Arruzazabala María de Lourdes, Molina Vivian, López Ernesto, Castaño Gladys, Fernández Lilia, Carbajal Daisy, Mas Rosa, Ferrer José I, Mendoza Sarahi, Ramírez Yoandri
National Center for Scientific Research, Havana City, Cuba.
Arzneimittelforschung. 2008;58(8):376-84. doi: 10.1055/s-0031-1296524.
Increased platelet aggregation contributes to vascular risk. D-003, a mixture of high molecular weight sugarcane wax acids, has shown antiplatelet effects in experimental models and healthy volunteers. This randomised, double-blinded, placebo-controlled study investigated the effects of titrated doses of D-003 (5-20 mg/d) on platelet aggregation in hypercholesterolemic patients. After a 4-week baseline phase, 56 patients were randomised to D-003 5 mg/d or placebo. The doses were doubled every 15 days if arachidonic acid (AA)-induced platelet aggregation was not inhibited at least by 15%. AA (0.75 and 1.5 mmol/L) and collagen (1 microg/mL)-induced platelet aggregation, laboratory and physical safety indicators were assessed at baseline and every 15 days thereafter, when adverse events (AE) were also reported. No significant change of platelet aggregation was found in the placebo group. After 15, 30 and 45 on therapy, D-003 reduced platelet aggregation induced with both AA 0.75 mmol/L (18.1%, 19.0% and 30.3%, respectively) and AA 1.5 mmol/L (17.0%, 16.3% and 22.5%, respectively), and also collagen-induced platelet aggregation (26.6%, 20.8% and 29.4%) (p < 0.01 at days 15 and 30 versus placebo, p < 0.0001 at study completion). The mean inhibition of platelet aggregation with D-003 at day 15, at which all patients had received the lowest dose, was over 15%. Nineteen out of 28 D-003 randomised patients (67.9%) required dose titration to achieve such goal. At trial completion, the mean estimated dose was 11.6 mg/d. D-003 lowered low-density lipoprotein (22.0 %), total cholesterol (14.7%) and raised high-density lipoprotein-cholesterol (10.9%) (p < 0.0001 versus placebo). Six patients (2 placebo, 4 D-003) withdrew from the trial, none due to AE. D-003 did not modify the safety indicators with respect to placebo. Four patients (2 placebo, 2 D-003-treated) reported AE: pruritus and increased blood pressure (2 placebo) and rash and polyphagla (2 D-003). In conclusion, D-003 (5-20 mg/d) given as doses titrated every 15 days (5-20 mg/d) inhibited AA- and collagen-induced platelet aggregation in hypercholesterolemic patients and was well tolerated.
血小板聚集增加会导致血管风险。D - 003是一种高分子量甘蔗蜡酸的混合物，已在实验模型和健康志愿者中显示出抗血小板作用。这项随机、双盲、安慰剂对照研究调查了滴定剂量的D - 003（5 - 20毫克/天）对高胆固醇血症患者血小板聚集的影响。在为期4周的基线期后，56名患者被随机分为接受5毫克/天的D - 003或安慰剂治疗。如果花生四烯酸（AA）诱导的血小板聚集未被抑制至少15%，则每15天剂量加倍。在基线期以及此后每15天评估AA（0.75和1.5毫摩尔/升）和胶原（1微克/毫升）诱导的血小板聚集、实验室和身体安全指标，同时报告不良事件（AE）。安慰剂组血小板聚集无显著变化。治疗15天、30天和45天后，D - 003降低了0.75毫摩尔/升AA诱导的血小板聚集（分别为18.1%、19.0%和30.3%）以及1.5毫摩尔/升AA诱导的血小板聚集（分别为17.0%、16.3%和22.5%），还降低了胶原诱导的血小板聚集（26.6%、20.8%和29.4%）（第15天和30天时与安慰剂相比p < 0.01，研究结束时p < 0.0001）。在第15天，所有患者均接受最低剂量时，D - 003对血小板聚集的平均抑制率超过15%。28名随机接受D - 003治疗的患者中有19名（67.9%）需要滴定剂量以达到该目标。试验结束时，平均估计剂量为11.6毫克/天。D - 003降低了低密度脂蛋白（22.0%）、总胆固醇（14.7%）并升高了高密度脂蛋白胆固醇（10.9%）（与安慰剂相比p < 0.0001）。6名患者（2名安慰剂组，4名D - 003组）退出试验，均非因不良事件。与安慰剂相比，D - 003未改变安全指标。4名患者（2名安慰剂组，2名接受D - 003治疗组）报告了不良事件：瘙痒和血压升高（2名安慰剂组）以及皮疹和多食（2名D - 003组）。总之，每15天滴定剂量给予D - 003（5 - 20毫克/天）可抑制高胆固醇血症患者中AA和胶原诱导的血小板聚集，且耐受性良好。
