Effect of the novel histamine H 4 receptor antagonist SENS-111 on spontaneous nystagmus in a rat model of acute unilateral vestibular loss.
Autor: | Petremann M; Preclinical & Translational Research & Development, Preclinical & Translational Research & Development, Sensorion SA, Montpellier, France., Gueguen C; Preclinical & Translational Research & Development, Preclinical & Translational Research & Development, Sensorion SA, Montpellier, France.; Neuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia., Delgado Betancourt V; Preclinical & Translational Research & Development, Preclinical & Translational Research & Development, Sensorion SA, Montpellier, France., Wersinger E; Preclinical & Translational Research & Development, Preclinical & Translational Research & Development, Sensorion SA, Montpellier, France.; UMR Inserm 1107 Neuro-Dol, Faculty of Pharmacy, University of Clermont Auvergne, Clermont-Ferrand, France., Dyhrfjeld-Johnsen J; Preclinical & Translational Research & Development, Preclinical & Translational Research & Development, Sensorion SA, Montpellier, France. |
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Jazyk: | angličtina |
Zdroj: | British journal of pharmacology [Br J Pharmacol] 2020 Feb; Vol. 177 (3), pp. 623-633. Date of Electronic Publication: 2019 Aug 28. |
DOI: | 10.1111/bph.14803 |
Abstrakt: | Background and Purpose: Histamine H Experimental Approach: Pharmacokinetics of SENS-111 in rats was determined to aid dose selection for efficacy testing. Vestibular lesions were induced in rats by unilateral transtympanic injection of kainic acid. The effect of SENS-111 (10 or 20 mg·kg -1 ) on spontaneous nystagmus was evaluated compared with placebo vehicle using video-nystagmography, and the effective dose was compared with those of similar drugs used clinically, as single agents or combined with SENS-111. Key Results: Doses were selected for plasma exposure were consistent with published phase 1 results from healthy volunteers. SENS-111 of 10 mg·kg -1 gave a 21-22% reduction in nystagmus at 1 hr post-administration, whereas a loss of efficacy was seen with 20 mg·kg -1 . Compared with SENS-111, meclizine and methylprednisolone had minimal effects on nystagmus as single agents, and meclizine abolished the effect of SENS-111 when combined with SENS-111. All evaluated drugs were well tolerated. Conclusions and Implications: The exposure-efficacy relationship for improved spontaneous nystagmus seen with SENS-111 in this in vivo model is consistent with phase 1 clinical results and provides preclinical support for pharmacokinetic/pharmacodynamic modelling and selection of effective clinical drug concentrations. Linked Articles: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc. (© 2019 The British Pharmacological Society.) |
Databáze: | MEDLINE |
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