Title: Pharmacokinetic, pharmacodynamic , and toxicological interactions among Opioids and Cabotegravir
标题:阿片类药物和卡博特韦之间的药代动力学、药效学和毒理学相互作用
基本信息
- 批准号:10548530
- 负责人:
- 金额:$ 37.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AIDS preventionAddressAdherenceAnti-Retroviral AgentsAntibodiesAutopsyBiological AvailabilityBiological ProcessBloodBlood Chemical AnalysisBlood specimenBrainCD34 geneClinicalComputer softwareCoupledDataDoseDrug InteractionsDrug KineticsDrug RegulationsDrug toxicityDrug userEnzyme-Linked Immunosorbent AssayEnzymesEpigenetic ProcessExcretory functionExhibitsFailureFatigueFecesFemaleGlucuronosyltransferaseGoalsGoldHIVHIV InfectionsHalf-LifeHepatotoxicityHeroinHistologyHistonesIllicit DrugsImaging TechniquesImmunohistochemistryInbred BALB C MiceIndividualInfectionInflammatoryInjectionsIntegraseKnowledgeLeadMacaca mulattaMass Spectrum AnalysisMeasuresMembraneMetabolismModelingMorphineMorphologyMusMutationNaltrexoneOpiate AddictionOpioidOpioid ReceptorOralPainPain managementPatientsPersonsPharmaceutical PreparationsPharmacodynamicsPharmacologic SubstancePlasmaPreventionPropertyProphylactic treatmentPublicationsPublishingRegimenReportingReverse Transcriptase Polymerase Chain ReactionRiskRoleSalineSolubilitySubstance Use DisorderSystemTailTestingThe Jackson LaboratoryTissuesToxic effectToxicologyUnited StatesUnited States Food and Drug AdministrationUridine DiphosphateUrineVariantViralViral Load resultWestern Blottingabsorptionantiretroviral therapyaqueousattenuationbasechronic paincomorbiditycost effectivedrug clearancedrug metabolismepigenetic variationexperimental studyhigh riskhumanized mouseinhibitorinsightion mobilityliquid chromatography mass spectrometrymRNA Expressionmalemeltingmouse modelmu opioid receptorsnephrotoxicitynonhuman primatenovelopioid abuseopioid epidemicopioid exposureopioid misuseopioid use disorderpharmacokinetics and pharmacodynamicsprescription opioidprescription opioid misuseresponsesynergism
项目摘要
SUMMARY STATEMENT
We have identified a previously overlooked problem regarding a possible drug-drug interaction (DDI) among
patients with opioid use disorders (OUDs) with high risk to HIV that are using Pre-Existing Prophylaxis (PrEP).
Morphine and cabotegravir are metabolized by the enzyme, uridine diphosphate glucuronosyltransferase (UGT)
and when combined, can influence the rate of drug metabolism, creating a potential risk for toxicity in people
with comorbid HIV and OUD. Opioids are the cornerstone of pain management, and as long as they are
continuing to be widely prescribed for chronic pain and/ or illicitly abused, the opioid epidemic in the United
States (US) will continue to soar. OUDs are often comorbid with HIV infection, and studies have shown that
individuals who misuse opioid analgesics, as well as other illicit drugs, are most likely to have difficulty adhering
to antiretroviral (ART) medication regimens. Adverse DDI between ART and opioid abuse and/or medications to
treat OUDs are frequently reported. In a recent publication, we showed that co-exposure with morphine and ART
in HIV-infected brain reservoirs led to failure in the attenuation of viral load and increased secretion of viral-
induced inflammatory molecules. Co-exposure with morphine and ART caused an increase in several histone-
modifying enzymes which correlated with an increase in the mRNA expression of different variants of the μ-
opioid receptor; suggesting that changes in epigenetic and opioid receptors may be involved in the regulation of
DDI. Gap in Knowledge: Not much is known about the potential DDI among cabotegravir and morphine and/or
medications to treat opioid use disorders (naltrexone). On that note, we hypothesize that when taken in
combination, cabotegravir and morphine and/or naltrexone exhibit synergism that can influence the
pharmacokinetic (PK) and pharmacodynamic (PD) responses, resulting in drug toxicity. We further posit that
epigenetic variations due to the combined exposure of cabotegravir and opioids control the PK/PD responses
by regulating drug-metabolizing enzymes, transporters, and/or the μ-opioid receptors. The goal of this new
application is to evaluate potential interactions among opioids and cabotegravir. Specific Aim 1 will evaluate
the PK responses among the three groups of drugs (cabotegravir - morphine - naltrexone) in healthy mice model.
Specific Aim 2 will evaluate the PD responses, and toxicological interactions among the three groups of drugs
in non-infected or HIV-infected humanized mouse model. Specific Aim 3 will evaluate the PK/PD, and
toxicological interactions among the three groups of drugs in non-human primates. Impact: Findings will provide
novel insights in the potential mechanisms involved in the adverse DDIs among cabotegravir and opioids which
are used in clinical settings. Furthermore, an understanding of the pharmacoepigenetics will identify new targets
that might help in the interference with pharmacokinetics or pharmacodynamics of opioids and cabotegravir.
简要说明
我们已经确定了一个以前被忽视的问题,即可能的药物相互作用(DDI),
正在使用既存预防(PrEP)的HIV高风险阿片类药物使用障碍(OUD)患者。
吗啡和cabotegravir通过尿苷二磷酸葡萄糖醛酸转移酶(UGT)代谢
当它们结合在一起时,会影响药物代谢的速度,从而对人体产生潜在的毒性风险。
患有艾滋病和口腔溃疡阿片类药物是疼痛管理的基石,只要它们是
继续被广泛用于慢性疼痛和/或滥用药物,阿片类药物在美国的流行,
美国(US)将继续飙升。OUD通常与HIV感染共病,研究表明,
滥用阿片类镇痛药以及其他非法药物的人最有可能难以遵守
抗逆转录病毒(ART)药物治疗方案。ART与阿片类药物滥用和/或药物之间的不良DDI,
经常报告治疗OUD。在最近的一份出版物中,我们表明,同时接触吗啡和ART,
在艾滋病毒感染的大脑水库导致病毒载量的衰减和病毒的分泌增加失败,
诱导炎症分子。吗啡和抗逆转录病毒疗法的共同暴露导致了几种组蛋白的增加,
修饰酶,这些修饰酶与μ-
阿片受体;表明表观遗传和阿片受体的变化可能参与调节
DDI。知识差距:关于cabotegravir和吗啡之间的潜在DDI和/或
治疗阿片类药物使用障碍的药物(纳洛酮)。在这一点上,我们假设,
在组合中,卡替拉韦和吗啡和/或纳洛酮表现出协同作用,其可以影响药物的耐受性。
药物代谢动力学(PK)和药效学(PD)反应,导致药物毒性。我们进一步重申,
卡替拉韦和阿片类药物联合暴露引起的表观遗传变异控制PK/PD反应
通过调节药物代谢酶、转运蛋白和/或μ-阿片受体。这个新的目标
应用的目的是评价阿片类药物和cabotegravir之间的潜在相互作用。具体目标1将评估
三组药物(卡替拉韦-吗啡-纳洛酮)在健康小鼠模型中的PK反应。
具体目标2将评价PD反应和三组药物之间的毒理学相互作用
在未感染或HIV感染的人源化小鼠模型中。具体目标3将评价PK/PD,以及
在非人类灵长类动物中,三组药物之间的毒理学相互作用。影响:调查结果将提供
关于卡替拉韦和阿片类药物不良DDI潜在机制的新见解,
用于临床环境。此外,对药物表观遗传学的理解将确定新的靶点
这可能有助于干扰阿片类药物和cabotegravir的药代动力学或药效学。
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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Shilpa J. Buch其他文献
Shilpa J. Buch的其他文献
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{{ truncateString('Shilpa J. Buch', 18)}}的其他基金
Single cell determinants of brain in the context of viral persistence in SIV/cART/cocaine non-human primates
SIV/cART/可卡因非人灵长类动物病毒持续存在时大脑的单细胞决定因素
- 批准号:
10683001 - 财政年份:2023
- 资助金额:
$ 37.4万 - 项目类别:
Title: Pharmacokinetic, pharmacodynamic , and toxicological interactions among Opioids and Cabotegravir
标题:阿片类药物和卡博特韦之间的药代动力学、药效学和毒理学相互作用
- 批准号:
10686187 - 财政年份:2022
- 资助金额:
$ 37.4万 - 项目类别:
Uncovering HIV/opioid effects in the brain at the single cell level: transcription, chromatin accessibility, and reservoir analysis in the SIV/cART/morphine/rhesus monkey model
在单细胞水平上揭示 HIV/阿片类药物对大脑的影响:SIV/cART/吗啡/恒河猴模型中的转录、染色质可及性和储库分析
- 批准号:
10665734 - 财政年份:2021
- 资助金额:
$ 37.4万 - 项目类别:
Uncovering HIV/opioid effects in the brain at the single cell level: transcription, chromatin accessibility, and reservoir analysis in the SIV/cART/morphine/rhesus monkey model
在单细胞水平上揭示 HIV/阿片类药物对大脑的影响:SIV/cART/吗啡/恒河猴模型中的转录、染色质可及性和储库分析
- 批准号:
10656918 - 财政年份:2021
- 资助金额:
$ 37.4万 - 项目类别:
Uncovering HIV/opioid effects in the brain at the single cell level: transcription, chromatin accessibility, and reservoir analysis in the SIV/cART/morphine/rhesus monkey model
在单细胞水平上揭示 HIV/阿片类药物对大脑的影响:SIV/cART/吗啡/恒河猴模型中的转录、染色质可及性和储库分析
- 批准号:
10220475 - 财政年份:2021
- 资助金额:
$ 37.4万 - 项目类别:
Uncovering HIV/opioid effects in the brain at the single cell level: transcription, chromatin accessibility, and reservoir analysis in the SIV/cART/morphine/rhesus monkey model
在单细胞水平上揭示 HIV/阿片类药物对大脑的影响:SIV/cART/吗啡/恒河猴模型中的转录、染色质可及性和储库分析
- 批准号:
10469423 - 财政年份:2021
- 资助金额:
$ 37.4万 - 项目类别:
Molecular mechanisms underlying HIV & Cocaine-mediated microglial activation: Targeting NLRP3 inflammasome
HIV的分子机制
- 批准号:
10161058 - 财政年份:2019
- 资助金额:
$ 37.4万 - 项目类别:
Molecular mechanisms underlying HIV & Cocaine-mediated microglial activation: Targeting NLRP3 inflammasome
HIV的分子机制
- 批准号:
10846423 - 财政年份:2019
- 资助金额:
$ 37.4万 - 项目类别:
Molecular mechanisms underlying HIV & Cocaine-mediated microglial activation: Targeting NLRP3 inflammasome
HIV的分子机制
- 批准号:
10450546 - 财政年份:2019
- 资助金额:
$ 37.4万 - 项目类别:
Molecular mechanisms underlying HIV & Cocaine-mediated microglial activation: Targeting NLRP3 inflammasome
HIV的分子机制
- 批准号:
10665604 - 财政年份:2019
- 资助金额:
$ 37.4万 - 项目类别:
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