Individualized treatment for allergic rhinitis based on key nasal clinical manifestations combined with histamine and leukotriene D4 levels / Tratamento individualizado para a rinite alérgica baseado nas principais manifestações clínicas nasais e dos níveis de histamina e leucotrieno D4

Abstract Introduction The types of allergic rhinitis are roughly classified based on the causative antigens, disease types, predilection time, and symptom severity. Objective To examine the clinical typing and individualized treatment approach for allergic rhinitis and to determine the optimal treatment method for this disease using various drug combination therapies. Methods A total of 108 participants with allergic rhinitis were divided into three groups based on symptoms. Subsequently, each group was further categorized into four subgroups based on the medications received. The efficacy of the treatments was evaluated using the visual analog scale VAS scores of the total and individual nasal symptoms, decline index of the symptom score, histamine and leukotriene levels, and mRNA and protein expression levels of histamine 1 and cysteinyl leukotriene 1 receptors. Results Loratadine + mometasone furoate and loratadine + mometasone furoate + montelukast significantly improved the sneezing symptom and reduced the histamine levels compared with the other combination therapies (p < 0.05). Meanwhile, montelukast + mometasone furoate and montelukast + mometasone furoate + loratadine considerably improved the nasal obstruction symptom and decreased the leukotriene D4 levels compared with the other combination therapies (p < 0.05). Conclusion Clinical symptom evaluation combined with experimental detection of histamine and leukotriene levels can be an objective and accurate method to clinically classify the allergic rhinitis types. Furthermore, individualized treatment based on allergic rhinitis classification can result in a good treatment efficacy.

Resumo Introdução A rinite alérgica é basicamente classificada de acordo com os antígenos causadores, tipos de doença, peridiocidade e gravidade dos sintomas. Objetivo Avaliar os tipos clínicos e a abordagem terapêutica individualizada para cada tipo de rinite alérgica e determinar o método de tratamento ideal utilizando várias terapias de combinação de fármacos. Método Um total de 108 participantes com rinite alérgica foram divididos em três grupos com base nos sintomas. Posteriormente, cada grupo foi subsequentemente categorizado em quatro subgrupos com base nos medicamentos recebidos. A eficácia dos tratamentos foi avaliada utilizando os escores da escala visual analógica EVA dos sintomas nasais totais e individualmente, índice de declínio do escore de sintomas, níveis de histamina e leucotrienos e níveis de expressão de mRNA e proteína dos receptores de histamina 1 e cisteinil-leucotrieno 1. Resultados As associações entre loratadina + furoato de mometasona, assim como a de loratadina + furoato de mometasona + montelucaste melhoraram significativamente o sintoma de espirros e reduziram os níveis de histamina em comparação às outras terapias combinadas (p < 0,05). Por outro lado, a associação montelucaste + furoato de mometasona, assim como a associação montelucaste + furoato de mometasone + loratadina melhoraram consideravelmente o sintoma de obstrução nasal e diminuíram os níveis de leucotrieno D4 em comparação com as outras combinações (p < 0,05). Conclusão A avaliação clínica dos sintomas combinada com a detecção experimental dos níveis de histamina e leucotrieno pode ser um método objetivo e preciso para classificar clinicamente os tipos de rinite alérgica. Além disso, o tratamento individualizado baseado na classificação da rinite alérgica pode resultar no aumento da eficácia do tratamento.

Histamine Excites Rat GABAergic Ventral Pallidum Neurons via Co-activation of H1 and H2 Receptors / 神经科学通报·英文版

The ventral pallidum (VP) is a crucial component of the limbic loop of the basal ganglia and participates in the regulation of reward, motivation, and emotion. Although the VP receives afferent inputs from the central histaminergic system, little is known about the effect of histamine on the VP and the underlying receptor mechanism. Here, we showed that histamine, a hypothalamic-derived neuromodulator, directly depolarized and excited the GABAergic VP neurons which comprise a major cell type in the VP and are responsible for encoding cues of incentive salience and reward hedonics. Both postsynaptic histamine H1 and H2 receptors were found to be expressed in the GABAergic VP neurons and co-mediate the excitatory effect of histamine. These results suggested that the central histaminergic system may actively participate in VP-mediated motivational and emotional behaviors via direct modulation of the GABAergic VP neurons. Our findings also have implications for the role of histamine and the central histaminergic system in psychiatric disorders.

Histamine H1-receptor antagonists against leishmania (L. ) infantum: an in vitro and in vivo evaluation using phosphatidylserine-liposomes

Considering the limited and toxic therapeutic arsenal available for visceral leishmaniasis (VL), the drug repositioning approach could represent a promising tool to the introduction of alternative therapies. Histamine H1-receptor antagonists are drugs belonging to different therapeutic classes, including antiallergics and anxyolitics. In this work, we described for the first time the activity of H1-antagonists against L. (L.) infantum and their potential effectiveness in an experimental hamster model. The evaluation against promastigotes demonstrated that chlorpheniramine, cinnarizine, hydroxyzine, ketotifen, loratadine, quetiapine and risperidone exerted a leishmanicidal effect against promastigotes, with IC50 values in the range of 13-84µM. The antihistaminic drug cinnarizine demonstrated effectiveness against the intracellular amastigotes, with an IC50 value of 21µM. The mammalian cytotoxicity was investigated in NCTC cells, resulting in IC50 values in the range of 57-229µM. Cinnarizine was in vivo studied as a free formulation and entrapped into phosphatidylserine-liposomes. The free drug was administered for eight consecutive days at 50mg/kg by intraperitoneal route (i.p.) and at 100mg/kg by oral route to L. infantum-infected hamsters, but showed lack of effectiveness in both regimens, as detected by real time PCR. The liposomal formulation was administered by i.p. route at 3mg/kg for eight days and reduced the parasite burden to 54% in liver when compared to untreated group; no improvement was observed in the spleen of infected hamsters. Cinnarizine is the first antihistaminic drug with antileishmanial activity and could be used as scaffold for drug design studies for VL.

H1 but not H2 histamine antagonist receptors mediate anxiety-related behaviors and emotional memory deficit in mice subjected to elevated plus-maze testing

This study investigated the role of H1 and H2 receptors in anxiety and the retrieval of emotional memory using a Trial 1/Trial 2 (T1/T2) protocol in an elevated plus-maze (EPM). Tests were performed on 2 consecutive days, designated T1 and T2. Before T1, the mice received intraperitoneal injections of saline (SAL), 20 mg/kg zolantidine (ZOL, an H2 receptor antagonist), or 8.0 or 16 mg/kg chlorpheniramine (CPA, an H1 receptor antagonist). After 40 min, they were subjected to the EPM test. In T2 (24 h later), each group was subdivided into two additional groups, and the animals from each group were re-injected with SAL or one of the drugs. In T1, the Student t-test showed no difference between the SAL and ZOL or 8 mg/kg CPA groups with respect to the percentages of open arm entries (%OAE) and open arm time (%OAT). However, administration of CPA at the highest dose of 16 mg/kg decreased %OAE and %OAT, but not locomotor activity, indicating anxiogenic-like behavior. Emotional memory, as revealed by a reduction in open arm exploration between the two trials, was observed in all experimental groups, indicating that ZOL and 8 mg/kg CPA did not affect emotional memory, whereas CPA at the highest dose affected acquisition and consolidation, but not retrieval of memory. Taken together, these results suggest that H1 receptor, but not H2, is implicated in anxiety-like behavior and in emotional memory acquisition and consolidation deficits in mice subjected to EPM testing.

Comparison of Serum Prolactin Level between I.V. Ranitidne and I.V Cimetidine Administration in Albino Rabbits and Possible Role of Histamine 1 and 2 Receptors in Prolactin Secretion.

The serum prolactin levels of eighteen normal rabbits are measured by using method of RIA. The values before drug treatment are taken as the control values of each group. Prolactin levels after 15, 30 and 45 minutes of i.v. Ranitidine treated group, when compared to its own control values, are not significantly raised whereas those levels after i.v. cimetidine are raised significantly in the paired t-test. Prolactin levels of i.v.cimetidine group , when compared with iv ranitidine group by unpaired t-test, are significantly raised [t = 2.737, 4.215 and 2.834 at 10,15, 45 minutes intervals respectively, at 10 degree of freedom, (p < 0.05)]. In the comparison between i.v. cimetidine and i.v. cimetidine pretreated with i.v. diphenhydramine groups (by unpaired t- test), presence of diphenhydramine HCl can cause statistically significant reduction at 30,45 minutes (at 10 degree of freedom. t- 2.666 and 2.440 respectively, (p < 0.05). The result shows that i.v.cimetidine can significantly liberate prolactin from the Ant. Pituitary, unlike i.v. ranitidine. Central H1 and H2 receptors contribute in prolactin secretion.

Olopatadine ophthalmic solution suppresses substance P release in the conjunctivitis models

BACKGROUND: Olopatadine hydrochloride ophthalmic solutions are treated for allergic conjunctival diseases that are a selective histamine H1 receptor antagonist and an inhibitor of the release of mediators including histamine from the human mast cells. Substance P (SP) levels are increased in tears of patients with allergic conjunctivitis. However, little is known about the regulation of SP release by anti-allergic ophthalmic solutions. OBJECTIVE: We investigated that the effect of olopatadine hydrochloride ophthalmic solutions (olopatadine 0.1% and olopatadine 0.2%) on rat conjunctivitis models compared with other anti-allergic ophthalmic solutions. METHODS: Conjunctivitis was induced by subconjunctival injection of histamine or intravenous injection of ovalbumin in rats passively sensitized with anti-ovalbumin anti-serum. The releases of SP were determined in the conjunctiva and tears using rat antigen-induced conjunctivitis models. RESULTS: Olopatadine 0.1% and 0.2% significantly inhibited the increased conjunctival dye leaked in the histamine- or antigen-induced hyperpermeability. The inhibitory effects by olopatadine were more potent than by other tested anti-allergic ophthalmic solutions. Moreover, olopatadine significantly inhibited the release of SP from the conjunctiva. CONCLUSION: These results indicate that olopatadine ophthalmic solutions appear to exert additional SP release inhibition besides dual-action such as selective histamine H1 receptor antagonistic action and mast cell stabilization action.

Investigation of the antiallergic activity of olopatadine on rhinitis induced by intranasal instillation of antigen in sensitized rats using thermography

BACKGROUND: The main symptoms of allergic rhinitis (AR) are sneezing, rhinorrhea and nasal obstruction. It was reported that the nasal skin temperature after intranasal administration of histamine or grass pollen rose. In patients with AR, the levels of nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) have increased in nasal fluids and mucosa. OBJECTIVE: The present study were to determine the temperature changes of the nose in rat allergic rhinitis model, and if olopatadine, an antiallergic agent with histamine H1 receptor antagonistic action, proved to be effective, were studied the productions of NGF and VEGF in nasal lavage fluids (NALF). In the present study, we used ovalbumin (OVA)-sensitized rats as an animal model of nasal allergy and examined the effects of olopatadine on the skin temperature of the nose area, and the productions of NGF and VEGF in NALF. METHODS: The temperature changes of the nose area were carried out with thermo tracer in rat passively sensitized with OVA antiserum. The numbers of sneezing episodes were counted and, NGF and VEGF levels in NALF were examined using the specific ELISA. RESULTS: In OVA-sensitized rats, the number of sneezing episodes increase and the nasal skin temperature rise were provoked after OVA challenge. The levels of NGF and VEGF in NALF also were increased. Olopatadine reduced the increased frequency of sneezing and the nasal skin temperature rise. It also inhibited the increased NGF and VEGF productions in NALF. CONCLUSION: The nasal skin temperature after OVA challenge rose even in OVA-sensitized rats. These results suggest that the suppression of the increased NGF and VEGF levels might partially be involved in the improvement of allergy-like behavior (sneezing and nasal skin temperature rise) by the treatment of olopatadine.

Revisão sobre a efícacia e segurança dos anti-histamínicos de primeira e segunda geração / Revision on efficacy and safety of antihistamines of first and second generation

Objetivo: Revisar a eficácia e segurança dos principais anti-histamínicos de primeira e segunda geração. Os anti-histamínicos correspondem a um grupo extenso de medicamentos que vêm apresentando grandes avanços no conhecimento de suas ações e estão entre os agentes mais utilizados na prática clínica em diversas doenças alérgicas. Método: Levantamento bibliográfico nos bancos de dados PubMed, Medline, LILACS, SCIELO e capítulos de livros nos últimos 10 anos, sendo incluídos artigos históricos. Resultados: Nessa revisão são destacadas as principais características da histamina, as diferenças entre os receptores de histamina, o desenvolvimento dos anti-histamínicos de primeira e segunda geração, sua classificação e os principais efeitos colaterais de cada grupo de anti-histamínicos. Conclusão: A presente revisão não pretende esgotar o assunto sobre eficácia e segurança dos anti-histamínicos, mas destaca a falta de estudos bem conduzidos sobre eficácia dos anti-histamínicos de primeira geração e o número crescente de metanálises sobre farmacodinâmica, potência, eficácia e segurança dos anti-histamínicos de segunda geração.

Objective: To review the efficacy and safety of the main antihistamines of first and second generation. The antihistamines represent an extensive group of drugs that are showing great advances in knowledge of their actions and are among the most common agents used in clinical practice in various allergic diseases. Method: Searches in PubMed, Medline, LILACS, SCIELO database and book chapters in the last 10 years, including historic articles. Results: This review highlights the main features of histamine, the differences between histamine receptors, development of first and second generation antihistamines, their classification, and the main side effects of each group of antihistamines. Conclusion: The present review is not intended to exhaust the subject on efficacy and safety of antihistamine, but it highlights the lack of well conducted studies of the efficacy of first-generation antihistamine and the rising number of meta-analysis of pharmacodynamics, potency, efficacy and safety of second-generation antihistamines.

Histamine H1 receptors modulate the discharge activities of inspiratory neurons in the medial region of neonatal rat nucleus retrofacialis ex vivo / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the role of histamine H1 receptors in modulating the discharge activities of the inspiratory neurons in the nucleus retrofacialis of neonatal rats.</p><p><b>METHODS</b>Brainstem slices were obtained from neonatal rats containing the medial region of the nucleus retrofacialis (mNRF) with the hypoglossal nerve (XII nerve) rootlets retained. The rhythmic discharges of the inspiratory neurons (I neurons) and activities of the XII nerve rootlets were simultaneously recorded using microelectrodes and suction electrodes, respectively. The role of H1 receptors in modulation of the discharge activities of the inspiratory neurons was investigated using the H1 receptor agonist histamine and its specific antagonist pyrilamine dissolved in modified Kreb's solution for slice perfusion.</p><p><b>RESULTS</b>Histamine shortened the respiratory cycle (RC) and expiratory time (TE) of the neurons in the brain slices, and pyrilamine produced the opposite effects. Neither histamine nor pyrilamine affected the inspiratory time (TI), integral amplitude (IA) or the peak discharge frequency (PF) of the I neurons.</p><p><b>CONCLUSION</b>H1 receptors play an excitatory role in the modulation of the discharge activities of the inspiratory neurons in neonatal rat brainstem slices.</p>

Block of hERG K+ Channel by Classic Histamine H1 Receptor Antagonist Chlorpheniramine

Chlorpheniramine is a potent first-generation histamine H1 receptor antagonist that can increase action potential duration and induce QT prolongation in several animal models. Since block of cardiac human ether-a-go-go-related gene (hERG) channels is one of leading causes of acquired long QT syndrome, we investigated the acute effects of chlorpheniramine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. We examined the effects of chlorpheniramine on the hERG channels expressed in Xenopus oocytes using two-microelectrode voltage-clamp techniques. Chlorpheniramine induced a concentration-dependent decrease of the current amplitude at the end of the voltage steps and hERG tail currents. The IC50 of chlorpheniramine-dependent hERG block in Xenopus oocytes decreased progressively relative to the degree of depolarization. Chlorpheniramine affected the channels in the activated and inactivated states but not in the closed states. The S6 domain mutations Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG current block. These results suggest that the H1 antihistamine, chlorpheniramine is a blocker of the hERG channels, providing a molecular mechanism for the drug-induced arrhythmogenic side effects.

Role of histamine H(1) and H(2) receptors in the modulation of respiratory rhythmical discharge in medulla oblongata slice preparation of neonatal rats / 生理学报

The present study was carried out to determine the role of histamine H(1) and H(2) receptors in the generation of basic respiratory rhythm. Neonatal (aged 0-3 d) Sprague-Dawley rats of either sex were used. The medulla oblongata slice containing the medial region of the nucleus retrofacialis (mNRF) and the hypoglossal nerve rootlets was prepared and the surgical procedure was performed in the modified Kreb's solution (MKS) with continuous carbogen (95% O(2) and 5% CO(2)), and ended in 3 min. Respiratory rhythmical discharge activity (RRDA) of the rootlets of hypoglossal nerve was recorded by suction electrode. Thirty medulla oblongata slice preparations were divided into 5 groups. In groups I, II and III, histamine (5 μmol/L), H(1) receptor specific antagonist pyrilamine (10 μmol/L) and H(2) receptor specific antagonist cimetidine (5 μmol/L) was added into the perfusion solution for 15 min separately. In group IV, after application of histamine for 15 min, additional pyrilamine was added into the perfusion for another 15 min. In group V, after application of histamine for 15 min, additional cimetidine was added into the perfusion for another 15 min. The discharges of the roots of hypoglossal nerve were recorded. Signals were amplified and band-pass filtered (100-3.3 kHz). Data were sampled (1-10 kHz) and stored in the computer via BL-420 biological signal processing system. Our results showed that histamine significantly decreased the respiratory cycle (RC) and expiratory time (TE), but changes of integral amplitude (IA) and inspiratory time (TI) were not statistically significant. Pyrilamine induced significant increases in RC and TE, but changes of TI and IA were not statistically significant. Cimetidine had no effects on RC, TE, TI and IA of RRDA. The effect of histamine on the respiratory rhythm was reversed by additional application of pyrilamine but not cimetidine. Taken together, with the results mentioned above, histamine H(1) receptors but not H(2) receptors may play an important role in the modulation of RRDA in the medulla oblongata slice preparation of neonatal rats.

Roles of the histaminergic receptors in the locus ceruleus in stress-induced carotid baroreflex resetting in rats / 中国应用生理学杂志

<p><b>AIM</b>To explore the roles of H1 and H2 receptors in the locus ceruleus (LC) in the carotid baroreflex (CBR) resetting resulted from foot-shock stress.</p><p><b>METHODS</b>Male SD rats were divided into two groups (n=18) at random: unstressed and stressed group. The latter were subjected to unavoidable electric foot-shock twice daily for a week and each session of foot-shock lasted 2 hours. The left and right carotid sinus regions were isolated from the systemic circulation in all animals anesthetized with pentobarbital sodium. The intracarotid sinus pressure (ISP) was altered in a stepwise manner in vivo. ISP-mean arterial pressure (MAP), ISP-Gain relationship curves and reflex characteristic parameters were constructed by fitting to the logistic function with five parameters. The changes in CBR performance induced by stress and the effects of microinjection with histaminergic receptors antagonists into the LC on the responses of CBR to stress were examined.</p><p><b>RESULTS</b>Stress significantly shifted the ISP-MAP relationship curve upwards (P < 0.05) and obviously moved the middle part of ISP-Gain relationship curve downwards (P < 0.05), and decreased the value of the MAP range and maximum gain (P < 0.05), but increased the threshold pressure, saturation pressure, set point and ISP at maximum gain (P < 0.05). Microinjection of selective H1 or H2 receptor antagonist, chlorpheniramine (CHL, 0.5 microg/microl) or cimetidine (CIM, 1.5 microg/microl) into the LC, significantly attenuated the above-mentioned changes in CBR performance induced by stress and the alleviate effect of CIM was less remarkable than that of CHL (P < 0.05). The responses of CBR under stress to H1 or H2 receptor antagonist generally occurred 20 min after the administration and lasted approximately for 16 min. Microinjection with the same dose of CHL or CIM into the LC in the unstressed group did not change CBR performance significantly (P > 0.05). However, microinjection of CHL or CIM into the LC could not completely abolish the stress-induced changes in CBR.</p><p><b>CONCLUSION</b>The stress results in a resetting of CBR and a decrease in reflex sensitivity. The stress-induced changes in CBR may be mediated, at least in part, by activating the brain histaminergic system. The H1 and H2 receptors in the LC, especially, Hi receptors may play an important role in the resetting of CBR under stress. The descending histaminergic pathway from the hypothalamus to LC may be involved in these effects. Moreover, the effects of stress on CBR also have other mechanisms.</p>

New antihistamines: a critical view

OBJETIVO: Avaliar criticamente os mais novos anti-histamínicos anti-H1 e os diferentes termos utilizados para denominá-los, com base na revisão de evidências sobre o papel dos anti-H1 no tratamento das doenças alérgicas. FONTES DOS DADOS: Artigos originais, revisões e consensos indexados nos bancos de dados MEDLINE e PUBMED de 1998 a 2006. Palavra chave: anti-histamínicos. SíNTESE DOS DADOS: Os anti-histamínicos de segunda geração diferenciam-se dos de primeira geração por sua elevada especificidade e afinidade pelos receptores H1 periféricos e pela menor penetração no sistema nervoso central (SNC), com conseqüente redução dos efeitos sedativos. Embora os anti-histamínicos de segunda geração sejam, geralmente, melhor tolerados do que seus predecessores, alguns efeitos adversos, principalmente cardiotoxicidade, surgiram com alguns deles. Nos últimos 20 anos, novos compostos, com diferentes farmacocinéticas, foram sintetizados. A maioria deles manifesta propriedades antiinflamatórias que independem de sua atividade no receptor H1. Aprimoramentos mais recentes, geralmente na forma de metabólitos ativos, levaram ao uso do termo anti-histamínico de terceira geração. Esse termo surgiu espontaneamente, sem uma descrição clara de seu significado e implicações clínicas, criando grande confusão entre os profissionais da saúde. CONCLUSÕES: Com base nas evidências sobre anti-histamínicos anti-H1, nenhum deles pode ser considerado como "anti-histamínico de terceira geração". Para tanto, seria preciso comprovar que a nova classe de anti-histamínicos possui vantagens clínicas distintas sobre os compostos existentes e preenche pelo menos três pré-requisitos: ausência de cardiotoxicidade, de interações medicamentosas e de efeitos sobre o SNC.

OBJECTIVE: To perform a critical evaluation of the more recent H1 antihistamines and the various terms used to describe them, based on a review of evidence on their role in the treatment of allergic disorders. SOURCES: Original articles, reviews and consensus documents published from 1998 to 2006 and indexed in the MEDLINE and PubMed databases. Keyword: antihistamines. SUMMARY OF THE FINDINGS: Second-generation antihistamines differ from first-generation ones because of their elevated specificity and affinity for peripheral H1 receptors and because of their lower penetration of the central nervous system (CNS), having fewer sedative effects as a result. Whilst second-generation antihistamines are in general better tolerated than their predecessors, some adverse effects, principally cardiotoxicity, have been observed with some of them. Over the last 20 years, new compounds with different pharmacokinetic properties have been synthesized. The majority of these exhibit anti-inflammatory properties that are independent of their action on the H1 receptor. More recent improvements, generally in the form of active metabolites, led to the use of the term third-generation antihistamines. This term emerged spontaneously, with no clear definition of its meaning or clinical implications, creating great confusion among healthcare professionals. CONCLUSIONS: On the basis of the evidence on H1 antihistamines, none of them deserve the title"third-generation antihistamine." As the Consensus Group on New Generation Antihistamines concluded, to merit this definition, a new class of antihistamines would have to demonstrate distinct clinical advantages over existing compounds and fulfill at least three prerequisites: they should be free from cardiotoxicity, drug interactions and effects on the CNS.

Effect of histamine on intracortical blood vessels of rats / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate histamine-induced changes of the intracortical vessels in the cortical slice of rat brain.</p><p><b>METHODS</b>Immunohistochemistry was employed to detect the expression of H1 and H2 receptors in the intracortical blood vessels of rats. Histamine-induced constriction of the intracortical blood vessels of the brain slices was observed with differential interference contrast microscope. Measurements of the luminal diameter were made on-line during the course of the experiment and confirmed off-line from the stored images. In order to observe whether histamine H1 and H2 receptors affected histamine-induced constriction, the intracortical blood vessels in the brain slices were pre-treated with H1 receptor antagonist diphenhydramine and H2 receptor antagonist cimetidine.</p><p><b>RESULTS</b>Expression of H1 and H2 receptors was detected in the intracortical blood vessels of the rat brain. Histamine (1-100 micromol/L) induced a concentration-dependent constriction from (1.48-/+0.67)% to (32.91-/+7.91)%. The reactions to each histamine concentration were significantly (P<0.01) different from each other, with the exception of the highest histamine concentrations (30 and 100 micromol/L) when maximal constriction due to histamine were observed (P>0.05). With pre-treatment of the slice with 10 micromol/L diphenhydramine, application of histamine did not elicit constriction. Pre-treatment of the slice with 10 micromol/L cimetidine did not completely inhibit but somehow significantly weakened vascular constriction in response to histamine treatment at 10 and 30 micromol/L (P<0.05).</p><p><b>CONCLUSION</b>Histamine can induce constriction of the intracortical blood vessels, which is mediated by H1 receptor.</p>

Effects of Antidepressants on Sleep / 대한정신약물학회지

The diverse effects of antidepressants on sleep are mediated by their agonistic or antagonistic properties on specific neurotransmitters: the catecholamine, serotonergic, cholinergic, and histaminergic neurotransmitter systems, which also regulate the timing and cycling of sleep. Therefore, antidepressants can have both class- and compound-specific effects on sleep/wake dynamics, sleep stages, and on motor control during sleep. For these reasons, the sedating or wake-promoting effects of these medications are important factors influencing specific drug selection. As these sleep-related effects may in turn influence both medication compliance as well as the course of the disease state itself, it is important for clinicians to understand and predict the possible effects of antidepressants on sleep. Some antidepressants, such as amitriptyline, doxepine, trazodone, and mirtazapine, possess sedating properties and improve sleep continuity via alpha-1 adrenoceptors and histamine H1 receptor blockade, combined with 5HT(2A/2C) receptor blockade. Other antidepressants, such as SSRI, SNRI and MAOIs, worsen sleep and may cause insomnia, an effect which may be linked to facilitation of 5HT(2A/2C) receptors. The majority of antidepressants are REM (rapid eye movement) suppressants, though some, such as nefazodone, bupropion, and mirtazapine, lack REM-suppressing effects. On the other hand, the effects of antidepressants on slow wave sleep (SWS) are much less consistent than their effects on REM sleep. Available data suggest that antidepressants, including some TCAs, and trazodone, increase SWS, possibly as a function of their 5-HT(2A/2C) receptor antagonism. In contrast, antidepressants lacking 5-HT(2A/2C) receptor antagonist effects, including SSRIs, SNRIs and MAOIs, may produce no change or even decrease in SWS. Knowledge of the effects of antidepressants on sleep will be helpful in estimating the sleep disturbance caused by these compounds, and can thus help in the selection of appropriate compound for individual patients.

Reversing effect of histamine on neuron death induced by N-methyl-D-aspartate / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To determine the effect of histamine on N-methyl-D-aspartate (NMDA) induced neuron death and to elucidate its mechanism.</p><p><b>METHODS</b>The primary cortical cell culture was adopted. Neuron morphology and MTT assay were used to evaluate the drugs effects.</p><p><b>RESULT</b>Histamine at doses of 10(-4) 10(-6) 10(-7) 10(-8) mol/L reversed the neuron death induced by NMDA (50 micromol/L) for 3 h. The protection of histamine peaked at doses of 10(-4) mol/L and 10(-7)mol/L. The effect of histamine of 10(-7) mol/L was reversed only by cimetidine an H(2)receptor antagonist. However, the effect of histamine of 10(-4) mol/L was reversed only by pyrilamine but not cimetidine.</p><p><b>CONCLUSION</b>Histamine could reduce neuron death induced by NMDA; its protection at a low dose might be mediated by H(2)receptor, and at a high dose by H(1)receptor.</p>

Effect of alahistidine on brain histamine content and seizure development / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the effect of alahistidine on brain histamine content and seizure development.</p><p><b>METHODS</b>The kindling seizure was induced by ip injection with subconvulsant dose of pentylenetetrazole every 48 h. Monoamines and their metabolites were measured using a HPLC system and fluorometric assay.</p><p><b>RESULT</b>Chronic low histamine feeding markedly decreased histamine content in cortex and hypothalamus, and promoted seizure development induced by pentylenetetrazole. However, alahistidine feed reversed the decreased histamine content and slowed seizure development caused by low histamine feed. Both low histamine and alahistidine feed had no effect on norepinephrine, dopamine and its metabolites.</p><p><b>CONCLUSION</b>Alahistidine may affect histaminergic system and seizure development.</p>

Possible role of histamine receptors in the central regulation of immune responses.

The present study was designed to delineate the role of H1- and H2-histamine receptors in the neuro-immune regulation in rats. The effects of H1- and H2-receptor antagonists on humoral and cell-mediated immune (HI and CMI) responses were investigated after intraperitoneal (i.p.) and intra-cerebroventricular (i.c.v.) administration. HI response was assayed by anti-sheep red blood cell (SRBC) antibody titre in presence and absence of 2-mercaptoethanol (2-ME). The CMI responses were evaluated by delayed type hypersensitivity (DTH) reaction (in vivo), i.e., measurement of footpad thickness, and lymphokine activity such as leucocyte migration inhibition (LMI) test (in vitro). On i.p. administration, both H1- (pheniramine and astemizole) and H2-receptor antagonists (ranitidine and cimetidine) were observed to produce significant enhancement of anti-SRBC antibody response. However, only H2- and not H1-receptor blockers were observed to stimulate CMI response significantly. When administered by icv route, only H2-receptor antagonists caused a statistically significant increase in both HI and CMI responses, while the H1-receptor blockers failed to modify the same. Thus, H2-receptors appear to play a major role in the histaminergic mechanisms involved in immunomodulation both at the level of immunocompetent cells active in the peripheral tissues as well as through the central nervous system structures involved in the central regulation of neuro-immune interaction.

Participación de receptores histaminérgicos involucrados en la permeabilidad vascular / Participation of histaminergic receptors involved in vascular permeability

La permeabilidad vascular puede ser modificada por la liberación de histamina endógena como resultado de la presencia de ciertos tiobarbitúricos (tiopental) en el organismo. Esta modificación en la permeabilidad es mediada por la activación del receptor histaminérgico H1, pero es incierta la participación del receptor H2. En este trabajo se evalúa la participación de receptores H1 y H2 durante los cambios de permeabilidad vascular inducidos por histamina, a través de la determinación de concentraciones séricas de albúmina, proteínas totales y globulinas, que indirectamente lo indican. Se formaron 5 grupos de organismos; un control y 4 experimentales denominados grupo A, B, C y D. A los organismos del grupo A se les aplicó histamina IV, 10 µg/Kg de peso, y finalmente al grupo D se le inyectó simultáneamente 0.16 mg/Kg de peso; al grupo C se le inyectó ranitidina IV, 0.13 mg/Kg de peso, y finalmente al grupo D se le inyectó simultáneamente 0.16 mg/Kg de peso y 0.13 mg/Kg de peso de astemizol y ranitidina IV, respectivamente. El grupo A mostró un decremento significativo en las concentraciones de albúmina, proteínas totales y globulinas. En los grupos B, C y D se observó una disminución en la concentración de proteínas totales y globulinas, pero no de albúmina. Estos resultados muestran que los receptores H1 y H2 están involucrados en el aumento de permeabilidad vascular a la albúmina, pero tal vez exista un proceso de permeabilidad diferencial en el cual el paso de globulinas desde la luz vascular hasta el intersticio esté regulado por otro mecanismo

An ab initio study of histamine agonists.

A systematic theoretical study on histamine agonists and their interaction with H1 and H2 receptor models has been carried out utilizing ab initio molecular orbital technique. The effect of substituents on histamine agonists' charge distribution and their agonistic activity has been studied in detail. Drug-receptor interaction models have been studied at the Hartree Fock level of theory with a split valence basis set keeping the cost and efficiency of the calculation in mind. The study indicates that the agonistic activity is controlled either by receptor conformation or by steric hinderances caused by the substituents. The monocationic form of histamine does not appear to be a necessity for a proton relay process which is similar to the one proposed earlier by Weinstein and coworkers. The study also indicates some importance of common cellular ions in neurotransmitter properties of histamine.