A possible solution to model nonlinearity in elimination and distributional clearances with α2 -adrenergic receptor agonists: Example of the intravenous detomidine and methadone combination in sedated horses.

The alpha(α)2 -agonist detomidine is used for equine sedation with opioids such as methadone. We retrieved the data from two randomized, crossover studies where detomidine and methadone were given intravenously alone or combined as boli (STUDY 1) (Gozalo-Marcilla et al., 2017, Veterinary Anaesthesia and Analgesia, 2017, 44, 1116) or as 2-hr constant rate infusions (STUDY 2) (Gozalo-Marcilla et al., 2019, Equine Veterinary Journal, 51, 530). Plasma drug concentrations were measured with a validated tandem Mass Spectrometry assay. We used nonlinear mixed effect modelling and took pharmacokinetic (PK) data from both studies to fit simultaneously both drugs and explore their nonlinear kinetics. Two significant improvements over the classical mammillary two-compartment model were identified. First, the inclusion of an effect of detomidine plasma concentration on the elimination clearances (Cls) of both drugs improved the fit of detomidine (Objective Function Value [OFV]: -160) and methadone (OFV: -132) submodels. Second, a detomidine concentration-dependent reduction of distributional Cls of each drug further improved detomidine (OFV: -60) and methadone (OFV: -52) submodel fits. Using the PK data from both studies (a) helped exploring hypotheses on the nonlinearity of the elimination and distributional Cls and (b) allowed inclusion of dynamic effects of detomidine plasma concentration in the model which are compatible with the pharmacology of detomidine (vasoconstriction and reduction in cardiac output).

Validation of the Italian version of the UNESP-Botucatu multidimensional composite pain scale for the assessment of postoperative pain in cats.

The study described in this paper had the goal to validate the Italian version of the UNESP-Botucatu multidimensional composite pain scale (UNESP-Botucatu MCPS) to assess postoperative pain in cats using video analysis and psycometric testing. The English version of the scale was translated into Italian. Thirty videos of the perioperative period of ovariohysterectomy surgery were analysed by 5 Italian observers with the aim to determine the pain score using the Italian version of the scale and to verify the need for analgesic treatment for each cat. Obtained scores were submitted to psycometric validity, responsiveness, and reliability tests. Of the 3 domains identified by factor analysis, the internal consistency was excellent for 'Psychomotor changes' and 'Protection of the painful area and vocal expressions of pain', while 'Physiological variables' showed moderate internal consistency. Significant changes in pain scores in response to surgery and analgesics confirmed content and construct validity. The agreement between the 'gold standard' and the blinded observers supported the criterion validity. Inter- and intra-rater reliability ranged from good to very good for all scale items. The cut-off point for rescue analgesia was > 7. The study concluded that the Italian version of the UNESP-Botucatu MCPS is a valid and reliable instrument for assessing postoperative pain in cats. The cut-off point for rescue analgesia provides an additional tool for guiding analgesic therapy.

Estudo da romifidina ou xilazina associadas à cetamina em cães pré-tratados com atropina, submetidos ou não à ovario-histerectomia

Estudou-se o efeito cardiorrespiratório das associações de romifidina ou xilazina e cetamina em 12 cães clinicamente sadios.Seis animais receberam como medicação pré-anestésica (MPA) 0,05 mg/kg de atropina por via subcutânea (SC), seguido daassociação de O, 1 mg/kg de romifidina e 15 mg/kg de cetamina por via intramuscular- ARC {IM) e seis animais receberam 0,05mg/kg de atropina SC, seguido de 1 rilg/kg de xilazina e 15 mg/kg de cetamina IM - AXC. Os parâmetros cardiorrespiratóriosforam avaliados antes da MPA e a cada 15 minutos por 120 minutos. Os protocolos anestésicos produziram hipotermia ehipercapnia com conseqüente acidose respiratória. Nenhuma alteração foi observada na freqüência cardíaca, oximetria,concentração de C02 expirado, bicarbonato, osmolaridade sangüínea, concentração sangüínea de sódio e potássio, glicosee hematócrito. A Pa02 reduziu apenas nos animais tratados com ARC aos 45 minutos. Observaram-se maiores valores decálcio e menores de pH aos 45 minutos, bradipnéia e menores valores do volume aos 1 05 minutos e de pressão arterial aos15 e 30 minutos nos animais tratados com ARC em relação aos tratados com AXC. Apesar das associações de ARC e AXCproduzirem estabilidade dos parâmetros cardiorrespiratórios, não houve analgesia e relaxamento muscular suficientes, jáque quatro animais de cada grupo necessitaram complementação anestésica com cetamina e destes, dois

Cardiovascular effects of midazolam in levomepromazine premedicated dogs / Efeitos do midazolam sobre o sistema cardiovascular em cães pré-medicados com levomepromazina

Experiments were performed on ten mongrel dogs with 10-18 kg body weight. They received levomepromazine 1.0 mg/kg body weight, I.V. as premedication, and 15 minutes later, midazolam was given in dosage of 2.0 mg/kg body weight intravenously. The result showed moderat increase on respiratory rate and decrease heart rate after 15 minutes and increase heart rate after 30 minutes. Mean and sistolic arterial pressure decreased significantly (p 0.05) but without clinical importance, remained in the physiologic range. Hipnosis duration was less than 20 minutes and at 30 minutes the dogs awaked and they tried to walk.

Foram utilizados 10 cães adultos, de ambos os sexos, sem raça definida, com peso corpóreo entre 10 e 18 kg. Os animais foram pré-medicados com 1,0 mg/kg de levomepromazina e 15 minutos após receberam 2,0 mg/kg de midazolam, ambos por via intravenosa. A freqüência respiratória mostrou um aumento moderado e a freqüência cardíaca redução aos 15 minutos e elevação aos 30 minutos. Houve redução da pressão arterial média e da pressão sistólica com significado estatístico e não clínico. Houve tendência de redução da pressão arterial diastólica. A hipnose durou aproximadamente 20 minutos e aos 30 minutos os cães estavam acordados e em tentativa de deambulação.