Disease relevance of Cocaethyline

• Ethanol might exacerbate cocaine hepatocyte toxicity by three different pathways: a) by increasing the oxidative metabolism of cocaine and hence the oxidative damage; b) by the formation of a more toxic metabolite, namely cocaethylene; or c) by decreasing the defence mechanisms of the cell (i.e. GSH) [1].
• A similar increase in seizure prevalence, noted as a kindling effect, was observed in cocaethylene-treated animals tested with cocaethylene in that 90% of the mice exhibited status epilepticus on the last test day [2].
• CONCLUSIONS: Cocaethylene caused hypertension and increased systemic vascular resistance [3].
• In the high-dose group, at maximal cocaethylene concentrations, stroke volume decreased by 42% (p < 0.0002), and circumflex blood flow decreased by 30% (p = 0.03) relative to baseline, when arrhythmias occurred [3].
• Cocaethylene injection during murine retrovirus infection greatly exacerbated the pathogenesis of CVB3 or CMV infection, whereas CMV-infected mice showed relatively moderate cardiac pathology compared with CVB3 infection [4].

Psychiatry related information on Cocaethyline

• These data indicate that, in this paradigm, cocaethylene did not selectively modify cocaine's reinforcing potency, but there appear to be individual differences with respect to ethanol's ability to stimulate rates of drug-maintained responding [5].
• These findings suggest that cocaethylene may play a role in the morbidity and mortality associated with concurrent cocaine/alcohol abuse [6].
• As expected both routes of cocaethylene administration produced an increase in locomotor activity compared to saline-vehicle rats, with no differences between i.v. or i.p. routes with respect to duration of behavioral activation [7].
• Taken together, these findings indicate that cocaethylene has neuroendocrine properties on its own, targeting a critical region of the brain that regulates stressful events in the body [7].
• Cocaethylene produced marked locomotor and exploratory behaviors in this strain, suggesting therefore that Long-Evans and Sprague-Dawley rat differ in their response to cocaethylene [8].

High impact information on Cocaethyline

• Furthermore, both cocaine and cocaethylene induced massive NADPH-dependent reactive oxygen species production in hepatic microsomal suspensions and in homogenates of cultured hepatocytes, as directly demonstrated by superoxide dismutase- and catalase-sensitive luminol chemiluminescence [9].
• The integrated photon emission and the maximal slopes of the luminol chemiluminescence displayed similar concentration-response curves for cocaine and cocaethylene [9].
• Oxygen free radical production mediated by cocaine and its ethanol-derived metabolite, cocaethylene, in rat hepatocytes [9].
• These data suggest that reactive oxygen species, generated during the interaction of cocaine and cocaethylene with cytochrome P-450, may be the common mediators of hepatotoxicity induced by these compounds [9].
• The data suggest that additional mechanisms, such as more stable cocaethylene binding, may be a more important determinant of recovery kinetics when the channels are inactivated [10].

Chemical compound and disease context of Cocaethyline

• The present study investigated the toxicity of repeated subcutaneous cocaine administrations combined with oral doses of ethanol, and discussed the role of the toxic metabolite cocaethylene [11].

Biological context of Cocaethyline

• Importantly, the structure provides a foundation for mutagenesis to enhance the binding affinity for cocaine and potent cocaine derivatives, such as cocaethylene, and for additional humanization of the antibody [12].
• A similar rate is observed for hydrolysis of cocaethylene, a more potent cocaine metabolite that has been observed in patients who concurrently abuse cocaine and alcohol [13].
• However, no information is available concerning the potency and pharmacokinetics of cocaethylene in comparison to those of cocaine in humans [14].
• RESULTS: Cocaethylene was less potent in elevating heart rate than equivalent doses of cocaine [15].
• Differences in bioavailability between cocaine and cocaethylene and their implications for drug-reward studies [16].

Anatomical context of Cocaethyline

• Moreover, they indicate that the potential for cocaethylene to induce acute lethal cell injury in hepatocytes through oxidative mechanisms is similar to that of its parent compound, cocaine [9].
• BACKGROUND: Cocaethylene (CE) is known to increase the permeability of human microvascular endothelial cell monolayers [17].
• Extracellular levels of dopamine in the nucleus accumbens were increased to approximately 400% of preinjection value by both cocaine and cocaethylene when administered intravenously [18].
• 5. These data indicate that both cocaine and cocaethylene act directly on cardiac myocytes to produce a negative inotropic effect that is due to decreased Ca2+ availability [19].
• Cocaine and cocaethylene binding to human milk [20].

Associations of Cocaethyline with other chemical compounds

• Hydrolysis of cocaine and cocaethylene to benzoylecgonine during extraction and analysis was less than 0.5% [21].
• We conclude that cocaethylene is slightly more potent than cocaine as a blocker of HERG, whereas methylecgonidine has much lower potency, and both benzoylecgonine and ecgonine methyl ester are essentially inactive at clinically relevant concentrations [22].
• In vitro transesterification of cocaethylene (ethylcocaine) in the presence of ethanol. esterase-mediated ethyl ester exchange esterase-mediated ethyl ester exchange [23].
• Quinidine inhibition of cocaethylene degradation in human serum in vitro: a preliminary study [24].
• Fluoxetine profoundly augmented cocaethylene-stimulated behaviors in this rat phenotype [8].

Gene context of Cocaethyline

• Cocaethylene Affects Human Microvascular Endothelial Cell p38 Mitogen-Activated Protein Kinase Activation and Nuclear Factor-{kappa}B DNA-Binding Activity [17].
• Differential potencies of cocaine and its metabolites, cocaethylene and benzoylecgonine, in suppressing the functional expression of somatostatin and neuropeptide Y producing neurons in cultures of fetal cortical cells [25].
• In splenocytes isolated from the cocaine- or cocaethylene-treated mice, mitogen-stimulated production of gamma-interferon, tumor necrosis factor, and interleukin-2 was suppressed, in all cases more severely when cocaethylene was used [26].
• The data indicate that deactivation and inactivation slow the recovery and potentiate the cocaethylene inhibition of the Nav1.5 channel by distinct mechanisms [10].
• CONCLUSIONS: Cocaethylene inhibits HERG by binding to the activated or open channels and by modulating the kinetics of inactivation [27].

Analytical, diagnostic and therapeutic context of Cocaethyline

• We report the performance of a liquid chromatography (LC) assay for detection and confirmation of cocaine and cocaethylene in serum [28].
• The maximal dose of cocaethylene base administered (0.25 mg/kg) produced subjective effects that were judged as milder and tachycardic effects that were comparable to those produced by the intravenous injection of an equivalent dose (0.25 mg/kg) of cocaine base [29].
• STUDY DESIGN: Pregnant rats with long-term catheter placement received an intravenous infusion of cocaethylene during a period of 30 minutes [30].
• We have used positron emission tomography (PET) and carbon-11 (t1/2:20.4 min) labeled cocaine and cocaethylene to compare the short-term kinetics of cocaine and cocaethylene in baboon brain [31].
• Thus, both low and high doses of cocaethylene are injurious to the cellular integrity and contractility of myocardial cell cultures [32].

References