Pharmacodynamic stimulation of thrombogenesis by angiotensin (1-7) in recurrent ovarian cancer patients receiving gemcitabine and platinum-based chemotherapy
Pharmacodynamic stimulation of thrombogenesis by angiotensin (1-7) in recurrent ovarian cancer patients receiving gemcitabine and platinum-based chemotherapy
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DOI：
10.1007/s00280-013-2089-x
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发表时间：
2013-04-01
影响因子：
3
通讯作者：
diZerega, Gere S.
中科院分区：
文献类型：
--
作者：
Huyen Pham;Schwartz, Benjamin M.;diZerega, Gere S.
这项随机、双盲、安慰剂对照的2期研究评价了A（1-7）减少接受骨髓抑制化疗患者3-4级血小板减少症的安全性和疗效。还测定了A（1-7）在血小板生成和预定剂量强度保持方面的药效学活性。对34例接受吉西他滨和卡铂或顺铂治疗的卵巢癌、输卵管癌或腹膜癌患者进行了评价。患者在化疗后随机接受100 mcg/kg（n = 11）、300 mcg/kg（n = 13）或安慰剂（n = 10）皮下注射研究药物，最多6个周期。在每个治疗周期中获得血液学变量，没有药物相关的安全性问题。在接受100 mcg/kg治疗的患者中没有发生4级血小板减少症，而在接受安慰剂的患者中，化疗周期发生率为6%（p = 0.07）。与安慰剂相比，接受100 mcg/kg A（1-7）的患者血小板浓度较基线的最大百分比增加更高（p = 0.02）。这种增加伴随着中性粒细胞绝对计数最低值的降低（p = 0.04）。与安慰剂相比，接受100 mcg/kg A（1-7）的患者联合化疗的相对剂量强度更高（p = 0.04）。与安慰剂相比，接受300 mcg/kg剂量的患者的结局无差异。100 mcg/kg剂量的A（1-7）显示对外周血血小板计数产生药效学作用，保持计划的剂量强度，并减少吉西他滨和铂类化疗后的3-4级血小板减少症。这些发现与骨髓毒性化疗后A（1-7）诱导的骨髓血栓形成刺激一致。
This randomized, double-blind, placebo-controlled Phase 2 study evaluated safety and efficacy of A(1-7) for reduction in Grade 3-4 thrombocytopenia in patients receiving myelosuppressive chemotherapy. Pharmacodynamic activity of A(1-7) in platelet production and retention of scheduled dose intensity were also determined.Thirty-four patients with ovarian, Fallopian tube, or peritoneal carcinoma receiving gemcitabine and carboplatin or cisplatin were evaluated. Patients were randomized to receive study drug subcutaneously at 100 mcg/kg (n = 11), 300 mcg/kg (n = 13), or placebo (n = 10) following chemotherapy for up to six cycles. Hematologic variables were obtained throughout each treatment cycle.There were no drug-related safety issues. There were no instances of Grade 4 thrombocytopenia in patients who received 100 mcg/kg treatment compared to 6 % of chemotherapy cycles for patients receiving placebo (p = 0.07). The maximal percentage increase in platelet concentration from baseline was higher for patients who received 100 mcg/kg A(1-7) compared to placebo (p = 0.02). This increase was accompanied by a reduction in the nadir absolute neutrophil count (p = 0.04). Relative dose intensity for the combination chemotherapy was higher for patients who received 100 mcg/kg A(1-7) compared to placebo (p = 0.04). There were no differences in outcomes for patients receiving 300 mcg/kg dose compared to placebo.A 100 mcg/kg dose of A(1-7) was shown to produce pharmacodynamic effects on peripheral blood platelet counts, preserve planned dose intensity, and reduce Grade 3-4 thrombocytopenia following gemcitabine and platinum chemotherapy. These findings are consistent with A(1-7)-induced stimulation of thrombogenesis in the bone marrow following marrow-toxic chemotherapy.