Interactions Between Intravenous Cocaine and Acetazolamide or Quinine
Condition: Cocaine Use; Pharmacokinetics
Study type: Interventional
Phase: Phase 1

Summary: 
      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: 
      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.
    

Intervention name(s): cocaine; quinine; acetazolamide
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 25 mg IV on days 1, 5, and 10; 80 mg orally on days 7-10; 15 mg orally on days 2-5
Intervention MeSH terms: Quinine; Acetazolamide; Cocaine
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Cocaine; Pharmacokinetics; Pharmacodynamics; Drug Interactions; Acetazolamide