Development of tolerance to the anticonvulsant effect of diazepam in dogs

Frey, H.‐H.; Philippin, Hans-Peter; Scheuler, W.

doi:10.1016/0014-2999(84)90365-0

Cited by 75 publications

(28 citation statements)

References 19 publications

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“…The development of tolerance to the anticonvulsant effects of diazepam in dogs has also been documented [49]; however tolerance to the anticonvulsant effects of imepitoin has not been demonstrated [33, 37]. Additionally, when looking at anxiolysis, the results of this study showed significant effects within the first week of treatment with continued improvements seen at week 11 and decision points which is not suggestive of tolerance developing within this time frame.…”

Section: Discussionmentioning

confidence: 66%

The use of imepitoin (Pexion™) on fear and anxiety related problems in dogs – a case series

McPeake

Mills

2017

BMC Vet Res

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BackgroundFear and anxiety based problems are common in dogs. Alongside behaviour modification programmes, a range of psychopharmacological agents may be recommended to treat such problems, but few are licensed for use in dogs and the onset of action of some can be delayed. The low affinity partial benzodiazepine receptor agonist imepitoin (Pexion™, Boehringer Ingelheim) is licensed for treating canine epilepsy, has a fast onset of action in dogs and has demonstrated anxiolytic properties in rodent models. This case series reports on the use of imepitoin in a group of dogs identified as having fear/anxiety based problems. Twenty dogs were enrolled into the study, attended a behaviour consultation and underwent routine laboratory evaluation. Nineteen dogs proceeded to be treated with imepitoin orally twice daily (starting dose approximately 10 mg/kg, with alterations as required to a maximum 30 mg/kg) alongside a patient-specific behaviour modification plan for a period of 11–19 weeks. Progress was monitored via owner report through daily diary entries and telephone follow-up every two weeks. A Positive and Negative Activation Scale (PANAS) of temperament was also completed by owners during baseline and at the end of the study.ResultsThe primary outcome measure was average weekly global scores (AWG) from the owner diaries. Average weekly reaction scores (AWR) for each type of eliciting context was used as a secondary outcome. Seventeen dogs completed the trial. Treatment with imepitoin alongside a behaviour modification programme resulted in owner reported improvement with reduced AWG and reduced AWR for anxiety across a range of social and non-social eliciting contexts including noise sensitivities. Significant improvement was apparent within the first week of treatment, and further improvements seen at the 11 week review point. There was a significant reduction in negative activation (PANAS) with 76.5% of owners opting to continue imepitoin at their own expense after completion of the study.ConclusionsThis study provides initial evidence indicating the potential value of imepitoin (Pexion™) alongside appropriate behaviour modification for the rapid alleviation of signs of fear and anxiety in dogs. Further research with a larger subject population and a placebo control would be useful to confirm the apparent efficacy reported here.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-017-1098-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 66%

The use of imepitoin (Pexion™) on fear and anxiety related problems in dogs – a case series

McPeake

Mills

2017

BMC Vet Res

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“…The chronic use of benzodiazepines has been reported to produce tolerance to their hypnotic and anticonvulsive effects (Greenblatt and Shader, 1978;File, 1982;Frey et al, 1984) and, in some cases, the efficacy of these drugs has been substantially hindered by the development of tolerance (Petursson and Lader, 1981;Sher, 1985). With regard to anxiolytic effects, however, there is little evidence that chronic treatment with benzodiazepines produces tolerance.…”

Section: Discussionmentioning

confidence: 97%

Development of tolerance to anxiolytic effects of chlordiazepoxide in elevated plus-maze test and decrease of GABAA receptors

Ishihara

Hiramatsu

Kameyama

et al. 1993

J. Neural Transmission

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Repeated administration of benzodiazepines has been reported to produce tolerance in animals and humans. Using an elevated plus-maze test and an autoradiographic technique, we investigated whether repeated administration of chlordiazepoxide produced tolerance to its anxiolytic effects, and whether such repeated administration altered benzodiazepine and GABAA receptors. Tolerance to the anxiolytic effect of chlordiazepoxide was produced when it was administered at a dose of 30 mg/kg (i.p.) once a day for 10 and 14 days. In the quantitative autoradiographical study, although repeated chlordiazepoxide treatment had no effect on [3H]flunitrazepam and [3H]Ro 15-4513 binding to benzodiazepine receptors, such treatment reduced [3H]muscimol binding to GABAA receptors in the cortex, caudate putamen, and hippocampus. These results suggest firstly, the production of tolerance to the anxiolytic effects of chlordiazepoxide, and, secondly, that this tolerance may be due to the down-regulation of GABAA receptors, but not of benzodiazepine receptors.

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“…Animal studies have suggested that administration of NDMC may be associated with less anticonvulsant tolerance than administration of clobazam, despite comparable plasma concentrations of NDMC in both instances . In a similar study of chemically-induced seizures in dogs, the major active metabolite of diazepam (Ndesmethyldiazepam) has been shown to produce less anticonvulsant tolerance than its parent compound (Frey et al, 1984). N-desmethyldiazepam has also been shown to produce less psychomotor impairment than diazepam (Aranko et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of N‐desmethylclobazam in healthy volunteers and patients with epilepsy.

Pullar

Haigh

Peaker

et al. 1987

Brit J Clinical Pharma

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1 The single dose pharmacokinetics of N-desmethylclobazam (NDMC) and clobazam were studied in eight healthy male volunteers. 2 Steady-state pharmacokinetic data are described from four healthy male volunteers and eight epileptic patients taking NDMC.3 A single 30 mg dose of NDMC produced a greater Cma. (P < 0.001) and AUC 0-oo (P < 0.005) and a shorter tmax (P < 0.05) and tv½ (P < 0.01) for NDMC than did 30 mg clobazam. 4 Mean steady-state NDMC concentrations were greater in male patients than in female patients and also in male patients compared with male volunteers. The differences between patients and volunteers might be explained by concomitant antiepileptic medication.

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Development of tolerance to the anticonvulsant effect of diazepam in dogs

Cited by 75 publications

References 19 publications

The use of imepitoin (Pexion™) on fear and anxiety related problems in dogs – a case series

The use of imepitoin (Pexion™) on fear and anxiety related problems in dogs – a case series

Development of tolerance to anxiolytic effects of chlordiazepoxide in elevated plus-maze test and decrease of GABAA receptors

Pharmacokinetics of N‐desmethylclobazam in healthy volunteers and patients with epilepsy.

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