Interactions Between Intravenous Cocaine and Acetazolamide or Quinine

Study Overview
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Brief Summary
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Background: - Scientists are studying medications that may be useful in treating cocaine addiction. It is important in these studies to know whether study participants are always taking their medications as directed. This study will look at two chemicals to see if they can be used to determine whether participants are taking their medications as directed. Because acetazolamide and quinine can be measured in plasma and urine, they are good test subjects for this study. They will be given alone, and combined with intravenous cocaine. Objectives: - To see how they body handles acetazolamide and quinine alone, and when combined with cocaine. Eligibility: - Individuals between 18 and 50 years of age who have smoked or used IV cocaine for at least one year and at least three times per month during the three months prior to screening. Urine test positive for cocaine within the prior 6 months Design: Participants will be screened with a physical exam and medical history. Blood and urine samples will also be collected. This study will involve a 12-day inpatient stay at the National Institutes of Health. On days 1, 5, and 10, participants will receive a dose of cocaine. Blood, urine, breath, and saliva samples will be collected up to 18 times a day for up to about 24 hours. On days 2, 3, 4, and 5, participants will receive acetazolamide. Regular blood samples will be collected on Day 4. Day 6 is a wash-out day with no drugs or blood tests. On days 7, 8, 9, and 10, participants will receive quinine. Regular blood samples will be collected on Day 9. On day 11, blood, urine, breath, and saliva samples will be collected in the early morning. Participants will be able to leave later in the day.

Detailed Description
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Background: Cocaine dependence is a public health concern worldwide, with no FDA-approved pharmacological treatment for this condition. Thus, there is a need for controlled clinical trials to evaluate potential new pharmacological treatments. Adherence to a medication regime is a major factor in the success of treatment. In controlled clinical trials, medication adherence is often monitored by measuring specific markers ingested with the medication. No such markers are validated for use in studies of cocaine dependence treatment. Objective: Evaluate the feasibility of oral acetazolamide and quinine as adherence markers in trials of cocaine dependence treatment by determining their pharmacodynamic and pharmacokinetic interactions with intravenous (IV) cocaine. Study Population: Up to 30 healthy cocaine users aged 18-50 years who smoked or used IV cocaine for at least one year and at least three times per month during the three months prior to screening and had a positive urine test for cocaine within the last 6 months. Experimental Design and Methods: Participants are admitted to a secure residential research unit on and undergo baseline assessments on Day -1, receive training on Day 0, and receive single doses of IV cocaine (25 mg) on Days 1, 5 and 10. On Days 1, 5, and 10, dried blood spot specimens are collected up to 3 times daily over 1.5 h. Single oral doses of acetazolamide (15 mg) are given on Days 2-5 and quinine (80 mg) on Days 7-10. Blood, oral fluid, and breath specimens are collected for up to 71 h, 70 h, and 22 h, respectively, after drug administration on Days 1, 4, 5, 9 and 10. Participants will wear the AutoSense device on Days 1, 3, 4, 5, 8, 9 and 10 for up to 12 hours each day. All voided urine is collected throughout the study. Outcome measures: Primary outcome measures include cocaine, benzoylecgonine, ecgonine methylester, norcocaine, acetazolamide, and quinine pharmacokinetics in plasma and urine and whether subjective and cardiovascular responses to IV cocaine are changed when coadministered with oral acetazolamide or quinine. Secondary outcome measures include cocaine pharmacokinetics in oral fluid and breath, plasma activity of BChE and carboxylesterase (enzymes which metabolize cocaine), and basal and post-cocaine administration serum concentrations of leptin and other appetitive peptides (e.g. ghrelin, GLP-1, insulin, PYY, amylin). Benefits: There is no direct benefit to participants, but the study is likely to yield generalizable knowledge about the feasibility of acetazolamide and quinine as markers of medication adherence in future studies of pharmacological treatment for cocaine dependence. Risks: <TAB>This study poses greater than minimal risk for participants because of IV cocaine administration.

Official Title
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Pharmacodynamic and Pharmacokinetic Interactions Between Intravenous Cocaine and Acetazolamide or Quinine

Conditions
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Cocaine Use, Pharmacokinetics

Intervention / Treatment
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* Drug: cocaine
* Drug: quinine
* Drug: acetazolamide


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Age 18-50 years old Smoked or used IV cocaine for at least six months and at least three times per month during the three months prior to screening. Urine test positive for cocaine within the prior 6 months Adequate venous access for catheter placement Serum sodium and potassium concentrations within normal limits (based on Johns Hopkins Bayview Medical Center clinical laboratory) Women with reproductive potential must use a medically acceptable form of contraception for the duration of the study. Medically acceptable forms of contraception include: oral contraceptive, intrauterine device (IUD), depot hormonal preparation (ring, injection implant), or a barrier method of contraception such as a diaphragm, sponge with spermicide, or a condom. EXCLUSION CRITERIA Current physical dependence on any drug other than cocaine, caffeine, or nicotine Current clinically significant medical or psychiatric disorder, such as heart disease, kidney disease, liver disease, adrenal insufficiency, myasthenia gravis, glucose-6-phosphate dehydrogenase deficiency, epilepsy, stroke, optic neuritis, hyperthyroidism, glaucoma; or psychosis, panic attacks, depression, or mania Current sulfa allergy Currently seeking treatment for a cocaine use disorder or in such treatment within the prior 3 months Current hypertension or blood pressure readings consistently above 140 mm Hg systolic or 90 mmHg diastolic while at rest Heart rate consistently above 90 bpm or below 50 bpm while at rest History of premature coronary artery disease or heart attack before age 50 in a first degree biological relative QTc greater than 450 ms or evidence of heart block, ischemia, or other clinically significant cardiovascular disease on a 12-lead resting ECG with three-minute rhythm strip Hemoglobin less than 12.5 g/dL Blood donation within 8 weeks of study entry History of clinically significant adverse reaction to ingestion of cocaine, acetazolamide, or quinine Hypersensitivity to acetazolamide, sulfonamides, sulfonamide derivatives, quinine, mefloquine or quinidine Women who are pregnant or nursing Currently on anti-hypertensive medication

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: cocaine|25 mg IV on days 1, 5, and 10|
|Drug: quinine|80 mg orally on days 7-10|
|Drug: acetazolamide|15 mg orally on days 2-5|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic changes for IV cocaine, acetazolamide, quinine |  | 24 hours | 
| Heart rate, blood pressure |  | 3 hours | 
| Subjective response to IV cocaine |  | 3 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Esterase activity in plasma |  | 4 days | 
| Pharmacokinetic parameters for IV cocain in oral fluid |  | 24 hours | 
| Window of dectection for cocaine in oral fluid and exhaled breath |  | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cocaine, Pharmacokinetics, Pharmacodynamics, Drug Interactions, Acetazolamide