抗组胺药物及其新药研究进展

组胺与组胺受体结合后引发以组胺为主的炎性介质释放,导致变态反应性疾病的发生.H1受体拮抗剂是抗组胺药物之一,可阻断组胺与Hl受体结合,从而抑制组胺发挥其生物学效应.Hl受体拮抗剂主要用于治疗由组胺释放诱发的变态反应性疾病.第一代抗组胺药作用时间短,有明显的镇静作用.第二代抗组胺药药效与第一代相近或强于第一代,作用时间长,无明显的中枢镇静作用,但有心脏毒性,故新药的研究成为热点.     

H1抗组胺药物研究进展

人体内组胺受体主要有H1、H2、H3和H4四种受体类型,组胺主要通过受体发挥生物学作用。目前H1抗组胺药物主要用于治疗荨麻疹及其他过敏性疾病,中枢神经系统疾病和前庭疾病。第一代H1抗组胺药物用于治疗过敏性疾病并无规范的研究,多数临床试验不符合当前随机双盲对照试验的标准。与之相比,第二代H1抗组胺药物均有大量充分的试验支持。临床上大部分H1抗组胺药物安全有效,但其中枢神经系统及心脏的不良反应不容忽视。     

第二代抗组胺药非索非那定中枢安全性研究进展

抗组胺药(H1受体拮抗剂)是对症治疗荨麻疹、变应性鼻炎、哮喘以及瘙痒等变态反应性疾病的主要药物.第一代抗组胺药因其镇静和抗胆碱能等副作用,已被相对无镇静作用的第二代抗组胺药所替代.非索非那定是第二代H1抗组胺药,无镇静、抗胆碱能作用,不能透过血脑屏障,因此该药能够在外周组织有效阻断H1受体,但无损害中枢神经系统(CNS)功能的作用.本文就非索非那定中枢安全性的研究进展进行综述.     

左西替利嗪和西替利嗪中枢神经系统抑制作用的临床观察

盐酸左西替利嗪是盐酸西替利嗪的左旋R-对映异构体,保留了西替利嗪的主要药效学特征,为高效、高选择性外周H1受体拮抗剂,体内外试验证实有较好的抗组胺和抗炎作用,并较西替利嗪有较好的生物利用度。两者同为第二代抗组胺药,与第一代抗组胺药相比,其H1受体选择性高,无镇静作用。     

荨麻疹

20121602关注抗组胺药治疗慢性荨麻疹应用的策略/郝飞(三军大西南医院皮肤科),钟华,宋志强∥实用皮肤病学杂志.-2012,5(1).-2～4①抗组胺药作用机制研究是临床用药策略变化的依据,竞争性与H1受体结合从而阻断变态反应;抗炎作用通过非H1受体依赖性和H1受体依赖性两个方面;反激动剂在组胺缺乏的情况下实施对组胺受体的抑制;镇静类抗组胺药、非镇静抗组胺药,既无中枢镇静作用又有明确抗炎作用。②抗组胺药物应用策略需     

抗组胺药物在皮炎湿疹类疾病中的应用

组胺参与荨麻疹和特应性皮炎等常见疾病的发病机制,故抗组胺药物是皮肤科最常用的系统用药之一.已发现的四种组胺G蛋白耦联受体中,人皮肤主要表达H1和H2亚型.抗组胺药物也称为组胺受体反向激动剂,除了抗组胺作用外,同时具有不依赖于H1受体的抗炎效应.虽然抗组胺药物在临床被广泛用于治疗皮炎湿疹类疾病,但其具体机制仍不明确,证据尚有待探讨.     

丹皮酚对RBL-2H3肥大细胞活化脱颗粒的影响

目的通过建立体外抑制肥大细胞脱颗粒的药效学模型,探讨丹皮酚抗Ⅰ型变态反应作用机制。方法用MTT比色法检测不同浓度的丹皮酚对RBL-2H3肥大细胞增殖的影响。通过ELISA法,明确体外RBL-2H3细胞活化分泌组胺及TNF-α动力学特征。检测不同浓度药物对RBL-2H3肥大细胞分泌组胺及TNF-α的影响。结果丹皮酚对RBL-2H3细胞增殖有抑制作用,IC50值为0.22 mg/mL。RBL-2H3细胞活化脱颗粒,分泌组胺的释放率在前30 m in上升较快,30 m in后上升进入平台期;TNF-α分泌的量在1h达高峰。丹皮酚抑制RBL-2H3细胞释放组胺和TNF-α作用不弱于色甘酸钠0.1,0.5 mg/mL。丹皮酚浓度的对数与其对RBL-2H3细胞释放组胺和TNF-α的抑制率呈线性相关(P=0.000<0.01)。结论丹皮酚呈剂量依赖性抑制RBL-2H3细胞分泌组胺和TNF-α。     

抗组胺药联合转移因子治疗慢性荨麻疹疗效观察

目的　观察抗组胺药联合转移因子治疗慢性荨麻疹的疗效。方法　分别采用组胺H1和H2 受体拮抗剂、转移因子及三者联合治疗。结果　抗组胺药组与转移因子组疗效相近 (P >0 .0 5 ) ,联合治疗组疗效与其它两组相比 ,疗效有极其显著性差异 (P <0 .0 1)。结论　联合治疗组治疗慢性荨麻疹疗效显著。     

组胺受体H4R对过敏性紫癜患儿体内树突状细胞的调节作用

目的:明确组胺受体H4R对过敏性紫癜(HSP)患儿体内树突状细胞(dentritic cells,DC)的调节作用。方法:1.流式细胞仪检测126例HSP急性期、112例缓解期患者及94名健康对照外周血单核细胞(PBMC)中DC标志性分子CD80及CD86的表达情况;2.体外活化和诱导得到DC,分为组胺组,组胺+H4R拮抗剂组和PBS对照组,Western blot检测组胺、H4R蛋白和人磷酸化信号传导子及转录激活子1(p-STAT1)的表达,酶联免疫吸附试验检测趋化因子CCL17、CXCL16表达水平。结果:1.HSP患者PBMC中CD86的表达明显高于健康对照组(P0.01)。急性期组CD80的表达低于缓解期组及健康对照组(P0.01),而缓解期组及健康对照组之间无显著性差异(P0.05);2.组胺+H4R拮抗剂组p-STAT1和H4R的蛋白及趋化因子CXCL16和CCL17水平明显低于组胺组。结论:组胺受体H4R可能通过促进DC的趋化因子CXCL16/CCL17的表达,激活JAK/STAT通路,引起HSP的发生发展。     

从抗组胺药的作用机制谈其治疗慢性荨麻疹的应用策略

抗组胺药物通常通过拮抗H1受体来阻断组胺与受体结合,从而影响变态反应发生的过程.近年来研究发现,抗组胺药可以通过H1受体依赖和非依赖途径起更广泛的抗炎作用,并可以成为反激动剂在组胺缺乏的情况下实施对组胺受体活性的抑制.这些机制促进抗组胺药临床治疗慢性荨麻疹产生新的理念.     

H1 and H2 histamine receptors are absent on Langerhans cells and present on dermal dendritic cells

Human monocyte-derived dendritic cells (MoDC) have both histamine H1 and H2 receptors and can induce CD86 expression by histamine. Nevertheless, it has not been reported whether human epidermal Langerhans cells (LC) have histamine receptors or not. In this study, using RT-PCR, we investigated the expression of H1 and H2 receptor mRNA on DC with the features of LC (LC-like DC) that were generated in vitro from peripheral blood monocytes, LC derived from CD34+ hematopoietic progenitor cells, and LC obtained from human epidermis. We compared the histamine-induced CD86 expression among these cells. In contrast to MoDC, LC and LC-like DC did not express H1 or H2 receptors. In addition, they could not augment the CD86 expression by histamine. Interestingly, when transforming growth factor-beta1 (TGF-beta1) was added to the culture of MoDC, the expression of H1 and H2 receptors and the histamine-induced CD86 expression were abrogated in a concentration-dependent fashion. Finally, in the assessment of the cell surface expression of histamine receptors using fluorescence-labeled histamine, histamine could bind to MoDC and dermal dendritic cells obtained from the skin, whereas there was no specific binding of histamine to LC-like DC or LC obtained from the skin. These data suggest that LC do not express either H1 or H2 receptors, mainly because of the effect of TGF-beta1. This made a striking contrast with the expression of the functional H1 and H2 receptors on MoDC and dermal dendritic cells.     

Histamine H1 and H2 receptor antagonists accelerate skin barrier repair and prevent epidermal hyperplasia induced by barrier disruption in a dry environment

Keratinocytes have histamine H1 and H2 receptors, but their functions are poorly understood. To clarify the role of histamine receptors in the epidermis, we examined the effects of histamine receptor antagonists and agonists applied epicutaneously on the recovery of skin barrier function disrupted by tape stripping in hairless mice. Histamine H2 receptor antagonists famotidine and cimetidine accelerated the recovery of skin barrier function, but histamine and histamine H2 receptor agonist dimaprit delayed the barrier repair. Application of compound 48/80, a histamine releaser, also delayed the recovery. Imidazole, an analog of histamine, had no effect. The histamine H1 receptor antagonists diphenhydramine and tripelennamine accelerated the recovery. Histamine H3 receptor agonist Nalpha-methylhistamine and antagonist thioperamide had no effect. In addition, topical application of famotidine or diphenhydramine prevented epidermal hyperplasia in mice with skin barrier disrupted by acetone treatment in a dry environment (humidity < 10%) for 4 d. In conclusion, both the histamine H1 and H2 receptors in the epidermis are involved in skin barrier function and the cutaneous condition of epidermal hyperplasia.     

卢帕他定药效学及应用进展

卢帕他定是一种具有组胺H1受体和血小板活化因子受体双重拮抗作用的新型抗过敏药,能够作用于过敏反应发生的不同环节进而抑制炎症反应.卢帕他定起效快速、疗效持久,故而推荐每日一次口服.临床研究表明,卢帕他定低剂量口服能有效地控制季节性和常年过敏性鼻炎的症状.近年研究表明,其对慢性自发性荨麻疹、寒冷性荨麻疹等皮肤病亦有较好疗效,且耐受性好.     

Histamine receptors on lymphocytes: distribution and functional significance

Several investigations reported modulation of lymphocyte functions following activation of the histamine H2 receptor. However, few data have accumulated with regard to the distribution of histamine H2 receptors on different lymphocyte subsets. Conversely, the distribution of histamine H1 receptors on different lymphocyte subsets has been thoroughly analyzed using specific radioligands, whereas the functional significance of histamine H1 receptor ligation on lymphocytes has not been fully elucidated yet. Recent investigations suggest that H1R signaling on lymphocytes may enhance whereas activation of the H2R may inhibit lymphocyte responses. In this review, the authors discuss the current knowledge on distribution and functional significance of histamine H1 and histamine H2 receptors on human lymphocytes.     

One‐year safety and efficacy study of bilastine treatment in Japanese patients with chronic spontaneous urticaria or pruritus associated with skin diseases

A number of second‐generation non‐sedating antihistamines are used in clinical practices over the world. However, long‐term safety and efficacy have not been proved high level evidence based medicine. We have performed an open‐label, multicenter, phase III study to evaluate the long‐term safety and efficacy of bilastine, a novel non‐sedating H₁‐antihistamine for patients with chronic spontaneous urticaria (CSU) or pruritus associated with skin diseases (trial registration no. JapicCTI‐142528). Patients aged 18–74 years were treated with bilastine 20 mg once daily for up to 52 weeks. Safety and tolerability were assessed on the basis of adverse events (AE), bilastine‐related AE, laboratory tests and vital signs. Efficacy was assessed based on rash score, itch score, overall improvement and quality of life. One hundred and ninety‐eight patients enrolled, 122 of whom (61.6%) completed the 52‐week treatment period. AE were reported in 64.5% and bilastine‐related AE in 2.5% of patients throughout the 52‐week treatment period. All AE were mild to moderate in severity. AE associated with the nervous system occurred in 10 patients (5.1%) including seven patients (3.6%) with headache. Somnolence reported in two of these patients (1.0%) was related to bilastine. All efficacy variables improved during treatment with bilastine. In conclusion, long‐term treatment with bilastine 20 mg once daily for 52 weeks is safe and well tolerated in Japanese patients with CSU or pruritus associated with skin diseases. Bilastine improved disease symptoms of both conditions early in treatment, and the efficacy was maintained throughout the treatment.     

Histamine and epidermal proliferation

Histamine is liberated in the inflammatory reaction and has been reported to inhibit epidermal cell division in vitro. This study has investigated the eflFects of histamine and H1 and H2 antagonists on epidermopoiesis in vivo in man. No direct stimulatory effect of histamine was detected for normal epidermis. A combination of H1 antagonist (chlorpheniramine) and H2 antagonist (cimetidine) led to further increases in epidermal labelling indices in mitotically stimulated epidermis. The administration of H1 antagonist alone led to a decrease in mean epidermal thickness. These data suggest that histamine release is unlikely to play a major role in the hyperplasia of inflammatory dermatoses, but that it may be possible to influence epidermal reactions via the H1 and H2 receptors.     

The effect of histamine on epidermal outgrowth: its possible dual role as an inhibitor and stimulator

We have investigated the effect of histamine on pig epidermal cell outgrowths in vitro. Histamine inhibited the epidermal cell outgrowths (and also mitosis). This inhibition was partially counteracted by a specific H2 antagonist, cimetidine. Inhibition was maximal at a histamine concentration of 10(-4) M and was less at 10(-3) M. These histamine concentrations respectively coincide with the optimal concentrations for accumulating intracellular cyclic AMP (via H2 receptors) and cyclic GMP (via H1 receptors) in the same pig epidermal slice system. 4-Methyl-histamine, a pure H2 agonist, which only increased the intracellular cyclic AMP level but not the cyclic GMP level, caused a maximal outgrowth inhibition at 10(-3) M. Attempts to counteract the histamine effects due to cyclic GMP accumulation by various H1 antagonists (so that 10(-3) M histamine would have caused maximal outgrowth inhibition) were unsuccessful, since the addition of each H1 antagonist alone strongly inhibited the outgrowth. These data strongly suggest a dual role of histamine through the cyclic nucleotide system; i.e., histamine inhibits epidermal cell growth by elevating the intracellular cyclic AMP level via an H2 receptor, while histamine at high concentrations (10(-3) M) partially counteracts the inhibition by increasing cyclic GMP via an H1 receptor.     

Histamine induces melanogenesis and morphologic changes by protein kinase A activation via H2 receptors in human normal melanocytes

Hyperpigmentation frequently accompanies chronic or acute inflammation. A number of inflammatory mediators have been shown to stimulate melanin synthesis in human melanocytes. Although histamine is ubiquitous as an inflammatory factor, its involvement in pigmentation remains obscure. In this work, we examined the effects of histamine on cultured human melanocytes. Treatment of human melanocytes with 0.1-10 microM histamine evoked morphologic changes and increases in tyrosinase activity. The concomitant increases in melanin content of the histamine-treated melanocytes indicated an elevation of melanin synthesis by tyrosinase activation. These stimulatory effects of histamine were completely inhibited by an H2 antagonist, famotidine, whereas H1 and H3 antagonists had no inhibitory effect whatsoever. In addition, an H2 agonist, dimaprit, induced the same degree of melanogenesis as histamine at concentrations of 0.1-10 microM. We observed an increase in the intracellular cAMP contents of human melanocytes induced by histamine via the H2 receptors. We know that this cAMP accumulation and subsequent protein kinase A activation plays a critical role in histamine-induced melanogenesis, because a specific protein kinase A inhibitor, H-89, completely suppressed these stimulatory effects of histamine, and because dibutylic cAMP, a specific protein kinase A activator, stimulated human melanocytes as potently as histamine. Taken together, we show here that histamine induces melanogenesis of human cultured melanocytes by protein kinase A activation via H2 receptors.     

Bilastine: a new H1‐antihistamine with an optimal profile for updosing in urticaria

This review set out to examine published papers detailing the efficacy of bilastine in skin models and urticaria to assess whether it meets the optimal profile for updosing in urticaria, that is, strong clinical efficacy and freedom from unwanted side effects, particularly sedation. Bilastine is a highly effective H₁‐antihistamine even when used at the basic dose of 20 mg daily. Its facilitated uptake after oral dosage gives it a rapid onset and long duration of action. In both wheal and flare studies and in urticaria updosing fourfold showed increased effectiveness. With respect to somnolence, bilastine is a substrate for P‐glycoprotein, a membrane pump which prevents it crossing the blood–brain barrier. Consequently, bilastine is a practically ‘non‐sedating’ H₁‐antihistamine. In conclusion, the excellent profile of bilastine in both efficacy and safety make it the ideal H₁‐antihistamine for updosing the daily dose fourfold in difficult‐to‐treat urticaria as recommended by the EAACI/GA²LEN/EDF/WAO guideline for the management of urticaria.     

H2 histamine receptor-mediated increase in intracellular Ca2+ in cultured human keratinocytes.

Histamine is present in the epidermis in intracellular and extracellular area and is released from mast cells and keratinocytes in the early stage of inflammation of the skin. Such release may contribute to common itching or intensify the inflammatory responses. Histamine binds to its receptors and participate in regulation of the inflammatory responses by acting on endothelial cells, nerve endings, lymphocytes, monocytes, and leukocytes. Histamine has direct effects on keratinocytes as well. Histamine modulates the proliferation of keratinocytes. The binding of histamine to the receptor on keratinocyte membrane induces activation of adenylate cyclase and phospholipase C through GTP binding protein. We previously reported that histamine induces transient increase in intracellular Ca2+ in cultured normal human epidermal keratinocytes (NHEK) and normal epidermis. H1 and H2 histamine receptors are widely distributed in many tissues and cells. In this study, we investigated which types of histamine receptors are related to the increase in intracellular Ca2+ by histamine stimulation in cultured human epidermal keratinocytes. NHEK were cultured in serum-free KGM medium. With H1 antihistamines, mepyramine and diphenhydramine, histamine responses were moderately but not statistically significantly inhibited. With H2 antihistamine, cimetidine, histamine response was significantly inhibited. Epinephrine response was not affected by these antihistamines. Thus, it is considered that H2 antihistamines specifically block histamine-mediated increase in intracellular Ca2+ of cultured normal human keratinocytes.