非咪唑类组胺H3受体拮抗药的研究进展

（1. ［摘要］组胺H3受体是新近发现的一种组胺受体的新亚型。近年来,以组胺H3受体作为靶点,设计和开发出的一些候选的H3受体拮抗药在治疗一些中枢神经系统疾病（如阿尔茨海默病 、帕金森病）等方面有一定的应用前景。目前H3受体拮抗药研究的重点已从经典的咪唑类H3受体拮抗药逐步向非咪唑类的H3受体拮抗药转变。     

组胺H_3受体拮抗药的抗痉挛效果

近年的研究阐明，存在控制神经性组胺释放的组胺H3受体，该受体拮抗药可促进脑内组胺释放，通过组胺H1受体达到抑制痉挛的作用。日本东北大学小儿科通过小鼠电击痉挛实验对组胺H3拮抗剂的抗痉挛效果进行了研究。使用药物为thioperamide，拮抗实验使用的药物为H3受体激动药α-甲基组胺和H1受体拮抗药美吡拉敏。实验结果显示，thioperamide呈用量依赖性，且明显地使痉挛各相持续时间缩短，此外，该抗痉挛效果可被摘抗实验所使用的两药物拮抗。这表明，组胺H。受体括抗药化如Peram－ide通过组胺H。受体促进脑内组胺释放，释放的组胺又刺激…     

常用抗变应性鼻炎药物

变应性鼻炎的治疗药物以抗组胺药物和皮质类激素为主。1　抗组胺类药物引起变态反应的介质很多 ,组胺是其中非常重要之一。所以抗组胺药物是临床上广泛使用的治疗变态反应疾病的药物。变态反应性鼻炎的大多数症状是通过H1 受体来表达的。组胺可通过H1 受体作用于鼻黏膜组织中不同的效应细胞上 ,导致血管渗透性增加、黏液腺分泌亢进、平滑肌收缩和刺激神经末梢等 ,临床上所指的抗组胺药物 ,主要是指组胺受体拮抗药 (或称阻滞药 ) ,作用机制是在靶细胞膜上与组胺H1 受体竞争结合 ,从而达到阻断或减轻由组胺所产生的一系列症状。1.1　第一代抗组胺类药物　这类抗组胺药物都属于脂溶性 ,可以穿过血脑屏障而阻断大脑中的H1 受体功能。所以都具有抑制中枢神经系统作用 ,如嗜睡现象。除副作用外 ,抗组胺药物还可产生其他效应 ,如阻断毒蕈碱胆碱能、α 肾上腺素能和 5 羟色胺受体及局部麻醉等作用。这种抗胆碱能作用可引起心脏兴奋而导致心悸、心动过速、视觉模糊、胃肠道蠕动减慢 (便秘 )和尿潴留 (尤其对患有前列腺肥大的患者 )等。这类抗组胺药物还可和一些药物发生相互作用 ,比如能加强一些药物或物质的作用 ,如单胺氧化酶抑制药、乙醇、抗帕金森...     

抗组胺药临床应用分析

随着感染性疾病的控制和工业化程度的提高，过敏性疾病已逐渐成为影响人类健康的全球性疾病，国内外流行病学资料表明，约有1／3以上的人一生中曾罹患过敏性疾病。过敏性疾病严重影响人们的生活质量、工作和学习，造成巨大的经济损失。目前抗组胺药种类较多，发展较快，抗组胺药主要分为组胺H1受体拮抗药和H2受体拮抗药，引起变态反应疾病的为H1受体，因此组胺H1受体拮抗药已广泛应用于临床。临床上选择安全、有效、经济的药物，在合理利用医药卫生资源的同时，可让患者获得最佳治疗效果。本文对2006年我院抗组胺药的应用情况总结分析如下。     

组胺H1受体拮抗药的合理应用

组胺H1受体拮抗药临床上正广泛应用，应高度重视此类药的合理正确使用，尽量避免不良反应的发生。现将我们合理应用组胺H1受体拮抗药的粗浅体会报道如下。     

H_3-受体存在部位及药理研究

组胺受体原分为 H_1-受体和 H_2-受体。1983年在脑组胺传出神经元突触前膜发现抑制组胺游离、合成的自身受体,这种受体的药理学特性与H3一和H2一受体不同,被命名为H3一受体     

M3受体通过激活MEK1/2-ERK1/2信号通路促进H9c2心肌细胞生存

目的研究毒蕈碱型胆碱受体(M受体)对H9c2心肌细胞MEK1/2-ERK1/2信号通路的调控作用及其对细胞活力的影响。方法 H9c2心肌细胞用非选择性或选择性M受体拮抗药处理30 min之后,以氨甲酰胆碱刺激细胞,然后用Western Blot检测全细胞蛋白质中MEK1/2和ERK1/2磷酸化水平的变化,采用Alamar Blue法检测细胞活力。结果以氨甲酰胆碱刺激H9c2心肌细胞能显著增加MEK1/2和ERK1/2的磷酸化水平,这种活化作用可被非选择性M受体拮抗药阿托品完全阻断;M3受体选择性拮抗药DAU 5884可以阻断氨甲酰胆碱对MEK1/2-ERK1/2的激活,但M1、M2和M4受体的选择性拮抗药则没有这种阻断作用;在无血清的培养基中,氨甲酰胆碱能增加H9c2心肌细胞的生存能力,这种细胞保护作用可被阿托品和DAU 5884消除。结论在H9c2心肌细胞中,氨甲酰胆碱通过M3受体调控MEK1/2-ERK1/2信号通路,并由此促进细胞的生存。     

新型抗精神病药伊潘立酮的研究进展

新型非典型抗精神病药伊潘立酮（iloperidone）是5-HT2/D2受体拮抗药,对多巴胺D3受体也有很高的亲和力,对肾上腺素α1受体、多巴胺D4受体,5-HT6和5-HT7受体也有适当的亲和力,对5-HT1A、多巴胺D1和组胺H1受体有较低的亲和力,对胆碱M受体和N-甲基-D-天冬氨酸（NMDA）受体几乎没有亲和力.     

地塞米松预防老年人吗啡术后镇痛期恶心呕吐效果观察

吗啡术后镇痛效果确切,但恶心呕吐发生率较高.常用的强效止吐药物有5-羟色胺受体拮抗药昂丹斯琼及格拉司琼,但临床上应用受到一定限制.另一类抗胆碱能药物多巴胺受体拮抗药或抗组胺类药物,止吐使用时副作用有失眠、口干、心律失常等.地塞米松可预防手术后恶心呕吐[1-2].本研究评价地塞米松对吗啡手术后恶心呕吐的预防作用.     

新型组胺受体:组胺H_4受体

组胺H4受体是近年发现的组胺新受体 ,它具有独特的药理学性质和特殊的组织分布特征 ,与组胺H3 受体有较高的同源性。该文对组胺H4受体的基因结构、组织分布、同源性分析、信号转导途径及与组胺配体亲和力等方面进行综述 ,并对其未来研究前景进行了展望。     

Pharmacological and therapeutic properties of lafutidine (stogar and protecadin), a novel histamine H2 receptor antagonist with gastroprotective activity]

Potent antisecretory agents, such as histamine H2-receptor antagonists and proton pump inhibitors, have achieved great improvement in peptic ulcer therapy. It has, however, been reported that incidence of ulcer relapse is high after discontinuation of these drugs. Insufficient efficacy against NSAID-induced ulcers is also critical. Lafutidine is a novel histamine H2 antagonist with gastroprotective activity. Lafutidine exhibited potent and long-lasting H2 antagonism and prolonged antisecretion. In addition, lafutidine showed a gastroprotective effect against noxious agents-induced gastric mucosal damage through capsaicin-sensitive afferent nerves. Lafutidine showed antiulcer activities against acute ulcer models, prevented gastric ulcer relapse of acetic ulcer, and accelerated the healing of indomethacin-induced antral ulcers in rats. These results suggest the advantage of the combined antisecretory and gastroprotective activities. In clinical studies, lafutidine showed prolonged antisecretion, healing effect against gastric and duodenal ulcers and gastritis, and its potency was equal or superior to that of conventional H2 antagonists. Additionally, lafutidine induced a high transition rate to the E0 stage determined by endoscopical ultrasonography, suggesting the high quality of ulcer healing. Furthermore, effectiveness of lafutidine against NSAIDs-induced ulcer was high. From these results, lafutidine is equal or superior to conventional H2 antagonists in antiulcer potency, and it may be useful for the prevention of ulcer relapse and or treatment of NSAIDs-induced gastroduodenal damage.     

Sensitizing effects of lafutidine on CGRP-containing afferent nerves in the rat stomach

1. Capsaicin sensitive afferent nerves play an important role in gastric mucosal defensive mechanisms. Capsaicin stimulates afferent nerves and enhances the release of calcitonin gene-related peptide (CGRP), which seems to be the predominant neurotransmitter of spinal afferents in the rat stomach, exerting many pharmacological effects by a direct mechanism or indirectly through second messengers such as nitric oxide (NO). 2. Lafutidine is a new type of anti-ulcer drug, possessing both an antisecretory effect, exerted via histamine H(2) receptor blockade, and gastroprotective activities. Studies with certain antagonists or chemical deafferentation techniques suggest the gastroprotective actions of lafutidine to be mediated by capsaicin sensitive afferent nerves, but this is an assumption based on indirect techniques. In order to explain the direct relation of lafutidine to afferent nerves, we conducted the following studies. 3. We determined CGRP and NO release from rat stomach and specific [(3)H]-resiniferatoxin (RTX) binding to gastric vanilloid receptor subtype 1 (VR1), which binds capsaicin, using EIA, a microdialysis system and a radioreceptor assay, respectively. 4. Lafutidine enhanced both CGRP and NO release from the rat stomach induced by a submaximal dose of capsaicin, but had no effect on specific [(3)H]-RTX and capsaicin binding to VR1. 5. In conclusion, our findings demonstrate that lafutidine modulates the activity of capsaicin sensitive afferent nerves in the rat stomach, which may be a key mechanism involved in its gastroprotective action.     

Lafutidine-induced increase in intracellular ca(2+) concentrations in PC12 and endothelial cells

Lafutidine, a histamine H(2) receptor antagonist, exerts gastroprotective effects in addition to gastric antisecretory activity. The gastrointestinal protective effects of lafutidine are mediated by capsaicin-sensitive neurons, where capsaicin excites neurons by opening a member of the transient receptor potential channel family (TRPV1). Since the effect of lafutidine on the intracellular Ca(2+) concentration ([Ca(2+)](i)) in cells has not been elucidated, we investigated the lafutidine response to [Ca(2+)](i) in rat pheochromocytoma PC12 and human endothelial cells. Lafutidine at pharmacological concentrations greater than 1 mM induced a sustained increase in [Ca(2+)](i) in the presence of extracellular CaCl(2) in PC12 cells, while capsaicin showed dual effects on [Ca(2+)](i) in PC12 cells, where it activated TRPV1 and inhibited store-operated Ca(2+) entry. The thapsigargin (an activator of store-operated Ca(2+) entry)-induced increase in [Ca(2+)](i) in PC12 cells was inhibited by capsaicin and SKF96365, an inhibitor of store-operated Ca(2+) entry, and the lafutidine response was inhibited by capsaicin but not by SKF96365. In endothelial cells, lafutidine induced an increase in [Ca(2+)](i) in a SKF96365-insensitive manner. These results suggest that lafutidine stimulates Ca(2+) entry via the capsaicin-sensitive pathway but not the SKF96365-sensitive pathway. The possible role of store-operated Ca(2+) entry induced by lafutidine on gastrointestinal function is also discussed.     

Lafutidine facilitates calcitonin gene-related peptide (CGRP) nerve-mediated vasodilation via vanilloid-1 receptors in rat mesenteric resistance arteries

Lafutidine is a histamine H(2)-receptor antagonist with gastric antisecretory and gastroprotective activity associated with activation of capsaicin-sensitive nerves. The present study examined the effect of lafutidine on neurotransmission of capsaicin-sensitive calcitonin gene-related peptide (CGRP)-containing vasodilator nerves (CGRPergic nerves) in rat mesenteric resistance arteries. Rat mesenteric vascular beds were perfused with Krebs solution and vascular endothelium was removed by 30-s perfusion with sodium deoxycholate. In preparations preconstricted by continuous perfusion of methoxamine (alpha(1) adrenoceptor agonist), perfusion of lafutidine (0.1 - 10 microM) concentration-dependently augmented vasodilation induced by the periarterial nerve stimulation (PNS, 1 Hz) without affecting vasodilation induced by exogenous CGRP (10 pmol) injection. Perfusion of famotidine (H(2)-receptor antagonist, 1 - 100 microM) had no effect on either PNS-induced or CGRP-induced vasodilation. Perfusion of lafutidine concentration-dependently augmented vasodilation induced by a bolus injection of capsaicin (vanilloid-1 receptor agonist, 30 pmol). The presence of a vanilloid-1 receptor antagonist, ruthenium red (10 microM) or capsazepine (5 microM), abolished capsaicin-induced vasodilation and significantly decreased the PNS-induced vasodilation. The decreased PNS-induced vasodilation by ruthenium red or capsazepine was not affected by perfusion of lafutidine. These results suggest that lafutidine facilitates CGRP nerve-mediated vasodilation by modulating the function of presynaptic vanilloid-1 receptors located in CGRPergic nerves.     

Antiulcer effect of lafutidine on indomethacin-induced gastric antral ulcers in refed rats.

Lafutidine is a new type antiulcer agent with antisecretory and gastroprotective activities. We investigated the effect of lafutidine on indomethacin-induced antral ulcer in refed rats. Subcutaneous indomethacin injection resulted in the formation of gastric antral ulcer. Lafutidine (1-10 mg/kg, p.o.) reduced the area of ulcer in a dose-dependent manner when administered immediately after the indomethacin injection. Capsaicin at 3 mg/kg, p.o. and 16,16-dimethyl prostaglandin E2 at 3 microg/kg, p.o. also reduced the ulcer area. Chemical deafferentation of capsaicin-sensitive neurons or N(G)-nitro-L-arginine treatment aggravated the ulcer formation and abolished the preventive effect of lafutidine and capsaicin. After the induction of gastric ulcer, lafutidine given twice daily for 2.5 days reduced the area of ulcer in a dose-dependent manner with a significant effect at 10 mg/kg, p.o., as compared with that of the control group. In chemically-deafferentated rats, lafutidine did not show any healing effect. Cimetidine (30 mg/kg, p.o.) and famotidine (1 mg/kg, p.o.) had no significant effect on indomethacin-induced antral ulcer. These results may suggest that lafutidine, unlike cimetidine and famotidine, can prevent the indomethacin-induced antral ulcer formation and accelerate the healing of the ulcer in refed rats through mechanisms involving the capsaicin-sensitive afferent neurons and nitric oxide.     

Gastroprotective mechanism of lafutidine, a novel anti-ulcer drug with histamine H2-receptor antagonistic activity.

Lafutidine (CAS 118288-08-7, FRG-8813) is a novel histamine H2-receptor antagonist with gastroprotective activity. The aim of this study was to investigate the property of the gastro-protective activity of lafutidine by examining the effect on ammonia-induced change in transmucosal potential difference (PD), basal gastric mucosal blood flow (GMBF) and noxious agent-induced cell damage. Intragastrical application of lafutidine accelerated the recovery of the PD reduction after exposure of the mucosa to 0.25% ammonia solution and the accelerating effect was abolished by chemical deafferentation, but not with indometacin, a cyclooxygenase inhibitor. The application of capsaicin, as a reference compound, significantly promoted the recovery of the ammonia-induced PD reduction and this effect was not altered with indometacin. Lafutidine given intragastrically caused a sustained increase in GMBF in a dose-dependent fashion, which was also completely inhibited in the deafferentated rats. In vitro studies revealed that, in contrast to 16,16-dimethyl prostaglandin E2, lafutidine did not protect isolated gastric superficial epithelial cells from ethanol- or ammonia-induced damage. In conclusion, the gastroprotection of lafutidine is induced by promoting the restitution of the damaged mucosa after a noxious agent, not by directly protecting the epithelial cells and this effect may be caused through the mechanism of capsaicin-sensitive afferent nerves.     

Pharmacokinetic and pharmacodynamic properties of lafutidine after postprandial oral administration in healthy subjects: comparison with famotidine

Lafutidine, a histamine H(2)-receptor antagonist, inhibits gastric acid secretion during the daytime, however, the relationship between the plasma concentration and the drug response remains unclear. The aim of this study was to compare the pharmacokinetic and pharmacodynamic properties of lafutidine and famotidine following postprandial oral administration. After a lafutidine tablet (10 mg), famotidine tablet (20 mg), or water only (control) was administered, blood samples were taken and intragastric pH was measured. The plasma concentrations of lafutidine and famotidine were determined by HPLC, and the median intragastric pH values per 30 min were used as the degrees of gastric acid suppression. Data were analyzed based on a one-compartment pharmacokinetic model and a sigmoid E(max) pharmacodynamic model. Lafutidine plasma concentrations rapidly increased after administration; famotidine required some time to increase the plasma concentrations, requiring an absorption lag time in the pharmacokinetic model. Between the plasma concentration and DeltapH (the difference in intragastric pH by the drug vs. control), lafutidine showed an anticlockwise hysteresis loop which indicated equilibration delay between the plasma concentration and effect site, requiring an effect site compartment in the pharmacodynamic model; famotidine showed more parallel relationship. These results indicated that the pharmacokinetic and pharmacodynamic properties of lafutidine after postprandial oral administration were different from those of famotidine at least 4.5 h after dosing.     

Lafutidine, a unique histamine H2-receptor antagonist, inhibits distention-induced gastric acid secretion through an H2 receptor-independent mechanism

Gastric acid secretion during the daytime has been implicated in the pathogenesis of acid-related diseases. Although daytime acid secretion is mainly governed by the parasympathetic vagal nerve, clinical observations have been accumulated that the H(2)-receptor antagonist lafutidine may have a strong effect. Here, we examined the actions of H(2)-receptor antagonists in a rat model of gastric acid secretion induced by stomach distention, a major post-meal stimulus. Indeed, the acid output during a 3h period after the instillation of saline into pylorus-ligated SD rats under urethane anesthesia was dependent on the instilled volume and was strongly suppressed by a vagotomy or the intraduodenal administration of atropine. Interestingly, lafutidine, but not famotidine or cimetidine, administered at a sufficient dose to block histamine-dependent acid secretion was capable of inhibiting distention-induced acid secretion. Moreover, gastric acid secretion induced by the intravenous perfusion of carbachol into SD rats was strongly inhibited by lafutidine but only partially inhibited by famotidine. The antisecretory action of lafutidine under these conditions was partly reversed by the co-administration of the nitric oxide synthase inhibitor L-NMMA, but was hardly affected by denervation with capsaicin or by the administration of the transient receptor potential channel V1 (TRPV1) antagonist capsazepine. Together with the observation that lafutidine increased the amount of intragastric nitric oxide, the present results suggest that lafutidine inhibits daytime gastric acid secretion not only by blocking H(2) receptors, but also through nitric oxide-mediated and histamine-independent indirect actions.     

High quality of ulcer healing in rats by lafutidine, a new-type histamine H2-receptor antagonist: involvement of capsaicin-sensitive sensory neurons

This study was conducted to determine whether the low recurrence rate of ulcers after treatment with lafutidine, an antiulcer drug possessing both an antisecretory and gastroprotective activities, was mediated by capsaicin-sensitive sensory neurons (CSSN). Chronic gastric ulcers in rats were induced by serosa-searing. The ulcer healing and recurrence were evaluated by endoscopy. Drugs were orally administered. Desensitization of CSSN was induced by pretreatment with capsaicin. Lafutidine (30 mg/kg) accelerated the ulcer healing significantly, and the recurrence rate was much lower than that for the vehicular control. In CSSN-desensitized rats, lafutidine also accelerated the ulcer healing significantly, but the low recurrence rate shown in normal rats was counteracted. The recurrence rate of the combination of famotidine (30 mg/kg) and teprenone (100 mg/kg) was lower than that of famotidine alone. In conclusion, the low recurrence rate of ulcers after lafutidine treatment in rats seems to depend on the gastroprotective mechanisms involving CSSN.     

Modifications of capsaicin-sensitive neurons in isolated guinea pig ileum by [6]-gingerol and lafutidine

A segment of guinea pig ileum was used to confirm the hypothesis that [6]-gingerol and lafutidine interact with capsaicin-sensitive neurons. Addition of 30 and 100 microM [6]-gingerol (a pungent constituent of ginger) induced contraction of the ileum immediately. Like capsaicin, [6]-gingerol-induced contraction was inhibited by antagonists of the vanilloid receptor (capsazepine and ruthenium red), tetrodotoxin, and atropine. Treatment with [6]-gingerol up to 0.3 microM, which alone had no effect, enhanced 3 microM capsaicin-induced contraction, but greater than 3 microM [6]-gingerol significantly inhibited capsaicin-induced contraction. Treatment with lafutidine (a new type of antagonist of the histamine H(2) receptor), which was suggested to interact with capsaicin-sensitive neurons in vivo, also showed both stimulatory and inhibitory effects on capsaicin-induced contraction depending on the concentrations. Lafutidine alone had no effect. The enhanced contraction induced by capsaicin in the [6]-gingerol- or lafutidine-treated ileum was also inhibited by antagonists of the vanilloid receptor, tetrodotoxin, and atropine. Capsaicin and [6]-gingerol, but not lafutidine, at 30 microM stimulated [(3)H]choline release from the prelabeled slices of the ileum. These findings suggest that [6]-gingerol and lafutidine act on capsaicin-sensitive cholinergic neurons and modulate the contraction in isolated guinea pig ileum.