Thomas Richard Kosten, M.D. - US grants

The proposed project is formulated in response to a request for service research in drug abuse treatment that includes the goal of "improving the ability of treatment programs to match clients with appropriate treatment and appropriate types and levels of treatment services, to measure the cost-effectiveness of treatment, and to deal with special populations" (NIDA RFA DA-9-02, January 1993). We propose to meet this goal by conducting a randomized clinical trial of two intensities of ancillary psychosocial treatment services that we will provide to a sample of low SBS, unemployed, methadone maintenance program (MMP) patients, utilizing many of the research methodologies employed in Project MATCH and, additionally, conducting comprehensive cost-effectiveness and cost-benefit analyses. Upon entry into methadone maintenance treatment, 480 unemployed patients, recruited from two MMPs, will be randomly assigned to either a weekly psychoeducational group or an intensive Day Treatment Program, each 12 weeks in duration. Outcomes will be assessed post-treatment and at a six-month follow-up in five domains: illicit drug-use, psychological functioning, vocational/social adjustment, medical status/high risk behaviors, and utilization of services. Five patient-treatment matching characteristics will be investigated: race, sex, cocaine abuse, comorbid depression, and antisocial personality disorder. The specific aims of the proposed study are fourfold: (1) to conduct a simultaneous replication study investigating the differential impact of two levels of psychosocial treatment intervention at two MMPs -- a small federally-funded VA MMP and a large inner-city State-funded MMP, both located in the same metropolitan area; (2) at the inner-city site, to determine whether the five identified subgroups of MMP patients differentially benefit from the two treatment intensities under investigation; (3) to determine if benefits derived from the two treatments are differentially maintained at a six-month follow-up, and if they are differentially maintained by the five patient subgroups; and (4) to determine which intensity of treatment is most cost-effective and cost-beneficial overall and for each subgroup.

biomedical equipment purchase;

vaccine development; cocaine; human therapy evaluation; active immunization; immunotherapy; antibody formation; drug addiction; drug addiction antagonist; drug abuse therapy; cooperative study; clinical research; human subject;

DESCRIPTION: (Applicant's Abstract) The Annual Scientific Meetings and Symposia of the American Academy of Addiction Psychiatry (AAAP) are one of the primary formal technology transfer mechanisms used by the Academy to present the latest research and clinical findings in the field of addictions. Supplementing the formal plenary sessions, the Annual Meetings offer participants the opportunity to informally exchange information in workshops, at Lunch with the Experts and through other networking activities. The American Academy of Addiction Psychiatry will hold its 9th Annual Scientific Meeting and Symposium on December 3-6, 1998 at the Ritz Carlton, Amelia Island, Florida. Meetings in subsequent years are scheduled as follows: December 2-5, 1999 - Nassau; December 7-10, 2000 - Phoenix; December 6-9, 2001 - Site TBD; and December 5-8, 2002 - Site TBD. Attendance ranges from 200-250 and our participants are primarily addiction psychiatrists and other addiction treatment professionals. We hope to increase the attendance of members in training (medical students and residents) with the assistance of NIDA. The overall educational objectives of the Annual Meetings flow directly from the purposes for which the Academy was incorporated in 1985; specifically, 1) To promote excellence in clinical practice in addiction psychiatry, 20 To provide continuing education for addiction professionals, 3) to disseminate new information in the field of addiction psychiatry, and 4) To encourage research on etiology, prevention, identification and treatment of the addictions. The following symposium topics have been identified for the 1998 meeting: 1. Forensic Issues in Addiction Psychiatry 2. The Genetic Basis for Alcohol and Drug Dependence 3. Contingency Management Approaches to the Treatment of Drug Abuse 4. New Developments in the Treatment of Opiate Dependence 5. Pain Management and Addiction 6. Methamphetamines: A scientific and Clinical Update

DESCRIPTION: Applicant's Abstract The Annual Scientific Meetings and Symposia of the American Academy of Addiction Psychiatry (AAAP) are the nucleus of several technology transfer mechanisms used by the Academy to present the latest research and clinical findings in the field of addictions to a broad array of health care providers. Supplementing the formal plenary sessions, the Annual Meetings offer workshops, small group discussions, Lunch with the Experts, Breakfast for Trainees, poster sessions, and committee meetings. Attendance at the Annual Meetings is approximately 250-275 participants. In the past two years, attendance has increased in numbers and in the breadth of the attendees; it is anticipated that attendance will increase by approximately 25-50 persons per year with an increasing percentage of trainees, members of underrepresented population groups and non-members. The following six symposium topics have been selected for the 11th Annual Meeting: Harm Reduction: Defining It and Doing It Properly in Order to Reduce Harm; Pharmacologic Treatment of Comorbid Depression, Adolescent Substance Abuse, Pathologic Gambling, Traumatic Brain Injury and Substance Use Disorders, and Substance Abuse in Native American Populations. The generic educational objectives of the Annual Meetings are: 1. To promote excellence in clinical practice in addiction psychiatry, 2. To provide continuing education for addiction professionals, 3. To disseminate new information in the field of addiction psychiatry, and 4. To encourage research on the etiology, prevention, identification and treatment of the addictions

DESCRIPTION (provided by applicant): This Center for Medications Development (MDU) has a theme of developing new GABA enhancing medications and using genetic approaches to optimally match successful cocaine pharmacotherapies such as disulfiram and the GABA reuptake blocker tiagabine to subgroups of cocaine dependent patients- We are conducting two outpatient randomized clinical trials and a series of five laboratory screening studies for new GABA enhancers. The first project is a randomized, placebo-controlled, 12-week clinical trial examining 150 cocaine-dependent methadone-stabilized patients in a trial of disulfiram and the GABA reuptake blocker tiagabine. These patients will be stratified based on a functional dopamine beta hydroxylase (DBH) polymorphism with the prediction of a treatment response to disulfiram only in those with the genetic haplotype that leads to low OBH levels and relatively higher dopamine (DA) levels. The second project includes 140 depressed. recently abstinent, cocaine-dependent patients in a randomized, placebo-controlled, 12-week relapse trial with four treatment groups: placebo, sertraline. sertraline + tiagabine and sertraline + gabapentin. This trial includes an initial 2 weeks of inpatient abstinence. The patients in both projects will undergo genetic screening of GABA related polymorphisms as potential predictors of treatment response to GABA enhancers in future studies. The third project will use cocaine administration to humans in a laboratory in order to screen five GABA enhancers for their potential utility as pharmacotherapies. These three projects involve examination of nine different potential cocaine pharmacotherapies in clinical trials and the human laboratory. These clinical trials offer an interesting contrast in DA enhancement by disulfiram or the DA reuptake blocker sertraline versus DA reduction by the GABA enhancers - tiagabine and gabapentin. Overall, over 300 patients will be studied in this Center and eight different agents in either outpatient Phase II trials or human laboratory studies.

DESCRIPTION (provided by applicant): This application renews a Research Scientist Award to enable Dr. Kosten to continue to pursue full time research and to train new researchers in the pharmacotherapy of cocaine and opioid dependence. During the last 5 years, Dr. Kosten has published over 100 articles, been a mentor for 5 junior faculty and 5 fellows, participated extensively in research reviews, and provided national and international consultations on pharmacotherapy. His broader roles include leadership in national organizations such as Presidency of the American Academy of Addiction Psychiatry and dissemination of buprenorphine treatment for opiate dependence through national education programs and leadership in the New England Clinical Trials Network. During the proposed award period, Dr. Kosten will continue mentoring and training activities and pursue two research goals. Goal 1 is to develop innovative cocaine pharmacotherapies (FDA Phase 1), conduct randomized clinical trials of them (FDA Phase 2), and develop new biomarkers of treatment response. Goal 2 is to use biological markers, such as genetic polymorphisms, to improve prediction of pharmacotherapy outcome and potentially match patients to the most effective treatment. His new NIDA Center (P50-DA18197) supports Goal 1 with a human laboratory for phase 1 testing of pharmacotherapies that currently include GABA agonists, and by 2006 will include a highly specific dopamine reuptake inhibitor (RTI 336) and a monoclonal antibody. Funded Phase 2 trials include: a cocaine vaccine, bupropion with contingency management, and 2 Center funded studies. A detailed Research Plan is provided for the cocaine vaccine study. This 20 week, randomized placebo-controlled, double blind clinical trial vaccinates 120 patients maintained on methadone for comorbid opioid and cocaine dependence. The Center's Phase 2 studies also address Goal 2 to examine pharmacogenetics of cocaine abuse treatment response. One study relates a functional polymorphism of dopamine beta hydroxylase to disulfiram response. Another study relates polymorphisms of GABA receptors and metabolism to treatment response with GABA agents, and a third relates the short/long promoter polymorphism of the serotonin transporter to treatment response with serotonin reuptake inhibitors. Coupled to these research goals are mentoring of junior researchers and the dissemination of information on new treatment approaches to addiction.

DESCRIPTION (provided by applicant): The high rate of smoking in schizophrenia, the improvement in cognition with tobacco use and the deterioration in cognition with tobacco withdrawal suggests that smoking may improve cognitive deficits or medication side effects. One manifestation of these cognitive deficits is auditory sensory gating, which measures suppression the evoked response to the second of two auditory stimuli. It is diminished in schizophrenia and is associated with impairment in attention and perceptual disturbances. This inhibitory process is associated with the 7 nicotinic acetylcholine receptor (7nAChR), which can be a target for pharmacotherapy in schizophrenia. We hypothesize that the alpha-7 nicotinic receptor agonist tropisetron may improve cognitive and perceptual disturbances and symptoms in schizophrenia when added on to the atypical neuroleptic risperidone. This 12-week, double-blind, randomized, placebo-controlled trial adds tropisetron (10 mg) or placebo on to 6 mg risperidone in 200 first-episode Chinese schizophrenics living in Beijing. Six Specific Aims assess whether tropisetron can: 1. ameliorate cognitive deficits as assessed by the MATRICS, 2. alleviate negative psychotic symptoms, 3. reduce the side effects of risperidone, 4. reverse the abnormality in P50 inhibition, when present, 5. improve cognitive impairments in the same patients who normalize P50 inhibition, 6. reduce nicotine use (tobacco smoking) among those schizophrenics who smoke, which is a planned stratification with half smokers and half non-smokers. Our Preliminary Data support the efficacy of tropisetron in normalizing the P50 abnormality of schizophrenia, and we are further evaluating its optimal dosing for improvement in cognitive functioning. We have an IND pending for tropisetron, and it is potentially available in the United States through the manufacturer (NabovanD, Novartis Pharmaceuticals Ltd.) Finally, we have validated Chinese neuropsychological assessment tools to use in Beijing, where we have had previous success in conducting large pharmacotherapy trials.

1,2-Benzenediol, 4-(2-amino-1-hydroxyethyl)-, (R)-; 1-(aminomethyl)cyclohexaneacetic Acid; 1-Naphthalenamine,1,2,3,4-tetrahydro-4-(3,4-dichlorophenyl)-N-methyl-, (1S-cis)-; 2 propylvalerate; 2,3-4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate; 3,4-Dihydroxyphenethylamine; 3,4-Dihydroxyphenethylamine, ascorbate[{..}]oxygen oxidoreductase (beta-hydroxylating); 3-(2-Aminoethyl)-1H-indol-5-ol; 3-Heptanone, 6-(dimethylamino)-4,4-diphenyl-; 4-(2-Aminoethyl)-1,2-benzenediol; 5-HT; 5-Hydroxytryptamine; 5HT; 5HT transporter; 5HTT protein; 8-Azabicyclo(3.2.1)octane-2-carboxylic acid, 3-(benzoyloxy)-8-methyl-, methyl ester, (1R-(exo,exo))-; Abstinence; Abuse, Cocaine; Active Follow-up; Adanon; Address; Agonist; Althose; Antabuse; Antidepressant Agent; Antidepressant Drugs; Antidepressants; Antidepressive Agents; Arkansas; Attenuated; Baclofen; Benzenepropanoic acid, beta-(aminomethyl)-4-chloro-; Bis(diethylthiocarbamoyl) Disulfide; Blood; Brain; British Isles; Butanoic Acid; Butanoic Acids; Butyric Acid; Butyric Acids; Carrier Proteins; Chlorophenyl GABA; Chronic; Clinical Pharmacology; Clinical Trials; Clinical Trials, Phase II; Clinical Trials, Unspecified; Cocaine; Cocaine Abuse; Collaborations; Connecticut; Consultations; Core Facility; Corpus Luteum Hormone; Coupled; DBH; Data; Delta4-pregnene-3,20-dione; Dependence, Substance; Depressed mood; Depression; Development; Disease; Disorder; Disulfiram; Dolophine; Dopamine; Dopamine Reuptake Inhibitors; Dopamine Uptake Inhibitors; Dopamine beta-Hydroxylase; Dopamine-beta-monooxygenase; Drug Therapy; Drug usage; Drugs; Electrophysiology; Electrophysiology (science); Emotional Depression; Encephalon; Encephalons; Enhancers; Enteramine; Forecast of outcome; Functional Magnetic Resonance Imaging; Future; GAT; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Screening; Genetics, Human; Glutamate Carboxy-Lyase; Glutamate Decarboxylase; Glutamic Acid Decarboxylase; Great Britain; Greece; Haplotypes; Hippophaine; Human; Human Genetics; Human, General; Hydroxytyramine; Idiopathic Parkinson Disease; Individual; Inpatients; Interdisciplinary Research; Interdisciplinary Study; International; Investigators; L-Glutamate-1-carboxy-lyase; L-glutamic acid, polymer with L-alanine &L- tyrosine; LTH; Laboratories; Laboratory Study; Lactogenic Hormone, Pituitary; Levarterenol; Levonorepinephrine; Lewy Body Parkinson Disease; MRI, Functional; Magnetic Resonance Imaging, Functional; Mammotropic Hormone, Pituitary; Mammotropin; Man (Taxonomy); Man, Modern; Measures; Medical Imaging, Single Photon Emission Computed Tomography; Medication; Medicine; Mental Depression; Methadone; Methadose; Method LOINC Axis 6; Methodology; Mexico; Mission; Molecular Genetic; Molecular Genetics; Multidisciplinary Collaboration; Multidisciplinary Research; N-(4,4-di(3-methylthien-2-yl)but-3-enyl)nipecotic acid; Nerve Impulse Transmission; Nerve Transmission; Nervous System, Brain; Neurobiology; Neuroendocrine; Neuroendocrine System; Neuronal Transmission; Neurontin; Neurophysiology / Electrophysiology; Neurosecretory Systems; New Agents; Noradrenaline; Norepinephrine; Numbers; Out-patients; Outcome; Outcome Assessment (Health Care); Outcomes Assessment; Outpatients; PBO; PCP-GABA; PRL; PRL (Prolactin); Paralysis Agitans; Paranoia; Paranoid Disorders; Parkinson; Parkinson Disease; Parkinson's; Parkinson's disease; Parkinsons disease; Patient Self-Report; Patients; Pennsylvania; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology, Clinical; Pharmacotherapy; Phase 2 Clinical Trials; Phase II Clinical Trials; Phenotype; Placebo Control; Placebos; Polymorphism (Genetics); Polymorphism, Genetic; Pregn-4-ene-3,20-dione; Pregnenedione; Prevention of relapse; Primary Parkinsonism; Procedures; Progesterone; Prognosis; Programs (PT); Programs [Publication Type]; Prolactin; Promoter; Promoter Regions; Promoter Regions (Genetics); Promoters (Genetics); Promotor; Promotor (Genetics); Promotor Regions; Promotor Regions (Genetics); Publications; Radionuclide Tomography, Single-Photon Emission-Computed; Randomized; Randomized Clinical Trials; Range; Receptor Protein; Relapse; Relative; Relative (related person); Research; Research Personnel; Researchers; Reticuloendothelial System, Blood; SPECT; SPECT imaging; SUBGP; Safety; Science of Medicine; Scientific Publication; Screening procedure; Selection (Genetics); Self-Report; Series; Serotonin; Sertraline; Sham Treatment; Site; Spain; Specificity; Study, Interdisciplinary; Subgroup; Substance Addiction; Support of Research; Symptoms of depression; Technology; Technology Transfer; Testing; Tetraethylthioperoxydicarbonic Diamide, ((H2N)C(S))2S2; Tetraethylthiuram Disulfide; Therapeutic Progesterone; Thioperoxydicarbonic diamide (((H2N)C(S))2S2), tetraethyl-; Tomography, Emission-Computed, Single-Photon; Toxicology; Training; Transcranial magnetic stimulation; Transcription Activation; Transcriptional Activation; Transport Proteins; Transporter Protein; Trials, Randomized Clinical; Universities; Up-Regulation; Up-Regulation (Physiology); Upregulation; Urinary System, Urine; Urine; Virginia; Week; Withdrawal Symptom; Work; base; beta-(Aminomethyl)-4-chlorobenzenepropanoic Acid; beta-(p-Chlorophenyl)-gamma-aminobutyric Acid; clinical investigation; clinical significance; clinically significant; depressed; depressive; depressive symptoms; disease/disorder; disorder later incidence prevention; dopamine beta hydroxylase; drug abuse chemotherapy; drug abuse pharmacotherapy; drug use; drug/agent; endophenotype; enzyme activity; fMRI; follow-up; gabapentin; genetic promoter element; glutamic acid-alanine-tyrosine terpolymer; improved; inhibitor; inhibitor/antagonist; innovate; innovation; innovative; interest; luteotropic hormone; luteotropin; neurobiological; neuroimaging; neurotransmission; new technology; outcome forecast; phase 2 study; phase 2 trial; phase II trial; poly(Glu(60)Ala(30)Tyr(10)); poly(L-glutamic acid(60)-L-alanine(30)-L-tyrosine(10)); polymorphism; prevention of disease recurrence; prevention of disorder recurrence; prevention of later incidences of a disorder; prevention of recurrence; programs; protocol, phase II; randomisation; randomization; randomly assigned; receptor; response; reuptake; sadness; screening; screenings; serotonin transporter; sham therapy; sodium-dependent serotonin transporter; study, phase II; tiagabine; topiramate; treatment program; valproate; week trial

DESCRIPTION (provided by applicant): This 16 week, six site, placebo-controlled randomized, clinical trial (PC-RCT) among 300 cocaine dependent patients is designed to test the efficacy of a newly developed active vaccine against cocaine (TA-CD). All six sites have substantial NIDA experience in conducting PC-RCT with cocaine pharmacotherapies. The primary objective of this study is to evaluate the efficacy of two different doses of TA-CD (100 or 400 ug) versus placebo to increase the number of cocaine-free days across treatment groups in cocaine-dependent patients. Secondary objectives of this study are: to evaluate safety and tolerability of five injections of TA-CD, to evaluate immunogenicity of TA-CD, to investigate any correlation between change in levels of cocaine use, craving, or subjective effects of cocaine and antibody levels, and finally, to examine predictors of treatment response. Previous work with the TA-CD vaccine has shown both doses (100 and 400 ug) and a regimen of 5 injections over 12 weeks are clinically safe and produce substantial levels of anti-cocaine antibody. During a previous PC-RCT, cocaine abusers with these anti-cocaine antibodies (AB) substantially reduced their smoked cocaine and had a significant reduction in overall cocaine use. That study also showed an expected variation in AB levels was a determinant of therapeutic response (e.g. higher AB levels were associated with a greater reduction in cocaine use). That previous PC-RCT provided effect size data for calculating the sample size of 300 with a potential dropout of up to 30%. In order to enhance retention in this 16-week study, we will use contingency management (CM), which in a pilot study provided outstanding retention of over 80% for a 16 week study. To complete this study within a 3 year period and have reasonable accrual and retention of this difficult population requires participation of six sites. These six extremely well-qualified research groups have comparable and complementary skills that can examine innovative ways to deliver a medical therapy through vaccination. The six sites are: Baylor College of Medicine (BCM), (lead); University of Cincinnati; Johns Hopkins University; University of Pennsylvania; New York University; and, Columbia University. All of these collaborators are working with the pharmaceutical manufacturer--Celtic, and NIDA to help with data management and laboratory-processing for quantitative urine toxicology. PUBLIC HEALTH RELEVANCE: New approaches are needed to help treat those addicted to cocaine to successfully keep from relapsing to drug abuse after withdrawal. Vaccines that stimulate strong antibody responses against cocaine will help such individuals by blocking the drug craving that occurs after re-exposure to cocaine in someone who has been abstinent. This research will define ways to make and effectively use such vaccines to stimulate high antibody levels that will have the best chance of success.

DESCRIPTION (provided by applicant): This Medications Development Center (MDC) for cocaine pharmacotherapy renewal has evaluated over 25 new medications, introduced many new technologies (fMRI, pharma MRI, SPECT, genetics), and facilitated multidisciplinary collaborations among clinical pharmacology, laboratory medicine, neuroimaging, and molecular genetics. We have 78 publications in the past 4 years, covering cocaine genetics (GABA transporter) to vaccines and opiate and nicotine research collaborations with the Chinese National Institute on Drug Dependence. In our continuation we will focus on medication development by modulating norepinephrine (NE) and dopamine (DA) and propose six Specific Aims. 1. To conduct human laboratory cocaine- and methamphetamine (MA)-administration studies with 4 new agents for safety and efficacy: RTI-336 (DA transporter blocker), SY117 (adenosine 2a inhibitor to increase DA activity), and two novel agents, YPK10A and JD-Tic (kappa opiate antagonist) (Proj 1). 2. To conduct two clinical trials of agents modulating NE activity through alpha 1-NE blockade (prazosin and carvedilol) or NE reduction by inhibiting dopamine beta hydroxylase (Proj 2 &3). 3. To test for NE genetic matching of patients to the 3 medications in our two clinical trials. 4. To continue pilot research focused on human genetics for matching new NE and other agents to effective cocaine &MA pharmacotherapies. 5. To attract and train new drug abuse pharmacotherapy investigators through our Center's Core facilities and projects. 6. To disseminate our findings through education and international collaborations. PUBLIC HEALTH RELEVANCE: Cocaine- and MA-dependence are major public health problems in the United States. No FDA-approved treatments for cocaine- or methamphetamine-dependence exist. A greater knowledge of the basic biology of cocaine- and methamphetamine dependence combined with genetic matching for medication response will lead to improved treatments for the disorder. CENTERS CHARACTERISTICS

This Medications Development Center (MDC) for cocaine pharmacotherapy renewal has evaluated over 25 new medications, introduced many new technologies (fMRI, pharma MRI, SPECT, genetics), and facilitated multidisciplinary collaborations among clinical pharmacology, laboratory medicine, neuroimaging, and molecular genetics. We have 78 publications in the past 4 years, covering cocaine genetics (GABA transporter) to vaccines and opiate and nicotine research collaborations with the Chinese National Institute on Drug Dependence. In our continuation we will focus on medication development by modulating norepinephrine (NE) and dopamine (DA) and propose six Specific Aims 1. To conduct human laboratory cocaine- and methamphetamine (MA)-adminlstration studies with 4 new agents for safety and efficacy: RTI-336 (DA transporter blocker), SY117 (adenosine 2a inhibitor to increase DA activity), and two novel agents, YPK10A and JD-Tic (kappa opiate antagonist) (Proj 1). 2. To conduct two clinical trials of agents modulating NE activity through alpha 1-NE blockade (prazosin and carvedilol) or NE reduction by inhibiting dopamine beta hydroxylase (Proj 2 &3). 3. To test for NE genetic matching of patients to the 3 medications in our two clinical trials. 4. To continue pilot research focused on human genetics for matching new NE and other agents to effective cocaine &MA pharmacotherapies. 5. To attract and train new drug abuse pharmacotherapy investigators through our Center's Core facilities and projects. 6. To disseminate our findings through education and international collaborations

PROJECT SUMMARY (See instructions): Comorbid cocaine dependence among methadone maintained patients interferes with treatment outcomes. Prazosin (alphai-adrenergic antagonist) and DpH inhibition (disulfiram) have shown promising results in the treatment of cocaine dependence. While inhibition of DpH activity is hypothesized to increase dopamine (DA) but decrease norepinephrine neurotransmission and to intensify the dysphoric experience of cocaine use, the selective inhibition of alphai-adrenergic receptor antagonist is hypothesized to attenuate DA neurotransmission primarily in the nucleus accumbens and to reduce the reinforcing effects of cocaine use. The objective of this proposal is to determine to what extend does prospective screening for a functional polymorphism of dopamine beta hydroxylase (DBH-1021C[unreadable]vT) or polymorphisms in the promoter region and the coding region ofthe alpha-la-adrenoceptor receptor gene (ADRAIA) predict the treatment efficacy of nepicastat (a new DpH inhibitor) or prazosin among newly admitted methadone treated patients. Based on our previous studies, we hypothesize that carriers ofthe low-OpH associated T allele will have significant reductions in cocaine use, because they are more susceptible to inhibition of DpH by nepicastat. We also will assess post-hoc the impact of functional variants ofthe ADRAIA on the response to prazosin. This 12- week double-blind, placebo controlled randomized clinical trial will provide treatment for 150 cocainedependent opioid dependent patients who have 2-weeks of methadone induction and 4 week discontinuation for 18-weeks total. Participants, aged 18-65 years, will be randomized to receive prazosin 10 mg/day, nepicastat 120mg/day, or placebo while concurrently receiving treatment with methadone. All participants receive weekly 1-hour psychotherapy (Cognitive Behavioral Treatment). The primary outcomes will be reduction in opioid and cocaine use, as assessed by self-report and confirmed by thrice-weekly urinalyses. The proposed study is expected to provide a better understanding ofthe role ofthe DpH inhibitor nepicastat and the selective alphaiA adrenergic receptor antagonist prazosin on cocaine using behavior among distinct DBH -1021C-+T genotypes or the functional variants in the promoter and coding region of ADRA1A.

DESCRIPTION (provided by applicant): Immunization against methamphetamine (MA) is potentially valuable in assisting patients in stopping their abuse. Vaccines against both nicotine and cocaine have been promising in both animal and human studies. Immunotherapeutic approaches to MA addiction also appear promising, but much work is needed to design a MA vaccine that induces high levels of specific antibody. Recent discoveries about regulatory cytokine and chemokine networks and innate immune system toll receptor signaling has opened the door to new ways to regulate immune responses to foreign antigens. We will use these advances in immunological adjuvants and carrier proteins to make a safe and effective MA vaccine. Our Preliminary Results with a new MA vaccine show substantial antibody levels and effects on locomotor activity, but indicate that the carrier protein and adjuvant will make a critical difference in efficacy. We will synthesize a panel of conjugate MA vaccines using different conjugates and different immunological carriers. Four carriers will be compared: Tetanus toxoid, neisseria meningitidis outer membrane protein (OMPC), cholera toxin B and a new lipopeptide based, self-adjuvanting vaccine carrier. In addition, a panel of adjuvants will be examined, carefully selected to complement the biological activity of the selected carrier. These adjuvants include CpG oligonucleotides, MPL, and a squalene-based adjuvant;CFA and alum will be included as controls. Outcomes will be the quantity, quality, and persistence of the antibody response in rodent models as well as inhibition of MA-induced locomotor activity. Based on these data, a clinical candidate and 2 back-ups will be selected and characterized in more detail in preparation for an IND filing. The ability of the vaccine to alter MA pharmacokinetics and metabolism will be assessed, as well as inhibition of reinstatement of MA self-administration. Finally, material suitable for use in a Phase I clinical trial will be manufactured and formal toxicology testing will be completed. At the completion of the funding period, we anticipate filing an IND and commencing clinical testing of a MA vaccine. The key investigators in this application have been successfully collaborating at Baylor for the last two years. Dr. Thomas Kosten has worked with our consultant Dr. Fox for over 10 years developing a cocaine vaccine from pre-clinical concept to successful clinical trials. Dr.Therese Kosten is a leading expert in animal models of stimulant abuse. Drs. Rossen, Baughn and Orson have extensive experience in immunology, and Drs. Orson and Kinsey have been working on the development of DMA vaccines. Our group's combined experience is ideally positioned to get a vaccine quickly into phase 1 human studies.

DESCRIPTION (provided by applicant): Four factors make this methamphetamine (MA) vaccine ready for clinical translation: 1. Our candidate vaccine has optimal adjuvant and antibody responses;2. Our partnering Chinese manufacturer has Chinese FDA support for the vaccine IND and matching clinical study funds;3. The PI has 15 years experience developing medications in China and a successful cocaine vaccine. We can accelerate MA vaccine development well beyond the 15 years needed for cocaine in the USA, because the manufacturer has Chinese government financial and FDA support and commercial incentives from the lack of approved treatments for MA. Our R01(DA023898) has identified an optimal carrier protein - Keyhole Limpet Hemocyanin (KLH), which is already approved for human use, and an approved Chinese squalene lipid adjuvant that is better than standard alum to optimize the anti-MA antibody response to vaccination. The optimal KLH-adjuvant vaccine combination will be determined within two years by correlating the quality and quantity of the induced antibodies with inhibition of MA locomotion and self-administration behavior in rats and primates. We then rapidly moved into cGMP synthesis, animal toxicology, CMC, IND filing and phase 1 and 2a clinical trials in years four/five. 4. Concurrently with this Chinese human vaccine, we plan to renew R01-DA023898 to develop a similar lipid adjuvant vaccine in collaboration with the Sabin Vaccine Institute, which is moving to Baylor in July 2011 and has a squalene adjuvant (Easai, E6020) with FDA approval. These two linked programs will have major practical impacts on MA's profound morbidity in the USA and China through collaborative vaccine development between American and Chinese investigators and manufacturers to produce a first and potentially a second generation vaccine quickly into clinical development in the USA and Asia. PUBLIC HEALTH RELEVANCE: MA vaccines will provide practical and cost effective treatment options, as cocaine and ni