第二代组胺H_1受体拮抗剂

目的:对第二代H1受体拮抗剂的作用特点、疗效及不良反应等进行综合评述。方法:以国外发表的文献为依据,对第二代H1受体拮抗剂的临床应用和注意问题进行介绍。结果:第二代H1受体拮抗剂能减少或消除第一代H1受体拮抗剂所产生的镇静和抗胆碱能不良反应,对H1受体具有较强的选择性。结论:临床使用无明显的精神运动性损害,是治疗鼻炎、荨麻疹和皮炎的有效药物。     

第二代组胺H_1受体阻滞药的不良反应

随着变态反应疾病发生率的不断增高,第二代组胺H_1受体拮抗剂在临床上的应用更加频繁,现检索近8a来有关其不良反应的报道,综述如下:1 心脏毒性 诱发心脏毒性较多的是特非那定、阿司咪唑、氯雷他     

组胺H1受体拮抗剂的临床评价与合理应用

目的 :为临床合理应用组胺H1 受体拮抗剂提供参考。方法 :综合近年来国内、外文献进行分析。结果 :第2代H1 受体拮抗剂新药不断上市 ,其作用强而持久 ,不良反应少 ,对中枢神经系统几乎无抑制作用 ,也无抗胆碱作用 ,但对心脏的毒性作用日益突出。结论 :组胺H1 受体拮抗剂的研制与开发具有广阔前景     

第二代组胺H1受体拮抗剂

目的：对第二代H1受体拮抗剂的作用特点、疗效及不良反应等进行综合评述。方法：以国外发表的文献为依据,对第二代H1受体拮抗剂的临床 应用和注意问题进行介绍。结果：第二代H1受体拮抗剂能减少或消除第一代H1受体拮抗剂所产生的镇静和抗胆碱能不良反应,对H1受体具有较强的选择性。结论：临床使用无明显的精神运动性损害,是治疗鼻炎、荨麻疹和皮炎的有效药物。     

组胺受体H_1和H_4在过敏性炎症中的作用:新型抗组胺药的研究

组胺在过敏性炎症中起关键性作用,长期以来人们认为组胺释放引起的炎性反应是由H1受体介导的。H1受体拮抗剂也称为抗组胺药,用于治疗过敏性反应已很多年。但是在哮喘和慢性瘙痒症的病理状态下组胺的重要性可能被低估。已证明组胺的确在炎症和免疫调节疾病中起作用,特别是H4受体的发现及其在多种免疫和炎性细胞中的表达,提示应重新评价组胺的作用,预示新型H4受体拮抗剂将被发现,且H1,H4受体拮抗剂在许多炎性反应靶标上可能有协同作用。     

我院1996～1998年组胺H_1受体阻滞药使用情况分析

以DDDs及药品消耗金额为量变参数,对我院1996～1998年口服组胺H_1受体阻滞药的药物消费结构进行了较全面的调研。结果表明:1996～1998年是此类组胺H_1受体阻滞药品种更换频繁的3年。1998年完成“换代”,用药结构基本固定,其中一代品种为赛庚啶,二代品种为氯环利嗪。     

组胺H_2受体拮抗剂的研究——胍基噻唑衍生物的合成

本文根据近年组胺H_2受体拮抗剂研究状况及有效药物结构的初探,设计、合成了十一个胍基噻唑衍生物,经体外药理筛选,证明所试的三个化合物,具有一定的拮抗H_2受体的活性。     

突触前组胺H_1和H_3受体对豚鼠输精管交感神经冲动传递的影响(英文)

(R)-α-甲基组胺(α-MeHA)低浓度抑制,高浓度增强电场刺激诱发的离体输精管收缩。上述效应可分别被thioperamide和氯苯那敏拮抗,Pyridelethyl-amine(Pyr)能增强电场刺激诱发的输精管收缩,α-MeHA和Pyr对于直接电刺激或去甲肾上腺素(NE)诱发的输精管收缩均无影响,以上表明,豚鼠输精管交感神经末稍分布有组胺H_3和H_1两种受体,它们分别介导抑制和促进NE的释放。     

Clinical pharmacology of new histamine H1 receptor antagonists.

The recently introduced H1 receptor antagonists ebastine, fexofenadine and mizolastine, and the relatively new H1 antagonists acrivastine, astemizole, azelastine, cetirizine, levocabastine and loratadine, are diverse in terms of chemical structure and clinical pharmacology, although they have similar efficacy in the treatment of patients with allergic disorders. Acrivastine is characterised by a short terminal elimination half-life (t1/2 beta) [1.7 hours] and an 8-hour duration of action. Astemizole and its metabolites, in contrast, have relatively long terminal t1/2 beta values; astemizole has a duration of action of at least 24 hours and is characterised by a long-lasting residual action after a short course of treatment. Azelastine, which has a half-life of approximately 22 hours, is primarily administered intranasally although an oral dosage formulation is used in some countries. Cetirizine is eliminated largely unchanged in the urine, has a terminal t1/2 beta of approximately 7 hours and a duration of action of at least 24 hours. Ebastine is extensively and rapidly metabolised to its active metabolite; carebastine, has a half-life of approximately 15 hours and duration of action of at least 24 hours. Fexofenadine, eliminated largely unchanged in the faeces and urine, has a terminal t1/2 beta of approximately 14 hours and duration of action of 24 hours, making it suitable for once or twice daily administration. Levocabastine has a terminal t1/2 beta of 35 to 40 hours regardless of the route of administration, but is only available as a topical application administered intranasally or ophthalmically in patients with allergic rhinoconjunctivitis. Loratadine is rapidly metabolised to an active metabolite descarboethoxyloratadine and has a 24-hour duration of action. Mizolastine has a terminal t1/2 beta of approximately 13 hours and duration of action of at least 24 hours. Most orally administered new H1 receptor antagonists are well absorbed and appear to be extensively distributed into body tissues; many are highly protein-bound. Most of the new H1 antagonists do not accumulate in tissues during repeated administration and have a residual action of less than 3 days after a short course has been completed. Tachyphylaxis, or loss of peripheral H1 receptor blocking activity during regular daily use, has not been found for any new H1 antagonist. Understanding the pharmacokinetics and pharmacodynamics of these new H1 antagonists provides the objective basis for selection of an appropriate dose and dosage interval and the rationale for modification in the dosage regimen that may be needed in special populations, including elderly patients, and those with hepatic dysfunction or renal dysfunction. The studies cited in this review provide the scientific foundation for using the new H1 antagonists with optimal effectiveness and safety.     

Constitutive activity of the histamine H(1) receptor reveals inverse agonism of histamine H(1) receptor antagonists

Transient expression of the wild-type human histamine H(1) receptor in SV40-immortalised African green monkey kidney cells resulted in an agonist-independent elevation of the basal levels of the second messenger inositoltrisphospate. Several histamine H(1) receptor antagonists, including the therapeutically used anti-allergics cetirizine, loratadine and epinastine reduced this constitutive histamine H(1) receptor activity. Inverse agonism, i.e., stabilisation of an inactive conformation of the human histamine H(1) receptor, may therefore be a key component of the anti-allergic mechanism of action of clinically used antihistamines.     

Nonsedating histamine H1-receptor antagonists

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosages of the nonsedating histamine H1-receptor antagonists terfenadine, astemizole, loratadine, and acrivastine are reviewed. Terfenadine and astemizole are chemically unrelated to histamine H1-receptor antagonists such as diphenhydramine and chlorpheniramine. Loratadine is structurally related to the antihistamine azatadine, and acrivastine is a side-chain-reduced metabolite of the antihistamine triprolidine. Like other histamine H1-receptor antagonists, they competitively block histamine receptor sites rather than inhibiting histamine release. All four drugs have relatively long half-lives and are rapidly absorbed after oral administration. Terfenadine, astemizole, and loratadine are metabolized extensively in the liver; terfenadine and astemizole are both 97% protein bound. Terfenadine 60 mg twice daily has been shown to be as effective as conventional antihistamines for the treatment of seasonal allergic rhinitis. In clinical trials, astemizole 10 mg daily was comparable to or better than chlorpheniramine for treatment of chronic rhinitis. Both terfenadine and astemizole were effective for treatment of chronic urticaria. For treatment of seasonal allergic rhinitis, loratadine combined with pseudoephedrine may be preferable to triprolidine-pseudoephedrine and acrivastine-pseudoephedrine combinations that require more frequent dosing. Acrivastine must be administered more frequently than the other nonsedating antihistamines. None of these four agents impairs psychomotor activity. Infrequently reported adverse effects include dry mouth, skin reactions, and weight gain. The absence of substantial sedative effects and the less-frequent dosing schedules make these agents good alternatives to the classic antihistamines for treatment of seasonal and chronic rhinitis and chronic urticaria.     

Nephrotoxicity and hepatotoxicity of histamine H2 receptor antagonists.

The extensive use of selective histamine H2 receptor antagonists provides a unique opportunity to describe very rare adverse drug reactions. Although mild elevation of serum creatinine level following the administration of cimetidine is relatively common, acute interstitial nephritis (AIN) is a rare hypersensitivity reaction. There have been 25 published reports of AIN associated with H2 antagonist therapy and we also identified 16 cases from the Australian Adverse Drug Reaction Advisory Committee (ADRAC) database. AIN was reported most commonly following cimetidine administration. AIN was supported by renal biopsy in 28 patients and by rechallenge in 6. H2 antagonist-induced AIN was more commonly reported in men older than 50 years. In the majority of cases the onset was within 2 weeks of initiation of therapy (1 day to 11 months). The clinical manifestations were nonspecific including sterile pyuria, elevated erythrocyte sedimentation rate, fatigue, proteinuria and leucocytosis whereas rash, arthralgia and flank pain were rarely reported. There were 170 cases of hepatotoxicity following H2 antagonist administration reported to ADRAC. These were more common following ranitidine and included cholestatic, hepatocellular and mixed reactions. Hepatotoxicity was proven following liver biopsy in several cases published in the literature and in 15 cases reported to ADRAC. Hepatotoxicity recurred upon rechallenge in 6 cases. Generally, renal and hepatic adverse effects resolved quickly after cessation of H2 antagonist therapy and did not require specific treatment. Nephrotoxicity and hepatotoxicity following administration of an H2 antagonist is rare and a high index of suspicion is necessary for early detection. Now that many H2 antagonists are available over the counter, awareness of these conditions and early detection with cessation of H2 antagonist therapy would appear paramount.     

Changes in pH differently affect the binding properties of histamine H1 receptor antagonists

We investigated the effect of acidic pH, a condition that can be encountered during inflammation accompanying allergic reaction, on the binding properties of histamine H₁ receptor antagonists, including levocetirizine ((2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)acetic acid; Xyzal®), fexofenadine (rac-2-[4-[1-Hydroxy-4-[4-(hydroxydiphenylmethyl) piperidin-1-yl]butyl]phenyl]-2-methylpropionic acid hydrochloride; Allegra®) and desloratadine (8-Chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine; Clarinex®). Lowering the pH from 7.4 to 5.8 decreased the affinity of [³H]mepyramine for histamine H₁ receptors from 1.7 to 7.5 nM while the opposite was observed with [³H]levocetirizine, whose affinity increased from 4.1 to 1.5 nM. Competition curves with [³H]mepyramine indicated that decreasing the pH from 7.4 to 5.8 led to a 2- to 5-fold increase in the affinity of fexofenadine and levocetirizine, no change in affinity for desloratadine and a 5- to 10-fold decrease in affinity for mepyramine and histamine. Kinetic experiments showed that the increase in affinity of levocetirizine and, to a lesser extent, fexofenadine were totally attributable to a lower dissociation rate at acidic pH (t_1/2 increasing from 77 to 266 min and from 71 to 135 min, respectively). Although the affinity of desloratadine remained unchanged, lowering the pH caused a decrease in its dissociation rate (t_1/2 of 50 and 256 min at pH 7.5 and 5.8, respectively) accompanied by a concomitant 3.5-fold decrease in its association rate constant. The loss of affinity of mepyramine at acidic pH was driven by a decrease in its association rate constant. Interaction between the carboxylic moiety of levocetirizine and Lys¹⁹¹ is responsible for its slow dissociation rate from the receptor. We found that the magnitude of the pH effect on the dissociation rate of levocetirizine was maintained after mutating Lys¹⁹¹ into alanine, suggesting that a tighter interaction of levocetirizine with Lys¹⁹¹ at lower pH is not the cause of its even slower dissociation rate from the receptor. Although these changes may seem limited in amplitude, we show that they may have substantial effects on receptor occupancy in vivo.     

Effects of second-generation histamine H1 receptor antagonists on the sleep-wakefulness cycle in rats

The present study was performed to examine the sedative effects of second-generation histamine H(1) receptor antagonist using power spectrum analysis in the rat. Similar to ketotifen, olopatadine caused a decrease in sleep latency at a dose of 50 mg/kg, while epinastine and cetirizine showed no significant effect even at a dose of 50 mg/kg. On the other hand, no significant difference was observed in the total times of wakefulness, non-rapid eye movement sleep and rapid eye movement sleep by any drugs used in the experiments. The number of sleep phases and interval between sleep phases were also unchanged by these drugs. Ketotifen and olopatadine inhibited [(3)H]mepyramine binding to rat brain homogenates in parallel with a decrease in sleep latency. No significant effect was observed with epinastine and cetirizine on [(3)H]mepyramine binding. These findings suggest that the differences in the central nervous system (CNS) depressant effect observed in second generation H(1) receptor antagonists may be due to their liability to penetrate into the CNS.     

Comparative anticholinergic activities of 10 histamine H1 receptor antagonists in two functional models

We determined the relative rank orders of anticholinergic potencies of 10 antihistamines in two functional bioassays: (1) an in vitro assay measuring inhibition of carbachol-induced contractions of isolated guinea pig trachealis muscle, (2) an in vivo bioassay comparing systemic hypotensive responses to bolus i.v. injections of acetylcholine before and after infusions of an antihistamine in anaesthetized rats. In vitro, the rank order of anticholinergic potencies of the antihistamines was cyproheptadine>promethazine>desloratadine>diphenhydramine>loratadine>chlorpheniramine>hydroxyzine>pyrilamine. The pA2 values ranged from 8.2+/-0.4 for cyproheptadine to 4.8+/-0.4 for pyrilamine. Fexofenadine and cetirizine (up to 3 x 10(-4) M) were inactive. In vivo, five antihistamines showed anticholinergic activity: cyproheptadine>promethazine>desloratadine>loratadine>diphenhydramine. The remaining antihistamines had no significant effect at i.v. infusion doses up to 50 imol/kg. Cetirizine and fexofenadine did not antagonize cholinergic responses in either model.     

Influences of histamine H1 receptor antagonists on maximal electroshock seizure in infant rats

The influences of histamine H1 receptor antagonists on maximal electroshock seizure were studied using infant rats. In this study, electroconvulsion was induced by stimulating rats using ear-clip electrodes, and the durations of electroencephalogram (EEG) seizure, tonic extensor (TE) seizure and clonic (CL) seizure induced by maximal electroshock were measured. Diphenhydramine, chlorpheniramine, cyproheptadine and ketotifen caused a dose-dependent and significant prolongation of both EEG seizure and TE seizure induced by maximal electroshock. On the other hand, epinastine and fexofenadine caused no such effects, even at a dose of 50 mg/kg. All drugs used in this study showed no significant effect on CL seizure induced by maximal electroshock. From these findings, it is suggested that epinastine and fexofenadine may cause no harmful influence on epilepsy, even when used in a little child.