治疗特应性皮炎新药及其临床药理学研究有关问题探讨

对近5年来特应性皮炎代表性新药的国内外批准情况进行介绍,总结了度普利尤单抗注射液、乌帕替尼缓释片、迪高替尼乳膏、克立硼罗软膏等4种不同作用机制、不同给药途径的特应性皮炎治疗药物的申报资料中临床药理学研究主要内容,以及国内外监管机构对特应性皮炎治疗药物的审评考量,旨在为特应性皮炎新药的早期临床研发和评价提供参考依据。     

儿童特应性皮炎的新药治疗进展

特应性皮炎是一种常见的慢性、复发性、炎症性皮肤病。目前的治疗方法仍有较多的局限性及不良反应，不能完全满足临床需求。近年来，随着对特应性皮炎复杂发病机制的深入研究，很多新药逐渐应用于治疗特应性皮炎，本文就这些药物在儿童特应性皮炎患者的应用及研究进展进行综述，以便临床医生更好地治疗和管理特应性皮炎患儿。     

特应性皮炎治疗药物临床试验设计的关键技术考虑

目的:探讨特应性皮炎治疗药物临床试验设计的技术考虑。方法:通过梳理近年来国内外特应性皮炎治疗药物临床研发情况,调研国内外特应性皮炎治疗药物技术指南进展,基于我国研发和审评的实践经验,形成相关技术考虑。结果与结论:特应性皮炎治疗药物临床试验设计应根据疾病特点、药物特性、研究目的制定整体临床研发计划。应在有前期研究证据支持并能确保受试者安全的前提下,尽早开展儿童患者临床试验。临床试验设计应选择适宜的研究人群,合理设置对照药、疗效和安全性指标、研究周期等一系列关键要素,以助力此类药物科学研发。研究人群定位应基于药物作用机制和药效作用强度选择对应严重程度的患者,疗效考察应全面评估患者皮损、症状、生活质量等改善情况,并关注用于儿童患者以及长期治疗时的疗效和安全性等。     

芪血颗粒联合二维亚铁治疗小儿缺铁性贫血的临床研究

《儿童湿疹/特应性皮炎中药临床试验设计与评价技术指南》为中华中医药学会标准化项目《儿科系列常见病中药临床试验设计与评价技术指南》之一。其目的是以临床价值为导向,在病证结合模式下,讨论具有湿疹/特应性皮炎、儿童和中药特点的临床定位、试验设计与实施等相关问题,为中药治疗儿童湿疹/特应性皮炎临床试验设计与评价提供思路和方法。制定过程中先后成立指南工作组、起草专家组和定稿专家组,采用文献研究和共识会议的方法,最终形成指南送审稿定稿。该《指南》的主要内容包括临床定位、试验总体设计、诊断标准与辨证标准、受试者的选择与退出、干预措施、有效性评价、安全性观察、试验流程、试验的质量控制9部分。希望其制定和发布,能为申办者/合同研究组织、研究者在中药治疗湿疹/特应性皮炎的临床试验设计,提供借鉴与参考。     

局部免疫调节剂他克莫司、吡美莫司在皮肤病的应用

局部应用的他克莫司软膏和吡美莫司乳膏是两种新的钙调磷酸酶抑制剂。作为局部免疫调节剂用于特应性皮炎的治疗。作为抗炎药其安全性和疗效较好的特点,使它们成为治疗许多皮肤病的有吸引力的候选药物。已发表的文献表明它们除应用于特应性皮炎外,尚可用于银屑病、脂溢性皮炎、扁平苔藓和其他疾病。     

儿童湿疹/特应性皮炎药物临床试验评价指标的研究进展

湿疹是儿科临床常见的皮肤病,特应性皮炎是其中最常见的一种.《儿童湿疹/特应性皮炎中药临床试验设计与评价技术指南》已正式发布,其中提到湿疹/特应性皮炎临床试验的核心指标集,包括客观体征、主观症状、生活质量和长期控制4个核心领域,并参考核心指标集所述,制定了疗效评价指标.综述国内外湿疹/特应性皮炎临床试验中关于上述4个核心...     

治疗特应性皮炎的新药——Eucrisa

Eucrisa是由美国安纳考尔医药公司研制的用于治疗特应性皮炎的软膏剂,2016年12月14日FDA批准其用于轻度至中度特应皮炎的外用治疗。Eucrisa的活性成分Crisaborole是磷酸二酯酶-4抑制剂,是一种含硼的小分子抗炎药,其作用机制尚未完全明确。临床研究表明,Crisaborole的疗效明显,29 d对轻至中度特应性皮炎患者的平均治愈可达到32%,且安全性高,对2岁及以上儿童和怀孕期妇女未见不良影响。Crisaborole是美国FDA在过去15年首次批准治疗特应性皮炎的新药,为特异性皮炎患者提供了一种重要的非类固醇替代疗法。笔者就该药的基本信息、作用机制、药动学、药效学、临床试验及应用等研发动态进行了概述,以期能为医院临床用药起到指导作用。     

对贵刊《他克莫司软膏治疗成人和儿童特应性皮炎51例》一文的验证

<正>笔者阅读了贵刊2005年第9期刊登的《他克莫司软膏治疗成人和儿童特应性皮炎51例》一文后深受启发,并采用此法于2006年10月—2007年5月,对门诊特应性皮炎病人进行临床验证,报道如下。一般资料36例符合特应性皮炎诊断标准的病人按随机数字表随机分为2组,对照组18例,其中     

他克莫司软膏联合氯雷他定治疗儿童特应性皮炎的临床疗效观察

目的探讨他克莫司软膏联合氯雷他定治疗儿童特应性皮炎的临床疗效。方法选取2009年9月至2011年5月我院诊治的特应性皮炎患儿共160例,随机分为实验组和对照组,其中治疗组采用他克莫司软膏司联合氯雷他定治疗,对照组单纯口服氯雷他定。治疗后观察患者的皮肤状况,每周复诊1次,观察患儿的皮损及瘙痒情况。结果实验组与对照组的临床疗效总有效率差异具有统计学意义(97.50%VS 78.75%,P<0.05),实验组患儿的疗效总有效率明显较高;治疗结束2周后实验组患儿的临床体征与症状评分明显较低(P<0.05)。结论他克莫司软膏联合氯雷他定治疗儿童特应性皮炎,能够有效提高临床效果及改善临床体征与症状,值得在临床上推广应用。     

我国儿童特应性皮炎药物临床试验分析

目的：基于我国儿童特应性皮炎药物临床试验的登记情况及特应性皮炎治疗药品在我国的上市情况进行分析,为药品研究提供参考。方法：检索国家药品监督管理局“药物临床试验登记与信息公示平台”和“药品查询”数据库(检索时间均为2017年1月1日至2023年4月17日),获得儿童特应性皮炎临床试验注册信息及特应性皮炎治疗药品的上市信息,进行分类统计。结果：平台共登记了40项包含儿童受试者的湿疹/特应性皮炎药物临床试验,目前数据库有36家国内外生产企业的10个品种的特应性皮炎治疗药品在我国获准上市。结论：国内制药企业在儿童特应性皮炎药物研发上多集中于仿制药,目前已有2种治疗用生物制品1类药物,需要继续深耕,进一步开展药物临床试验,同时发挥我国中医药优势,发掘中药品种开展临床试验,为儿童用药添砖加瓦。     

The effects of olopatadine hydrochloride on the number of scratching induced by repeated application of oxazolone in mice

It is suggested that atopic dermatitis is a skin disease associated with itching as subjective symptoms, and histamine H(1) receptor antagonists are used in order to prevent the itching, and the deterioration for scratch by itching. Histamine H(1) receptor selective anti-histamine olopatadine hydrochloride (olopatadine; Allelock shows consistent efficacy and safety in the treatment of allergic disorders. We investigated the possible efficacy of olopatadine on the number of scratching induced by repeated application of oxazolone in BALB/c mice. The repeated treatment of olopatadine significantly inhibited the ear swelling and the increased number of scratching. It significantly inhibited the increased production of interleukin (IL)-4, IL-1beta and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the lesioned ear. Moreover, it significantly inhibited the increased production of nerve growth factor (NGF) and substance P. On the other hand, loratadine, bepotastine and chlorpheniramine did not inhibit the ear swelling and the increased number of scratching. These results indicate that olopatadine inhibited not only the increased production of cytokines but also NGF and substance P unlike other histamine H(1) receptor antagonists. It was suggested that olopatadine suppressed the increased number of scratching by the anti-inflammatory effects. Therefore, olopatadine appears to exert additional biological effects besides its blockade of a histamine H(1) receptor.     

Properties of olopatadine hydrochloride, a new antiallergic/antihistaminic drug

Olopatadine hydrochloride (CAS 140462-76-6, KW-4679, AL-4943A; hereinafter referred to as olopatadine) is a novel antiallergic drug that is a selective histamine H1 receptor antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. Olopatadine also inhibits the tachykininergic contractions in guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. Oral administration of olopatadine at doses of 0.03 mg/kg or higher reduces the symptoms of experimental allergic cutaneous responses and rhinoconjunctivitis in sensitized animals. Preclinical and clinical evaluations have demonstrated that olopatadine is a safe drug. After oral administration to healthy volunteers, olopatadine was rapidly and extensively absorbed. Unlike most other antiallergic drugs which are eliminated via hepatic metabolism, olopatadine is mainly excreted into urine. Olopatadine did not affect cytochrome P450 activities in human liver microsomes and consequently drug-drug metabolic interactions are unlikely. In double-masked clinical trials, olopatadine was shown to be effective at alleviating symptoms of allergic diseases. The drug (Allelock) was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, cutaneous pruritis, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. An ophthalmic solution of olopatadine is also useful for the treatment of allergic conjunctivitis: this formulation (Patanol) was approved in the USA and the European Union for the treatment of seasonal and perennial allergic conjunctivitis in 1996 and 2002, respectively.     

Effects of olopatadine hydrochloride on the cutaneous vascular hyperpermeability and the scratching behavior induced by poly-L-arginine in rats.

Intradermal injections of poly-L-arginine induce cutaneous vascular hyperpermeability and scratching behavior in rats. Recently, we elucidated that the plasma extravasation involved both histamine and substance P, while the scratching behavior involved substance P, but not histamine. This study examined the effects of olopatadine hydrochloride (olopatadine), an antiallergic drug with histamine H1-antagonistic action, on the poly-L-arginine-induced responses. Olopatadine (1 mg/kg, p.o.) significantly inhibited both the plasma extravasation and the scratching behavior, suggesting that its inhibitory effects are mediated by the suppression of neuropeptidergic action as well as histaminic action. Olopatadine seems to be a novel-type drug for the treatment of dermatitis.     

Pharmacological,pharmacokinetic and clinical properties of olopatadine hydrochloride,a new antiallergic drug

Olopatadine hydrochloride (olopatadine, 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid monohydrochloride) is a novel antiallergic/histamine H1-receptor antagonistic drug that was synthesized and evaluated in our laboratories. Oral administration of olopatadine at doses of 0.03 mg/kg or higher inhibited the symptoms of experimental allergic skin responses, rhinoconjunctivitis and bronchial asthma in sensitized guinea pigs and rats. Olopatadine is a selective histamine H1-receptor antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. Olopatadine also inhibited the tachykininergic contraction in the guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. Olopatadine exerted no significant effects on action potential duration in isolated guinea pig ventricular myocytes, myocardium and human ether-a-go-go-related gene channel. Olopatadine was highly and rapidly absorbed in healthy human volunteers. The urinary excretion of olopatadine accounted for not less than 58% and the contribution of metabolism was considerably low in the clearance of olopatadine in humans. Olopatadine is one of the few renal clearance drugs in antiallergic drugs. Olopatadine was shown to be useful for the treatment of allergic rhinitis and chronic urticaria in double-blind clinical trials. Olopatadine was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, pruritis cutaneous, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. Ophthalmic solution of olopatadine was also approved in the United States for the treatment of seasonal allergic conjunctivitis in December, 1996 (Appendix: also in the European Union, it was approved in February 2002).     

Effect of olopatadine hydrochloride, a novel antiallergic agent, on the QT interval in dogs]

Olopatadine hydrochloride (olopatadine), a novel antiallergic agent, is effective in the treatment of allergic rhinitis, chronic urticaria, eczema and dermatitis. It has been reported that terfenadine and astemizole cause side effects on the circulatory system such as QT prolongation followed by serious ventricular arrhythmias (torsades de pointes). To investigate the possibility of QT prolongation, we used both conscious normal dogs and hypokalemia-anesthetized dogs under two conditions: 1) olopatadine used alone and 2) olopatadine used in combination with itraconazole, the CYP3A4-inhibiting antifungal agent, in the present investigation. The group treated with terfenadine alone (30 mg/kg, p.o.) and the group treated with a combination of terfenadine (10 mg/kg, p.o.) and itraconazole (100 mg/kg, p.o.) had a significantly prolonged QT interval. On the other hand, the group treated with olopatadine alone (30 mg/kg, p.o.) and the group treated with a combination of olopatadine (30 mg/kg, p.o.) and itraconazole (100 mg/kg, p.o.) did not show any significant changes in QT interval. Moreover, olopatadine (1 and 5 mg/kg, i.v.) did not influence the QT interval in hypokalemia-anesthetized dogs. These results suggest that there is very little possibility of QT prolongation as a result of clinically used olopatadine.     

Analysis of disease-dependent sedative profiles of H(1)-antihistamines by large-scale surveillance using the visual analog scale

Sedation is the most frequent side effect of H(1)-antihistamines, and, sometimes, it may be life-threatening for patients. Evaluation of the sedative properties of H(1)-antihistamines is important to improve the patients' quality of life (QOL). Therefore, we carried out a large-scale surveillance quantified through a questionnaire using visual analog scale (VAS) from 1,742 patients. The results showed that the degree of sleepiness caused by some nonsedative second-generation antihistamines, including fexofenadine, olopatadine and cetirizine, was disease dependent. In atopic dermatitis, an unexpectedly low VAS score of sleepiness was obtained for the first-generation antihistamine d-chlorpheniramine, which is similar to those obtained for bepotastine and epinastine. d-Chlorpheniramine also showed a high VAS score in efficacy. Meanwhile, fexofenadine showed a higher VAS score of sleepiness in atopic dermatitis than those obtained in the other allergic diseases including allergic rhinitis, urticaria and asthma. In asthma, a higher VAS score of sleepiness was found for olopatadine, ebastine and cetirizine, when compared with d-chlorpheniramine. On the other hand, bepotastine showed the lowest VAS score for sleepiness. Our findings suggest the existence of unknown factors influencing the sedative properties of H(1)-antihistamines. Therefore, appropriate H(1)-antihistamines may need to be selected, depending on allergic diseases, to improve patients' QOL.     

Effect of olopatadine and other histamine H1 receptor antagonists on the skin inflammation induced by repeated topical application of oxazolone in mice

Histamine H1 receptor antagonists have long been prescribed for atopic dermatitis as an adjuvant therapy with topical therapy by local applied steroids. Olopatadine is one of the second-generation histamine H1 receptor antagonists that are treated for allergic disorders. We investigated that the effect of olopatadine on oxazolone-induced chronic contact hypersensitivity response in BALB/c mice compared with other histamine H1 receptor antagonists loratadine, cetirizine and fexofenadine. The chronic contact hypersensitivity induced by repeated application of oxazolone was treated with olopatadine and other histamine H1 receptor antagonists at the effective doses on histamine-induced paw edema in mice. The effects of these drugs in the oxazolone-induced model were quantified by measurements of ear swelling, and levels of cytokines in the lesioned ear. Olopatadine significantly inhibited the ear swelling and the increased production of IL-4, IL-1beta, IL-6, GM-CSF and NGF in the lesioned ear. On the other hand, the other histamine H1 receptor antagonists did not significantly suppress the increase in ear thickness. Moreover, they did not affect the production of cytokines in the lesioned ear. These results indicate that olopatadine appears to exert additional biological effects besides its blockade of the histamine H1 receptor.     

Olopatadine hydrochloride inhibits capsaicin-induced flare response in humans

Capsaicin, a vanilloid, has the potential for releasing substance P (SP) from sensory nerves. Topical application of capsaicin induces a flare response in the skin. However, it has not been clarified whether the release of SP is involved in the process of flare response or not. A potent antihistamine drug, olopatadine hydrochloride, is known to have inhibitory action against the release of SP. We examined the effects of olopatadine (at a dose of 5 mg) on skin reaction induced by topical application of capsaicin in 10 healthy subjects. The scores of capsaicin-induced flare responses after olopatadine administration were significantly lower at 30 min than at baseline. Our findings suggest that olopatadine hydrochloride could inhibit capsaicin-induced flare responses.     

Pharmacological, pharmacokinetic and clinical properties of olopatadine hydrochloride' (olopatadine), an antiallergic drug

Olopatadine is a selective histamine H1-receptor antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. Olopatadine also inhibited the tachykininergic contraction in the guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. Oral administration of olopatadine inhibited passive cutaneous anaphylaxis in rats, experimental allergic rhinitis and bronchial asthmatic responses in actively sensitized guinea pigs. Olopatadine exerted no significant effects on action potential duration in isolated guinea pig myocardium and ventricular myocytes. Olopatadine was highly and rapidly absorbed in healthy volunteers. The urinary excretion of olopatadine accounted for not less than 58% and the contribution of metabolism was low in the elimination of olopatadine. Olopatadine was shown to be useful for the treatment of allergic rhinitis and chronic urticaria in double-blind clinical trials. Olopatadine was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, pruritus cutaneous, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000.     

奥洛他定滴眼液治疗变态反应性结膜炎的临床观察

目的观察奥洛他定滴眼液在变态反应性结膜炎中的临床疗效。方法入选变态反应性结膜炎患者56例（88眼）,给予患者0．196盐酸奥洛他定滴眼液,每眼1滴,早晚各1次,共7d。观察治疗前后变态反应性结膜炎各项症状与体征的变化情况。结果奥洛他定滴眼液治疗变态反应性结膜炎的总有效率为94．696．变态反应性结膜炎的各项症状和体征均得到显著的改善。治疗期间未观察到明显的不良反应。结论奥洛他定滴眼液治疗变态反应性结膜炎具有较好的疗效和安全性。