Glycine and Oral D-Cycloserine in Alcoholic Patients and Healthy Subjects - Full Text View

Sponsor:	Yale University
Information provided by:	Yale University
ClinicalTrials.gov Identifier:	NCT00635102

Purpose

Question #1: Will glycine ameliorate cognitive deficits? Hypothesis #1: Based on positive findings conducted with glycine and milacemide, a glycine prodrug, in schizophrenia and dementia, we expect that glycine will ameliorate cognitive deficits.

Question #2: Will alcoholic patients show enhanced endocrinal effects to glycine? Hypothesis #2: Based on the dose-related effects of glycine in healthy subjects, we expect that glycine will increase the endocrinal response to glycine in alcoholic patients with, supposedly, dysregulated NMDA receptor function.

Question #3: Will D-cycloserine have ethanol-like effects? Hypothesis #3: If inhibition of NMDA receptor function is fundamental to the subjective effects of ethanol, then the NMDA antagonist properties of D-cycloserine should be recognized as ethanol-like (relative to placebo) in recently detoxified alcoholics and healthy subjects.

Question #4: Will D-cycloserine reverse cognitive benefits of glycine? Hypothesis 4: Based on the dose related NMDA antagonist activity of D-cycloserine, we expect that D-cycloserine will compete with the agonist activity of glycine and therefore it will reverse the cognitive benefits of glycine.

Question #5: Will D-cycloserine inhibit endocrinal effects of glycine? Hypothesis #5: If the agonist activity of glycine is necessary to determine endocrine response, then the dose-related NMDA antagonist properties of D-cycloserine should block these effects.

Condition	Intervention
Alcohol Dependent	Drug: D-Cycloserine PO and Glycine IV Drug: Placebo

Yale University has indicated that access to an investigational treatment associated with this study is available outside the clinical trial.

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacokinetics/Dynamics Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Outcomes Assessor) Primary Purpose: Prevention
Official Title:	Glycine and Oral D-Cycloserine in Alcoholic Patients and Healthy Subjects

Resource links provided by NLM:

Drug Information available for: Glycine Cycloserine

U.S. FDA Resources

Further study details as provided by Yale University:

Primary Outcome Measures:

Gordon box test is a measure of attention and distractibility, Hopkins Verbal Learning Test measures verbal memory and hippocampus function, Visual Analog Scales of Mood States (high , mellow, confused, anxious) [ Time Frame: Baseline, -60, +30, +60, +90, +120 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Wisconsin Card Sorting Test, Visual Analog Scales of Similarity to Drugs of Abuse; number of drinks of alcohol; Positive & Negative Symptom Scale; Clinician Administered Dissociative States Scale; Biphasic Ethanol Effects; Visual Analog Scales of Craving [ Time Frame: Baseline, -60, +30, +60, +90, +120 ] [ Designated as safety issue: No ]

Enrollment:	40
Study Start Date:	October 1997
Study Completion Date:	February 2008
Primary Completion Date:	February 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Cycloserine/Placebo D-Cycloserine (1000mg) PO in am, 30 minute Placebo glycine infusion	Drug: D-Cycloserine PO and Glycine IV Test days will involve administration of D-Cycloserine in the morning in pill form then 4 hours later a 30 minute infusion of Glycine.
Active Comparator: Cycloserine/Glycine D-Cycloserine (1000mg) PO in am, 30 minute glycine 300mg/kg infusion	Drug: D-Cycloserine PO and Glycine IV Test days will involve administration of D-Cycloserine in the morning in pill form then 4 hours later a 30 minute infusion of Glycine.
Placebo Comparator: Placebo/Placebo Placebo D-Cycloserine in am, 30 minute placebo glycine infusion	Drug: Placebo Placebo
Active Comparator: Placebo/Glycine Placebo D-Cycloserine PO in am, 30 minute glycine 300mg/kg infusion	Drug: D-Cycloserine PO and Glycine IV Test days will involve administration of D-Cycloserine in the morning in pill form then 4 hours later a 30 minute infusion of Glycine.

Detailed Description:

The purpose of this study is to investigate the interaction between glycine and D-cycloserine in alcoholic patients and healthy subjects. Preclinical studies have shown that compounds acting at the glycine site of the NMDA receptor complex, such as glycine, may reverse the effects of ethanol on the NMDA receptor function (Rabe et al., 1990). The amino acid glycine is a co-agonist of the NMDA receptor complex (Kemp et al., 1993). It binds to the strychnine-insensitive site and positively modulates the NMDA receptor (Mc Donald et al., 1990). Physiologically, the glycine site is not saturated, and administration of glycine can potentiate NMDA receptor mediated responses. In contrast, D-cycloserine (Hood et al., 1989) is a partial-agonist at the glycine site of the NMDA receptor, with dose-dependent NMDA antagonist properties. The NMDA antagonist activity of D-cycloserine should produce ethanol like-effects that can be reversed by the agonist glycine. This study is intended to evaluate possible contributions of the glycine site to the reduction of cognitive deficits of alcoholism and complements the current work at VA Connecticut Healthcare System on the NMDA antagonists in alcoholic and healthy subjects.

Eligibility

Ages Eligible for Study:	21 Years to 70 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion / Exclusion Criteria Alcoholic subjects:

Male or female (post-menopausal, surgically sterile, or negative pregnancy test at screening and agreement to utilize an established birth control during the testing period) between the age of 21 and 70 yrs.
Meet DSM IV criteria for alcohol dependence by structured clinical interview
Meet von Knorring criteria for early onset (type II) alcoholism
Without other DSM IV Axis I diagnoses by SCID.
Without lifetime history of other substance abuse diagnosis by SCID (excluding tobacco) and urine toxicology screen negative for drug of abuse.
Medically and neurologically healthy on the basis of history, physical examination, SMAC-20, CBC w/diff. and EKG. In light of the proximity to alcohol dependence, LFT elevations of twice normal will be accepted into the study.
Patients with stable medical problems may be included in the study if their medications have not been adjusted in the month prior to participation and if these medications lack prominent CNS effects.
Absence of alcohol within the past 15 days.
Patients must be free of medications utilized to facilitate detoxification (lorazepam, oxazepam) for at least 3 days prior to initiating testing.
Patients must have no history of alcoholic hallucinosis.
Patients must not be in acute alcohol withdrawal as evidence by a score no more than 2 for each item of the Clinical Institute Withdrawal Assessment Scale
Patients taking ethionamide or isoniazid will be not be allowed to participate in the study.

Inclusion / Exclusion Criteria Healthy subjects:

Male or female (post-menopausal, surgically sterile, or negative pregnancy test at screening and agreement to utilize an established birth control during the testing period) between the age of 21 and 70 yrs.
Absence of a lifetime substance abuse diagnosis by the non-patient version of the SCID.
Medically and neurologically healthy on the basis of history, physical examination, SMAC-20, CBC w/diff. and EKG. In light of the proximity to alcohol dependence, LFT elevations of twice normal will be accepted into the study.
Absence of alcohol within the past 14 days
Healthy subjects will be matched to the patient group for age, sex and educational level.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00635102

Sponsors and Collaborators

Yale University

Investigators

Principal Investigator:

John H Krystal, M.D.

Yale University

More Information

No publications provided

Responsible Party:	John H Krystal, Yale University School of Medicine
ClinicalTrials.gov Identifier:	NCT00635102 History of Changes
Other Study ID Numbers:	12449, VA Merit Grant
Study First Received:	March 6, 2008
Last Updated:	March 12, 2008
Health Authority:	United States: Food and Drug Administration

Keywords provided by Yale University:

Alcohol Dependence, Alcoholism, Glycine, D-Cycloserine

Additional relevant MeSH terms:

Cycloserine
Glycine
Anti-Infective Agents, Urinary
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Renal Agents
Antibiotics, Antitubercular

Anti-Bacterial Agents
Antitubercular Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Glycine Agents
Neurotransmitter Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on February 09, 2012