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Human Laboratory Trial of Doxazosin for Cocaine Dependence: Accumulating evidence implicates noradrenergic (NE) systems in mediating the effects of stimulants (1-8). Mice lacking NE £\ -1 receptor mice show reduced sensitivity to cocaine and amphetamine (8, 9). Local depletion of prefrontal cortex (PFC) NE reduced rewarding effects of amphetamine and reduced amphetamine-induced dopamine (DA) release in the PFC and accumbens (7), suggesting that PFC NE contributes to the rewarding effects of stimulants. Treatment with the NE ƒÑ-1 antagonist prazosin has been shown to antagonize a variety of effects produced by cocaine and amphetamine. In rats, prazosin (1-2 mg/kg) significantly attenuated the locomotor activating effects produced by cocaine (10-12) and for amphetamine (4, 13, 14). Similar findings have been observed for the discriminative stimulus effects produced by cocaine and amphetamine in mice (15) and for food-maintained responding in pigeons (16). More recently, prazosin (0.3 mg/kg) reduced reinstatement of extinguished cocaine-seeking behavior in rats without affecting responding for food, suggesting that prazosin my blunt the motivational effects of drug cues (5). Clinical Experience with Alpha-1 Adrenergic Antagonists: Prazosin is a prototypical antagonist at NE £\-1 receptors. When first released the medication was thought to produce relaxation of smooth muscles in the vasculature. Since then however it has been determined that prazosin antagonizes norepinephrine and this mediates the antihypertensive effect (17). The medication has been assessed extensively for the treatment of hypertension (18). The initial dose is 1mg two or three times per day. The usual dose range is 6mg/day to 15mg/day, with some patients requiring up to 40mg/day in divided doses. The most common side effects are: dizziness 10.3%, headache 7.8%, drowsiness 7.6%, lack of energy 6.9%, weakness 6.5%, palpitations 5.3%, and nausea 4.9%. In most instances side effects have disappeared with continued therapy or have been tolerated with no decrease in dose of drug. More recently, prazosin has been successfully used to treat post traumatic stress disorder (19, 20). For this indication, prazosin was initiated at 1mg at bedtime and increased as needed to control symptoms to up to 15mg at bedtime by day 28. This approach resulted in no change in systolic and diastolic blood pressure compared to pretreatment measurements. Several subjects reported transient dizziness upon standing (9/14 in the prazosin group and 6/15 in the placebo group), but none reported syncope. Prazosin has a relatively short elimination half-life of 3.5 h (21). Longer-lasting cogeners (e.g. terazosin and doxazosin) are available, but there is no experience using these medications as treatments for cocaine dependence. The purpose of this study is to evaluate the effects of doxazosin on the cardiovascular and subjective effects of cocaine in a human laboratory study. Doxazosin was selected because it has a longer elimination half-life (22h) compared to terazosin (12h). The side-effect profile of doxazosin closely resembles that of prazosin.
Allocation: Randomized, Control: Placebo Control, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Health Services Research
Sugar Pill, Doxazosin
Michael Debakey VA Medical Center
National Institute on Drug Abuse (NIDA)
Published on BioPortfolio: 2014-08-27T03:16:08-0400
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The purified, alkaloidal, extra-potent form of cocaine. It is smoked (free-based), injected intravenously, and orally ingested. Use of crack results in alterations in function of the cardiovascular system, the autonomic nervous system, the central nervous system, and the gastrointestinal system. The slang term "crack" was derived from the crackling sound made upon igniting of this form of cocaine for smoking.
Disorders related or resulting from use of cocaine.
An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake.
A selective alpha-1-adrenergic blocker that lowers serum CHOLESTEROL. It is also effective in the treatment of HYPERTENSION.
Reversibly catalyzes the oxidation of a hydroxyl group of sugar alcohols to form a keto sugar, aldehyde or lactone. Any acceptor except molecular oxygen is permitted. Includes EC 1.1.1.; EC 1.1.2. and EC 1.1.99.
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