Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA.
Int J Pharm. 2018 Sep 5;548(1):104-112. doi: 10.1016/j.ijpharm.2018.06.046. Epub 2018 Jun 21.
d-β-hydroxybutyrate and melatonin (BHB/MLT) infusion improves survival in hemorrhagic shock models. The original BHB/MLT formulation contains dimethyl sulfoxide (DMSO) to increase melatonin solubility. We formulated BHB/MLT solutions wherein DMSO was replaced either with 10% polyvinylpyrrolidone (BHB/MLT/PVP) or with 5% hydroxypropyl-β-cyclodextrin/2.5% PVP/2.5% polyethylene glycol 400 (BHB/MLT/CD). Safety and efficacy of the new and the original BHB/MLT solution were tested in a lethal rat hemorrhagic shock model, with seven groups: 1) sham, 2) shock, untreated, 3) shock, lactated Ringer's solution (LR), 4) shock, 4 M BHB/MLT/DMSO, 5) shock, 2 M BHB/MLT/DMSO, 6) shock, BHB/MLT/PVP and 7) shock, BHB/MLT/CD. BHB/MLT/DMSO was given at full strength and 1:1 dilution to match the concentration of the novel formulations. Rats were anesthetized, instrumented, and 40% of the total blood volume was withdrawn in three steps, followed by four-hour long shock. Treatment boluses were infused half-way throughout hemorrhage. Survival was highest in BHB/MLT/CD-treated rats (8/10), followed by the BHB/MLT/PVP (6/10), 4 M BHB/MLT/DMSO (5/10) or 2 M BHB/MLT/DMSO (5/10), LR (3/10) and the untreated group (0/11). Survival did not differ significantly between BHB/MLT groups (p > 0.05), but was significantly higher in BHB/MLT/CD than in LR-treated animals (p = 0.018). BHB/MLT/PVP and BHB/MLT/CD constitute promising candidates for clinical hemorrhagic shock treatment.
β-羟基丁酸和褪黑素（BHB/MLT）输注可提高失血性休克模型的存活率。原始的 BHB/MLT 配方含有二甲基亚砜（DMSO）以增加褪黑素的溶解度。我们将 BHB/MLT 溶液中的 DMSO 分别用 10%聚乙烯吡咯烷酮（BHB/MLT/PVP）或 5%羟丙基-β-环糊精/2.5%PVP/2.5%聚乙二醇 400（BHB/MLT/CD）替代。新配方和原始 BHB/MLT 溶液的安全性和疗效在致命性大鼠失血性休克模型中进行了测试，共分为七组：1）假手术组，2）未治疗的休克组，3）休克，乳酸林格氏液（LR）组，4）休克，4M BHB/MLT/DMSO 组，5）休克，2M BHB/MLT/DMSO 组，6）休克，BHB/MLT/PVP 组和 7）休克，BHB/MLT/CD 组。BHB/MLT/DMSO 以全强度和 1:1 稀释给药，以匹配新配方的浓度。大鼠麻醉、仪器化，在三个步骤中抽取总血量的 40%，然后进行长达四小时的休克。治疗推注在出血过程中进行了一半的输注。BHB/MLT/CD 治疗组大鼠的存活率最高（8/10），其次是 BHB/MLT/PVP（6/10）、4M BHB/MLT/DMSO（5/10）或 2M BHB/MLT/DMSO（5/10）、LR（3/10）和未治疗组（0/11）。BHB/MLT 组之间的存活率无显著差异（p>0.05），但 BHB/MLT/CD 组与 LR 治疗组相比，存活率显著更高（p=0.018）。BHB/MLT/PVP 和 BHB/MLT/CD 是有前途的临床失血性休克治疗候选药物。
