The anti-platelet agent Clopidogrel and the vasodilator isradipine are proposed to treat chronic cocaine abusers who have regional cerebral blood flow (rCBF) defects identified with Tc-HMPAO-SPECT. These rCBF defects may be related to highly abnormal platelet activation that can- lead to platelet thrombi as small cerebral arterioles vasoconstrict secondary to release of vasoactive compounds from these platelets. We are currently engaged in a randomized clinical trial comparing a standard clinical dose of an antiplatelet agent aspirin to placebo, but in a preliminary analysis- in which Aspirin is reducing platelet adhesion, the rCBF defec~are only partially responding. However, the new antiplatelet agent clopidogrel, which also vasodilates, has been shown to be more effective than aspirin in clearing platelet thrombi. Thus, we will test it and isradipine because this calcium channel blocker aftenuates -cocaine-induced vasoconstriction. Three hypotheses are considered. First, inhibition ofplateletfi?nction and vasodilation in chronic cocaine abusers could enhance the resolution of cocaine-related CBF abnormalities. Second, we hypothesize a positive correlation between improvement in rCBF defects and neuropsychological test peiformance, which has shown impairment in over 50% of cocaine dependent patients. We also have previously shown a correlation between these baseline cognitive deficits and rCBF defects. Third, with improvement in cognitive~nction then the efficacy for relapse prevention of our subsequent outpatzent care using cognitive behavioral therapy will be improved. To test these hypotheses the study design is a four-week, residential trial followed by 8 weeks of outpatient care. Cocaine-dependent subjects with defects in rCBF are randornized to placebo vs clopidogrel 75 mg during years 1-3 and to placebo vs isradipine 10 mg during years 3-5. We will measure rCBF and neuropsychological test performance at intake and after four weeks of treatment and then assess urine toxicologies three thnes weekly for weeks 5-12 as outpatients. Regional cerebral perfiision will be assessed using technetiurn~99m-D,L-hexamethyl propyleneamine oxime (HMPAO) and single photon emission computed tomography (SPECT) on a Prism 3000 xP, a state-of-the-art triple-headed garmna camera. For these studies we also have developed irnage analyses using distribution based scaling and deficit burden analysis that compare our scans to our own normal database for statistical parametric mapping.
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