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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Characterisation of the in vivo interactions between detomidine and methadone in horses: Pharmacokinetic and pharmacodynamic modelling

Texto completo
Autor(es):
Gozalo-Marcilla, M. [1] ; Luna, S. P. L. [1] ; Moreira da Silva, R. [2] ; Crosignani, N. [1] ; Lopes, N. P. [2] ; Taylor, P. M. [3] ; Pelligand, L. [4]
Número total de Autores: 7
Afiliação do(s) autor(es):
[1] Sao Paulo State Univ UNESP, Sch Vet Med & Anim Sci, Dept Vet Surg & Anaesthesiol, Botucatu, SP - Brazil
[2] Univ Sao Paulo, Sch Pharmaceut Sci, NPPNS, Ribeirao Preto, SP - Brazil
[3] Taylor Monroe, Ely, Cambs - England
[4] Royal Vet Coll, Dept Clin Serv & Sci & Comparat Biomed Sci, Hatfield, Herts - England
Número total de Afiliações: 4
Tipo de documento: Artigo Científico
Fonte: EQUINE VETERINARY JOURNAL; v. 51, n. 4, p. 517-529, JUL 2019.
Citações Web of Science: 3
Resumo

Background Pharmacokinetic (PK)/pharmacodynamic (PD) modelling offers new insights to design protocols for sedation and analgesia in standing horses. Objectives To evaluate the parameters and interactions between detomidine and methadone when given alone or combined in standing horses. Study design Randomised, placebo-controlled, blinded, crossover. Methods Eight adult healthy horses were given six treatments intravenously: saline (SAL); detomidine (5 mu g/kg bwt; DET); methadone (0.2 mg/kg bwt; MET) alone or combined with detomidine (2.5 {[}MLD], 5 {[}MMD] or 10 {[}MHD] mu g/kg bwt). Venous blood samples were obtained at predetermined times between 0 and 360 min after drug administration. Plasma detomidine and methadone were measured using a single, liquid/liquid extraction technique by liquid chromatography coupled with a triple quadrupole mass spectrometer (LC-MS/MS). Sequential PK/PD modelling compared rival models, with and without PK and PD interaction between drugs, to fit the PD data including height of the head above the ground (HHAG), a visual analogue scale for sedation (VAS), electrical (ET), thermal (TT) and mechanical (MT) nociceptive thresholds and gastrointestinal motility (GIM) {[}1]. Results Two and three compartment models best described the PK of detomidine and methadone, respectively. Detomidine decreased its own clearance as well as the clearance of methadone. The interaction of methadone on the effect of detomidine revealed an infra-additive (partial antagonism) effect for HHAG (alpha = -1.33), VAS (alpha = -0.98) and GIM (alpha = -1.05), a positive potentiation for ET (pot = 0.0041) and TT (pot = 0.133) and a synergistic to additive effect for MT (alpha = 0.78). Main limitations This is a small experimental study. Conclusions Different PK/PD interactions were demonstrated for each PD parameter and could be modelled in vivo. The modelling of our data will allow us to simulate and predict the effect of constant rate infusions of both drugs for future investigations. (AU)

Processo FAPESP: 10/08967-0 - Avaliação da dor clínica e experimental em animais
Beneficiário:Stelio Pacca Loureiro Luna
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 14/00474-5 - Efeitos antinociceptivos e farmacocinética em equinos tratados com diferentes doses baixas de metadona e detomidina
Beneficiário:Miguel Gozalo Marcilla
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 14/50265-3 - Metabolismo e distribuição de xenobióticos naturais e sintéticos: da compreensão dos processos reacionais à geração de imagens teciduais
Beneficiário:Norberto Peporine Lopes
Linha de fomento: Auxílio à Pesquisa - Programa BIOTA - Temático
Processo FAPESP: 17/01425-6 - Aplicação clínica de diferentes taxas de infusão de detomidina e metadona em cavalos em estação.
Beneficiário:Miguel Gozalo Marcilla
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado