益髓颗粒剂治疗难治性血小板减少性紫癜临床研究

【作者】 许亚梅；

【导师】 陈信义； 麻柔；

【作者基本信息】 北京中医药大学 ， 中西医结合临床， 2003， 博士

【摘要】 难治性血小板减少性紫癜（Refractory idiopathic thrombocytopenic purpura，RITP）是指既往确诊的特发性血小板减少性紫癜(ITP)病例，经使用糖皮质激素和脾脏切除术无效，并需要采用其它综合治疗措施来维持血小板数量在安全范围的血液系统难治病。约三分之一ITP患者为RITP。目前，RITP还没有公认较好的治疗方案，诸多药物单独或联合应用，可取得一定疗效，但疗效维持时间短，停药后易复发，毒副作用大，或价格昂贵，限制了临床应用。RITP属于中医"血证"等范畴。我们通过临床观察发现，约70%的RITP患者具备“气阴两虚、血瘀内阻”证候，故确立“益气养阴活血法”为基本治疗原则，并以"益髓颗粒剂"为治疗药物，进行小样本病例观察，与长春新碱对照，初步总结了临床疗效。根据临床研究方案，自2001年3月～2003年3月，对符合RITP诊断与中医证候标准的37例患者按5：1分配原则，随机分入治疗组与对照组，疗程结束时，治疗组可供统计的有效病例30例，对照组6例。研究结果表明：①按RITP临床疗效标准，治疗组显效2例，占6.67%；良效12例，占40.00%；进步15例，占50.00%；无效1例，占3.33%；总显效率与总有效率分别为46.67%与96.67%。对照组显效1例，占16.67%；良效1例，占16.67%；进步2例，占33.33%；无效2例，占33.33%；总显效率与总有效率分别为33.33%与66.67%。两组总有效率比较，具有统计学意义，P<0.05，治疗组优于对照组。②疗程结束后临床主症总评分与治疗前比较，治疗组具有统计学意义，P<0.05；两组间比较，具有统计学意义，P<0.05。疗程结束后神疲懒言、头晕乏力、手足心热、口干咽燥、血瘀主症单项症状评分改善差值两组间比较，均具有统计学意义，P<0.05。治疗组疗后2周、4周、8周、12周及对照组疗后2周、4周、8周与自身疗前出血症状评分比较，均具有统计学意义，P<0.05。③治疗组从疗后第1周开始血小板计数升高，与治疗前比较，具有统计学意义，P<0.05。两组间血小板计数比较，第2、3、4、6周，对照组血小板计数高于治疗组，具有统计学意义，P＜0.01，P＜0.05；12周时两组间比较无统计学意义，P＞0.05。④治疗组疗后骨髓颗粒型、裸核巨核细胞数减少，产板型巨核细胞数增多，与治疗前比较，具有统计学意义，P<0.05与0.01。⑤治疗组疗程结束后，抗血小板抗体、血凝指标的PT与INR、总补体活性、IgG以及T细胞亚群的CD4+与Th/Ts数值较疗前改善，均具有统计学意义，P<0.05。以上指标两组间比较均无统计学意义，P＞0.05。⑥治疗组女性、病程≤36个月、年龄≤55岁以及中度以上病情临床症状改善更明显，年龄≤45岁者临床疗效好于年龄>55岁者。⑦益髓颗粒剂临床应用仅6.67％患者出现胃脘不适等不良反应，不影响治疗。我们认为，益髓颗粒剂作用机制与调控患者机体免疫，促进巨核细胞向成熟方向分化，维持神经-内分泌-免疫功能，影响造血调控因子，促进造血细胞增殖、诱导巨核细胞分化以及增加血小板功能，改善凝血机制有关。更多还原

【Abstract】 The term chronic refractory idiopathic thrombocytopenic purpura(RITP) is applied to cases that do not respond to standard doses of steroid and splenectomy and require some other form of therapy to raise their platelet count. It may occur in as many as one third of adults with ITP. The treatment of refractory ITP is barely effective. There is no accepted algorithm for management of patients with chronic refractory ITP.The methods that are currently used to treat immune thrombocytopenic purpura are directed at different aspects of this cycle of antibody production and platelet sensitization, clearance, and production. Many treatments are expensive. Response rates are low, or frequency of administration weight ,or frequent side effects against their use. The goal of treatment is not to cure the ITP, but to achieve a safe platelet count, which is arbitrarily assumed to be greater than 50,000/microL. We conducted a prospective study to evaluate the effect of Yi Sui granule (the chinese herb) in patients with RITP who had platelet counts below 50 ×109/L.In the theory of traditional chinese medicine ,there are mainly 3 pathogens to ITP: deficiency of qi and yin and blood stasis. Clinical symptoms include lassitude of spirit and lackadaisical speech ,dizziness, physical fatigue, baking fever in extremities ,dry mouth and dry pharynx ,internal blood stasis and so on. According to the pathogens , the treatment is to supplement qi and yin, activate blood and stanch bleeding. The Chinese herb Yi Sui granule can make it. Because oral Yi Sui granule therapy has been proved to be effective for adults with ITP, we assessed the short-term efficacy and toxicity of Yi Sui granule in patients with RITP. In our clinical study ,36 patients with RITP were divided into two groups at random. Thirty patients with RITP (group 1)were treated with Yi Sui granule. Six patients with RITP(group2) were treated with vincristine.In patients with RITP of group 1 , 24g of Yi Sui granule should be administered orally three times daily for 3 months. The interval from diagnosis ranged from 4 to 180 months, and patients had previously received a median of 2 treatments (including splenectomy in two cases). 29 out of 30 patients had a clinical improvement (96.67%), of whom 1 had a complete response of 7 months duration(3.33%), after which relapsed.One patients had no response(3.33%). The patients’ clinical symptoms were improved significantly than those before treatment (P<0.001).The improvement of hematopoiesis symptoms was earlier than the increase of blood platelet.The patient’s platelet count (±s) increased from (28.33±13.91) ×109/L to (58.63±18.79) ×109/L(P<0.001)and platelet-associated IgG(PAIgG) (±s) was decreased from (379.71±149.53) ng/107 cells to (205.29±111.44) ng/107 cells (P<0.01). Naked-megakaryocyte (±s) decreased from 15.44±11.50 to 9.59±7.67(P<0.01).CD4+T cell(±s) increased from 30.69±5.39 to 33.13±4.62 and Th/Ts increased from 1.01±0.25 to1.17±0.28 (P<0.05).INR(±s) decreased from 2.12±0.36 to 1.85±0.40（P<0.01).Neither sex,duration of the disease nor combined use of adrenocortical steroids was likely<WP=5>to have influenced the therapeutic effect. The age was likely to have influenced the therapeutic effect. The patient younger than 45 have better therapeutic effect than those elder than 56. Adverse effects were minimal. Side effects such as gastrointestinal symptoms were only observed in two patients.In group2, six patients with RITP were treated with weekly slow infusions of vincristine (2 mg/week up to a total dose of 4 mg). The interval from diagnosis ranged from 20 to 64 months. Four patients showed good to excellent responde (66.67%) after four infusions, of whom one patient had a complete response(16.67%) and two patients had no response(33.33%). All but three responses were transitory, and platelets returned to initial values after vincristine discontinuation. The patient’s platelet count (±s) increased from (25.0±16.30) ×109/L to (77.50±34.18) ×109/L after two scheduled courses of tr更多还原