King Edward Memorial Hospital, Perth, Western Australia, Australia.
Paediatr Drugs. 2010 Oct 1;12(5):301-11. doi: 10.2165/11532600-000000000-00000.
Sepsis, necrotizing enterocolitis (NEC), and chronic lung disease (CLD) in preterm neonates are associated with significant mortality and morbidity, including long-term neurodevelopmental impairment and socioeconomic burden. Safe and effective drugs for the prevention and treatment of these conditions are urgently needed. Pentoxifylline, a synthetic theobromine derivative, is a non-steroidal immunomodulating agent with unique hemorrheologic effects which has been used in a range of infectious, vascular, and inflammatory conditions in adults and children. The unique properties of pentoxifylline explain its potential benefits in preterm neonates with sepsis, NEC, and CLD, conditions characterized by activation of the inflammatory cytokine cascade, free radical toxicity, and impaired microcirculation. Pentoxifylline has anti-inflammatory properties resulting from inhibition of erythrocyte phosphodiesterase. It lowers blood viscosity and improves microcirculation and tissue perfusion. As a phosphodiesterase inhibitor, pentoxifylline downregulates pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-6, and interferon-gamma. Methylxanthines, including caffeine, theophylline, and theobromine are relatively non-toxic drugs; of these, theobromine is the least toxic. Pentoxifylline-related significant adverse events are thus very rare. Unlike other methylxanthines, pentoxifylline does not have significant cardiac and bronchodilating effects at therapeutic doses. Although it is contraindicated in adults with recent cerebral hemorrhage due to its effect on platelets, red blood cells, and plasma fibrinogen levels, no significant adverse effects including thrombocytopenia and bleeding have been reported in critically ill preterm neonates with sepsis or NEC after treatment with pentoxifylline. Based on data from pilot randomized trials and observational studies, our systematic review suggests that pentoxifylline may reduce mortality and/or morbidity in preterm neonates with sepsis, NEC, and CLD. Results of experimental studies also indicate that pentoxifylline may potentially be beneficial in meconium aspiration syndrome and hypoxic ischemic encephalopathy. Given the substantial burden of sepsis, NEC, and CLD in high-risk preterm neonates, and the findings of this systematic review, pentoxifylline needs to be evaluated urgently as a preventative and therapeutic agent for these conditions in randomized controlled trials that can detect minimal clinically significant effect sizes. Further clinical and experimental studies are also necessary to evaluate whether pentoxifylline is safe and effective in meconium aspiration syndrome and hypoxic ischemic encephalopathy.
早产儿的败血症、坏死性小肠结肠炎 (NEC) 和慢性肺病 (CLD) 与显著的死亡率和发病率相关，包括长期的神经发育损伤和社会经济负担。目前迫切需要安全有效的药物来预防和治疗这些疾病。己酮可可碱是一种合成的可可碱衍生物，是一种具有独特血液流变学作用的非甾体免疫调节剂，已在成人和儿童的一系列感染、血管和炎症疾病中使用。己酮可可碱的独特特性解释了其在患有败血症、NEC 和 CLD 的早产儿中的潜在益处，这些疾病的特征是炎症细胞因子级联的激活、自由基毒性和微循环受损。己酮可可碱具有抗炎特性，这是由于其抑制红细胞磷酸二酯酶的作用。它可降低血液粘度，改善微循环和组织灌注。作为磷酸二酯酶抑制剂，己酮可可碱下调肿瘤坏死因子-α、白细胞介素-6 和干扰素-γ等促炎细胞因子。甲基黄嘌呤，包括咖啡因、茶碱和可可碱，都是相对无毒的药物；其中，可可碱的毒性最小。因此，与己酮可可碱相关的严重不良事件非常罕见。与其他甲基黄嘌呤不同，己酮可可碱在治疗剂量下对心脏和支气管没有明显的舒张作用。尽管由于其对血小板、红细胞和血浆纤维蛋白原水平的影响，己酮可可碱在有近期脑出血的成人中被禁忌使用，但在接受己酮可可碱治疗的败血症或 NEC 危重早产儿中，没有报告血小板减少症和出血等显著不良反应。基于试点随机试验和观察性研究的数据，我们的系统评价表明，己酮可可碱可能降低败血症、NEC 和 CLD 早产儿的死亡率和/或发病率。实验研究的结果也表明，己酮可可碱可能对胎粪吸入综合征和缺氧缺血性脑病有益。鉴于高危早产儿的败血症、NEC 和 CLD 负担沉重，以及本系统评价的结果，己酮可可碱需要在随机对照试验中紧急评估作为这些疾病的预防和治疗药物，这些试验能够检测到最小的临床显著效应量。还需要进一步的临床和实验研究，以评估己酮可可碱在胎粪吸入综合征和缺氧缺血性脑病中的安全性和有效性。
