Victor Suresh, Forbes Ben, Greenough Anne, Edwards A David
Centre for the Developing Brain, Department of Perinatal Imaging and Health, School of Biomedical Engineering and Imaging Sciences, King's College London, St. Thomas' Hospital, London SE1 7EH, UK.
Institute of Pharmaceutical Science, King's College London, Franklin-Wilkins Building, Stamford Street, London SE1 9NH, UK.
Pharmaceuticals (Basel). 2023 Oct 27;16(11):1530. doi: 10.3390/ph16111530.
Worldwide, three-quarters of a million babies are born extremely preterm (<28 weeks gestation) with devastating outcomes: 20% die in the newborn period, a further 35% develop bronchopulmonary dysplasia (BPD), and 10% suffer from cerebral palsy. Pioglitazone, a Peroxisome Proliferator Activated Receptor Gamma (PPARγ) agonist, may reduce the incidence of BPD and improve neurodevelopment in extreme preterm babies. Pioglitazone exerts an anti-inflammatory action mediated through Nuclear Factor-kappa B repression. PPARγ signalling is underactive in preterm babies as adiponectin remains low during the neonatal period. In newborn animal models, pioglitazone has been shown to be protective against BPD, necrotising enterocolitis, and lipopolysaccharide-induced brain injury. Single Nucleotide Polymorphisms of PPARγ are associated with inhibited preterm brain development and impaired neurodevelopment. Pioglitazone was well tolerated by the foetus in reproductive toxicology experiments. Bladder cancer, bone fractures, and macular oedema, seen rarely in adults, may be avoided with a short treatment course. The other effects of pioglitazone, including improved glycaemic control and lipid metabolism, may provide added benefit in the context of prematurity. Currently, there is no formulation of pioglitazone suitable for administration to preterm babies. A liquid formulation of pioglitazone needs to be developed before clinical trials. The potential benefits are likely to outweigh any anticipated safety concerns.
在全球范围内，每年有75万婴儿极早产（妊娠<28周），并伴有严重后果：20%在新生儿期死亡，另有35%会发展为支气管肺发育不良（BPD），10%会患脑瘫。吡格列酮是一种过氧化物酶体增殖物激活受体γ（PPARγ）激动剂，可能会降低极早产婴儿患BPD的发生率，并改善其神经发育。吡格列酮通过抑制核因子-κB发挥抗炎作用。由于新生儿期脂联素水平仍然较低，PPARγ信号在早产婴儿中不活跃。在新生动物模型中，吡格列酮已被证明对BPD、坏死性小肠结肠炎和脂多糖诱导的脑损伤具有保护作用。PPARγ的单核苷酸多态性与早产脑发育抑制和神经发育受损有关。在生殖毒理学实验中，胎儿对吡格列酮耐受性良好。短期治疗疗程可避免成年人中罕见的膀胱癌、骨折和黄斑水肿。吡格列酮的其他作用，包括改善血糖控制和脂质代谢，可能会在早产的情况下带来额外益处。目前，尚无适合给早产婴儿使用的吡格列酮制剂。在进行临床试验之前，需要开发一种吡格列酮液体制剂。潜在益处可能超过任何预期的安全担忧。
