CONTROLLED TRIAL OF CHLORAMBUCIL THERAPY IN PRIMARY BILIARY CIRRHOSIS

苯丁酸氮芥治疗原发性胆汁性肝硬化的对照试验

• 批准号: 3964822
• 负责人: E A JONES
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3964822
• 关键词: adult human (21+); alkylating agents; autoimmune disorder; azathioprine; biliary tract disorder; biliary tract disorder chemotherapy; bilirubin; biopsy; blood cell count; chlorambucil; copper; corticosteroids; cyclophosphamide; drug adverse effect; histopathology; human subject; human therapy evaluation; immunoglobulin M; immunosuppressive; liver cirrhosis; longitudinal human study; orphan disease /drug; penicillamine; serology /serodiagnosis

Primary biliary cirrhosis (PBC) is a disease of unknown etiology characterized by slowly progressive intrahepatic cholestasis due to non-suppurative, presumably autoimmune, destruction of septal and the larger interlobular bile ducts. Because certain other autoimmune diseases appear to respond favorably to alkylating agents, a controlled trial of chlorambucil therapy for patients with symptomatic PBC has been conducted. Twenty-four patients were admitted to this trial: 13 were randomized to receive chlorambucil therapy (0.5-4.0 mg/day) and 11 to the control (no treatment) group. The dose of chlorambucil was adjusted to reduce the peripheral blood lymphocyte count by 50% and maintain the polymorphonuclear leukocyte count above 1000 per c.mm. All patients have been followed for 3-6 years (mean = 55 months). During follow-up, two patients died: both were controls. Mean serum bilirubin levels remained almost constant in the treated group but increased by an average of about 50% each year in the controls. Mean serum albumin values increased slightly in treated patients but decreased in controls. Mean serum transaminase and alkaline phosphatase levels changed little in treated patients, but tended to rise in controls. Mean serum immunoglobulin (IgM and IgG) levels decreased from elevated values to values within the normal range in all chlorambucil-treated patients, but did not change appreciably in controls. Liver biopsy histopathology after one, two and four years revealed less inflammation, slightly less fibrosis and less progression of the stage of disease in the treated than in the control patients. Potential side effects of chlorambucil therapy included the onset of menopause in two patients, localized herpes simplex or zoster in 3 and, in 4 patients, persistent leukopenia or thrombocytopenia requiring discontinuation of the drug. These findings strongly suggest that chlorambucil therapy retards the progression of primary biliary cirrhosis, and they provide an impetus to search for safer (e.g. noncarcinogenic) and more effective immunosuppressive regimes for treatment.

原发性胆汁性肝硬化（PBC）是一种病因不明的疾病 其特点是缓慢进行性肝内胆汁淤积 非化脓性，可能是自身免疫性的，隔膜和 小叶间胆管较大。 因为某些其他自身免疫性疾病 似乎对烷化剂有良好的反应，一项对照试验 已对有症状的 PBC 患者进行苯丁酸氮芥治疗。 24 名患者被纳入该试验：其中 13 名患者被随机分配到 接受苯丁酸氮芥治疗（0.5-4.0 毫克/天），对照组接受 11 次治疗（无 治疗）组。 调整苯丁酸氮芥剂量以减少 外周血淋巴细胞计数减少50%并维持多形核 白细胞计数每厘米超过 1000 个。 所有患者均已接受随访 3-6 年（平均 = 55 个月）。 随访期间，两名患者死亡：均为 是控制。 平均血清胆红素水平几乎保持恒定 但治疗组平均每年增加约 50% 控制。 治疗患者的平均血清白蛋白值略有增加 但控制量有所减少。 平均血清转氨酶和碱性 治疗患者的磷酸酶水平变化不大，但有上升的趋势 在控制中。 平均血清免疫球蛋白（IgM 和 IgG）水平从 所有数值均升高至正常范围内 苯丁酸氮芥治疗的患者中，但在对照组中没有明显变化。 一年、两年和四年后的肝活检组织病理学显示较少 炎症，纤维化程度稍低，并且阶段进展较少 接受治疗的患者的疾病程度高于对照患者。 潜力面 苯丁酸氮芥治疗的影响包括两名妇女开始绝经 3 名患者出现局部单纯疱疹或带状疱疹，4 名患者出现局部单纯疱疹或带状疱疹， 持续性白细胞减少或血小板减少需要停药 药品。 这些发现强烈表明苯丁酸氮芥治疗可延缓 原发性胆汁性肝硬化的进展，它们提供了推动力 寻找更安全（例如非致癌）和更有效的 免疫抑制方案进行治疗。