通用名：地西他滨 商品名：Dacogen 英文名称：Decitabine 化学名称：4-氨基-1-(2-脱氧-β-D-赤式-顺-呋喃核糖)-1，3，5-三嗪-2(氢)-1。 规格：地西他滨注射液单次剂量20mL，其中包括50mg地西他滨，68mg磷酸二氢钾，11.6mg氢氧化钠。 用法用量： 第一治疗周期的推荐剂量为静脉注射地西他滨15mg/m2 3小时，间隔8小时重复一次，连续三天。患者须提前服用止吐剂。此疗程每六周重复一次。患者最少应经过四个疗程，直到病情得到控制与好转。第一和第二治疗周期中，骨髓抑制和中性粒细胞减少症较常见。较严重的中性粒细胞减少症发生率为87%，血小板减少症为85%，热性的中性粒细胞减少症为23%，白细胞减少为22%。骨髓抑制是减少剂量或中断治疗的主要原因。在整个治疗的过程中须密切关注血小板数量，随时调整剂量或暂停治疗。 适应症： 骨髓异常综合征(MDS), 包括所有符合法－美－英分类各型且国际预后评分系统为中－1、中－2和高风险组的已经治疗、未经治疗、复发性和继发性脊髓发育不良综合症的患者。 剂型：冻干 规格：50mg 特点: 地西他滨(decitabine)：5-氮杂-2′-脱氧胞苷酸，一种天然2′-脱氧胞苷酸的腺苷类似物，通过抑制DNA甲基转移酶，减少DNA的甲基化，从而抑制肿瘤细胞增殖以及防止耐药的发生。 地西他滨是一种去甲基化药物，具有独特的甲基化转移酶抑制剂的治疗机制。2004年3月，SuperGen公司完成了地西他滨治疗MDS患者的一期临床试验。MGI制药和SuperGen公司宣布地西他滨是一类低甲基化试剂。2006年，美国FDA批准了地西他滨(decitabine)注射液的上市申请，商品名为Dacogen，获批用于治疗骨髓异常综合征(MDS)。MGI制药与SuperGen公司达成协议，拥有该产品在全世界的独占开发、生产和经销权。两公司目前正计划将该药运用到更多的血液肿瘤疾病中，包括所有法、美、英型(FAB型)的已接受治疗和未接受治疗的，新发病的和继发性的MDS患者，以及按IPSS系统分为高危险、中度2级危险、中度1级危险的MDS患者。 药理学研究 因为去甲基化药物可活化肿瘤细胞抑癌基因，增强分化基因等调控基因的表达，所以可达到治疗MDS的目的。地西他滨被磷酸化后，发挥其抗肿瘤作用。它直接作用于DNA，抑制DNA甲基转移酶，从而使DNA低甲基化，细胞分化死亡。地西他滨在体外抑制DNA甲基化，却不影响DNA的合成。它可导致肿瘤细胞去甲基化，可以恢复基因的正常功能，这对于控制细胞的分化和增殖是非常重要的。但非增殖性细胞对地西他滨不敏感。 杨力等以MDS-RAEB细胞株SKM-1为研究对象，了解地西他滨促进SKM-1株分化和诱导凋亡作用以及可能机制。 研究表明，3.2 mmol/L地西他滨可使异常甲基化的Pl5INK4B恢复正常的去甲基化，表达增强，从而抑制SKM-l细胞增殖，促进分化，可能是其治疗MDS的主要机制。 Bahar等最近报道，应用地西他滨可重新激活肿瘤细胞中DNA损伤诱导生长抑制基因(GADD45beta)的表达。Alleman等报道，地西他滨可使移植肾肿瘤细胞老鼠身上的肿瘤明显变小。Miotto等则报道，地西他滨可使CDH4肿瘤抑制基因在肠癌和胃癌细胞中重新表达。KAWAKAMI等研究则表明，地西他滨可使膀胱癌DNA修复基因（hMSH3)恢复表达，从而影响膀胱癌的生长。 Romaih.KI等在免疫缺陷大鼠的肾下被膜进行U2OS异种嫁接，进而研究地西他滨在体内对肿瘤生长和分化的影响。通过免疫组织化学方法，采用5-甲基胞苷抗体能检测到异种嫁接大鼠细胞核的甲基化水平降低了。地西他滨能显著地减小肿瘤异种嫁接的尺寸（P <0.05）。 临床药理和药物代谢动力学 SuperGen公司对17O例确诊的成年MDS患者进行了标记开放性多中心随机对照临床研究。试验组89例患者随机接受地西他滨治疗加支持性医护治疗，对照组81例患者随机仅接受支持医疗。试验组患者每8小时接受本品治疗，剂量为15 mg/m2静脉滴注3小时，连续用药3天。每6周使用地西他滨治疗1次。支持疗法包括输血或血液制品、预防性使用抗菌药物及生长因子。治疗288天后，本品治疗组平均总有效率为17%，支持疗法组为0(P <0.001)。本品组完全应答率为9%，部分应答率为8%。病理学确诊的MDS患者，以地西他滨至少治疗2个疗程，总有效率为21%。此外，本品组13%的患者血液学得到改善，支持疗法组改善率仅为7%。 Wijermans等用地西他滨治疗具有高危MDS的老年病人，每6周1个疗程，每疗程持续3天，剂量为15 mg/m2，每疗程总剂量在120～150 mg/m2之间。结果在121例中，49%对治疗有良好反应，其中20%完全好转，10%部分好转，19%血液学指标有改善。 Issa等采用地西他滨15 mg/m2/天，静脉滴注>1h，每周5天，连续两周治疗50例（其中，AMI/MDS 44例，CML 5例，ALL 1例），有效率为65%。而Kantarjian等认为地西他滨最佳剂量为20 mg/m2/天，静脉滴注>1h连续5天，且定期重复治疗，疗效更好。由于MDS的表现异质性，对IPSS系统中度-2和高危病人至少应接受4个疗程，部分可达6个疗程或更多，为了最大限度地增加低甲基化药物的疗效，应尽可能长期治疗。 目前，暂时无注射地西他滨15 mg/m2的药物代谢动力学有效数据。实体瘤患者注射地西他滨20～30 mg/m2/天，治疗72小时后，其药代动力学数据呈二相性分布特征。总体清除率为（124±19 ）L/m2/时,终相消除半衰期为（0.51±0.31）小时。地西他滨的血浆蛋白结合率可忽略不计(<1%)。人体中的地西他滨准确代谢和消除途径机理尚未研究明确。在肝、粒细胞、肠的上皮组织中，地西他滨通过胞二磷胆碱的脱氨作用而消除，但这仅仅是一种可能的途径。 常见副反应：中性白细胞减少(症)、血小板减少(症)、贫血、疲劳、发热、咳嗽、恶心、便秘、腹泻、高血糖、热性的中性白细胞减少(症)。 地西他滨慎用于下列情况的患者：肾病、肝机能障碍、血清肌酸肝>20 mg/dl、转氨酶高于正常人两倍、血清胆红素>1.5mg/dl。孕妇及哺乳期妇女禁用。 -------------------------------------------------------- 产地国家: 美国 原产地英文药品名: DECITABINE 原产地英文化合物名称: 5-Aza-2'-deoxycytidine 中文参考商品译名: 达克金 50毫克/瓶 中文参考药品译名: 地西他滨 中文参考化合物名称: 5-氮杂胞嘧啶脱氧胞苷，5-氮杂-2’-脱氧胞苷 生产厂家中文参考译名: 卫材药业 生产厂家英文名: EISAI INC DACOGEN® (decitabine) for Injection Dacogen® (decitabine) for Injection is indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British (FAB) subtypes (refractory anemia, refractory nemia with ringed sideroblasts, refractory nemia with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia) and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System (IPSS) groups. Dacogen has two treatment dosing options: 1) Dacogen is administered at a dose of 15 mg/m2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. This cycle should be repeated every 6 weeks.  2) Dacogen is administered at a dose of 20 mg/m2 by continuous intravenous infusion over 1 hour repeated daily for 5 days. This cycle should be repeated every 4 weeks. Please see Important Safety Information below. Myelodysplastic syndromes, or MDS, are a potentially life-threatening group of bone marrow diseases that alter the production of functional blood cells. People with MDS may experience anemia, neutropenia, and/or thrombocytopenia which can lead to a variety of symptoms including fatigue, shortness of breath, infections, bruising and bleeding. In the United States, between 10,000 and 15,000 new cases of MDS are diagnosed each year. Important Safety Information Treatment with Dacogen is associated with neutropenia and thrombocytopenia. Complete blood and platelet counts should be performed as needed to monitor response and toxicity but at a minimum prior to each dosing cycle. Clinicians should consider the need for early institution of growth factors and/or antimicrobial agents for the prevention or treatment of infections in patients with MDS. Dacogen may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Dacogen and for 1 month following completion of treatment. Men should be advised not to father a child while receiving treatment with Dacogen and for 2 months following completion of treatment. In the phase 3 clinical trial, the highest incidences of Grade 3 or Grade 4 adverse events in the Dacogen arm were neutropenia (87%), thrombocytopenia (85%), febrile neutropenia 23%), and leukopenia (22%). Bone marrow suppression was the most frequent cause of dose reduction, delay, and discontinuation. Six patients had fatal events associated with their underlying disease and myelosuppression (anemia, neutropenia, and thrombocytopenia) that were considered at least possibly related to drug treatment. Of the 83 Dacogen-treated patients, 8 permanently discontinued therapy for adverse events compared to 1 of 81 patients in the supportive care arm. In the single-arm study, the highest incidence of Grade 3 or Grade 4 adverse events was neutropenia (37%), thrombocytopenia (24%), and anemia (22%). Seventy-eight percent of patients had dose delays. Hematologic toxicities and infections were the most frequent causes of dose delays and discontinuation. Eight patients had fatal events due to infection and/or bleeding that were considered at least possibly related to drug treatment. Nineteen of 99 patients permanently discontinued therapy for adverse events. Other commonly occurring reactions include fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia. If hematologic recovery from a previous Dacogen treatment cycle requires more than 6 weeks when administering the 3-day dosing, then the next Dacogen cycle should be delayed and dosing temporarily reduced. When administering the 5-day dosing, the Dacogen cycle should be delayed until there is hematologic recovery. If the following nonhematologic toxicities are present, Dacogen treatment should not be restarted until the toxicity is resolved: (1) serum creatinine ≥2 mg/dL; (2) SGPT, total bilirubin ≥2 × ULN; and (3) active or uncontrolled infection. Because there are no data on use of Dacogen in patients with renal or hepatic dysfunction, Dacogen should be used with caution in these patients.