RABBIT DEEP SEDATION AND PLASMA CONCENTRATIONS AFTER TRANSNASAL ADMINISTRATION OF A DEXMEDETOMIDINE BUTORPHANOL AND MIDAZOLAM COMBINATION

Aim of this study was to correlate the clinical and sedative effects of a combination of Dexmedetomidine, Midazolam and Butorphanol (DBM) with their respective plasma concentrations after transnasal (TN) administration in healthy rabbits. This study was approved by the Ethics Committee of the University of Naples (CESA). A combination of 0.1 mg/kg of Dexmedetomidine (D- Dexdomitor® Pfizer Italia srl, 0.05%), 0.4 mg/kg of Butorphanol (B- Dolorex® Intervet, 1%) and 2 mg/kg of Midazolam (M- Midazolam IBI®, 0.5%) (DBM), was delivered by trans-nasal (TN) catheterization (Levin probe CH 6) onto the nasopharyngeal mucosa of 5 NZW Rabbits. Vital parameters were recorded (Mindary PM-9000 Exspress®) for 60 minutes along with sedation score (SS) and pain response by a numeric (0-12) rating scale (1). SS was classified (1) as insufficient (0-3), moderate (4-7) or deep (8-12). Blood samples (2 mL) were collected before (T-0) and at T-: 5, 10, 15, 30, 45, 60, 90, 120, 180 and 240 (minutes) after TN DBM administration. Plasma samples were then frozen and stored at -80°C. Single drug pharmacokinetics were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) using AB Sciex 3200 triple quadrupole with positive ion electrospray ionization. Chromatographic separation (LC Agilent 1200) was performed on column ZORBAX DB-C18 (4.6 x 50 mm, particle size 1,8 mm). Identification and quantification was based on selected reaction monitoring (SRM). Calibration curves were prepared using fortified plasma samples. All numerical data were processed by ANOVA for repeated measures. Significant differences were analyzed by a post hoc Tukey???s HSD test (P??? 0.05). Deep sedation ensued in all rabbits 1.5??? after TN DBM administration along with moderate respiratory and cardiovascular depression. Peak sedation and analgesia (T-5) coincided with mean plasma concentrations of about 23 ng/ml for D, of 34. ng/ml for B and of 560 ng/ml for M. Rabbits were still fairly sedated (T-60) at plasma levels of about 4 ng/ml for D, 12 ng/ml for B and 118 ng/ml for M. Insufficient sedation (T-90) was scored at plasma levels of about 2 ng/ml for D, 12 ng/ml for B and 85.40 ng/ml for M. No anesthetic complications were observed in any of the subjects. TN administration of our DBM combination in healthy rabbits produced a deep, long-lasting sedation and analgesia. Plasma concentrations of single molecules correlated well with sedation scores. 1)Raekallio M et al. (2002) J Vet Pharmacol Ther, 25(1):39-42.