A Double-Blind, Placebo-Controlled, Parallel Design Phase 3 Study to Assess the Efficacy, Safety, Tolerability, and Pattern of Use of SM-1 in Adult Subjects With a History of Transient Insomnia

The purpose of this study is to assess the efficacy and pattern of use of the combination drug product SM-1 in adults who sometimes have difficulty in falling asleep or staying asleep, but who do not have chronic insomnia. Participants will receive SM-1 or placebo to take at home as needed over the course of 3 months treatment period.

开始日期2023-05-01

申办/合作机构

Sequential Medicine Ltd.

NCT04396327 / Not yet recruiting临床2期

A Randomized, Double-Blind, Single-Dose, 2-Way Cross-Over Study to Assess the Pharmacodynamic Effects of SM-1 vs. Active Comparator in a 3-Hour Phase Advance Model of Transient Insomnia

The purpose of this study is to investigate the effectiveness, safety and tolerability of a combination drug product (SM-1) containing diphenhydramine, zolpidem and lorazepam, in adult participants who sometimes have difficulty in falling asleep or staying asleep, but who do not have chronic insomnia. Participants will receive SM-1 or a combination of diphenhydramine and lorazepam during 2 one-night stays at a sleep center.

开始日期2020-05-27

申办/合作机构

Sequential Medicine Ltd.

NCT03331042 / Completed临床3期

A Randomized, Double-Blind, Single-Dose, 4-Way Crossover Study to Assess the Efficacy and Safety of SM-1 (50-mg Diphenhydramine, 5-mg Delayed-Release Zolpidem, and 0.5-mg Delayed-Release Lorazepam) Versus 2 Comparators (50-mg Diphenhydramine and 5-mg Delayed-Release Zolpidem; 50-mg Diphenhydramine and 0.5-mg Delayed-Release Lorazepam) and Placebo in a 5-Hour Phase Advance Model of Transient Insomnia.

The purpose of this study is to investigate the effectiveness, safety and tolerability of a combination drug product (SM-1) containing diphenhydramine, zolpidem and lorazepam, in adult participants who sometimes have difficulty in falling asleep or staying asleep, but who do not have chronic insomnia. Participants will receive SM-1, or a combination of diphenhydramine and zolpidem, or a combination of diphenhydramine and lorazepam, or placebo during 4 one-night stays at a sleep center.

开始日期2017-10-09

申办/合作机构

Sequential Medicine Ltd.

100 项与 H1 receptor x GABAA receptor 相关的临床结果

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100 项与 H1 receptor x GABAA receptor 相关的转化医学

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0 项与 H1 receptor x GABAA receptor 相关的专利（医药）

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项与 H1 receptor x GABAA receptor 相关的文献（医药）

2007-08-22·Behavioural Brain Research3区 · 心理学

Histamine H1-receptors differentially mediate the action of amylin on hypothalamic neurons in control and in overweight rats

3区 · 心理学

Article

作者: Davidowa, Helga

The hypothalamic arcuate, dorsomedial and paraventricular nuclei are involved in regulation of body weight and food intake and contain binding sites for the anorexigenic amylin. Effects of amylin on medial arcuate and paraventricular neurons studied in adult rats overweight through early postnatal overfeeding in small litters (SL) differed from those of control litters (CL). Now we observed that also dorsomedial neurons respond differentially to this satiety signal. They were significantly inhibited by amylin in SL but not CL rats. Since the histaminergic system seems to be involved in mediating effects of amylin, we studied the role of histamine H(1)-receptors. Single unit activity was recorded in brain slices of CL and SL rats in each of the three hypothalamic nuclei. The histamine H(1)-receptor antagonist pyrilamine differentially altered or reduced responses to amylin, not depending on the kind of litter but on the functional effect of the peptide. Pyrilamine prevented significant inhibition of medial arcuate neurons in controls as well as inhibition of dorsomedial and paraventricular neurons in SL rats. Searching for further mechanisms possibly contributing to the change of neuronal responses we found that in the presence of a GABA(A)-receptor antagonist amylin induced a significant inhibition of medial arcuate neurons in SL rats similar to that in CL without antagonist. Activation of medial arcuate neurons expressing the orexigenic neuropeptide Y and inhibition of dorsomedial and paraventricular neurons in SL rats may in vivo contribute to hyperphagia and overweight. Histamine H(1)-receptors and GABA(A)-receptors seem to be differentially involved in mediation of these effects.

2007-04-01·Pharmacogenetics and Genomics4区 · 医学

Genomic and functional conservation of sedative-hypnotic targets in the zebrafish

4区 · 医学

Article

作者: Bonaventure, Pascal ; Mignot, Emmanuel ; Rosa, Frederic ; Bourgin, Patrice ; Renier, Corinne ; Faraco, Juliette H. ; Motley, Timothy

OBJECTIVESThe zebrafish is an ideally suited vertebrate animal model for large-scale genetic screens and is emerging as a model organism in pharmacological and behavioral research. We investigated the effects of sedative hypnotics commonly used in humans on zebrafish locomotor activity and identified the corresponding genomic and receptor binding targets.METHODSWe studied radioreceptor binding and behavioral responses to compounds with known sedative hypnotic properties representing multiple pharmacological classes. These included GABAergic hypnotics such as benzodiazepines, barbiturates, and baclofen; alpha-2 adrenergic agonists; and histaminergic H1 antagonists. An automated system was used to quantify behavioral effects. Zebrafish homologs of histamine receptor H1, gamma-amino-n-butyric acid type A (alpha-subunit), and gamma-amino-n-butyric acid type B (1 and 2) receptor genes were identified through translating queries of the zebrafish Zv4 database with human receptor protein sequences. A pilot screen of 154 N-ethyl-N-nitroso-urea-mutagenized F2 families was conducted with pentobarbital, flurazepam and mepyramine.RESULTSRadioreceptor binding studies revealed high affinity binding sites for known gamma-amino-n-butyric acid type A, gamma-amino-n-butyric acid type B, and histaminergic ligands. Drug immersion of 5-7-day-old larvae reduced mobility and, in some cases, produced a complete state of unresponsive immobility similar to anesthesia. These effects were dose-dependent and rapidly reversible in water. As established in mammals, (R)-baclofen was more active behaviorally and had higher affinity in binding studies when compared with (S)-baclofen. In this model, (S)-baclofen only partially reduced activity at high dose and blocked (R)-baclofen behavioral hypnotic effects. Genomic sequences with high similarity to the corresponding pharmacological targets were identified, but no mutants were found in the pilot screen.CONCLUSIONSThese results demonstrate conservation of gene, protein and function for many established sedative hypnotic pathways. The results indicate feasibility of conducting large-scale pharmacogenomic screens to isolate novel proteins modulating susceptibility to hypnotic compounds in a vertebrate system.

1999-11-01·Naunyn-Schmiedeberg's Archives of Pharmacology

Histaminergic neurons modulate acetylcholine release in the ventral striatum: role of H1 and H2 histamine receptors

Article

作者: M. Kraus ; K. Grass ; H. Prast ; Manh Hung Tran ; H. Fischer ; C. Lamberti ; A. Philippu

To investigate whether H1 and H2 histamine receptors are implicated in the modulation of acetylcholine release by endogenous histamine, the ventral striatum of the conscious, freely moving rat was superfused by the push-pull superfusion technique with drugs and the release of acetylcholine was determined in the superfusate. Superfusion with the H1 receptor agonist 2-thiazolylethylamine (TEA, 50 micromol/l) enhanced the release of acetylcholine, while the H1 receptor antagonist triprolidine (50 micromol/l) reduced acetylcholine outflow and abolished the TEA-evoked release of the neurotransmitter. The inhibitory effect of triprolidine was not influenced either on simultaneous superfusion with 10 micromol/l (+/-)-7-bromo-1-(fluoresceinylthioureido)phenyl-8-hydroxy-3-methyl -2,3,4,5-tetrahydro-1H-benzazepine (SKF-83566, D1 dopamine receptor antagonist) and 50 micromol/l quinpirole (D2/D3 dopamine receptor agonist) or on superfusion with the GABAA receptor antagonist bicuculline (50 micromol/l). The H2 receptor antagonists ranitidine or famotidine (50 micromol/l each) greatly enhanced acetylcholine release rate in the ventral striatum. Presuperfusion with alpha-fluoromethylhistidine (FMH, 1 mmol/l), which inhibits neuronal synthesis of histamine, abolished the famotidine-induced release of acetylcholine. The releasing effect of famotidine was also abolished on simultaneous superfusion with 10 micromol/l SKF-83566 and 50 micromol/l quinpirole. The release of acetylcholine elicited by famotidine was reversed to a decreased acetylcholine outflow when the striatum was superfused with the GABA(A) receptor antagonist bicuculline (50 micromol/l) prior to famotidine. Superfusion with the H2 receptor agonist impromidine (1 micromol/l) decreased acetylcholine outflow, while the H2 agonist dimaprit (50 micromol/l) exerted the opposite effect. The releasing effect of dimaprit was not influenced by FMH (1 mmol/l), but it was abolished in the presence of SKF-83566 (10 micromol/l) and quinpirole (50 micromol/l). In the presence of bicuculline the release of acetylcholine by dimaprit was enhanced and prolonged. It seems possible that dimaprit and impromidine stimulate different subtypes of H2 receptors. The findings suggest that the release of acetylcholine in the striatum is modulated by neighbouring histaminergic neurons in a complex way. Stimulation of H1 histamine receptors, probably located on cholinergic neurons, enhances acetylcholine release. Stimulation by histamine of H2 receptors located on cholinergic or GABAergic neurons enhances the release of acetylcholine, while stimulation of H2 receptors located on dopaminergic neurons exerts the opposite effect.