Effect of chronic antipsychotic medication administration on cocaine poisoning

长期服用抗精神病药物对可卡因中毒的影响

基本信息

批准号：
7817120
负责人：
KENNON James HEARD
金额：
$ 15.87万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7817120
关键词：
A Mouse Accident and Emergency department Acute Adrenergic Agents Affect Affinity Animals Antipsychotic Agents Attenuated Autoradiography Basic Science Binding Brain Brain region Cerebral cortex Cessation of life Chronic Clozapine Cocaine Cocaine Users Comorbidity Continuous Infusion Corpus striatum structure Dopamine Dopamine Receptor Dose Emergency Situation Future GABA Receptor Glutamates HTR2A gene Haloperidol Hearing Hippocampus (Brain)Human In Vitro Infusion procedures Intoxication K-Series Research Career Programs Lethal Dose 50 Long-Term Effects Measures Mediating Medical Mentors Modeling Mus Muscarinics N-Methylaspartate Neurotransmitter Receptor Neurotransmitters Norepinephrine Nucleus Accumbens Patients Pharmaceutical Preparations Pharmacology Physicians Placebos Poisoning Predisposition Relative (related person)Research Personnel Research Project Grants Research Training Seizures Serotonin Substance abuse problem Synapses System Testing Time Toxic effect Treatment Protocols Work Writing adrenergic aripiprazole attenuation career development cholinergic clinically relevant cocaine use density drug of abuse experience frontal lobe improved monoamine mouse model novel professor programs radioligand receptor receptor density research study response responsible research conduct severe mental illness sigma receptors skills ziprasidone

项目摘要

DESCRIPTION (provided by applicant): This K08 Career Development Award will provide Assistant Professor Kennon Heard, MD, protected time so he can obtain the basic research training and experience that he requires to become a successful independent investigator focusing on poisoning from drugs of abuse. As an emergency physician and medical toxicologist, Dr. Heard encounters patients suffering from acute abused drug intoxication every day. His long-term objective as an independent investigator is to evaluate novel therapies for such acute poisoning. He will work closely with his sponsor, Dr. Nancy R. Zahniser, an experienced cocaine researcher who has successfully mentored 20 graduate and post-graduate trainees. His proposed career development program includes writing a scholarly review summarizing the mechanisms of cocaine toxicity, taking graduate classes in CMS pharmacology and the responsible conduct of research, and completing a project to help him develop effective mentoring skills. His proposed research project arose from the observation that while almost a quarter of cocaine users have serious mental illness, little is known about the effects of psychiatric medications on the toxic effects of cocaine. A mouse model will be used to study the effect of long-term antipsychotic medication (ARM) administration on the toxic effects of a single high dose of cocaine. Cocaine blocks all three monoamine transporters, and chronic ARM administration increases the density of several neurotransmitter receptors. Dr. Heard hypothesizes that long-term administration of particular APMs will differentially alter the regional density of receptors that mediate cocaine toxicity and that these changes will differentially alter the dose-response for cocaine toxicity. Aim 1 will measure regional receptor and monoamine transporter density in mice treated for 28 days with continuous infusions of clinically relevant APMs (haloperidol, clozapine, ziprasidone, and aripiprazole) or placebo. In vitro radioligand binding and autoradiography will be used to measure the regional density of D1 and D2 dopamine; 5-HT1A, 5-HT2A, 5-HT2C and 5-HT3 serotonin; a1- and a2-adrenergic; NMDA and AMPA glutamate; GABAA; muscarinic cholinergic; and sigma receptors and of monoamine transporters. Aim 2 will determine the effect of the 28-day APM infusion on the cocaine dose required to produce seizures and lethality (ED50 and apparent LD50, respectively). Aim 3 will determine whether selective antagonists of the receptors found to be increased in Aim 1 will attenuate any altered sensitivity to cocaine observed in Aim 2. The results will identify which receptors are altered and how the susceptibility to cocaine toxicity is related to these receptor changes. This experiment will model acute cocaine use by patients taking APMs. Identifying the involved receptor systems will facilitate future studies to determine if chronic APM therapy causes the same receptor changes in humans and, therefore, may cause similar altered susceptibility to cocaine poisoning.

描述（由申请人提供）：这项K08职业发展奖将为医学博士助理教授肯诺·赫德（Kennon Heard）提供保护时间，以便他获得基础研究培训和经验，他需要成为成功的独立研究者，专注于从虐待药物中毒药。作为急诊医师和医学毒理学家，Heard博士每天都会遇到急性滥用药物中毒的患者。他作为独立研究者的长期目标是评估这种急性中毒的新疗法。他将与他的赞助商Nancy R. Zahniser博士密切合作，他是一位经验丰富的可卡因研究人员，他成功地指导了20名研究生和研究生学员。他提出的职业发展计划包括撰写一份学术回顾，总结了可卡因毒性的机制，参加CMS药理学的研究生课程和负责任的研究，并完成了一个项目，以帮助他发展有效的指导技能。他提出的研究项目来自于观察到，尽管将近四分之一的可卡因使用者患有严重的精神疾病，但对精神药物对可卡因毒性影响的影响知之甚少。小鼠模型将用于研究长期抗精神病药（ARM）给药对单剂量可卡因的毒性作用的影响。可卡因阻止了所有三个单胺转运蛋白，而慢性ARM给药增加了几种神经递质受体的密度。 Heard博士假设特定APM的长期给药会差异改变介导可卡因毒性的受体的区域密度，并且这些变化将差异地改变可卡因毒性的剂量反应。 AIM 1将测量与临床相关的APM（氟哌啶醇，氯氮平，Ziprasidone和Aripiprazole）或安慰剂连续输注的小鼠中的区域受体和单胺转运蛋白密度。体外放射性结合和放射自显影将用于测量D1和D2多巴胺的区域密度。 5-HT1A，5-HT2A，5-HT2C和5-HT3 5-羟色胺； A1和A2-肾上腺素能； NMDA和AMPA谷氨酸；加巴;毒蕈碱胆碱能；和Sigma受体和单胺转运蛋白。 AIM 2将确定28天APM输注对产生癫痫发作和致死性所需的可卡因剂量的影响（ED50和明显的LD50）。 AIM 3将确定在AIM 1中发现的受体的选择性拮抗剂是否会减轻AIM 2中观察到的可卡因的敏感性的改变。结果将确定哪些受体被改变以及可卡因毒性的易感性与这些受体变化有关。该实验将对服用APM的患者进行急性可卡因使用。识别所涉及的受体系统将促进未来的研究，以确定慢性APM治疗是否引起人类的相同受体变化，因此可能导致类似的可卡因中毒易感性改变。

项目成果

期刊论文数量（51）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prevalence of levamisole in urine toxicology screens positive for cocaine in an inner-city hospital.

在市中心一家医院，尿液毒理学中左旋咪唑的患病率筛查出可卡因呈阳性。

DOI：
10.1001/jama.2011.531
发表时间：
2011
期刊：
JAMA : the journal of the American Medical Association
影响因子：
0
作者：
Buchanan,JennieA;Heard,Kennon;Burbach,Cynthia;Wilson,MichaelL;Dart,Richard
通讯作者：
Dart,Richard

Inappropriate prescribing in elderly ED patients.

对老年 ED 患者的处方不当。

DOI：
10.1016/j.ajem.2007.10.027
发表时间：
2008
期刊：
The American journal of emergency medicine
影响因子：
0
作者：
Heard,Kennon;Wilber,Scott;Shah,ManishN
通讯作者：
Shah,ManishN

Effect of therapeutic doses of acetaminophen (up to 4 g/day) on serum alanine aminotransferase levels in subjects consuming ethanol: systematic review and meta-analysis of randomized controlled trials.

DOI：
10.1002/j.1875-9114.2012.01122.x
发表时间：
2012-09
期刊：
PHARMACOTHERAPY
影响因子：
4.1
作者：
Rumack, Barry;Heard, Kennon;Green, Jody;Albert, Donald;Bucher-Bartelson, Becki;Bodmer, Michael;Sivilotti, Marco L. A.;Dart, Richard C.
通讯作者：
Dart, Richard C.

Severe lactic acidosis after an iatrogenic propylene glycol overdose.

医源性丙二醇过量后出现严重乳酸酸中毒。