Objectives: Zolpidem belongs to Z-drugs, a group of non-benzodiazepine drugs with effects similar to benzodiazepines, used in the treatment of human insomnia. The hypothesis is that zolpidem, could be used in cases of acute-onset and severe phobic states, such as thunderstorm phobia and separation anxiety, where there is the need for safe and rapid reduction in responsiveness to environmental stimuli and initiation of sleep, with relatively short duration of action and rapid recovery. The aim of the present work is to evaluate the PK/PD of zolpidem in dogs after single oral administration at different doses. Materials & Methods: Eight adult dogs of different breeds were orally administered with zolpidem according to a two treatment groups (0.15 and 0.50 mg/kg), using an open, single-dose, two-strength, two-period, cross-over design. Drug plasma concentrations were evaluated by a validated HPLC-FL method, while the pharmacodynamics by sedation scale and the evaluation of basic clinical parameters. Compartmental pharmacokinetic evaluation for each individual animal’s time vs. blood concentration profiles for zolpidem was performed by WinNonLin 5.3.0 program. Results & Conclusion: The pharmacokinetics in dogs was dose depended. In this study lower drug plasma concentration were found than in humans administered with the same dose of drug. Zolpidem at 0.15 mg/kg did not produce any clinical of adverse effect, while at 0.5 mg/kg generated a paradoxical CNS stimulation (about 1 h long lasting) in all the subjects. The first sign showed up was vocalization, followed by restlessness, anxiety, euphoria, acute rage reaction, excitement, scialorrea and increased muscle spasticity. These effects were showed up in a variable time (ranging from 15 to 50 min) and lasted for about 1 h. In some subjects, a subsequent short and light phase of sedation was reported. This latter was classified as no clinically relevant. The drug showed clinically ineffective plasma levels up to 30 ng/mL. This level is very close to the calculated minimal plasma concentration producing side effects of 60 ng/mL. In conclusion, zolpidem is a drug not suitable for the hypnosis in canine species. Keywords: zolpidem; Z-drugs; PK-PD; paradoxical reaction; dogs; hypnotic.

A PK/PD STUDY AFTER SINGLE ORAL ADMINISTRATION OF TWO DOSE LEVELS OF ZOLPIDEM IN DOGS

BRIGANTI, ANGELA;BREGHI, GLORIA;GIORGI, MARIO
2011

Abstract

Objectives: Zolpidem belongs to Z-drugs, a group of non-benzodiazepine drugs with effects similar to benzodiazepines, used in the treatment of human insomnia. The hypothesis is that zolpidem, could be used in cases of acute-onset and severe phobic states, such as thunderstorm phobia and separation anxiety, where there is the need for safe and rapid reduction in responsiveness to environmental stimuli and initiation of sleep, with relatively short duration of action and rapid recovery. The aim of the present work is to evaluate the PK/PD of zolpidem in dogs after single oral administration at different doses. Materials & Methods: Eight adult dogs of different breeds were orally administered with zolpidem according to a two treatment groups (0.15 and 0.50 mg/kg), using an open, single-dose, two-strength, two-period, cross-over design. Drug plasma concentrations were evaluated by a validated HPLC-FL method, while the pharmacodynamics by sedation scale and the evaluation of basic clinical parameters. Compartmental pharmacokinetic evaluation for each individual animal’s time vs. blood concentration profiles for zolpidem was performed by WinNonLin 5.3.0 program. Results & Conclusion: The pharmacokinetics in dogs was dose depended. In this study lower drug plasma concentration were found than in humans administered with the same dose of drug. Zolpidem at 0.15 mg/kg did not produce any clinical of adverse effect, while at 0.5 mg/kg generated a paradoxical CNS stimulation (about 1 h long lasting) in all the subjects. The first sign showed up was vocalization, followed by restlessness, anxiety, euphoria, acute rage reaction, excitement, scialorrea and increased muscle spasticity. These effects were showed up in a variable time (ranging from 15 to 50 min) and lasted for about 1 h. In some subjects, a subsequent short and light phase of sedation was reported. This latter was classified as no clinically relevant. The drug showed clinically ineffective plasma levels up to 30 ng/mL. This level is very close to the calculated minimal plasma concentration producing side effects of 60 ng/mL. In conclusion, zolpidem is a drug not suitable for the hypnosis in canine species. Keywords: zolpidem; Z-drugs; PK-PD; paradoxical reaction; dogs; hypnotic.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/194040
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