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125-5-第五节 霉酚酸醋的不良反应及处理
MMF主要通过阻断嗓吟核昔酸的经典合成途径,高度选择性地抑制T和B淋巴细胞的增殖,而对尚存在补救途径的正常体细胞影响较小,因此,MMF相对于其他免疫抑制剂而言具有较少的副作用。其主要的不良反应有:胃肠道反应,包括腹泻、便秘、恶心、呕吐、消化不良;骨髓抑制,特别是白细胞减少;合并某些感染等。其中胃肠道反应多为自限性,停药可恢复,并与剂量有关。同年轻人相比,老年人不良反应的危险性增加。近期有两篇关于MMF所致的严重肺部反应如肺炎和肺纤维化的报道。 8 F, Y$ e6 r& @! p8 P$ |
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较完整的MMF口服耐受性的数据主要来自大样本的器官移植后首次服药、随机、双盲、多中心的试验。与安慰剂组对照,MMF 2g/d的胃肠道毒性的发生率是45.5%,常见胃肠道副作用包括腹泻(大剂量时)、恶心、呕吐和胃肠炎。大规模研究已经筛除了患有活动性消化溃疡和其他严重胃肠道疾病的患者,但是应用MMF的患者中仍有一小部分出现了消化道溃疡、出血或穿孔(<1%--5%),因此MMF应慎用于有活动性严重消化系统疾病的病人。持续J性腹痛提示可能胃肠道巨细胞病毒感染。白细胞减少在MMF2g/d组发生率为19%,相对照的硫哇嚷吟组为30%。因此应定期监测血象,WBC < 3.0 x 109/L时MMF应减半量,待WBC计数恢复后MMF剂量可考虑回到原量;如WBC<2.0 x 109 /L则应停药。个别出现贫血,减量后可恢复,但较快出现的严重贫血(如2周内下降2g/dl)则应停药。如血小板下降至60 x 1护/L以下,也应及时停药。目前所有的免疫抑制治疗都会使病人更易于感染,感染的危险性随免疫抑制负荷而增加,而且在风湿病治疗中又常合并使用糖皮质激素,使患者更易于发生感染。在免疫抑制治疗方案中包含MMF时报道的感染有疙疹病毒、巨细胞病毒感染、结核、细菌性肺炎、尿路感染等,严重威胁生命的感染,如脑膜炎、感染性心内膜炎和脓毒血症亦偶有报道。有趣的是一些研究显示,MMF能增强阿昔洛韦和H2G的抗肝炎病毒活性。国内在应用MMF治疗风湿性疾病时,所使用的剂量为1.0-2.Og/d,而且多在1.0-1.5g/d,可能是所报道的副作用发生率较器官移植患者为低的主要原因。MMF在动物实验中具有致畸作用,因此应避免用于孕妇。研究人员推荐,使用MMF期间以及之后至少6周内,应采用有效的避孕措施。由于很多药物可从乳汁中分泌,且此药对哺乳婴儿有不良作用,应根据 MMF对乳母的重要性,决定中止哺乳或停药。服用 MMF的病人患淋巴增殖性疾病、淋巴瘤和皮肤癌的发生率大约为 1%0MMF比较其他免疫抑制剂最突出的耐受性是它很少有肝毒性和肾毒性,但对于严重慢性肾功能损害的病人,应避免使用大于lg一日2次的剂量,并应密切观察。
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