Drug development of clavulanic acid, a GLT-1 activator: proof of concept for cocaine use disorder
GLT-1 激活剂克拉维酸的药物开发:可卡因使用障碍的概念证明
基本信息
- 批准号:10597589
- 负责人:
- 金额:$ 138.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-15 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AbstinenceAddressAdultAmoxicillin-Potassium Clavulanate CombinationAnimalsAnteriorAntibioticsAreaBackBehaviorBehavior TherapyBiological MarkersBrainBrain regionCause of DeathCensusesCessation of lifeChronicClavulanic AcidsClinicalCocaineCocaine AbuseCocaine DependenceCocaine use disorderCorpus striatum structureCuesDataDeath RateDedicationsDevelopmentDevelopment PlansDisease remissionDoseEffectivenessExtracellular SpaceFormulationFunctional Magnetic Resonance ImagingGlutamate TransporterGlutamatesGoalsHalf-LifeHumanInpatientsIntellectual PropertyIntravenousInvestigationMagnetic Resonance SpectroscopyMeasuresMediatingMethamphetamineModelingMotivationMusNeurotransmittersNucleus AccumbensOralOutpatientsOverdosePatient Self-ReportPatientsPersonsPharmaceutical PreparationsPharmacologic SubstancePhasePlacebo ControlPlacebosPublishingRandomizedRattusReportingResearchRestRodentSafetyScheduleSerumSiteTestingTherapeutic EffectTitrationsToxic effectUrineaddictionalcohol preferring ratsbenzoylecgoninebeta-Lactamscingulate cortexclinical developmentcocaine cravingcocaine cuecocaine exposurecocaine seekingcocaine self-administrationcocaine useconditioned place preferencecravingdrug developmentefficacy studyextracellularimprovedmeetingsnovel therapeuticsoverdose deathpreclinical developmentpreclinical studypsychostimulantresponsesafety studytherapeutic effectivenesstimelinevolunteer
项目摘要
Cocaine-related overdose deaths are rapidly rising in the U.S. An effective medication for cocaine addiction is
urgently needed. This proposal aims to determine whether clavulanic acid (CLAV) is effective in treating
cocaine use disorder. Animal studies suggest that activation of GLT-1, the dominant astroglial glutamate
transporter responsible for clearing extracellular glutamate, may provide a breakthrough approach to managing
cocaine addiction. Studies in rodents demonstrate that CLAV, a non-antibiotic component of the commonly
used antibiotic Augmentin, has short-term effects to a) increase GLT-1 activity, thus reducing extracellular
glutamate in brain areas associated with addiction, i.e., the nucleus accumbens (NAc) and its afferent limbic
region, the anterior cingulate cortex (AC), and b) inhibit the reinforcing strength of cocaine in a model of
cocaine self-administration. We have concluded an inpatient study, required by the FDA, showing that the co-
administration of CLAV and cocaine to volunteer non-treatment-seeking adults with cocaine use disorder is
associated with decreased cocaine craving and produces no serious toxicity. Using magnetic resonance
spectroscopy (MRS) at 3T, we have human pilot data demonstrating changes in brain glutamate in the AC
after the first dose of CLAV, and this is maintained for 10 days of daily CLAV dosing. We now propose two
human trials to assess the therapeutic effectiveness of CLAV: 1) We will determine whether CLAV maintains
its therapeutic effects to reduce cocaine craving when given orally once-a-day, since CLAV has a very short
half-life in the serum. Glutamate levels in the AC, measured after cessation of CLAV dosing, will be used as a
biomarker to assess whether CLAV can be dosed once daily. Resting state functional connectivity will
determine whether the AC increases target engagement with the NAc, and whether network deficits associated
with chronic cocaine use are improved by repeated CLAV. 2) In subjects who tolerate CLAV 500 mg/day, we
will determine the effects, safety and tolerability of CLAV 750 mg/day. 3) Finally, we will conduct a
randomized, placebo controlled multi-site, outpatient efficacy study of CLAV in cocaine-addicted patients
seeking treatment, using a formulation for once-daily dosing as determined in 2). If efficacy is confirmed (Go-
No Go decision point), the project will transition to our pharmaceutical company partner, VistaGen, who will be
supporting formulation development, intellectual property and regulatory strategy, as well as clinical and
preclinical development during this proposal. With VistaGen, we will schedule an FDA meeting to explore
breakthrough therapy status and discuss development plans leading to a New Drug Application submission.
在美国,与可卡因有关的过量死亡人数正在迅速上升。一种治疗可卡因成瘾的有效药物是
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Mary F. Morrison其他文献
How to study the impact of sex and gender in medical research: a review of resources
- DOI:
10.1186/s13293-016-0099-1 - 发表时间:
2016-10-01 - 期刊:
- 影响因子:5.100
- 作者:
Alyson J. McGregor;Memoona Hasnain;Kathryn Sandberg;Mary F. Morrison;Michelle Berlin;Justina Trott - 通讯作者:
Justina Trott
6.60 DEMOGRAPHICS OF CHILDREN WITH ATTENTION-DEFICIT/HYPERACTIVITY DISORDER AND TREATMENT MODALITIES: AN ANALYSIS OF NATIONAL AMBULATORY MEDICAL CARE SURVEY DATA FROM 2009 - 2012
- DOI:
10.1016/j.jaac.2016.09.379 - 发表时间:
2016-10-01 - 期刊:
- 影响因子:
- 作者:
Jaclyn Dietzold;Anisha Garg;Ian Peters;Christopher Combs;Rachel M. Peters;Mary F. Morrison - 通讯作者:
Mary F. Morrison
Depression in the medical setting: biopsychological interactions and treatment considerations.
医疗环境中的抑郁症:生物心理学相互作用和治疗注意事项。
- DOI:
- 发表时间:
1999 - 期刊:
- 影响因子:5.3
- 作者:
Dwight L. Evans;Jeffrey P. Staab;J. Petitto;Mary F. Morrison;M. Szuba;Herbert E. Ward;B. J. Wingate;M. P. Luber;J. O'reardon - 通讯作者:
J. O'reardon
Specialized community disease management to reduce substance use and hospital readmissions
- DOI:
10.1016/j.drugalcdep.2016.08.115 - 发表时间:
2017-02-01 - 期刊:
- 影响因子:
- 作者:
Jaclyn E. Chambers;Adam C. Brooks;Mary F. Morrison;James R. McKay;David R. Gastfriend - 通讯作者:
David R. Gastfriend
Mary F. Morrison的其他文献
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