Resveratrol exhibits a wide range of biological properties, including anti-glycation, antioxidant, anti-inflammation, neuroprotective (including against advanced dementia and Alzheimer’s disease), anti-cancer, and anti-aging activity in experimental models (Galiniak et al., Acta Biochim Pol 66:13-21, 2019). Unfortunately, this compound exhibits low bioavailability and solubility (Galiniak et al., Acta Biochim Pol 66:13-21, 2019), requiring large doses that can cause nausea and GI distress. JOTROLTM is a micellar 10% resveratrol solubilization formulation that is thought to increase bioavailability of resveratrol via lymphatic system absorption. Jupiter Neurosciences (formerly Jupiter Orphan Therapeutics; “Jupiter”) is pursuing the use of resveratrol in mucopolysaccharidosis type 1 (MPS 1), Friedreich’s ataxia, and Alzheimer’s disease/mild cognitive impairment. This paper describes a first in human study (FIH) to evaluate the bioavailability of resveratrol after ascending, single oral doses up to 700 mg resveratrol as JOTROLTM. After a single 500 mg dose of JOTROLTM, a Cmax of 455 ng/mL was observed, vs. 85 ng/mL Cmax after a 1 g encapsulated dose (Turner et al., Neurology 85:1383-91, 2015) and 1942 ng/mL after a 2.5 g micronized dose (Howells et al., Cancer Prev Res (Phila) 4:1419-1425, 2011). In this study, resveratrol exposures (AUCs and Cmax) increased with increasing doses. This increase appears to be higher than dose-proportional for AUC0-t and Cmax. Resveratrol and its three major conjugates accounted for 40 to 55% of the dose in urine, consistent with a high extent of absorption, but < 1% of drug-related material was intact relative to key metabolites in plasma and urine. Studies in Alzheimer’s patients and in MPS 1 are currently in development to test the effect this improved bioavailability has on those patient populations (Clintrials.gov, NCT04668274, 12/16/2020, https://clinicaltrials.gov/ct2/show/NCT04668274 ).

中文翻译：

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高生物利用度白藜芦醇制剂 (JOTROL TM) 的安全性和药代动力学

白藜芦醇在实验模型中表现出广泛的生物学特性，包括抗糖化、抗氧化、抗炎、神经保护（包括针对晚期痴呆和阿尔茨海默病）、抗癌和抗衰老活性（Galiniak 等人，Acta Biochim Pol 66:13-21, 2019)。不幸的是，这种化合物表现出低生物利用度和溶解度（Galiniak 等人，Acta Biochim Pol 66:13-21, 2019），需要大剂量可能导致恶心和胃肠道不适。JOTROLTM 是一种胶束 10% 白藜芦醇增溶配方，被认为可通过淋巴系统吸收增加白藜芦醇的生物利用度。Jupiter Neurosciences（前身为 Jupiter Orphan Therapeutics；“Jupiter”）正在寻求将白藜芦醇用于治疗 1 型粘多糖贮积症（MPS 1）、弗里德赖希的共济失调、和阿尔茨海默病/轻度认知障碍。本文描述了首次在人体研究 (FIH) 中评估白藜芦醇在上升后的生物利用度，单次口服剂量高达 700 毫克白藜芦醇作为 JOTROLTM。在单次 500 mg 剂量的 JOTROLTM 后，观察到 455 ng/mL 的 Cmax，而 1 g 封装剂量（Turner 等人，Neurology 85:1383-91, 2015）和 1942 ng 后的 Cmax 为 85 ng/mL /mL 在 2.5 g 微粉化剂量后 (Howells 等人，Cancer Prev Res (Phila) 4:1419-1425, 2011)。在这项研究中，白藜芦醇的暴露量（AUC 和 Cmax）随着剂量的增加而增加。这种增加似乎高于 AUC0-t 和 Cmax 的剂量比例。白藜芦醇及其三种主要结合物占尿中剂量的 40% 至 55%，与高度吸收一致，但 < 相对于血浆和尿液中的关键代谢物，1% 的药物相关物质是完整的。阿尔茨海默病患者和 MPS 1 的研究目前正在开发中，以测试这种提高的生物利用度对这些患者群体的影响（Clintrials.gov, NCT04668274, 12/16/2020, https://clinicaltrials.gov/ct2/show/NCT04668274 ）。