Interactions Between Intravenous Cocaine and Acetazolamide or Quinine

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: This study poses greater than minimal risk for participants because of IV cocaine
administration.

- 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