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Multiple sclerosis is an autoimmune disease with a strong neuroinflammatory component that contributes to severe demyelination, neurodegeneration and lesions formation in white and grey matter of the spinal cord and brain. Increasing attention is being paid to the signaling of the biogenic amine histamine in the context of several pathological conditions. In multiple sclerosis, histamine regulates the differentiation of oligodendrocyte precursors, reduces demyelination, and improves the remyelination process. However, the concomitant activation of histamine H1-H4 receptors can sustain either damaging or favorable effects, depending on the specifically activated receptor subtype/s, the timing of receptor engagement, and the central versus peripheral target district. Conventional drug development has failed so far to identify curative drugs for multiple sclerosis, thus causing a severe delay in therapeutic options available to patients. In this perspective, drug repurposing offers an exciting and complementary alternative for rapidly approving some medicines already approved for other indications. In the present work, we have adopted a new network-medicine-based algorithm for drug repurposing called SAveRUNNER, for quantifying the interplay between multiple sclerosis-associated genes and drug targets in the human interactome. We have identified new histamine drug-disease associations and predicted off-label novel use of the histaminergic drugs amodiaquine, rupatadine, and diphenhydramine among others, for multiple sclerosis. Our work suggests that selected histamine-related molecules might get to the root causes of multiple sclerosis and emerge as new potential therapeutic strategies for the disease.

Objectives: The cost-effectiveness of available pharmacological treatments for narcolepsy is largely unknown. Available pharmacological treatments are associated with tolerability, abuse, and adherence issues. Pitolisant is the first inverse agonist of the histamine H3 receptor to be prescribed for the treatment of narcolepsy with and without cataplexy. Studies suggest that pitolisant is both as effective as previously introduced drugs and is associated with fewer adverse effects. The objective in this study was to estimate the cost-effectiveness of pitolisant as monotherapy, and pitolisant as an adjunctive treatment to modafinil, compared with standard treatment., Materials & Methods: Calculations were performed using a Markov model with a 50-year time horizon. Healthcare utilization and quality-adjusted life years (QALYs) for each treatment alternative were calculated assuming no treatment effect on survival. Probabilistic sensitivity analyses were performed for treatment effectiveness and healthcare cost parameters., Results: The cost per additional quality-adjusted life year was estimated at SEK 356 337 (10 SEK ≈ 1 Euro) for pitolisant monotherapy, and at SEK 491 128 for pitolisant as an adjunctive treatment, as compared to standard treatment. The cost-effectiveness measure was demonstrated to be particularly sensitive to the assumptions made concerning indirect effects on total healthcare utilization and the pitolisant treatment cost., Conclusions: The incremental cost-effectiveness ratios were below the unofficial willingness-to-pay threshold at SEK 500 000. The estimated costs per additional QALY obtained here are likely to overestimate the true cost-effectiveness ratio since significant potential indirect effects-pertaining both to labor-market and household-related productivity-of treatment are not taken into account., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The neural histaminergic system is involved in a wide range of physiological processes, including anxiety. Histaminergic neurons are localized in the tuberomammillary nucleus of the posterior hypothalamus and share bidirectional connections with the lateral septum, an area well implicated in anxiety. The current study examined whether the histaminergic system of the lateral septum regulates rats' defensive behaviors in two animal models of anxiety, the elevated plus maze (EPM) and novelty-induced suppression of feeding paradigm (NISF). We found that bilateral infusions of histamine (1.0 μg and 5.0 μg) into the lateral septum selectively decreased rats' defensive behaviors in the EPM (both doses) and NISF (1.0 μg only). Follow-up studies found that pre-infusions of the H1 and H2 antagonists, pyrilamine (20 μg) and ranitidine (20 μg) respectively, reversed the anxiolytic-like effects of intra-LS histamine (1.0 μg) in the NISF but not in the EPM, while pre-infusions of the H3 antagonist ciproxifan (200 pg) attenuated the anxiolytic-like effects of intra-LS histamine in the EPM but not in the NISF. This double dissociation suggests that H1 and H2 receptors in the lateral septum, likely via a post-synaptic mechanism, mediate the anxiolytic-like effects of histamine in the NISF but not in the EPM. In contrast, lateral septal H3 receptors mediate, likely pre-synaptically, the anxiolytic-like effects of histamine in the EPM but not in the NISF. Our findings indicate that these receptors differentially contribute to rats' specific defensive behaviors in the EPM and NISF, that is, avoidance of open spaces and neophagia respectively., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Addiction is a behavioral disorder characterized by the compulsive seeking and taking of drugs despite serious negative consequences. In particular, the chronic use of drugs impairs memory and cognitive functions, which aggravates the loss of control over drug use and complicates treatment outcome. Therefore, cognitive enhancers targeting acetylcholine have been proposed to treat addiction. Interestingly, histamine H(3) receptor (H(3)R) antagonists/inverse agonists stimulate acetylcholine transmission in different brain areas, facilitate memory in animal models and can reverse learning deficits induced by drugs such as scopolamine, dizocilpine and alcohol. Moreover, several studies found that compounds capable of activating the histaminergic system generally decrease the reinforcing effects of drugs, namely alcohol and opioids, in preclinical models of addiction. Finally, several H(3)R antagonists/inverse agonists increase histamine in the brain and have proven to be safe in humans. However, no studies have yet investigated the therapeutic potential of cognitive enhancing H(3)R antagonists/inverse agonists in the treatment of addiction in humans. The present review first describes the impact of addictive drugs on learning processes and cognitive functions that play an important role for addicts to remain abstinent. Second, our work briefly summarizes the relevant literature describing the function of histamine in learning, memory and drug addiction. Finally, the potential therapeutic use of histaminergic agents in the treatment of addiction is discussed. Our review suggests that histaminergic compounds like H(3)R antagonists/inverse agonists may improve the treatment outcome of addiction by reversing drug-induced cognitive deficits and/or diminishing the reinforcing properties of addictive drugs, especially opioids and alcohol., (Copyright © 2012 Elsevier B.V. All rights reserved.)

During the last decade, the identification of a number of novel drug targets led to the development of promising new compounds which are currently under evaluation for their therapeutic prospective in CNS related disorders. Besides the established pleiotropic regulatory functions in the periphery, the interest in the potential homeostatic role of histamine in the brain was revived following the identification of H(3) and H(4) receptors some years ago. Complementing classical CNS pharmacology, the development of selective histamine receptor agonists, antagonists, and inverse agonists provides the lead for the potential exploitation of the histaminergic system in the treatment of brain pathologies. Although no CNS disease entity has been associated directly to brain histamine dysfunction until now, the H(3) receptor is recognized as a drug target for neuropathic pain, sleep-wake disorders, including narcolepsy, and cognitive impairment associated with attention deficit hyperactivity disorder, schizophrenia, Alzheimer's, or Parkinson's disease, while the first H(3) receptor ligands have already entered phase I-III clinical trials. Interestingly, the localization of the immunomodulatory H(4) receptor in the nervous system exposes attractive perspectives for the therapeutic exploitation of this new drug target in neuroimmunopharmacology. This review focuses on a concise presentation of the current "translational research" approach that exploits the latest advances in histamine pharmacology for the development of beneficial drug targets for the treatment of neuronal disorders, such as neuropathic pain, cognitive, and sleep-wake pathologies. Furthermore, the role of the brain histaminergic system(s) in neuroprotection and neuroimmunology/inflammation remains a challenging research area that is currently under consideration., (© 2010 Blackwell Publishing Ltd.)

Multiple sclerosis (MS) is an autoimmune disease associated with chronic inflammatory demyelination of the central nervous system (CNS). Due to disease complexity and heterogeneity, its pathogenesis remains unknown and despite extensive studies, specific effective treatments have not yet been developed. The factors behind the initiation of the inflammatory reactions in CNS have not been identified until now. MS is considered as a complex disease depending on genetic as well as environmental factors. Experimental autoimmune encephalomyelitis (EAE) is the preferential experimental rodent model for MS. Histamine [2-(4-imidazole) ethylamine] is a ubiquitous inflammatory mediator of diverse physiological processes including neurotransmission, secretion of pituitary hormones, and regulation of the gastrointestinal and circulatory systems which can modulate immune responses. Histamine functions are mediated through four G-protein coupled receptors that are named H1-H4 receptor. Histamine is implicated as an important factor in pathophysiology of MS and EAE. It has been shown that histamine can change the permeability of blood brain barrier, which leads to elevation of infiltrated cells in CNS and neuroinflammation. In contrast, there are evidence that show the protective role of histamine in MS and its animal model, EAE. In this review, we try to clarify the role of histamine in pathogenesis of MS, as well as we evaluate the efficacy of histamine receptors agonists and antagonists in treatment of this disease., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The role of histaminergic neurotransmission in the promotion of waking has been extensively studied in preclinical species. Appreciation for the role of histamine continues to expand with increasing understanding of the interaction of histamine within the broad network of neuromodulators that regulate sleep and wake. The effects of histamine on waking are transduced through the H(1) and the H(3) receptors in the central nervous system. Brain penetrant over-the-counter antihistamines comprised of antagonist actions at H(1) receptors as well as varying degrees of antimuscarinic properties are marketed as sleep aids, based on their well-known daytime drowsiness side effects. The data supporting their use as sedatives, however, are not consistent. H(3) receptors are presynaptic receptors that limit histamine release as well as that of monoamine neurotransmitters thought to participate in the maintenance of waking. In this review, we discuss 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. In addition, we review the current data available on the use of ligands at H(3) receptors for the modulation of sleep and wake.

The purpose of this investigation was to evaluate the efficacy of the histaminergic drug "Betahistine dihydrochloride" in experimental motion sickness in 10 healthy volunteers (mean age 19.4 y.o.) with high susceptibility to motion sickness. Motion sickness was modeled using Coriolis (precession) accelerations (cumulative Coriolis stimulation test--CCST). Each subject took 32 mg of "Betahistine dihydrochloride" or placebo under "double-blind" conditions 1 hour before testing. The duration and slow phase velocity of the post-rotational nystagmus, the pursuit eye tracking test, and the latency, velocity and accuracy of saccades were estimated. The tolerability level of the CCST in volunteers in the betahistine series was shown to be significantly (p<0.001) higher, as compared to placebo and baseline. The mean illusory sensations score for the experimental series was significantly lower than that in the placebo and baseline series (p < 0.01). It was found that "Betahistine" demonstrated antimotion sickness efficacy and improved oculomotor activity (increased gain during pursuit movements, faster and more accurate saccades).

An effect of betaserc on the character and intensity of vertigo (V), psycho-autonomic state of patients, vestibular functions and oculomotor system, using computer stimulating programs, has been studied in 39 patients with V. After 4 weeks of the treatment, betaserc exerted a positive effect on patients; however, the optimal effect was shown in patients with psychogenic V (73%). In this group, betaserc reduced both V and other psycho-autonomic disturbances. After betaserc treatment, patients with psychogenic V demonstrated a normalization of the vestibular responsiveness parameters in 70% of the cases and of the parameters of spontaneous oculomotor activity and pursuit eye function in 40 to 90%.

Headache and vertigo often emerge simultaneously. Fifty six (40%) out of 140 patients complaining of vertigo were studied. Emerging in the aura and/or in headache phases, vertigo was more frequently registered in patients suffered from migraine with aura (57%). Vertigo associated with migraine was diagnosed in 25% of the cases. The patients were randomized into 2 equal identical groups, one of which was treated by betaserc (16 mg, 3 times daily before meal) and the other one was given cinnarizine (25 mg, 3 times daily). Treatment duration was 12 weeks. Reduction of vertigo attacks frequency and headache by 50% and over, in comparison to the baseline period, was considered as beneficial. Fifty three (95%) patients completed the treatment course. Decrease of a risk for negative results and a frequency of positive effect of vertigo therapy were significantly higher in the group receiving betaserc. Reduction of monthly relapses by 50% and over was detected in 79% of the patients of betaserc group and in 52% of those of cinnarizine one. Migraine attacks monthly frequency was diminished by 43% and 64%, respectively. Therefore, betaserc is considered for using as vertigolytic medication and for migraine attacks prevention.

Low-dose histamine therapy has been prescribed by otolaryngologists primarily to treat Bell's palsy, vestibular disorders, vascular headache, Ménière's attacks, and urticaria vasculitis. The scientific explanations for the usefulness of this once-empiric treatment are becoming more apparent. Two methods of establishing the appropriate dosages have emerged: the empiric, optimum-dosage approach and the objective, endpoint-titration approach. In this article, the author describes and recommends the latter approach. The author also reports on a 100-patient retrospective clinical study that revealed that the objective, endpoint-titration approach was effective in treating 80% of patients. In light of such success and the ease and economy of this treatment, low-dose histamine therapy appears to be a valuable clinical tool.

Autonomic receptors play a part in the physiology and pathology of the nasal mucosa. The effect of an alpha-agonist and an anti-muscarinic agent on histamine-challenge was examined on patients with perennial allergic rhinitis. Nine patients received saline, oxitropium bromide 0.075%, or xylometazoline hydrochloride 0.1% in a double-blind fashion. Sequential challenge with increasing doses of histamine were given and resistance changes, sneezes and volume and content of secretion measured. Histamine challenge produced dose-related increases in nasal resistance (P < 0.0001), lavage fluid volume (P < 0.01) and total protein (P < 0.01). Following xylometazoline, histamine produced little increase in resistance compared with saline and oxitropium bromide (P < 0.0001). The latter reduced the dose-related increase in resistance (P < 0.01) and nasal lavage fluid volume (P = 0.0007) and total protein (P = 0.023) seen with saline. These results confirm the importance of alpha-adrenergic and muscarinic receptors in the human nasal mucosa and suggest mechanisms of action for these drugs in perennial allergic rhinitis.