Christopher Kemper, Dariush Benham, Shaun Brothers, Claes Wahlestedt, Claude-Henry Volmar, Daniel Bennett, Marshall Hayward
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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 JOTROL<sup>TM</sup>. After a single 500 mg dose of JOTROL<sup>TM</sup>, 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 AUC<sub>0-t</sub> 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).</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1186/s41120-022-00058-1.</p>","PeriodicalId":453,"journal":{"name":"AAPS Open","volume":" ","pages":"11"},"PeriodicalIF":0.0000,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243782/pdf/","citationCount":"6","resultStr":"{\"title\":\"Safety and pharmacokinetics of a highly bioavailable resveratrol preparation (JOTROL <sup>TM</sup>).\",\"authors\":\"Christopher Kemper, Dariush Benham, Shaun Brothers, Claes Wahlestedt, Claude-Henry Volmar, Daniel Bennett, Marshall Hayward\",\"doi\":\"10.1186/s41120-022-00058-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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). 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引用次数: 6
摘要
在实验模型中，白藜芦醇表现出广泛的生物学特性，包括抗糖基化、抗氧化、抗炎症、神经保护(包括抗晚期痴呆和阿尔茨海默病)、抗癌和抗衰老活性(Galiniak et al.， Acta biochem Pol 66:13- 21,2019)。不幸的是，这种化合物具有较低的生物利用度和溶解度(Galiniak等人，Acta biochem 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%白藜芦醇增溶制剂，被认为可以通过淋巴系统吸收增加白藜芦醇的生物利用度。Jupiter Neurosciences(原Jupiter Orphan Therapeutics;“Jupiter”)正在寻求将白藜芦醇用于1型粘多糖病(MPS 1)、弗里德赖希共济失调和阿尔茨海默病/轻度认知障碍。本文描述了一项首次人体研究(FIH)，以评估白藜芦醇的生物利用度，单次口服剂量高达700 mg白藜芦醇作为JOTROLTM。单次给药500 mg JOTROLTM后，Cmax为455 ng/mL，而1 g胶囊剂量后Cmax为85 ng/mL (Turner等人，Neurology 85:1383-91, 2015)， 2.5 g微胶囊剂量后Cmax为1942 ng/mL (Howells等人，Cancer Prev Res (Phila) 4:1419-1425, 2011)。在本研究中，白藜芦醇暴露量(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缀合物占尿中剂量的40 - 55%，与高吸收程度一致，但补充信息:在线版本含有补充资料，可在10.1186/s41120-022-00058-1获取。
Safety and pharmacokinetics of a highly bioavailable resveratrol preparation (JOTROL TM).
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).
Supplementary information: The online version contains supplementary material available at 10.1186/s41120-022-00058-1.
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