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Background: Cocaine abuse is associated with an increased risk of cardiac and cerebrovascular events, such as myocardial infarction, sudden cardiac death, and ischemic stroke. The underlying mechanisms leading to these complications are not fully understood although intravascular thrombus formation and accelerated atherosclerosis are prominent findings. In this sense, in vitro studies have demonstrated that cocaine may induce damage and/or activation of endothelial cells. The structural and functional integrity of the endothelium is essential for the maintenance of vascular homeostasis and its damage plays a critical role in the pathogenesis of vascular disease. Endothelial dysfunction may be assessed by testing the impaired vasodilator response to a stimulus or by measuring the release of plasma markers of endothelial damage. Increased number of circulating endothelial cells (CECs) has been reported in several pathologic conditions associated with severe vascular damage and its enumeration in peripheral blood is currently considered a reliable method to assess endothelial damage. We hypothesized that chronic exposure to cocaine induces endothelial damage which could be expressed by increased CEC counts in peripheral blood. Methods: Twenty cocaine-dependent subjects (aged 19–52 years, mean age 30 years) and 25 healthy, matched controls (aged 20–49 years, mean age 31 years) were studied; all patients fulfilled DSM-IV criteria for cocaine dependence with drug exposure within the 72 hours prior to blood sampling. CECs were isolated from peripheral blood by use of immunomagnetic beads coated with anti-CD146, stained for CD45 and Ulex Europaeus lectin 1 and counted under fluorescence microscopy. MCP-1, sICAM-1, von Willebrand factor and high-sensitivity C-reactive protein (hsCRP) were measured by enzyme-linked immunosorbent assay. Results: Compared to controls, CECs were significantly elevated among cocaine users (632 ± 281 vs 67 ± 54 cells/mL, p<0.0001). Plasma levels of sICAM-1 (360±92 ng/mL) and MCP-1 (166±71 pg/mL) were increased in cocaine-dependent individuals compared to the controls (261±34 and 67±29, respectively; p< 0.01). The hsCRP levels were significantly increased (6.8 mg/L); however plasma von Willebrand factor concentration was not different between patients and controls (86.4±22 vs 70.5±16%, respectively; NS). Levels of CECs correlated positively with sICAM-1 (r: 0.7; p: 0.003) and hsCRP (r: 0.56; p: 0.0037). Conclusions: Highly increased number of CECs and significant increments in soluble plasma markers of endothelial perturbation were found in cocaine dependent individuals. This is the first demonstration of endothelial dysfunction among these individuals and our findings support the notion that cocaine-induced endothelial damage may play a pathogenic role in the ischemic vascular disease observed in chronic cocaine users.

Objectives: It is known that the interindividual and interethnic variability of the genetic polymorphisms of CYP2D6 plays an important role in the presentation of adverse drug reactions and concerning lack of therapeutic effects in humans. However, there are few data available from mixed populations of Latin America, including the Chilean. The aim of this study was therefore to estimate the frequencies of CYP2D6 variants in two samples of hospitals from the northern (Hospital San José, HSJ) and eastern (Clínica Las Condes, CLC) parts of Santiago, Chile, with different degrees of Amerindian admixture (HSJ: 34.5%; CLC: 15.9%). Methods: We used polymerase chain reaction followed by restriction endonuclease digestion (PCR-RFLP) to genotype 7 CYP2D6 alleles in 250 healthy unrelated individuals of Chilean Mestizo background. The detection of allele CYP2D6*5 and the duplication of this gene was performed by long-PCR. Results: The degrees of Amerindian admixture are reflected in the observed frequencies of the CYP2D6*1 (HSJ: 58.26%; CLC: 41.06%), CYP2D6*2 (HSJ: 28.10%; CLC: 40.65%), and CYP2D6*4 (HSJ: 8.26%; CLC: 12.60%) alleles; the frequencies of CYP2D6*1 (p = 0.0002) and CYP2D6*2 (p = 0.0036) are significantly different between the samples. Four individuals (CLC: 0.41%; HSJ: 1.24%) could not be assigned to a genotype. We identified 3.25% of the genotypes which predict a poor metabolizer phenotype in CLC and 1.65% in HSJ. Conclusion: Our data indicate ethnic group-dependent genetic differences in the vulnerability to treatment with the large variety of drugs metabolized by the enzyme CYP2D6.

4205 Background. Cocaine abuse is associated with an increased risk of cardiac and cerebrovascular events, such as myocardial infarction, sudden cardiac death, and ischemic stroke. The underlying mechanisms leading to these complications are not fully understood although intravascular thrombus formation and accelerated atherosclerosis are prominent findings. We have previously shown (Pereira et al. J Thromb Haemost 2009; 7[suppl 2]: 232a) that chronic cocaine use is associated with markers of endothelial dysfunction and platelet activation in subjects studied after recent consumption. It has been suggested that many of the adverse effects of cocaine on the vessel wall are due to its acute effects related to the sympathomimetic properties of the drug. However, from a pathogenic standpoint, we hypothesized that important pathologic consequences, such as early onset atherosclerosis and regional brain perfusion, defects, are not solely explained by the acute vasomotor actions of cocaine. Objectives. The main aim of this work was to investigate the effect of short-term abstinence on markers of endothelial injury and platelet activation in chronic cocaine consumers. methods . We studied 23 cocaine dependent individuals (aged 19–52years mean age 30 years) who met DSM-IV criteria for cocaine dependence, seeking treatment for cocaine abuse and 25 healthy controls (aged 20–49 years, mean age 31 years). Samples were obtained at admission within 72 hours of drug exposure and after 4 weeks of strict, controlled abstinence in a rehabilitation clinic. Endothelial cell damage was assessed by enumerating circulating endothelial cells (CECs) and plasma levels of soluble markers: soluble intercellular adhesion molecule (sICAM); monocyte chemoattractant protein (MCP-1), von Willebrand factor (VWF) and high-sensitivity C reactive protein (hs-CRP). Plasma levels of soluble CD40L (sCD40L), NAP-2 and RANTES were determined to demonstrate platelet activation in vivo. Results. Markers of endothelial cell damage/activation and platelet activation, were significantly higher in cocaine dependents individuals after recent consumption (baseline) as compared with the controls. The variations observed after 4 weeks drug withdrawal (post-abstinence) are shown in Table 1: Conclusions. Our results demonstrate that cocaine use is associated to endothelial dysfunction and platelet activation which are prominent findings after recent consumption. Evidence of endothelial cell activation/damage is still present after 4 weeks of strict and controlled abstinence when markers of platelet activation returned to their baseline levels. Taken together, these observations suggest that cocaine induced-endothelial cell damage is maintained independent of the acute effect of the drug on the blood vessels. The persistence of this condition may play a role in long-term ischemic complications associated with cocaine abuse such as early onset atherosclerosis and regional brain perfusion defects. Further studies on the mechanisms underlying cocaine-induced endothelial dysfunction might provide novel strategies to improve endothelial function as part of the treatment in recently abstinent cocaine addicts. Disclosures: No relevant conflicts of interest to declare.