Evaluation of the potential of Ashwagandha extracts to produce CYP-mediated drug interactions.
评估 Ashwagandha 提取物产生 CYP 介导的药物相互作用的潜力。
基本信息
- 批准号:10436380
- 负责人:
- 金额:$ 7.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdverse effectsAffectAgingAshwagandhaBiological AssayBotanical dietary supplementsBotanicalsCYP1A2 geneCYP2B6 geneCYP2C19 geneCYP2C9 geneCYP2D6 geneCYP2E1 geneCYP3A4 geneCarrier ProteinsChemicalsClinical ResearchClinical TrialsCognitionCognitiveComplexCytochrome P450DangerousnessDataDatabasesDepositionDrug EvaluationDrug InteractionsDrug KineticsElderlyEnsureEnzymesEuterpeEvaluationFundingFutureHealthHealth SciencesHepaticHepatocyteHumanIn VitroInvestigationIsoenzymesKnowledgeLaboratoriesLiver MicrosomesMeasuresMediatingMessenger RNAMetabolismMethanolNational Center for Complementary and Integrative HealthNatural Product DrugNatural ProductsNatural Products ChemistryNeurologicNuclear ReceptorsOregonOutcomePeer ReviewPharmaceutical PreparationsPharmacognosyPharmacy SchoolsPhasePilot ProjectsPlant LeavesPlant RootsPoliciesPopulationProtein IsoformsPublicationsPublishingReportingResearchResearch PersonnelResourcesReverse Transcriptase Polymerase Chain ReactionRiskSleepSleeplessnessStressTestingTherapeutic AgentsTimeUnited StatesUnited States National Institutes of HealthUniversitiesVeterinary MedicineWorkage groupaqueousbasecollegedietary supplementsdrug developmentdrug metabolismenzyme activityimprovedmRNA Expressionnovel therapeuticsresilienceresponse
项目摘要
Project Summary
Although drug-drug interactions are routinely evaluated during new drug development, the potential for
botanicals and botanical dietary supplements to cause natural product-drug interactions is rarely evaluated. To
correct this deficiency, we are responding to the PAR-20-228: Pilot Projects Increasing the Impact of the NIH
Centers for Advancing Research on Botanicals and Other Natural Products (PI2 CARBON). Specifically, we
propose to evaluate Ashwagandha (Withania somnifera), one of the top 40 selling botanicals used by US
consumers in 2018, for inhibition and induction of the most important Phase I drug metabolizing enzymes, the
cytochromes P450 (CYPs). To date, there have been limited reports regarding the inhibitory effects of
Ashwagandha extracts on the CYPs, and no published studies examined whether Ashwagandha extracts have
the potential to induce CYP expression. Ashwagandha is used by older adults in particular to ameliorate stress,
insomnia, and cognitive deficiencies; and this population is often taking conventional medications for other
health conditions. Thus, use by the elderly makes a study of how Ashwagandha affects CYP activity and
expression an important concern. Ashwagandha is one of two botanicals being studied for its ability to improve
resilience in the BENFRA Botanical Dietary Supplements Research Center (BDSRC) at Oregon Health and
Science University (U19 AT010829). Our work will synergize with that of the BENFRA BDSRC, which will
provide authenticated and chemically characterized extracts of Ashwagandha roots and leaves for testing in
the applicant’s laboratory at the University of Auburn. For our project, we propose two Specific Aims. In Aim 1,
we will screen different types of Ashwagandha extracts for inhibition of 9 human hepatic CYPs (including all
CYPs recommended for drug-drug evaluation by the FDA). Inhibition of CYPs in pooled human liver
microsomes will be measured using CYP probe substrates and our ultrafast UHPLC-MS/MS cocktail assay. In
Aim 2, we will assess induction of CYP mRNA expression caused by Ashwagandha extracts using primary
human hepatocytes in sandwich culture according to the FDA Guidance on in vitro drug-drug interactions
studies. The resulting comprehensive data of Ashwagandha extract-CYP interactions will be made available
through scientific publications. Demonstration of inhibition or induction of CYPs by Ashwagandha will be
followed by future studies that seek to identify the compounds responsible for the observed effects.
Demonstration of interactions with CYP enzymes will be followed by confirmatory clinical studies of
Ashwagandha-drug pharmacokinetic interactions.
项目摘要
尽管在新药开发期间会定期评估药物与药物的相互作用,但
植物性药物和植物性膳食补充剂引起的天然产品-药物相互作用很少得到评价。至
纠正这一不足,我们正在响应PAR-20-228:增加NIH影响的试点项目
植物及其他天然产物先进研究中心(PI2碳)。具体来说,我们
建议对美国最畅销的40种植物药之一--艾希瓦甘达进行评估
2018年消费者,对于抑制和诱导最重要的I期药物代谢酶,
细胞色素P450(Cyps)。到目前为止,关于苯丙氨酸的抑制作用的报道有限。
阿什瓦甘达提取物对CyPS的影响,没有发表的研究检验阿什瓦甘达提取物是否有
诱导CYP表达的可能性。阿什瓦甘达尤其被老年人用来缓解压力,
失眠和认知缺陷;这一人群经常服用传统药物治疗其他
健康状况。因此,老年人使用Ashwagandha研究了Ashwagandha如何影响CYP活动和
表情是一个重要的问题。阿什瓦甘达是正在研究的两种植物之一,因为它有能力改善
俄勒冈州卫生与公众服务部BENFRA植物膳食补充剂研究中心的复原力
理科大学(U19 AT010829)。我们的工作将与BENFRA BDSRC的工作协同,后者将
提供经过鉴定和化学特征的阿什瓦甘达根和叶提取物,用于在
申请人在奥本大学的实验室。对于我们的项目,我们提出了两个具体目标。在目标1中,
我们将筛选不同类型的阿什瓦甘达提取物对9种人肝细胞色素P450的抑制作用(包括所有
被FDA推荐用于药物评价的环磷酰胺)。细胞色素P450在人肝脏中的抑制作用
微生物体将使用CYP探针底物和我们的超高速UHPLC-MS/MS鸡尾酒试验进行测量。在……里面
目的2,我们将评估艾希瓦甘达提取物对CYP基因表达的诱导作用。
根据FDA关于药物与药物体外相互作用的指南在三明治培养中培养人肝细胞
学习。由此产生的阿什瓦甘达提取物-CYP相互作用的综合数据将可用
通过科学出版物。阿什瓦甘达对Cyps的抑制或诱导将被证明
随后将进行进一步的研究,试图找出造成观察到的影响的化合物。
在演示与CYP酶的相互作用之后,将进行验证性的临床研究
阿什瓦甘达-药物药代动力学相互作用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Robert D Arnold其他文献
Prospective pilot study evaluating a vitamin D3 loading dose in critically ill children with vitamin D deficiency
评估维生素 D3 负荷剂量对维生素 D 缺乏症危重儿童的前瞻性试点研究
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:2.9
- 作者:
Elizabeth W. Covington;Shaneese L Jasper;Robert D Arnold;Raj Amin;Susan Egbert;Allison Chung - 通讯作者:
Allison Chung
Robert D Arnold的其他文献
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{{ truncateString('Robert D Arnold', 18)}}的其他基金
Evaluation of the potential of Ashwagandha extracts to produce CYP-mediated drug interactions.
评估 Ashwagandha 提取物产生 CYP 介导的药物相互作用的潜力。
- 批准号:
10271857 - 财政年份:2021
- 资助金额:
$ 7.45万 - 项目类别:
Secretory Phospholipases sPLA2 and their Receptors for Delivering Nanoparticles
分泌型磷脂酶 sPLA2 及其用于递送纳米颗粒的受体
- 批准号:
8419881 - 财政年份:2013
- 资助金额:
$ 7.45万 - 项目类别:
Secretory Phospholipases sPLA2 and their Receptors for Delivering Nanoparticles
分泌型磷脂酶 sPLA2 及其用于递送纳米颗粒的受体
- 批准号:
8777093 - 财政年份:2013
- 资助金额:
$ 7.45万 - 项目类别:
Secretory Phospholipases sPLA2 and their Receptors for Delivering Nanoparticles
分泌型磷脂酶 sPLA2 及其用于递送纳米颗粒的受体
- 批准号:
8601531 - 财政年份:2013
- 资助金额:
$ 7.45万 - 项目类别:
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