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。     

卵巢癌的治疗药物研究进展

卵巢癌是女性生殖器官常见的恶性肿瘤之一,其死亡率居妇科恶性肿瘤首位,且发病率逐年增加。全球新批准并上市的治疗卵巢癌的药物有贝伐单抗、曲贝替定、人参皂苷以及一些新制剂,处于研发后期的抗卵巢癌药物有奥拉帕尼、西地尼布、nintedanib、trebananib以及一些抗卵巢癌药的新剂型品种等。对近年来上市和处于研发后期的卵巢癌的治疗药物进行了详细介绍,同时对抗卵巢癌药的未来发展方向进行了展望,以期为抗卵巢癌药物的研发提供参考。     

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。     

非小细胞肺癌EGFR-T790M突变药物的研究进展

原发性肺癌(简称肺癌)是常见的恶性肿瘤之一,发生率居恶性肿瘤首位。非小细胞肺癌(NSCLC)约占所有肺癌的80%。近年来,表皮生长因子受体–酪氨酸激酶抑制(EGFR-TKI)在NSCLC治疗中起到重要作用;随着EGFR-TKI在临床上的广泛应用,耐药问题日益加剧;T790M基因突变是导致EGFR-TKI获得性耐药最主要的机制。全球新批准并上市的治疗NSCLC EGFR-T790M突变的药物有brigatinib、奥莫替尼、atezolizumab等;处于上市申请阶段的有丁磺氨酸、阿拉莫林盐酸盐、ABP-215;处于研发阶段的主要有naquotinib、TG-4010等。对近年来处于研发后期的NSCLC治疗药物进行详细介绍,同时对抗NSCLC药物的未来发展方向进行了展望,以期为抗NSCLC药物的研发提供参考。     

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。     

EGFR-TKIs治疗非小细胞肺癌进展

目前,肺癌依然是导致人类恶性肿瘤死亡的首位疾病。在过去10年中,EGFR-TKI药物的出现,显著改善了患者的生存,从而改变了肺癌的标准治疗模式。作为一线、二线或其他治疗,EGFR-TKI药物,包括吉非替尼和厄洛替尼,在特定人群中(腺癌、女性、非吸烟、亚裔患者)疗效显著。除上述两种药物,由浙江贝达药业有限公司研发的EGFR-TKIs埃克替尼也已经完成了其III期临床试验(ICOGEN),并取得可喜的结果。本文将对以上3种EGFR-TKI药物治疗非小细胞肺癌进展进行综述。     

ALK阳性非小细胞肺癌靶向治疗药物研究进展

非小细胞肺癌(NSCLC)是严重危害人类生命的疾病之一,其中ALK阳性患者占3%~5%。近年来,众多小分子ALK抑制剂被开发出来,用于ALK阳性NSCLC的治疗。与传统化疗药物相比,第1代ALK抑制剂克唑替尼对ALK阳性NSCLC患者效果显著,已经成为ALK阳性NSCLC治疗的一线用药,但是耐药性的出现限制了其临床应用。新一代ALK抑制剂色瑞替尼和艾乐替尼也相继被FDA批准上市。更多安全性更佳、选择性更高或活性更好的新型ALK抑制剂正在开发中,这些药物有望克服克唑替尼和其他已上市药物的耐药性,从而给ALK阳性NSCLC患者带来更多的选择。     

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。     

治疗转移性结直肠癌新药:呋喹替尼

呋喹替尼是我国自主研发的新型抗肿瘤药物,于2018年9月经国家药品监督管理局批准上市,用于转移性结直肠癌的治疗。呋喹替尼是一种强效、高选择性血管内皮生长因子受体(VEGFR)抑制剂,与瑞戈非尼相比,呋喹替尼对VEGFR的选择性更高,对转移性结直肠癌的效果更明确。呋喹替尼常见不良反应为手足综合征、高血压、声音嘶哑、蛋白尿和天冬氨酸转氨酶升高等。     

BRAF突变型黑色素瘤的耐药性机制及治疗最新研究进展 #br#

黑色素瘤是发病率和病死率极高的皮肤原发恶性肿瘤,其中50%携带原癌基因鼠类肉瘤滤过性毒菌致癌 同源体B1（BRAF）突变。BRAF抑制剂和丝裂原活化的细胞外信号调节激酶（MEK）抑制剂联用是BRAF突变型黑色 素瘤的主要治疗方法,但已出现一定耐药性和药物不良反应。目前认为BRAF突变型黑色素瘤耐药性包括原发性耐 药、适应性耐药和继发性耐药,相应分子机制存在一定联系和区别。同时,为了减少BRAF突变型黑色素瘤耐药性发 生,已开展新靶点抑制剂、免疫疗法和表观遗传学方面的基础及临床应用方面的研究,并取得了一定进展。就BRAF 突变型黑色素瘤发生耐药性的可能机制、治疗方案优化的现状及前景进行总结。     

治疗黑色素瘤的DC疫苗研究新进展

黑色素瘤是最具侵袭性的皮肤恶性肿瘤,易发生早期转移和治疗后复发。治疗性肿瘤疫苗是新兴的免疫疗法,具有毒性低以及可抑制肿瘤转移的特点。目前已有多个针对黑色素瘤治疗性疫苗的研究,其中黑色素瘤治疗性树突状细胞（DC）疫苗引起了广泛关注。虽然肿瘤治疗性DC疫苗在黑色素瘤中的疗效已被多项研究证实,但该类疫苗存在免疫效应不足、单独使用疗效不佳等问题,仍具有较大的改进空间。本文对黑色素瘤的治疗性DC疫苗的研究现状进行了综述,并对肿瘤治疗性DC肿瘤的研究重点及优化策略进行展望。     

Morin inhibits proliferation and self-renewal of CD133+ melanoma cells by upregulating miR-216a

Melanoma is one of the most malignant skin tumors with high mortality rate. Morin has been reported to treat several cancers. However, whether or how Morin affects melanoma progression is still poorly understood. Either Morin treatment or miR-216a overexpression reduced cell viability, sphere formation ability and expressions of stem cell marker genes CD20, CD44, CD133 and Wnt-3A. MiR-216a was induced by Morin treatment in CD133⁺ melanoma cells. Melanoma xenograft model treated by Morin showed reduced tumor size, weight as well as expressions of stemness markers and Wnt-3A. Inhibition of the stemness marker gene expressions in CD133⁺ melanoma cells is mediated by downregulating Wnt-3A through miR-216a. MiR-216a and Wnt-3A may potentially serve as clinical biomarkers of melanoma, and Morin may contribute to the treatment of melanoma.     

Epigenetic lesions in malignant melanoma

Malignant melanoma arises through a series of genetic and epigenetic events. A more profound understanding of the biology of metastatic melanoma should greatly aid in the development of new and effective treatments. Currently, avenues being pursued to improve treatment of metastatic melanoma include dendritic cell vaccines and other vaccination strategies, tyrosine kinase inhibitors, adoptive transfer of ex vivo stimulated T cells, and, as reviewed here, epigenetic approaches. The "methylator phenotype", with inactivation by promoter hypermethylation of numerous genes in malignant melanoma cell lines and primary tumors (p16, PTEN, RASSF1, estrogen receptor, retinoic acid receptor beta, SOCS1 and -2, MGMT etc.) offers a strong rationale for treatment approaches based on the use of DNA demethylating agents. The clinical literature on treatment of metastasized malignant melanoma with either 5-azacytidine or 5-aza-2'-deoxycytidine (decitabine) is reviewed. Future trials in malignant melanoma with these compounds might profit from prolonged low-dose exposure, since they unfold their full effects not immediately but with a certain delay, which may be associated with their DNA demethylating activity. Combinations of DNA demethylation agents with either histone deacetylase inhibitors, interleukin-2, chemotherapy or tamoxifen have been embarked on both in in vitro models of melanoma and recent clinical trials. The in vitro synergism between inhibitors of DNA methylation and histone deacetylation strongly invites a systematic study of combinations of both groups of agents. Up-regulation of cancer testis antigens by epigenetic therapy in melanoma also offers a very strong rationale to place these drugs and schedules within a larger treatment concept of immunotherapy which may include also T cell activation e.g. by interleukin-2, and vaccination strategies. In conclusion, the epigenome of malignant melanoma, with a well-established in vitro reversal potential, holds promise as a novel molecular target.     

Angiogenesis and metastasis inhibitors for the treatment of malignant melanoma

Malignant melanoma is one of the most highly invasive and metastatic tumors. Melanoma is an increasingly common malignancy as well, and its mortality rates have been rapidly increasing above those of any other cancer in recent years. Surgical resection and systemic chemotherapy are the main therapeutic strategies for the treatment of malignant melanoma. However, these approaches are insufficiently effective and may be associated with significant adverse effects. Angiogenesis, a process by which new vascular networks are formed from pre-existing capillaries, is required for tumors to grow, invade and metastasize. Tumor vessels are genetically stable, and less likely to accumulate mutations that allow them to develop drug resistance in a rapid manner. Therefore, targeting vasculatures that support tumor growth, rather than cancer cells, is considered the most promising approach to malignant melanoma therapy. Now, novel anti-angiogenic agents with tolerable side effects is actually desired for the treatment of patients with malignant melanoma. In this paper, we review the current understanding of anti-angiogenic therapy for malignant melanoma, especially focusing on pigment epithelium-derived factor (PEDF), which was recently identified as the most potent endogenous inhibitor of angiogenesis in the mammalian eye. We also discuss here the involvement of a receptor for advanced glycation end products (RAGE) in angiogenesis, melanoma growth and metastasis, and the therapeutic implications of the blockers of RAGE in this devastating disorder.     

干扰素α治疗黑素瘤

黑素瘤是一种难治性恶性肿瘤,近年来其发病率有增高趋势,增高速度超过其他肿瘤.临床研究显示,干扰素α(IFNα)作为高危黑素瘤手术切除后的辅助治疗药物能有效延长患者无复发生存时间,但是大剂量IFNα治疗可引起明显不良反应.此文介绍了IFNα辅助治疗黑素瘤患者的临床试验,并讨论了减轻IFNα不良反应的药物和方法,诸如聚乙二醇IFNα和联合治疗等.

Abstract：

Melanoma is one of the most treatment-refractory malignancies, and the incidence of melanoma is increasing faster than any other cancer. Clinical studies have shown that interferon α (IFNα)adjuvant treatment of high-risk resected melanoma can effectively improve relapse-free survival, but high-dose IFNα can induce significant adverse reactions. In this article, the clinical trials of IFNα adjuvant treatment for patients with melanoma are reviewed and the drugs and strategies for reducing adverse reactions of IFNα, such as PEG-IFNα and combination therapy, are discussed.     

Perspectives in melanoma treatment with signal transduction

Data from all parts of the world show a rising incidence of cutaneous malignant melanoma. The latter is one of the most difficult malignancies to treat. Early stage melanoma is curable but once metastatic it is almost uniformly fatal. Systemic therapy for advanced melanoma includes chemotherapy, either with dacarbazine alone or a multiagent combination chemotherapy, and biological therapy with recombinant interferon-alpha and/or interleukine-2. However none of these treatments options has produced long-term control of the disease except on rare occasion. In the present review, new strategies in the treatment of malignant melanoma that are now under investigations are discussed. Such new strategies might could be open new perspectives avoiding the toxicity of the conventional treatments too. In particular, possible agents acting on signal transduction pathways, such as Protein Kinase C modulators, and on the cell cycle are reviewed. Melanoma is the most immunogenic tumor among all tumor neoplasia. The feature has led to test several immunological strategies for manipulating immune responses in order to induce tumor growth control in vivo. Thus, the most interesting and recent strategies in this field and in particular the possibility to use specific vaccines are also considered.     

Non-steroidal Anti-Inflammatory Drugs and Melanoma

Inflammation is an important contributor to the development and progression of all human cancers. Inflammatory lipid metabolites, prostaglandins, formed from arachidonic acid by prostaglandin H synthases commonly called cyclooxygenases (COXs), bind to specific receptors that activate signaling pathways driving to the development and progression of tumors. Inhibitors of prostaglandin formation, COX inhibitors, including non-steroidal anti-inflammatory drugs (NSAIDs), are well documented agents that inhibit tumor growth and prevent tumor development specially due to long-term use. NSAIDs also alter gene expression independently of COX inhibition which also appear to contribute to the anti-tumorigenic activity of these drugs. In a dermatologic point of view, most investigations are oriented to improve the current knowledge related to the pathogenesis of malignant melanoma, a prevalent skin cancer characterized by a rapid progression with frequent metastases and a poor response to the different available treatments. In the present issue we review the role of inflammation in cutaneous malignant melanoma and its impact on cancer pathogenesis. This topic represents an exciting new area of research, and could potentially result in new targets for melanoma therapy in the future.     

An Overview of the Changing Landscape of Treatment for Advanced Melanoma

Melanoma—the deadliest form of skin cancer—leads to thousands of deaths each year. Although melanoma is less common than basal cell and squamous cell skin cancers, melanoma is more dangerous because it is more likely to spread to other parts of the body, such as lymph nodes, if not diagnosed and treated early. Data from the National Cancer Institute indicate a steady rise in new cases of melanoma and, unfortunately, a steady rate in the number of deaths through 2013. Ninety percent of melanomas are linked to inadequate sun protection from ultraviolet rays or the tanning habits of young adults. Over the past 5 years, however, there have been a variety of new pharmacologic treatments for advanced melanoma including immunotherapy, targeted agents (BRAF and MEK inhibitors), and oncolytic viral therapy. In this article, we review the current literature on the treatment of melanoma, with a focus on emerging therapies.