Boneu B, Navarro C, Cambus J P, Caplain H, d'Azemar P, Necciari J, Duret J P, Gaud C, Sié P
Laboratoire de Recherche sur l'Hémostase et la Thrombose, Hôpital Purpan, Toulouse, France.
Thromb Haemost. 1998 Feb;79(2):338-41.
Venous thromboembolism may be efficiently treated by once-a-day (o.d.) administration of a high dose of low molecular weight heparin (LMWH) instead of administration of the same total dose in two injections a day (b.i.d.). To reduce the volume of the subcutaneous (s.c.) injection, a more concentrated form of the drug is advisable. This study was designed to compare the bioavailability of 2 formulations of nadroparin containing 10,250 and 20,500 anti-Xa IU x ml(-1) respectively. This was an open, randomized, cross-over study where 12 healthy volunteers (age 18-35) were enrolled. They received either 90 anti-Xa IU x kg(-1) b.i.d. of the 10,250 IU preparation (treatment A), or 180 anti-Xa IU x kg(-1) o.d. of the 20,500 IU preparation (treatment B) for 10 days. On day 1, the subjects were sampled between 0 and 12 h (treatment A) or between 0 and 24 h (treatment B). On day 10, they were sampled between 0 and 12 h and between 12 and 24 h (treatment A) or between 0 and 24 h (treatment B). Anti-Xa and anti-IIa activities were determined by specific chromogenic assays. The main result of the study was that the bioavailability of the anti-Xa activity of the 2 nadroparin formulations was equivalent, as shown by the comparison of the AUC(0-12 h) plus AUC(12-24 h) (treatment A) and the AUC(0-24 h) (treatment B), calculated on day 10. This study also allowed a number of interesting observations to be made. 1) Between day 1 and day 10, there was an accumulation of the anti-Xa activity for treatment A but not for treatment B (accumulation factors: 1.6 and 1.1 respectively); 2) On day 10, the AUC(0-12 h) were slightly but significantly lower than the AUC(12-24 h) suggesting a circadian effect for anti-Xa and anti-IIa activities; 3) the clearance of the anti-Xa activity was comparable at the 2-dose regimens, while that of the anti-IIa activity was lower in treatment B than in treatment A, indicating a significant dose effect for the pharmacodynamics of the longer heparin chains; 4) On average, the clearance of the anti-IIa activity was twice as high as that of the anti-Xa activity; 5) For treatment B, significant APTT prolongations were noticed at Tmax (prolongation factor: 1.7 +/- 0.25), in relation with the anti-IIa activity (0.3 +/- 0.1 IU x ml(-1)).
静脉血栓栓塞症可通过每日一次（o.d.）给予高剂量低分子量肝素（LMWH）进行有效治疗，而不是将相同总剂量分两次每日注射（b.i.d.）。为减少皮下（s.c.）注射体积，建议使用更浓缩的药物剂型。本研究旨在比较两种那屈肝素制剂的生物利用度，这两种制剂分别含有10,250和20,500抗Xa国际单位/毫升（IU x ml⁻¹）。这是一项开放、随机、交叉研究，招募了12名健康志愿者（年龄18 - 35岁）。他们接受10天的治疗，其中一组为每日两次（b.i.d.）给予10,250 IU制剂，剂量为90抗Xa国际单位/千克（IU x kg⁻¹）（治疗A），另一组为每日一次（o.d.）给予20,500 IU制剂，剂量为180抗Xa国际单位/千克（IU x kg⁻¹）（治疗B）。在第1天，治疗A组在0至12小时之间取样，治疗B组在0至24小时之间取样。在第10天，治疗A组在0至12小时以及12至24小时之间取样，治疗B组在0至24小时之间取样。通过特定的显色测定法测定抗Xa和抗IIa活性。该研究的主要结果是，如在第10天计算的AUC(0 - 12小时)+AUC(12 - 24小时)（治疗A）与AUC(0 - 24小时)（治疗B）的比较所示，两种那屈肝素制剂的抗Xa活性生物利用度相当。该研究还得出了一些有趣的观察结果。1）在第1天至第10天期间，治疗A组出现抗Xa活性蓄积，而治疗B组未出现（蓄积因子分别为1.6和1.1）；2）在第10天，AUC(0 - 12小时)略低于但显著低于AUC(12 - 24小时)，表明抗Xa和抗IIa活性存在昼夜节律效应；3）两种剂量方案下抗Xa活性的清除率相当，而治疗B组抗IIa活性的清除率低于治疗A组，表明较长肝素链的药效学存在显著剂量效应；4）平均而言，抗IIa活性的清除率是抗Xa活性清除率的两倍；5）对于治疗B组，在达峰时间（Tmax）观察到活化部分凝血活酶时间（APTT）显著延长（延长因子：1.7±0.25），这与抗IIa活性（0.3±0.1 IU x ml⁻¹）有关。
