用于治疗特应性皮炎的小分子JAK抑制剂及其专利研究

本文梳理了全球已获批上市与正在研发中的用于治疗特应性皮炎的小分子JAK抑制剂药物品种情况,对5个重点药物磷酸芦可替尼、巴瑞替尼、乌帕替尼、迪高替尼、阿布昔替尼的研发进展以及其涉及在多个不同技术主题如化合物、新用途等方面已公开的专利进行研究和分析,以期为生物医药企业在进行立项与开发用于治疗特应性皮炎的小分子JAK抑制剂以及进行新的专利挖掘、专利保护与专利布局时,提供有效的产品信息和专利信息。     

小分子靶向抗肿瘤药物临床研究策略探讨及案例分析

小分子靶向抗肿瘤药物是当前国内外创新药研发的热点,近些年不断有新产品上市,还有数百个产品正处于临床研发阶段。因为作用机制的不同,小分子靶向药物体现出与传统细胞毒类药物不一样的安全有效性特点,在临床研究设计和开发模式上也有所不同。本文对近年来批准上市的吉非替尼、克唑替尼、埃克替尼等小分子靶向药物临床研究经典案例进行了回顾,分析不同类型药物的临床研发策略,期望能对抗肿瘤药物相关研发人员提供参考。     

慢性粒细胞白血病临床治疗药物选择

目的:为慢性粒细胞白血病患者治疗药物选择提供参考。方法:查阅国内外相关文献,综述分析已上市的临床用于治疗慢性粒细胞白血病的一线药物,包括酪酸激酶抑制剂伊马替尼、达沙替尼、尼罗替尼、博舒替尼、帕纳替尼和非酪酸激酶抑制剂高三尖杉酯碱的标准使用剂量、药效学、毒副作用、药物禁忌、药物相互作用。结果:第一代酪氨酸激酶抑制剂伊马替尼对未使用过其他酪氨酸激酶抑制剂治疗的初始患者有很好的疗效,但患者用药后很容易发生Bcr-Abl基因突变而耐受或者耐药。第二代酪氨酸激酶抑制剂达沙替尼、尼罗替尼、博舒替尼对大部分Bcr-Abl基因突变有效,对伊马替尼产生耐受或者耐药的患者有较好的治疗效果,但是均对T315I突变无效。第三代酪氨酸激酶抑制剂帕纳替尼对大部分Bcr-Abl基因突变有效,而且是目前唯一对T315I突变有效的已上市激酶抑制剂,但有严重的致血管阻塞、心脏衰竭和肝毒性的风险。另外,非酪氨酸激酶抑制剂高三尖杉酯碱主要用于难治性白血病患者。结论:在临床治疗中,应根据患者病情的发展阶段,用药、耐药情况及药物本身的疗效和毒副作用等综合评估,合理选择药物进行治疗,充分发挥药物疗效和提高药物使用安全性。     

临床药师对1例服用分子靶向药物舒尼替尼的肿瘤患者的药学监护

目的：通过临床药师对患者的药学监护,保障肿瘤患者使用药物的安全有效。方法：临床药师通过熟练掌握新药舒尼替尼的药理作用、不良反应以及应采取的防范措施,对1例服用舒尼替尼的患者进行药学监护。结果：临床药师对舒尼替尼所致高血压的降压药物选择、胃肠道不良反应的处理及药物选择、皮肤毒性反应的治疗方法、心血管毒性的监测及防范措施以及血液系统毒性等方面与临床医生共同制定方案,患者最终顺利完成本周期治疗。结论：临床药师通过对患者的药学监护,与临床医生协作,可以协助临床避免不良事件的发生。     

新型中重度特应性皮炎治疗药物——阿布昔替尼

阿布昔替尼（abrocitinib）是由辉瑞公司开发的一种口服小分子Janus激酶1(JAK1)抑制剂,可通过阻断三磷酸腺苷结合位点可逆地抑制JAK1,用于治疗接受其他系统治疗（包括生物制剂）应答不足或不宜使用这些疗法的难治性中重度特应性皮炎（AD）成人患者。临床试验表明,阿布昔替尼具有可控的耐受性和安全性,适合用于难治性中重度AD患者。本文就其药理作用及作用机制、药物代谢动力学、临床疗效、安全性等方面进行综述,旨在为临床合理应用提供参考。     

阿帕替尼在恶性肿瘤治疗中的临床应用与研究进展

抗血管生成靶向治疗是近年来肿瘤治疗的研究热点。其中,血管新生抑制剂阿帕替尼是我国自主研制的1.1类新药。临床前研究和临床试验研究表明,阿帕替尼对胃癌、肺癌、乳腺癌等多种肿瘤均具有显著的抑制活性,其安全性和有效性良好。然而,阿帕替尼的相关研究显示,目前仍存在作用机制不十分明确等问题。因此,开展进一步研究以不断提高药物的安全性、有效性和经济性,是阿帕替尼广泛应用于临床的前提。总结阿帕替尼在国内外研究现状,从作用机制、药动学过程、临床疗效、安全性和生物标志物等角度进行归纳,探讨了近年来阿帕替尼研究的热点与争议问题,实现对阿帕替尼的临床应用前景展望。     

伊马替尼耐药胃肠间质瘤治疗药物的研究进展

胃肠间质瘤是胃肠道发生频率最高的间质来源的恶性肿瘤,彻底手术切除是其获得根治的唯一方法,但术后复发和转移的频率较高。伊马替尼在2002年被美国食品药品管理局(FDA)批准用于胃肠间质瘤的治疗,但治疗失败的病例依然不可避免。原发耐药和继发耐药是伊马替尼治疗胃肠间质瘤失败的主要耐药机制。相关指南推荐已获批准的用于伊马替尼治疗失败后的酪氨酸激酶抑制剂舒尼替尼和瑞戈非尼作为二、三线药物治疗,同时ATP类似物索拉非尼、尼洛替尼、帕唑帕尼、帕纳替尼和马赛替尼,其他TKI药物,如达沙替尼、瓦塔拉尼、莫特塞尼,以及其他靶向治疗药物依维莫司和ganetespib在临床试验中显示出对伊马替尼耐药胃肠间质瘤有效。综述伊马替尼治疗失败后用于临床治疗胃肠间质瘤的治疗药物的作用机制、临床应用、作用特点和主要副作用,为临床胃肠间质瘤的治疗药物选择提供参考。     

临床药师对1例服用分子靶向药物吉非替尼的肿瘤患者的药学监护

目的通过临床药师对患者的药学监护,保障肿瘤患者使用药物的安全有效。方法临床药师通过熟练掌握新药吉非替尼的药理作用、不良反应以及防范措施,对1例服用吉非替尼的患者进行药学监护。结果临床药师在吉非替尼所致的胃肠道不良反应的处理及药物选择;对皮肤毒性反应的治疗方法;肝脏毒性的监测及防范中,与临床医生共同制定方案,使患者最终顺利完成治疗。结论临床药师通过对患者的药学监护,可以协助临床避免不良事件的发生,使患者用药更加安全,有效和合理。     

骨髓纤维化新药卢索替尼药理及临床评价

骨髓纤维化（MF）是临床常见的复杂难治性疾病,Incyte公司研发的新药卢索替尼（Ruxolitinib）是首个获得美国FDA批准的口服治疗MF的药物。本文对其作用机制,药动学和药代学特性,临床药效学评价及药物不良反应等方面进行了综述。卢索替尼对重症MF患者具有重要的临床治疗作用,其批准上市将为骨髓纤维化的治疗带来希望。     

Janus激酶抑制药巴瑞替尼和乌帕替尼的药理机制及临床应用研究

巴瑞替尼和乌帕替尼是一类用于治疗免疫介导性疾病的小分子靶向药，通过阻断Janus激酶(JAK)通路的信号传导发挥作用，被称为JAK抑制药。随着药物研究的不断深入，巴瑞替尼和乌帕替尼在临床的应用也越来越广泛，今年第一季度2种药物在中国均又获批了新的适应证。这2种药物在作用机制及临床应用上有同有异，而针对其进行系统性比较的报道较少。鉴于此，本文对这2种药物从化学结构、药代动力学特征、药理作用机制、国内外正在申报或已获批的临床适应证等几个方面进行了梳理和比较，以供临床参考，并使患者获益更多。     

Recent advances in treatment strategies for atopic dermatitis

A wide range of different therapeutic regimens are used for atopic dermatitis. Although many treatment modalities are well established worldwide among clinicians, only the minority of these therapy recommendations are based on results of randomised controlled trials (RCTs). To close the gap between such 'generally' recommended therapies and therapies that are based on data from controlled trials, this review focuses not only on the pharmacological and clinical aspects of the currently proven agents, but also on the advantages and disadvantages of therapies that have not yet been completely tested.A review of the available literature concerning the pharmacological profile and also the level of evidence of therapeutic efficacy of all currently known topical and systemic agents for the treatment of atopic dermatitis reveals a large gap between the knowledge concerning the pharmacological action in vitro and the evidence of clinical efficacy in many cases.We agree with the conclusion of previous reviews that numerous therapies for atopic dermatitis urgently require more independent RCTs and especially comparative trials (e.g. corticosteroids vs calcineurin inhibitors). These are required in order to facilitate the choice of therapeutic strategy for the individual treatment of atopic dermatitis, with its broad spectrum of clinical manifestations and potential complications in adult patients and, particularly, in children.Finally, we also review preclinical trials with several new drugs. Immunomodulators appear to promise a new dimension for the future of therapy for atopic dermatitis, especially for severe and otherwise refractory forms or as alternatives to corticosteroids, that is, to treat facial atopic eczema without the risk of adverse effects.     

靶向药物治疗儿童中重度特应性皮炎的临床研究进展

特应性皮炎(atopic dermatitis,AD)是一种以湿疹和皮肤瘙痒为特征的慢性皮肤病,是儿童最常见的皮肤病之一。AD的治疗目前以药物治疗为主,但儿童患者尤其是中重度AD患者的治疗需求尚未被完全满足,安全、有效的长期治疗方案仍待探索实践。以生物制剂和小分子抑制剂为代表的靶向药物是治疗中重度特应性皮炎的新兴药物,本文检索近年来国内外相关文献,分别从生物制剂和小分子抑制剂两方面进行综述,为儿童中重度特应性皮炎靶向药物的进一步开发与应用提供参考。     

Neuroimmunological Mechanism of Pruritus in Atopic Dermatitis Focused on the Role of Serotonin

Although pruritus is the critical symptom of atopic dermatitis that profoundly affect the patients’ quality of life, controlling and management of prurirtus still remains as unmet needs mainly due to the distinctive multifactorial pathogenesis of pruritus in atopic dermatitis. Based on the distinct feature of atopic dermatitis that psychological state of patients substantially influence on the intensity of pruritus, various psychotropic drugs have been used in clinic to relieve pruritus of atopic dermatitis patients. Only several psychotropic drugs were reported to show real antipruritic effects in atopic dermatitis patients including naltrexone, doxepin, trimipramine, bupropion, tandospirone, paroxetine and fluvoxamine. However, the precise mechanisms of antipruritic effect of these psychotropic drugs are still unclear. In human skin, serotonin receptors and serotonin transporter protein are expressed on skin cells such as keratinocytes, melanocytes, dermal fibroblasts, mast cells, T cells, natural killer cells, langerhans cells, and sensory nerve endings. It is noteworthy that serotonergic drugs, as well as serotonin itself, showed immune-modulating effect. Fenfluramine, fluoxetine and 2, 5-dimethoxy-4-iodoamphetamine significantly decreased lymphocyte proliferation. It is still questionable whether these serotonergic drugs exert the immunosuppressive effects via serotonin receptor or serotonin transporter. All these clinical and experimental reports suggest the possibility that antipruritic effects of selective serotonin reuptake inhibitors in atopic dermatitis patients might be at least partly due to their suppressive effect on T cells. Further studies should be conducted to elucidate the precise mechanism of neuroimmunological interaction in pruritus of atopic dermatitis.     

New methods of prevention and treatment of allergic diseases

Over the past decades, the increasing number of patients with allergic conditions has posed a heavy burden on health care systems worldwide. This article will review recent treatments and patented methods for preventing allergies and related inflammatory and immunologic diseases. New drugs are commonly directed to known mechanisms, but there are many other pathways on which drugs can exert their action. New drug development is expected in the future as a consequence of discoveries in the pathophysiology and mechanisms of these diseases. Pharmaceuticals which would prevent the development of atopic diseases could allow us treating patients with genetic or environmental risk factors according to their conditions. Currently, a good and effective set of treatments is available for these diseases. However, the search for new treatment modalities to improve the currently available is especially important for those patients unresponsive to current therapy. In this review, we summarize anti-cytokines therapies, Toll-like receptor (TLR)-mediated treatments, antiimmunoglobulin molecules, new immunomodulatory treatments and new antihistamines. The use of probiotics remains a matter of discussion and debate, since available studies have had contradictory results. In the present article, we discuss current treatments for atopic diseases such as extrinsic asthma, atopic dermatitis and allergic rhinitis and relevant patents.     

他克莫司在皮肤病治疗中的应用研究进展

选择近几年国内外运用他克莫司治疗银屑病、白癜风、特异性皮炎、脂溢性皮炎、糜烂型口腔扁平苔藓及红斑狼疮等疾病的文献进行整理、分析,为临床应用研究提供参考.     

他克莫司药理作用及临床疗效的研究进展

目的:总结他克莫司的药理作用和临床疗效,以期为临床合理使用提供参考。方法:查阅近期国内外相关文献,对他克莫司重要药理作用及疗效、药物相互作用、不良反应进行归纳、总结。结果:他克莫司具有免疫抑制、促神经再生作用,能有效治疗特应性皮炎、类风湿性关节炎、重症肌无力等疾病,与许多药物存在相互作用,可引起神经毒性、心肌增厚、牙龈增生等不良反应。结论:他克莫司临床应用广泛,明确其药理作用及疗效、药物相互作用、不良反应,为临床安全、合理使用提供参考。     

Editorial update on emerging treatments of atopic dermatitis

Various new agents are in the research pipeline for atopic dermatitis. These include IL-4 receptor antagonist, cis-urocanic acid, κ-opiod receptor agonist, neurokinin receptor antagonist and antimicrobial peptide. The current review updates the status of these clinical trials and provides insight into other potential molecular targets including IL-22 and TLR-2.     

Editorial update on emerging treatments of atopic dermatitis

Various new agents are in the research pipeline for atopic dermatitis. These include IL-4 receptor antagonist, cis-urocanic acid, κ-opiod receptor agonist, neurokinin receptor antagonist and antimicrobial peptide. The current review updates the status of these clinical trials and provides insight into other potential molecular targets including IL-22 and TLR-2.     

布比卡因/美洛昔康复方缓释溶液的研究进展

Zynrelef(HTX-011,布比卡因/美洛昔康)缓释溶液是一种新型、非阿片类、缓释双重作用局部麻醉药,应用于手术切口部位周围组织后,可以发挥72 h以上持续稳定的镇痛作用,为患者术后疼痛提供了新的用药选择。该文通过查阅国内外相关文献,对Zynrelef缓释溶液的作用机制、药代动力学特征、临床研究、安全性、特殊人群用药进行综述,以期为该药的临床使用及未来的探索研究提供参考。