Characterization of Novel Selective H<sub>1</sub>-Antihistamines for Clinical Evaluation in the Treatment of Insomnia
Journal of Medicinal ChemistryPublished 7 August 2009Open access
Wilna J. Moree, Bin-Feng Li, Florence Jovic, Timothy Coon, Jinghua Yu, Raymond S. Gross
Citations79
Generate an AI Snapshot to get a quick, structured summary of this paper.
Study Snapshot
ObjectiveStudy objective
MethodsResearch methodology
PopulationPopulation studied
Sample sizeSample sizes
OutcomesStudy outcomes here
ResultsStudy results comes here
LimitationsResearch study limitations comes here
A concise AI-generated summary of the paper will appear here once you click Generate AI Snapshot.
TL;DR
Analogues of the known H(1)-antihistamine R-dimethindene and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing but did not show an in vivo cardiovascular effect from weak hERG channel inhibition.
Abstract
Analogues of the known H(1)-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.
Keywords
Agricultural and Biological SciencesMedicineNeuroscience
Cardiovascular ResearchRelationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development
1,531 Citations2003W REDFERN, Leif Carlsson +8 more
The dataset confirms the widely-held belief that most drugs associated with TdP in humans are also associated with hERG K(+) channel block at concentrations close to or superimposed upon the free plasma concentrations found in clinical use.
BMJSedative hypnotics in older people with insomnia: meta-analysis of risks and benefits
1,138 Citations2005Jennifer R. Glass, Krista L. Lanctôt +3 more
Improvements in sleep with sedative use are statistically significant, but the magnitude of effect is small, and the increased risk of adverse events is statistically significant and potentially clinically relevant in older people at risk of falls and cognitive impairment.
New England Journal of MedicineAdvances in H<sub>1</sub>-Antihistamines
670 Citations2004F. Estelle R. Simons
There are clinically relevant differences among H1-antihistamines in their pharmacology and safety profiles in allergic rhinoconjunctivitis and chronic urticaria.
AddictionAbuse and dependence potential for the non‐benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data
395 Citations2003Göran Hajak, Wernér E.G. Müller +3 more
The findings offer the conclusion that zolpidem and zopiclone are relatively safe drugs, however, as both drugs are psychotropic drugs, patients with a history of abuse or dependence and those with psychiatric diseases seem to be at increased risk of abuse of these agents.
SLEEPEfficacy and Safety of Doxepin 1 mg, 3 mg, and 6 mg in Adults with Primary Insomnia
338 Citations2007Thomas Röth, Roberta Rogowski +6 more
In adults with primary insomnia, doxepin 1 mg, 3 mg, and 6 mg was well-tolerated and produced improvement in objective and subjective sleep maintenance and duration endpoints that persisted into the final hour of the night.
Journal of Clinical Sleep MedicineOral Nonprescription Treatment for Insomnia: An Evaluation of Products With Limited Evidence
154 Citations2005Amy Meoli, Carol L. Rosen +10 more
Sparse or no scientific data were found to support the efficacy of most products as hypnotics, including chamomile and St. John's wort, and preliminary but conflicting evidence suggesting Valerian officinalis L. and first-generation histamine-1-receptor antagonists have efficacy as mild hypnotics over short-term use.
Anesthesia ProgressFundamentals of Electrocardiography Interpretation
147 Citations2006Daniel E. Becker
The purpose of this continuing education article is to review basic principals of ECG monitoring and interpretation.
The Japanese Journal of PharmacologyAntimuscarinic effects of antihistamines : Quantitative evaluation by receptor-binding assay.
147 Citations1987Nobuo Kubo, Osamu Shirakawa +2 more
A broad range of antimuscarinic potencies among the antihistamines was demonstrated and should provide helpful information with regard to the clinical and experimental use of antihistamine.
British Journal of PharmacologySedation and histamine H<sub>1</sub>‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene
117 Citations1991A. N. Nicholson, Peta A. Pascoe +5 more
The findings strongly suggest that sedation can arise from H1‐receptor antagonism alone, and provide further support for the belief that the histaminergic system is concerned with the regulation of alertness in man.
Current Topics in Medicinal ChemistryOrexin Receptor Antagonists: Medicinal Chemistry and Therapeutic Potential
90 Citations2008Anthony J. Roecker, Paul J. Coleman
This review will focus on the medicinal chemistry of orexin antagonists and the potential therapeutic value of this therapy for the treatment of insomnia.
Clinical ToxicologyCompulsive activity and anterograde amnesia after zolpidem use
59 Citations2007Ming‐Jun Tsai, Yi‐Hung Tsai +1 more
It is demonstrated that compulsive activity combined with anterograde amnesia may be associated with the use of zolpidem and Physicians and pharmacists should be aware of this potential side effect.
L EncéphaleSommeil et principaux indicateurs d’insomnie dans la population générale française
53 Citations2004Maurice M. Ohayon, Patrick Lemoine
The results showed that men and women have different sleep habits and that evening or night workers showed irregularities in their sleep patterns, and bedtime and wake up hours were more related in regions with more than 100,000 inhabitants compared to small localities (fewer than 5,000 residents).
British Journal of Clinical PharmacologyA pharmacokinetic evaluation of five H<sub>1</sub> antagonists after an oral and intravenous microdose to human subjects
52 Citations2009Ajay Madan, Zhihong O’Brien +9 more
Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection.
CNS & Neurological Disorders - Drug TargetsHistaminergic Control of Sleep-Wake Cycles: Recent Therapeutic Advances for Sleep and Wake Disorders
47 Citations2007Ann Barbier, M. W. B. Bradbury
This review discusses the existing studies on various antihistamines and antagonists of the H(1) receptor in the regulation of sleep in preclinical studies, normal subjects and in subjects with sleep disorders and the current data available on the use of ligands at H(3) receptors for the modulation of sleep and wake.
The Japanese Journal of PharmacologyAntimuscarinic Effects of Antihistamines: Quantitative Evaluation by Receptor-Binding Assay
44 Citations1987Nobuo Kubo, Osamu Shirakawa +2 more
Journal of Medicinal ChemistryStructure−Activity Relationships of Dimethindene Derivatives as New M<sub>2</sub>-Selective Muscarinic Receptor Antagonists
40 Citations2003Thomas Böhme, Christine Keim +6 more
The results demonstrate that the diisopropyl analogue 19 has a similar high affinity as (S)-dimethindene at M(2) receptors, and might be useful to test the hypothesis that blockade of muscarinic M( 2) receptors in the brain is a viable mechanism by which to produce improved cognition.
Acta Pharmacologica et ToxicologicaSingle Dose Pharmacokinetics of Doxepin in Healthy Volunteers
35 Citations1980R Virtanen, Mika Scheinin +1 more
The pharmacokinetics of orally administered doxepin (50 mg) was studied in 8 healthy volunteers and initially the plasma concentrations were 3-4 times higher than the respective RBC concentrations, but at later time points more DOX and DDOX could be found from the RBCs than from plasma.
Biological and Pharmaceutical BulletinSlow Wave Sleep-inducing Effects of First Generation H1-Antagonists.
34 Citations1999Koichi Saitou, Y. Kaneko +3 more
Results clearly show that H1-antagonists are effective in mild to moderate insomnia as sedative-hypnotic drugs.
Journal of Chromatography B Biomedical Sciences and ApplicationsStudies of the metabolism of the antihistaminic drug dimethindene by high-performance liquid chromatography and capillary electrophoresis including enantioselective aspects
13 Citations1997D. Prien, Gottfried Blaschke
A reversed-phase high-performance liquid chromatography method for the determination of dimethindene and its main metabolites N-demethyldimeth Indene, 6-hydroxydimethindenes and 6-Hydroxylated metabolites in human urine was developed and the assay was also applied to the quantification of dimETHindene-N-oxide in rat urine.
Expert Opinion on PharmacotherapyEmerging pharmacotherapeutic agents for insomnia: a hypnotic panacea?
7 Citations2006Pedram Navab, Christian Guilleminault
This article profiles the most contemporary, therapeutic options in lieu of older hypnotics, over-the-counter medications and supplements that address the vital need to combat insomnia and prevent the perpetuation in its chronic form.
Inflammation ResearchComparison of the central and peripheral antihistamine effects of dimethindene maleate (Fenistil®) and its enantiomers
4 Citations1992Lucienne Cicurel, J.C. Péchadre +2 more
Monitoring of H1 histamine receptor antagonist activity and sedative effects of dimethindene maleate racemate and the individual enantiomers showed that the peripheral antihistamine activity of DIM+/− resided mainly in the DIM− enantiomer.