Novel Liposomal Rolipram Formulation for Clinical Application to Reduce Emesis.
Novel Liposomal Rolipram Formulation for Clinical Application to Reduce Emesis.
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DOI：
10.2147/dddt.s355796
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发表时间：
2022
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磷酸二酯酶4 （PDE4）抑制剂罗利普兰对包括肝脏在内的组织炎症、损伤和纤维化有有益作用。由于罗利普兰在人体中引起显著的中枢神经系统副作用（即恶心和呕吐），我们的团队开发了一种针对肝脏的fusogenic脂质囊泡（FLV）药物递送系统，以避免不良事件。我们评估了这种新型罗利普兰脂质体制剂是否能减少呕吐。以C57Bl/6J雄性小鼠为研究对象，比较三种剂量的游离型和flv - rol型罗利普兰在罗利普兰致呕吐行为相关模型中的作用。采用LC-MS/MS法测定组织中罗利普兰和罗利普兰代谢物水平。研究了FLVs-Rol对脑和肝脏PDE4活性的影响。低、中剂量游离罗利普兰可显著缩短麻醉时间，而相同剂量的FLVs-Rol则无效果。然而，高剂量罗利普兰引起的不良反应（麻醉时间缩短）的发生和持续时间并没有得到FLVs-Rol的改善。脑和肝组织的死后分析表明，flv影响肝和脑对罗利普兰的摄取率。最后，给予中等剂量的FLVs-Rol可减弱内毒素诱导的肝脏PDE4活性，对大脑的影响可以忽略不计。研究发现，低剂量和中剂量的FLV - rol并没有缩短麻醉持续时间，这表明FLV的递送阻止了临界水平的药物穿过血脑屏障（BBB），从而引起中枢神经系统的副作用。然而，高剂量FLVs-Rol无法预防中枢神经系统的副作用表明，有足够的未包封的罗利普兰穿过血脑屏障，缩短麻醉时间。值得注意的是，中等剂量的FLVs-Rol能够降低肝脏中PDE4的活性，而不影响大脑。综上所述，FLVs-Rol在无副作用的肝脏疾病治疗方面具有很强的临床应用潜力。
The phosphodiesterase 4 (PDE4) inhibitor, rolipram, has beneficial effects on tissue inflammation, injury and fibrosis, including in the liver. Since rolipram elicits significant CNS side-effects in humans (ie, nausea and emesis), our group developed a fusogenic lipid vesicle (FLV) drug delivery system that targets the liver to avoid adverse events. We evaluated whether this novel liposomal rolipram formulation reduces emesis. C57Bl/6J male mice were used to compare the effect of three doses of free and FLV-delivered (FLVs-Rol) rolipram in a behavioral correlate model of rolipram-induced emesis. Tissue rolipram and rolipram metabolite levels were measured using LC-MS/MS. The effect of FLVs-Rol on brain and liver PDE4 activities was evaluated. Low and moderate doses of free rolipram significantly reduced anesthesia duration, while the same doses of FLVs-Rol had no effect. However, the onset and duration of adverse effects (shortening of anesthesia period) elicited by a high dose of rolipram was not ameliorated by FLVs-Rol. Post-mortem analysis of brain and liver tissues demonstrated that FLVs affected the rate of rolipram uptake by liver and brain. Lastly, administration of a moderate dose of FLVs-Rol attenuated endotoxin induced PDE4 activity in the liver with negligible effect on the brain. The findings that the low and moderate doses of FLVs-Rol did not shorten the anesthesia duration time suggest that FLV delivery prevented critical levels of drug from crossing the blood-brain barrier (BBB) to elicit CNS side-effects. However, the inability of high dose FLVs-Rol to prevent CNS side-effects indicates that there was sufficient unencapsulated rolipram to cross the BBB and shorten anesthesia duration. Notably, a moderate dose of FLVs-Rol was able to decrease PDE4 activity in the liver without affecting the brain. Taken together, FLVs-Rol has a strong potential for clinical application for the treatment of liver disease without side effects.