Department of Pharmacology-Toxicology, Radboud University Nijmegen Medical Center, Geert Grooteplein 10, 6500 HB, Nijmegen, The Netherlands.
Crit Care. 2011;15(6):R289. doi: 10.1186/cc10576. Epub 2011 Nov 30.
In animal models of systemic inflammation, the endogenous nucleoside adenosine controls inflammation and prevents organ injury. Dipyridamole blocks the cellular uptake of endogenous adenosine and increases the extracellular adenosine concentration. We studied the effects of oral dipyridamole treatment on innate immunity and organ injury during human experimental endotoxemia.
In a randomized double-blind placebo-controlled study, 20 healthy male subjects received 2 ng/kg Escherichia coli endotoxin (lipopolysaccharide; LPS) intravenously after 7-day pretreatment with dipyridamole, 200 mg slow release twice daily, or placebo.
Nucleoside transporter activity on circulating erythrocytes was reduced by dipyridamole with 89% ± 2% (P < 0.0001), and the circulating endogenous adenosine concentration was increased. Treatment with dipyridamole augmented the LPS-induced increase in the antiinflammatory cytokine interleukin (IL)-10 with 274%, and resulted in a more rapid decrease in proinflammatory cytokines tumor necrosis factor-α (TNF-α) and IL-6 levels directly after their peak level (P < 0.05 and < 0.01, respectively). A strong correlation was found between the plasma dipyridamole concentration and the adenosine concentration (r = 0.82; P < 0.01), and between the adenosine concentration and the IL-10 concentration (r = 0.88; P < 0.0001), and the subsequent decrease in TNF-α (r = -0.54; P = 0.02). Dipyridamole treatment did not affect the LPS-induced endothelial dysfunction or renal injury during experimental endotoxemia.
Seven-day oral treatment with dipyridamole increases the circulating adenosine concentration and augments the antiinflammatory response during experimental human endotoxemia, which is associated with a faster decline in proinflammatory cytokines.
ClinicalTrials (NCT): NCT01091571.
在全身炎症的动物模型中，内源性核苷腺苷可控制炎症并预防器官损伤。双嘧达莫可阻断细胞摄取内源性腺苷并增加细胞外腺苷浓度。我们研究了口服双嘧达莫治疗对人类实验性内毒素血症期间固有免疫和器官损伤的影响。
在一项随机、双盲、安慰剂对照研究中，20 名健康男性在接受 7 天双嘧达莫（200mg 缓释，每日 2 次）或安慰剂预处理后，静脉内给予 2ng/kg 大肠杆菌内毒素（脂多糖；LPS）。
双嘧达莫使循环红细胞上的核苷转运体活性降低 89%±2%（P＜0.0001），并增加了循环内源性腺苷浓度。双嘧达莫治疗增强了 LPS 诱导的抗炎细胞因子白细胞介素（IL）-10 的增加，使其在达到峰值后迅速降低促炎细胞因子肿瘤坏死因子（TNF）-α和 IL-6 的水平（P＜0.05 和＜0.01）。血浆双嘧达莫浓度与腺苷浓度之间存在很强的相关性（r=0.82；P＜0.01），与 IL-10 浓度之间存在很强的相关性（r=0.88；P＜0.0001），与随后 TNF-α的下降之间也存在很强的相关性（r=-0.54；P=0.02）。双嘧达莫治疗并不影响实验性内毒素血症期间 LPS 诱导的内皮功能障碍或肾损伤。
7 天口服双嘧达莫治疗可增加循环腺苷浓度并增强人类实验性内毒素血症期间的抗炎反应，与促炎细胞因子迅速下降相关。
ClinicalTrials（NCT）：NCT01091571。
