An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin−/− mice and patients

Lin, Jian‐Sheng; Dauvilliers, Yves; Arnulf, Isabelle; Bastuji, Hélène; Anaclet, Christelle; Parmentier, Régis; Kocher, Laurence; Yanagisawa, Masashi; Lehert, Philippe; Ligneau, Xavier; Perrin, David; Robert, Philippe; Roux, Michel; Lecomte, J; Schwartz, Jean

doi:10.1016/j.nbd.2007.12.003

Cited by 249 publications

(193 citation statements)

References 43 publications

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“…Preclinical studies have shown that antagonists of the H3 receptor can induce wakefulness and that these effects are, unlike the wake promoting effects of modafinil, abolished in H3 receptor KO mice, demonstrating the very different mechanisms of actions of the two compounds (Parmentier et al 2007). In one clinical study, reduction of sleepiness in narcoleptic patients was observed after administration of a H3-inverse agonists (Lin et al 2008). In that study, however, no objective EEG data during either wakefulness or sleep were reported and it is currently not known how H3 antagonists and H3 inverse agonists affect the EEG during wakefulness and sleep.…”

Section: )mentioning

confidence: 99%

Effect of a novel histamine subtype-3 receptor inverse agonist and modafinil on EEG power spectra during sleep deprivation and recovery sleep in male volunteers

et al. 2011

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Rationale: Histamine and dopamine contribute to the maintenance of wakefulness.Objective: Exploratory analysis of the effects of 10 and 50 mg of MK-0249, a novel histamine subtype-3 receptor inverse agonist, and 200 mg of modafinil, a presumed dopaminergic compound, on EEG power spectra during sleep deprivation and subsequent recovery sleep. Methods: 25 healthy men were recruited to a double-blind placebocontrolled cross-over design. EEG power spectra, an electrophysiological marker of changes in sleepiness and vigilance, were obtained at the beginning of wake maintenance tests at 2 hourly intervals throughout a night and day of sleep deprivation, which is an established model of excessive sleepiness. Results: After placebo, sleep deprivation was associated with enhancements in delta, theta and reductions in alpha and beta activity.Following dosing at 02:00, MK-0249 and modafinil reduced delta and theta activity and enhanced alpha and beta activity, compared to placebo. During recovery sleep initiated at 21:00 h, latency to sleep onset, and number of awakenings were not different from placebo for any of the active treatments. Wake after sleep onset and stage 1 % was increased and total sleep time, SWS % and REM% were reduced after both doses of MK-0249. Compared to placebo, MK-0249 and the 50 mg dose in particular, reduced activity in some delta and theta/alpha frequencies and enhanced beta activity during NREM sleep and REM sleep.After modafinil, no changes were observed for power spectra during sleep. Conclusion: both MK-0249 and modafinil exert effects on the EEG which are consistent with wake promotion.

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Section: )mentioning

confidence: 99%

Effect of a novel histamine subtype-3 receptor inverse agonist and modafinil on EEG power spectra during sleep deprivation and recovery sleep in male volunteers

et al. 2011

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“…The 6 mg once-daily dose was terminated in young adults due to increased incidence of adverse events and overall poor tolerability. The safety profile of ABT-288 appears to be consistent with other H3 receptor antagonists with typical sleep-related adverse events (insomnia, sleep disturbances, abnormal dreams) and other likely histamine-mediated adverse events (headache, nausea, sweating/hot flushes) [20][21][22][23]. Titration to improve the tolerability of higher doses was considered.…”

Section: Figurementioning

confidence: 99%

Safety, tolerability and pharmacokinetics of the histamine H₃ receptor antagonist, ABT‐288, in healthy young adults and elderly volunteers

Othman

Haig

Florian

et al. 2013

Brit J Clinical Pharma

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AIMThe objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. METHODSSingle doses (0.1, 0.3,1,3,10, and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. RESULTSABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4-to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. CONCLUSIONSBased on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Histamine H3 receptor antagonists increase the release of the brain neurotransmitters that are known to modulate cognitive processes. H3 receptor antagonists have demonstrated pro-cognitive effects in preclinical studies. ABT-288 is a highly selective histamine H3 receptor antagonist designed for symptomatic treatment of cognitive disorders. WHAT THIS STUDY ADDS• In the present article, we present the safety, tolerability and pharmacokinetics of ABT-288 in healthy young adults and in elderly human subjects. Results from these trials, along with preclinical data, were the basis for advancing ABT-288 to proof-of-concept phase 2 evaluation in Alzheimer's disease and the presented studies guided dose selection for phase 2 testing. In general, results presented in the current article provide the most comprehensive characterization of the safety and tolerability profiles of pharmacological H3 receptor antagonism in young adults and elderly human subjects.

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“…Indeed, acute administration of GSK189254 reduced narcoleptic episodes in orexin-knockout mice [105]. Moreover, in a pilot single-blind clinical trial on 22 patients diagnosed with narco lepsy receiving a placebo for 1 week, followed by tiprolisant (BF2.649) for a second week, the Epworth sleepiness scale (ESS) score was reduced from a baseline value of 17.6 by 1.0 with the placebo (p > 0.05), and 5.9 with tiprolisant (p < 0.001) [106]. EDS, unaffected under placebo, was nearly suppressed on the last days [108]).…”

Section: Characteristics Of the H 3 Rmentioning

confidence: 99%

Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

Blandina¹,

Munari

Giannoni

et al. 2010

Future Neurol.

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Much has been learned over the past 20 years about the role of histamine as a neurotransmitter. This brief article attempts to evaluate the progress accomplished in this field, and discusses the therapeutic potential of the H3 receptor (H3R). All histaminergic neurons are localized in the tuberomammillary nucleus of the posterior hypothalamus and project to almost all regions of the CNS. Histamine exerts its effect via interaction with specific receptors (H1R, H2R, H3R and H4R). Antagonists of both H1R and H2R have been successful as blockbuster drugs for treating allergic conditions and gastric ulcers. H4R is still awaiting better functional characterization, but the H3R is an attractive target for potential therapies of CNS disorders. Indeed, considerable interest was raised by reports that pharmacological blockade of H3Rs exerted procognitive effects in a variety of animal tasks analyzing different types of memory. In addition, blockade of H3Rs increased wakefulness and reduced bodyweight in animal models. Such findings hint at the potential use of H3R antagonists/inverse agonists for the treatment of Alzheimer’s disease and other dementias, attention-deficit hyperactivity disorder, obesity and sleep disorders. As a result, an increasing number of H3R antagonists/inverse agonists progress through the clinic for the treatment of a variety of conditions, including attention-deficit hyperactivity disorder, cognitive disorders, narcolepsy and schizophrenia. Moreover, the use of H3R antagonists/inverse agonists that weaken traumatic memories may alleviate disorders such as post-traumatic stress syndrome, panic attacks, specific phobias and generalized anxiety. The use of H3R ligands for the treatment of neurodegenerative disorders is demonstrated in several studies, indicating a role of the histamine neurons and H3Rs in neuroprotection. Recently, direct evidence demonstrated that histaminergic neurons are organized into functionally distinct circuits, impinging on different brain regions, and displaying selective control mechanisms. This could imply independent functions of subsets of histaminergic neurons according to their respective origin and terminal projections. The possibility that H3Rs control only some of those functions implies that H3R-directed therapies may achieve selective effects, with minimal side effects, and this may increase the interest regarding this class of drugs.

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An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin−/− mice and patients

Cited by 249 publications

References 43 publications

Effect of a novel histamine subtype-3 receptor inverse agonist and modafinil on EEG power spectra during sleep deprivation and recovery sleep in male volunteers

Effect of a novel histamine subtype-3 receptor inverse agonist and modafinil on EEG power spectra during sleep deprivation and recovery sleep in male volunteers

Safety, tolerability and pharmacokinetics of the histamine H₃ receptor antagonist, ABT‐288, in healthy young adults and elderly volunteers

Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

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An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin−/− mice and patients

Cited by 249 publications

References 43 publications

Effect of a novel histamine subtype-3 receptor inverse agonist and modafinil on EEG power spectra during sleep deprivation and recovery sleep in male volunteers

Effect of a novel histamine subtype-3 receptor inverse agonist and modafinil on EEG power spectra during sleep deprivation and recovery sleep in male volunteers

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT‐288, in healthy young adults and elderly volunteers

Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

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Product

Resources

About

Safety, tolerability and pharmacokinetics of the histamine H₃ receptor antagonist, ABT‐288, in healthy young adults and elderly volunteers