Ceplene-急性髓性白血病治疗药 欧盟批准EpiCept公司的二盐酸组胺注射剂（histamine dihydrochloride，Ceplene）上市，用于持续缓解和防止急性髓细胞样白血病（AML）成人患者首次缓解治疗后的复发。本品应与小剂量白介素-2联合用药。本品已获准在欧盟27个成员国以及冰岛、列支敦士登和挪威上市。 　　 二盐酸组胺注射剂获准上市是基于其与白介素-2联合用药对320例患者关键的Ⅲ期临床研究结果：完全缓解显著降低了AML患者的复发。接受Ceplene　/　白介素-2联合用药治疗的患者长期无白血病的比例大于50％。而且，患者对本品耐受性好。 　 　 二盐酸组胺注射剂是EpiCept公司获准治疗AML的专利药品，用于防护淋巴细胞免受残留的白血病细胞免疫调节时的破坏。研究表明，本品减少自吞噬细胞产生的氧基、抑制烟酰胺腺嘌呤二核苷磷酸（NADPH）氧化酶和防止白介素-2激活NK细胞和T细胞。 【化学名】1H-Imidazole-4-ethanamine,dihydrochloride 【作用机理】氧自由基抑制剂，恶性肿瘤及丙肝治疗药物 【ATC分类】全身用抗病毒药（J05）/其他类抗肿瘤药（L01X）/其他类细胞因子和免疫调节剂（L03A-X） 【开发公司】Maxim制药公司 【开发阶段】 报批（美国和欧洲，适应症为恶性黑色素瘤）；Ⅲ期临床试验（适应症为恶性黑色素瘤、急性髓细胞白血病、多发性骨髓瘤和肾癌）；Ⅱ期临床试验（适应症为丙肝）；临床前研究（适应症为前列腺癌） 【给药方式】皮下注射 【简介】 Maxim制药公司开发了组胺二盐酸盐，这种化合物可以特异性地阻断可以诱导自然杀伤细胞凋亡的吞噬细胞信号。该化合物的商品名为Ceplene。该化合物可以抑制氧自由基的产生和释放，并以次增强T细胞和自然杀伤细胞激活的细胞因子的活性。氧自由基可以抑制T细胞和自然杀伤细胞的抗病毒和抗肿瘤的功能。Ceplene和干扰素或细胞因子联合使用可以治疗多种恶性肿瘤和丙肝，这种联合治疗方式已经被命名为Ceplene治疗。Ceplene治疗的适应症包括多种肿瘤，其中针对恶性黑色素瘤、急性髓细胞白血病、多发性骨髓瘤、肾癌均已不同国家进入了III期临床试验。美国FDA已经授予该药治疗急性髓细胞白血病和恶性黑色素瘤的罕见药资格。针对丙肝的Ⅱ期临床试验也在进行之中。目前已经完成或正在进行的临床试验包括：3项针对进展期恶性黑色素瘤的III期临床试验、1项针对急性髓细胞白血病的III期临床试验、多项针对丙肝的Ⅱ期临床试验、3项针对进展期肾细胞癌的Ⅱ期临床试验。2000年9月，Maxim公司向FDA提交的Ceplene新药申请获得优先审评资格。但在2000年12月FDA驳回了该项申请，主要原因是Maxim公司在关键性的针对恶性黑色素瘤的III期临床试验在病人的选择上有失误。研究结果显示Ceplene治疗组的患者生存期要显著长于对照组，但研究人员认为接受药物治疗的患者病情本来就没有对照组的患者严重。Ceplene在近两年的重要事件还包括：治疗急性髓细胞白血病的代号为MP-MA-0201的III期临床试验接近完成；2003年9月完成针对进展期恶性黑色素瘤的代号为MP-8899-0104确证性III期临床试验患者征募工作；2003年11月，公司提交Ceplene和白细胞介素-2(IL-2)联用治疗晚期恶性黑素瘤欧洲集中审批程序上市申请。 【毒理学和不良反应】 动物毒性：在临床前小鼠模型中，Ceplene可以降低白介素-2相关的血管渗漏综合征相关的小鼠死亡发生率。Ceplene在白介素-2注射前或注射后给药，可以产生剂量依赖性的对白介素-2诱导毒性的保护作用，也可以保护动物免于死亡。 【不良反应】 I期临床试验结果显示，Ceplene和干扰素-α联合使用，每日给药2次，治疗3周，患者耐受性良好，患者可以在家自己注射，没有发生意料之外的不良反应。在针对黑色素瘤和肾癌的I/II期临床试验中，面色潮红是最常见的与Ceplene相关的不良反应。Ceplene没有增加白介素-2或干扰素-α2b的毒性。一项治疗慢性丙肝的为期24周的II期临床试验结果显示Ceplene仅能引起轻度和暂时性的不良反应，主要包括暂时性的潮红、头痛、低血压和心动过速，没有病人因为不良反应中止治疗。 【临床试验】 在主要的科学和临床研究国际会议上已经发表了超过80篇以组胺二盐酸盐为主题的论文，在杂志上也发表了300多篇和组胺二盐酸盐治疗有关的基础研究和临床研究论文的。Ceplene已经完成和正在进行的临床试验超过17项，参加的患者达到2000人，适应症包括恶性黑色素瘤、急性髓细胞白血病、丙肝、肾细胞癌等，有关Ceplene2001-2004年临床试验的新进展已经收录进我们建立的《世界在研新药数据库》，读者可自行查阅。 【最新开发动态】 Ceplene是组胺二盐酸盐的注射剂型，Maxim制药公司还在开发一种组胺二盐酸盐的口服极刑，这种药物被暂时命名为HD-O。HD-O主要针对慢性肝脏疾病，包括慢性丙肝、酒精性肝病和非酒精性脂肪肝。2003年3月23日，Maxim公司宣布已经完成HD-O一项Ⅰa期临床试验，这也是该口服剂型的第一项临床试验。该试验有23名健康志愿者参加，主要考察HD-O的药代动力学并探索药物的剂量安全范围。 Ceplene® Ceplene®, generically named histamine dihydrochloride, is our proprietary product approved for the remission maintenance and prevention of relapse in adult patients with AML in first remission. Ceplene® is to be administered in conjunction with low-dose IL-2. Ceplene® is designed to protect lymphocytes responsible for immune-mediated destruction of residual leukemic cells. Ceplene® reduces the formation of oxygen radicals from phagocytes, inhibiting nicotinamide adenine dinucleotide phosphate-oxidase, or NADPH oxidase, and protecting IL-2-activated Natural Killer cells, or NK-cells, and Thymus cells, or T-cells. These two kinds of cells, NK-cells and T-cells, possess an ability to kill and support the killing of cancer cells and virally infected cells.   In October 2008, we received a full marketing authorization from the European Commission, or EU, for Ceplene®. The approval allows Ceplene® to be marketed in the 27 member states of the EU, as well as in Iceland, Liechtenstein and Norway. The approval by the European Commission is based, in part, on the results of the pivotal 320-patient Phase III trial for Ceplene® in conjunction with IL-2. The primary result of this trial was that treatment with Ceplene/IL-2 significantly reduced the occurrence of relapse among AML patients in complete remission. The improvement of long-term leukemia-free survival in patients receiving Ceplene/IL-2 exceeded 50%. Moreover, Ceplene® was well tolerated in this patient population and conferred an acceptable risk benefit profile for AML patients.   Ceplene was designated as an orphan medicinal product in the EU on April 11, 2005 for the treatment of AML. As a result of its designation as an Orphan Medical Product, we have been granted 10 years of market exclusivity in the EU for Ceplene®. As part of receiving marketing authorization under Exceptional Circumstances for Ceplene®, we will perform two post-approval clinical studies. One of the studies will seek to further elucidate the clinical pharmacology of Ceplene® by assessing certain biomarkers in AML patients in first remission. The other study will assess the effect of Ceplene/IL-2 on the development of minimal residual disease in the same patient population. We are considering combining these studies into a single clinical trial.   We have also advanced our efforts to gain approval for Ceplene® as a remission maintenance treatment for AML patients in North America. In December 2008, we received permission to proceed with a New Drug Submission filing for Ceplene® with Health Canada for the treatment of AML in Canada. In January 2009, we received permission to proceed with a New Drug Application Filing for Ceplene® with the U.S. FDA.   AML is the most common type of acute leukemia in adults. There are approximately 40,000 AML patients in the EU, with 16,000 new cases occurring each year. Additionally, there are approximately 12,000 new cases of AML and 9,000 deaths caused by this cancer each year in the United States. Indication：Acute Myeloid Leukemia Remission Maintenance Therapy  Target Population：EU Big 5 34,000+ patients Total EU 47,000+ patients  Description：Histamine Dihydrochloride Dosage and Administration：Ceplene: 0.5 mg, bid, sub-q + Interleukin-2 (Proleukin®): 16,400 IU/kg, bid, sub-q Treatment comprises 10 cycles 3 cycles comprised of 3 weeks of treatment, followed by 3 weeks of rest 7 cycles comprised of 3 weeks of treatment, followed by 6 weeks of rest  Adverse：Reactions Well tolerated with mild flushing, headache and fatigue Ceplene + IL-2 self-administered at home  Description Ceplene (histamine dihydrochloride), which has received marketing authorization by the European Commission, is administered in conjunction with low dose interleukin-2 (IL-2), for maintenance of first remission in patients with Acute Myeloid Leukemia (AML). AML is the most common type of leukemia in adults. There are approximately 12,000 new cases of AML and 9,000 deaths caused by this cancer each year in the U.S. There are approximately 47,000 AML patients in the EU, with 16,400 new cases occurring each year. There are currently no other effective medical-based remission therapies for AML patients. AML patients receive intensive induction treatment with chemotherapeutic drugs at diagnosis, and typically become free of detectable leukemia ("complete remission"). However, the majority of patients will experience a relapse of leukemia, usually within one to two years. The survival prognosis after a leukemic relapse is poor. Approximately 75-80 percent of patients who achieve their first complete remission will relapse, and the median time in remission before relapse is only 12 months with current treatments. Treatment with Ceplene in conjunction with low dose IL-2 is designed to prevent leukemic relapses in AML patients in remission and prolong leukemia-free survival while maintaining a good quality of life for patients during treatment. In a Phase III clinical study of 320 patients, Ceplene met its primary endpoint of increased leukemia-free survival (p <0.01) among AML patients in remission. The results of this trial were published in Blood, a leading scientific journal in hematology, (Blood; The Journal of the American Society of Hematology, volume 108, number 1, pp. 88-96, July 1, 2006). Stage of Development The European Commission has approved Ceplene for the remission maintenance and prevention of relapse in adult patients with Acute Myeloid Leukemia in first remission. Marketing rights have been licensed to Meda AB, which expects to launch the product commercially in 2010. An NDS was filed and accepted in Canada in 2009, and an NDA filing is expected in the U.S. in 2010. Ceplene has been granted orphan drug status for the treatment of AML by the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA). A Named Patient Program has been established to make Ceplene available in most countries of the world except for the U.S. Maxim公司Ceplene/IL-2用于晚期恶性黑素瘤的III期临床方案获FDA批准 Maxim Pharmaceuticals公司宣布，其候选药物Ceplene（histamine dih ydrochloride，二盐酸组胺）和白介素－2（IL－2）联用治疗晚期恶性黑素瘤的临床方案日前获FDA批准。先前的临床研究发现，Ceplene/IL-2 联用法可能会延长晚期恶性黑素瘤患者的生存期，因此FDA同意公司扩大患者受试人数，进行III期临床研究。 本品拥有FDA授予的罕见药物地位。2003年9月24日，Maxim宣布完成了本品和IL－2联用治疗晚期恶性黑素瘤肝转移患者的受试者募集工作。这项随机双盲安慰剂对照的III期临床研究纳入了230例病患，旨在比较本品和IL－2联用法与单用 IL－2 对患者生存率的影响，初步预计将在2004年晚些时候完成。2003年11月，公司已向欧盟药监当局提交了本品用于治疗晚期恶性黑素瘤的新药申请。 晚期转移性黑素瘤是一种最致命的皮肤癌。 近年来，在发达国家中的发病率日渐上升。但是目前临床上还没有一种确定的或标准的治疗方法。自然杀伤细胞 （NK细胞）和细胞毒性T细胞具有杀死和辅助杀死癌细胞与病毒感染细胞的功能。 当前，临床上采用的免疫疗法大多是基于细胞因子如IL－2、干扰素，或者那些能够刺激NK细胞和T细胞功能的蛋白类药物。 有研究表明，某些特定的免疫细胞所释放出来的氧自由基会抑制NK细胞和T细胞的活性，损伤正常组织，这个过程通常指氧化应激。氧化应激参与了许多疾病的病理过程。大多数报道是在肝脏中。本品是在天然存在的组胺分子上研制而成的小分子药物，可以减少氧化应激，防止氧自由基的生成和释放，从而保护NK细胞和T细胞，提升由细胞因子如IL－2、干扰素或其他免疫调节剂引起的这两种细胞的激活作用，使关键的细胞和组织免受伤害。 除了这项适应证之外，本品还在进行两项用于治疗丙型肝炎和晚期肾细胞癌的II期临床研究。公司还在研制组胺的口服制剂，以用于慢性肝病的治疗。 该公司为一全球性的生物技术公司，主要致力于危及生命的癌症和肝脏疾病治疗药物的研究和开发 ------------------------------------------------------------------ 原产地英文商品名: CEPLENE 0.5mg/0.5ml/vial 14vials/box 原产地英文药品名: HISTAMINE DIHYDROCHLORIDE 原产地英文化合物名称: 1H-Imidazole-4-ethanamine,dihydrochloride 中文参考商品译名: CEPLENE 0.5毫克/0.5毫升/瓶 14瓶/盒 中文参考药品译名: 二盐酸组胺 中文参考化合物名称: 二盐酸-1H-咪唑-4-乙胺 产地国家: 挪威 所属类别: 抗癌药物->治疗白血病药物 处方药:处方药 包装规格: 0.5毫克/0.5毫升/瓶 14瓶/盒 销售单价(美元 US$): 2,265 美元 销售单价(人民币 RMB): 14,949 元 计价单位: 盒