PDF(Pubmed)
Abstract：
UNASSIGNED: Sildenafil, a common over-the-counter pill often self-administered at high doses for erectile dysfunction, has been reported to rarely cause prothrombotic events and sudden cardiac death in a few case reports. Therefore, we investigated the in vitro and in vivo effect of sildenafil treatment and dosage on platelet activation and mitogen-activated protein kinase (MAPK) phosphorylation. BALB/C mice were segregated into four groups, each having four mice each (control, low [3.25 mg/kg], medium [6.5 mg/kg], and high [13 mg/kg] sildenafil), and after the treatment, blood was drawn from each mouse and washed platelets prepared. Washed platelets were incubated with CD41 PE-Cy7 and Phospho-p38 MAPK PE antibodies and analyzed using a flow cytometer for platelet activation and adenosine 5\'- diphosphate (ADP)/collagen-induced MAPK phosphorylation. Washed platelets obtained from the venous blood of 18 human volunteers, were incubated with PAC-1 FITC and Phospho-p38 MAPK PE antibodies, and platelet activation (ADP and collagen), followed by flow cytometry analysis. There was a significant increase in both platelet activation as well as MAPK phosphorylation in the presence of collagen in the high-dose (13 mg/kg) sildenafil group (P = 0.000774). Further, increased platelet activation was observed in samples that were treated with high-dose sildenafil as compared to the untreated samples (P < 0.00001). These studies show the risk of prothrombotic episodes in patients on high-dose sildenafil (100 mg), in those with even mild endothelial dysfunction due to ADP, and collagen-induced platelet activation through MAPK phosphorylation, which was not seen in the low-and intermediate-dose cohorts.
摘要：
■西地那非，一种常见的非处方药，通常在高剂量下自行服用，用于治疗勃起功能障碍，据报道，在少数病例报告中，很少引起血栓前事件和心源性猝死。因此,我们研究了西地那非治疗和剂量对血小板活化和丝裂原活化蛋白激酶（MAPK）磷酸化的体内外影响。将BALB/C小鼠分为四组，每个有四只老鼠(对照，低[3.25mg/kg]，培养基[6.5mg/kg]，和高[13毫克/千克]西地那非），治疗后,从每只小鼠抽取血液并制备洗涤的血小板。将洗涤的血小板与CD41PE-Cy7和磷酸-p38MAPKPE抗体一起孵育,并使用流式细胞仪分析血小板活化和腺苷5'-二磷酸(ADP)/胶原诱导的MAPK磷酸化。从18名志愿者的静脉血中获得的洗涤血小板，与PAC-1FITC和磷酸-p38MAPKPE抗体孵育，和血小板活化（ADP和胶原蛋白），然后进行流式细胞术分析。在高剂量（13mg/kg）西地那非组中，存在胶原蛋白的情况下，血小板活化和MAPK磷酸化均显着增加（P=0.000774）。Further,与未处理样品相比,大剂量西地那非治疗样品的血小板活化增加(P<0.00001).这些研究表明，高剂量西地那非（100毫克）患者发生血栓前发作的风险，在那些由于ADP导致甚至轻度内皮功能障碍的患者中，和胶原蛋白诱导的血小板活化通过MAPK磷酸化，在低剂量和中剂量队列中未发现。
