RESUMO
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.
Assuntos
Histamínicos , Esclerose Múltipla , Remielinização , Reposicionamento de Medicamentos , Histamina , Histamínicos/uso terapêutico , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Receptores Histamínicos H4RESUMO
Alzheimer's disease (AD) represents the principal cause of dementia among the elderly. Great efforts have been established to understand the physiopathology of AD. Changes in neurotransmitter systems in patients with AD, including cholinergic, GABAergic, serotoninergic, noradrenergic, and histaminergic changes have been reported. Interestingly, changes in the histaminergic system have been related to cognitive impairment in AD patients. The principal pathological changes in the brains of AD patients, related to the histaminergic system, are neurofibrillary degeneration of the tuberomammillary nucleus, the main source of histamine in the brain, low histamine levels, and altered signaling of its receptors. The increase of histamine levels can be achieved by inhibiting its degrading enzyme, histamine N-methyltransferase (HNMT), a cytoplasmatic enzyme located in astrocytes. Thus, increasing histamine levels could be employed in AD patients as co-therapy due to their effects on cognitive functions, neuroplasticity, neuronal survival, neurogenesis, and the degradation of amyloid beta (Aß) peptides. In this sense, the evaluation of the impact of HNMT inhibitors on animal models of AD would be interesting, consequently highlighting its relevance.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Histamina N-Metiltransferase/genética , Histamina/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Histamínicos/uso terapêutico , Histamina N-Metiltransferase/antagonistas & inibidores , HumanosRESUMO
Atypical antipsychotic drugs were introduced in the early 1990s. Unlike typical antipsychotics, which are effective only against positive symptoms of schizophrenia, atypical antipsychotics are effective against negative and cognitive symptoms as well. Furthermore, they are effective not only in psychotic but also in affective disorders, on their own or as adjuncts to antidepressant drugs. This review presents the neural mechanisms of currently existing atypical antipsychotics and putative antipsychotics currently being investigated in preclinical and clinical studies and how these relate to their effectiveness in mood disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD). Typical antipsychotics act almost exclusively on the dopamine system. Atypical drugs, however, modulate serotonin (5-HT), norepinephrine, and/or histamine neurotransmission as well. This multimodal mechanism of action putatively underlies the beneficial effect of atypical antipsychotics in mood and anxiety disorders. Interestingly, novel experimental drugs having dual antipsychotic and antidepressant therapeutic potential, such as histamine, adenosine, and trace amine-associated receptors (TAAR) ligand, are also characterized by a multimodal stimulatory effect on central 5-HT, norepinephrine, and/or histamine transmission. The multimodal stimulatory effect on central monoamine neurotransmission may be thus primarily responsible for the combined antidepressant and antipsychotic therapeutic potential of certain central nervous system (CNS) drugs.
Assuntos
Antidepressivos/uso terapêutico , Antipsicóticos/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Neurônios/efeitos dos fármacos , Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Dopaminérgicos/farmacologia , Dopaminérgicos/uso terapêutico , Neurônios Dopaminérgicos/efeitos dos fármacos , Histamínicos/farmacologia , Histamínicos/uso terapêutico , Humanos , Receptores Adrenérgicos/efeitos dos fármacos , Receptores Purinérgicos/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Receptores de Serotonina/fisiologiaAssuntos
Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Histamínicos/uso terapêutico , Narcolepsia/tratamento farmacológico , Piperidinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Sono/efeitos dos fármacos , Comorbidade , Humanos , Masculino , Narcolepsia/diagnóstico , Narcolepsia/fisiopatologia , Esquizofrenia/diagnóstico , Resultado do Tratamento , Adulto JovemRESUMO
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.
Assuntos
Análise Custo-Benefício , Histamínicos/economia , Narcolepsia/tratamento farmacológico , Piperidinas/economia , Uso de Medicamentos , Histamínicos/uso terapêutico , Humanos , Piperidinas/uso terapêutico , Anos de Vida Ajustados por Qualidade de Vida , Resultado do TratamentoRESUMO
The brain histaminergic system plays a pivotal role in energy homeostasis, through H1- receptor activation, it increases the hypothalamic release of histamine that decreases food intake and reduces body weight. One way to increase the release of hypothalamic histamine is through the use of antagonist/inverse agonist for the H3-receptor. Histamine H3-receptors are auto-receptors and heteroreceptors located on the presynaptic membranes and cell soma of neurons, where they negatively regulate the synthesis and release of histamine and other neurotransmitters in the central nervous system. Although several compounds acting as H3-receptor antagonist/inverse agonists have been developed, conflicting results have been reported and only one has been tested as anti-obesity in humans. Animal studies revealed the opposite effect in food intake, energy expeditor, and body weight, depending on the drug, spice, and route of administration, among others. The present review will explore the state of art on the effects of H3-receptor ligands on appetite and body-weight, going through the following: a brief overview of the circuit involved in the control of food intake and energy homeostasis, the participation of the histaminergic system in food intake and body weight, and the H3-receptor as a potential therapeutic target for obesity.
Assuntos
Histamina/metabolismo , Obesidade/metabolismo , Receptores Histamínicos H3/metabolismo , Animais , Histamínicos/farmacologia , Histamínicos/uso terapêutico , Humanos , Obesidade/tratamento farmacológicoRESUMO
The control of food intake and body weight is very complex. Key factors driving eating behavior are hunger and satiety that are controlled by an interplay of several central and peripheral neuroendocrine systems, environmental factors, the behavioral state and circadian rhythm, which all concur to alter homeostatic aspects of appetite and energy expenditure. Brain histamine plays a fundamental role in eating behavior as it induces loss of appetite and has long been considered a satiety signal that is released during food intake (Sakata et al., 1997). Animal studies have shown that brain histamine is released during the appetitive phase to provide a high level of arousal preparatory to feeding, but also mediates satiety. Furthermore, histamine regulates peripheral mechanisms such as glucose uptake and insulin function. Preclinical research indicates that activation of H1 and H3 receptors is crucial for the regulation of the diurnal rhythm of food consumption; furthermore, these receptors have been specifically recognized as mediators of energy intake and expenditure. Despite encouraging preclinical data, though, no brain penetrating H1 receptor agonists have been identified that would have anti-obesity effects. The potential role of the H3 receptor as a target of anti-obesity therapeutics was explored in clinical trials that did not meet up to the expectations or were interrupted (clinicaltrials.gov). Nonetheless, interesting results are emerging from clinical trials that evaluated the attenuating effect of betahistine (an H1 agonist/H3 antagonist) on metabolic side effects associated with chronic antipsychotics treatment. Aim of this review is to summarize recent results that suggest the clinical relevance of the histaminergic system for the treatment of feeding disorders and provide an up-to-date summary of preclinical research. This article is part of the Special Issue entitled 'Histamine Receptors'.
Assuntos
Histamina/metabolismo , Síndrome Metabólica/metabolismo , Síndrome Metabólica/prevenção & controle , Obesidade/metabolismo , Obesidade/prevenção & controle , Animais , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Histamínicos/farmacologia , Histamínicos/uso terapêutico , Humanos , Síndrome Metabólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Receptores Histamínicos/metabolismoRESUMO
Adult Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent psychiatric condition associated with high disability and frequent comorbidity. Current standard pharmacotherapy (methylphenidate and atomoxetine) improves ADHD symptoms in the short-term, but poor data were published about long-term treatment. In addition a number of patients present partial or no response to methylphenidate and atomoxetine. Research into the main database sources has been conducted to obtain an overview of alternative pharmacological approaches in adult ADHD patients. Among alternative compounds, amphetamines (mixed amphetamine salts and lisdexamfetamine) have the most robust evidence of efficacy, but they may be associated with serious side effects (e.g. psychotic symptoms or hypertension). Antidepressants, particularly those acting as noradrenaline or dopamine enhancers, have evidence of efficacy, but they should be avoided in patients with comorbid bipolar disorder. Finally metadoxine and lithium may be particularly suitable in case of comorbid alcohol misuse or bipolar disorder.
Assuntos
Antidepressivos/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Dopaminérgicos/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Agonistas alfa-Adrenérgicos/uso terapêutico , Adulto , Anfetaminas/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Bupropiona/uso terapêutico , Desipramina/uso terapêutico , Droxidopa/uso terapêutico , Combinação de Medicamentos , Cloridrato de Duloxetina/uso terapêutico , Guanfacina/uso terapêutico , Histamínicos/uso terapêutico , Humanos , Dimesilato de Lisdexanfetamina/uso terapêutico , Compostos de Lítio/uso terapêutico , Lobelina/uso terapêutico , Mecamilamina/uso terapêutico , Memantina/uso terapêutico , Modafinila , Morfolinas/uso terapêutico , Antagonistas Nicotínicos/uso terapêutico , Nomifensina/uso terapêutico , Paroxetina/uso terapêutico , Piridinas/uso terapêutico , Piridoxina/uso terapêutico , Ácido Pirrolidonocarboxílico/uso terapêutico , Quinazolinonas/uso terapêutico , Reboxetina , Cloridrato de Venlafaxina/uso terapêutico , Promotores da Vigília/uso terapêuticoRESUMO
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.
Assuntos
Ansiedade/tratamento farmacológico , Comportamento Exploratório/efeitos dos fármacos , Histamínicos/uso terapêutico , Aprendizagem em Labirinto/efeitos dos fármacos , Receptores Histamínicos/metabolismo , Septo do Cérebro/efeitos dos fármacos , Análise de Variância , Animais , Ansiolíticos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Histamínicos/farmacologia , Masculino , Ratos , Ratos Long-Evans , Tempo de Reação/efeitos dos fármacos , Septo do Cérebro/metabolismoRESUMO
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.
Assuntos
Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Histamínicos/uso terapêutico , Histamina/metabolismo , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Encéfalo/metabolismo , Encéfalo/patologia , Histamínicos/farmacologia , Humanos , Receptores Histamínicos/metabolismo , Transtornos Relacionados ao Uso de Substâncias/complicaçõesRESUMO
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.
Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Fármacos do Sistema Nervoso Central/uso terapêutico , Histamínicos/farmacologia , Histamínicos/uso terapêutico , Histamina/fisiologia , Receptores Histamínicos/efeitos dos fármacos , Animais , Encéfalo/fisiologia , Química Encefálica/fisiologia , Transtornos Cognitivos/tratamento farmacológico , Humanos , Esclerose Múltipla/tratamento farmacológico , Neuralgia/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Acoplados a Proteínas G/fisiologia , Receptores Histamínicos/fisiologia , Receptores Histamínicos H3/efeitos dos fármacos , Receptores Histamínicos H3/fisiologia , Receptores Histamínicos H4 , Transtornos do Sono-Vigília/tratamento farmacológicoAssuntos
Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Anticonvulsivantes/uso terapêutico , Antidepressivos/uso terapêutico , Quimioterapia Combinada , Fármacos Gastrointestinais/uso terapêutico , Histamínicos/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Simpatomiméticos/uso terapêuticoRESUMO
Interest in the histaminergic system as a potential target for the treatment of feeding disorders is driven by the unsatisfactory history of the pharmacotherapy of obesity. Eating behavior is regulated by a complex interplay of central neurotransmitter systems, peripheral endocrine stimuli, the circadian rhythm, and environmental cues, all factors that change the behavioral state and alter homeostatic aspects of appetite and energy expenditure. Key factors driving eating behavior are appetite and satiety that are regulated through different mechanisms. Brain histamine has long been considered a satiety signal in the nervous system. Recent observations, however, indicate that histamine does not meet the criteria for being a satiety signal, because augmented histamine release accompanies the appetitive phase of feeding behavior rather than food consumption and satiety. The appetitive phase requires a high and yet optimal arousal state, and the histaminergic system is crucial for sustaining a high degree of arousal during motivated behavior. Histamine H(1) receptors in the brain are crucial for the regulation of the diurnal rhythm of food intake and the regulation of obesity; however, from a therapeutic standpoint, no brain-penetrating H(1) receptor agonists have been identified that would have antiobesity effects. Despite conflicting preclinical data, insights are emerging into the potential role of histamine H(3) receptors as a target of antiobesity therapeutics. The aim of this review is to outline the relevance of the histaminergic system in controlling feeding behavior and evaluate the potential therapeutic use of histaminergic ligands for the treatment of eating disorders.
Assuntos
Comportamento Alimentar/fisiologia , Receptores Histamínicos H3/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Histamínicos/metabolismo , Histamínicos/farmacologia , Histamínicos/uso terapêutico , Humanos , Obesidade/tratamento farmacológico , Obesidade/metabolismoRESUMO
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.
Assuntos
Histamínicos/uso terapêutico , Histamina/metabolismo , Esclerose Múltipla/tratamento farmacológico , Receptores Histamínicos/fisiologia , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/fisiopatologia , Histamina/uso terapêutico , Humanos , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Receptores Histamínicos/classificaçãoRESUMO
Weight gain is a significant problem for many patients taking various psychotropic medications. The U.S. Food and Drug Administration (FDA) has approved certain medications for the treatment of obesity. Other medications known to be associated with weight loss could be used for treating obesity, although they are not FDA approved for this indication. This article briefly describes the sympathomimetic, antidepressant, anticonvulsant, histamine-modulating, antidiabetic, and gastrointestinal drugs that have been found to cause weight loss and might be considered for adjunctive use in the overall management of psychotropic drug-related weight gain. However, even if such drugs are effective, all patients should receive ongoing dietary and physical activity counseling.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Obesidade , Psicotrópicos/efeitos adversos , Aumento de Peso/efeitos dos fármacos , Anticonvulsivantes/uso terapêutico , Aprovação de Drogas , Fármacos Gastrointestinais/uso terapêutico , Histamínicos/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Estilo de Vida , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Educação de Pacientes como Assunto , Seleção de Pacientes , Fatores de Risco , Simpatomiméticos/uso terapêutico , Estados UnidosRESUMO
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.
Assuntos
Ritmo Circadiano/fisiologia , Histamínicos/uso terapêutico , Histamina/fisiologia , Transtornos do Sono do Ritmo Circadiano/tratamento farmacológico , Animais , Ritmo Circadiano/efeitos dos fármacos , Histamínicos/farmacologia , Humanos , Receptores Histamínicos H3/fisiologiaRESUMO
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).
Assuntos
beta-Histina/uso terapêutico , Histamínicos/uso terapêutico , Enjoo devido ao Movimento/tratamento farmacológico , Adolescente , Adulto , Força Coriolis , Humanos , Masculino , Nistagmo Patológico/tratamento farmacológico , Rotação , Doenças Vestibulares/tratamento farmacológicoRESUMO
Diferentes grupos de pesquisa têm se dedicado à investigação dos mecanismos cerebrais de controle da sede. O avanço neste campo da Neurociência tem trazido importantes contribuições para a compreensão da regulação da homeostasia hidrossalina, o que pode levar a futuras aplicações clínicas. Desde a década de 1950 tem sido sugerido que a histamina pode atuar como neuromodulador/neurotransmissor no sistema nervoso central, entretanto sua função ainda não é clara, especialmente no que concerne ao controle da homeostasia hidrossalina. Assim o objetivo do presente trabalho foi investigar o papel das vias histaminérgicas centrais no controle da ingestão hídrica e ingestão de água pós-prandial. Foram utilizados quatro modelos de estudo: ingestão hídrica em animais normoidratados, em animais desidratados por privação hídrica e por sobrecarga de sódio e pós-prandial. No primeiro grupo ratos normoidratados receberam microinjeções bilaterais no núcleo ventromedial hipotalâmico (VMH), de HTMT, agonista específico para os receptores histaminérgicos do tipo H1, nas doses de 100 e 200 nmol e dimaprite agonista para os receptores H2 na dose de 100 nmol. No segundo grupo, animais em privação hídrica por 14 horas "overnight" foram injetados no VMH com mepiramine, antagonista dos receptores histaminérgicos H1, e cimetidine, antagonista específico para os receptores H2 nas doses de 100 e 200 nmol. No terceiro grupo foi realizado em animais sob desidratação osmótica induzida por sobrecarga da salina hipertônica (solução salina 9% num volume de 10% do peso corporal). Nesses três grupos o volume ingerido pelos animais foi monitorado a cada 15 minutos durante 2 horas. No quarto grupo as 18:00 horas foram aplicadas microinjeçóes de mepiramine e cimetidine na dose de 200 nmol para a investigação da ingestão hídrica pós-prandial. A ingestão alimentar e o volume hídrico ingeridos deste grupo foram monitorados a cada 30 minutos durante as primeiras 4 horas do período noturno e ao fim deste período (6:00 h)...
Assuntos
Animais , Ratos , Histamínicos/uso terapêutico , Apetite/fisiologia , Cloreto de Sódio , Comportamento de Ingestão de Líquido , Homeostase , Histamina/uso terapêutico , Experimentação Animal , Ingestão de LíquidosRESUMO
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%.