Pharmacokinetics and pharmacodynamics of the injectable formulation of methadone hydrochloride and methadone in lipid nanocarriers administered orally to horses.

We investigated the thermal, electrical and mechanical antinociceptive and physiological effects (heart rate, respiratory rate, arterial blood pressure, head height and abdominal auscultation score), and pharmacokinetics, of 0.5 mg/kg of the injectable formulation (ORAL) or nanoparticulated methadone (NANO) given orally, in six adult mares, using a crossover, blind and prospective design. Repeated-measure models were used to compare parametric data between and within treatments, followed by Tukey's test. Nonparametric data were analysed with Wilcoxon signed-rank, adjusted by Bonferroni tests. Blood samples were also collected up to 6 h after dosing for plasma drug quantification by LC-MS/MS. Methadone pharmacokinetic parameters were determined by noncompartmental and compartmental approaches. There were no differences in pharmacodynamic parameters. No statistical differences were observed in the pharmacokinetic parameters from noncompartmental analysis for both groups, except a significant decrease in peak plasma concentration, increase in apparent volume of distribution per fraction absorbed (Vdss /F) and increased mean residence time (MRT) for NANO. One-compartment open model with first order elimination best described the pharmacokinetic profiles for both groups. Neither ORAL nor NANO administered orally to horses produced antinociception. The nanoencapsulated formulation of methadone given orally to horses did not improve methadone pharmacokinetic parameters or increased systemic body exposure to methadone.

Comparative study between atropine and hyoscine-N-butylbromide for reversal of detomidine induced bradycardia in horses.

REASONS FOR PERFORMING STUDY: Bradycardia may be implicated as a cause of cardiovascular instability during anaesthesia. HYPOTHESIS: Hyoscine would induce positive chronotropism of shorter duration than atropine, without adversely impairing intestinal motility in detomidine sedated horses. METHODS: Ten minutes after detomidine (0.02 mg/kg bwt, i.v.), physiological saline (control), atropine (0.02 mg/kg bwt) or hyoscine (0.2 mg/kg bwt) were randomly administered i.v. to 6 horses, allowing one week intervals between treatments. Investigators blinded to the treatments monitored cardiopulmonary data and intestinal auscultation for 90 min and 24 h after detomidine, respectively. Gastrointestinal transit was assessed for 96 h via chromium detection in dry faeces. RESULTS: Detomidine significantly decreased heart rate (HR) and cardiac index (CI) from baseline for 30 and 60 min, respectively (control). Mean ± s.d. HR increased significantly 5 min after atropine (79 ± 5 beats/min) and hyoscine (75 ± 8 beats/min). After this time, HR was significantly higher after atropine in comparison to other treatments, while hyoscine resulted in intermediate values (lower than atropine but higher than controls). Hyoscine and atropine resulted in significantly higher CI than controls for 5 and 20 min, respectively; but this effect coincided with significant hypertension (mean arterial pressures >180 mmHg). Auscultation scores decreased from baseline in all treatments. Time to return to auscultation scores ≥12 (medians) did not differ between hyoscine (4 h) and controls (4 h) but atropine resulted in significantly longer time (10 h). Atropine induced colic in one horse. Gastrointestinal transit times did not differ between treatments. CONCLUSION: Hyoscine is a shorter acting positive chronotropic agent than atropine, but does not potentiate the impairment in intestinal motility induced by detomidine. Because of severe hypertension, routine use of anticholinergics combined with detomidine is not recommended. POTENTIAL RELEVANCE: Hyoscine may represent an alternative to atropine for treating bradycardia.