controlled, prospective clinical trial. ANIMALS: Sixty dogs scheduled for an ovariohysterectomy as part of a population control program. METHODS: Dogs were randomly allocated to be administered maropitant (1 mg kg(-1)) SC simultaneously (group M0) or 30 minutes prior to (group M30) administration of morphine (0.5 mg kg(-1)) and acepromazine (0.05 mg kg(-1)) IM. A control group was administered normal saline (C) at T-30 and T0. Dogs were observed for 30 minutes after morphine-acepromazine administration. The occurrence of vomiting, retching and salivation were recorded, as well as the time to first emesis and the number of emetic events per dog. RESULTS: The occurrence of salivation was not different between the groups. Retching and vomiting occurred significantly less frequently in M30 than in the other two groups (p < 0.02). The number of emetic events was also significantly less for M30 than for the other two groups (p = 0.01). When emesis occurred, the time to the first emetic event was similar among the groups. CONCLUSIONS AND CLINICAL RELEVANCE: Maropitant (1 mg kg(-1)) SC reduced the frequency of morphine-induced emesis by as much as 70% when administered 30 minutes in advance. Simultaneous administration of maropitant and morphine-acepromazine produced no measurable effect on the frequency of retching or vomiting.

Evaluation of neostigmine antagonism at different levels of vecuronium-induced neuromuscular blockade in isoflurane anesthetized dogs.

Residual neuromuscular block (NMB) during recovery from general anesthesia may be minimized by antagonizing NMB with neostigmine. We examined neostigmine for restoring neuromuscular function when administered at 2 levels of vecuronium-induced NMB in dogs. Eight healthy adult dogs received vecuronium 0.1 mg/kg body weight (BW), IV, during isoflurane anesthesia. Recovery from vecuronium occurred spontaneously (control group; C), or was enhanced with neostigmine, 0.04 mg/kg BW, IV, administered when 2 (N2) or 4 (N4) responses to train-of-four (TOF) stimulation were first observed. Duration of NMB was significantly shorter for N2 and N4 than for C. The period of complete NMB was equal for all groups; differences were observed during the recovery phase of NMB. Time of neostigmine-enhanced recovery was significantly shorter for N4 than N2, but overall duration of NMB was not reduced. Recovery from NMB was faster with neostigmine. There is no clinical advantage in delaying neostigmine administration once 2 responses to TOF are present.

Évaluation de l'antagonisme de la néostigmine à différents niveaux de blocage neuromusculaire induits par vécuronium chez les chiens anesthésiés à l'isoflurane. Le bloc neuromusculaire résiduel (BNR) durant le réveil de l'anesthésie générale peut être minimisé en antagonisant le BNR avec de la néostigmine. Nous avons examiné la néostigmine pour le rétablissement de la fonction neuromusculaire lors de l'administration à 2 niveaux de BNR induit par le vécuronium chez les chiens. Huit chiens adultes en santé ont reçu du vécuronium 0,1 mg/kg poids corporel (PC), IV, durant l'anesthésie à l'isoflurane. Le réveil de vécuronium s'est produit spontanément (groupe témoin; C) ou a été rehaussé avec de la néostigmine, 0,04 mg/kg PC, IV, administrée lorsque des réponses 2 (N2) ou 4 (N4) à une stimulation de quatre impulsions «train-of-four¼ (TOF) ont d'abord été observées. La durée du BNR a été significativement écourtée pour N2 et N4 par rapport à C. La période du BNR complet a été égale pour tous les groupes; les différences ont été observées durant la phase de réveil de BNR. La durée du réveil rehaussée à la néostigmine a été significativement écourtée pour N4 par rapport à N2, mais la durée globale de BNR n'a pas été réduite. Le réveil du BNR a été plus rapide avec la néostigmine. Il n'y a pas d'avantage clinique à retarder l'administration de la néostigmine une fois que 2 réponses à TOF sont présentes.(Traduit par Isabelle Vallières).