Sandbox Reserved 987: Difference between revisions

The wild-type cocaine esterase is not stable at physiological temperature, which poses a problem for its use as a pharmaceutical drug. Mutations have been conducted in order to increase its thermostability. In vivo testing showed the wild-type having a 11 min half-life. A mutant having its threonine swapped for a arginine at position 172 was found to last 9 times as long, and a mutant that further had its glycine swapped for a glutamine was found to last 24 times as long (~4hr 20min)^{<ref>Gao D., Narasimhan D. L., Macdonald J., Brim R., Ko M., Landry D. W., Woods J. H., Sunahara R. K., Zhan C. (2009) Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol. Pharmacol. 75, 318-323.</ref>}

Cocaine is a tropane alkaloid produced by the South American plant Erythroxylon coca.^{<ref>Benowitz NL. Clinical pharmacology and toxicology of cocaine. Pharmacol. Toxicol. 1993; 72(1): 3–12. [PubMed: 8441738]</ref>} Cocaine’s psychological effects occur via binding to neurotransmitter reuptake transporters in the presynaptic nerve termini and blocking them, leading to prolonged presence of neurotransmitters in the synapse.^{<ref>Johanson CE, Fischman MW. The pharmacology of cocaine related to its abuse. Pharmacol. Rev. 1989; 41(1):3–52. [PubMed: 2682679]</ref>} Large amounts of dopamine and serotonin in the synapse results in feelings of euphoria and wellbeing. This lingering increase in neurotransmitters within the synapse can lead to self-administration and, therefore, addiction. When cocaine is bound to noradrenergic transporters, elevated noradrenergic signaling occurs, resulting in increased heart rate (HR), blood pressure and vasoconstriction which are often seen in cocaine users.^{<ref>Crumb WJ Jr, Kadowitz PJ, Xu YQ, Clarkson CW. Electrocardiographic evidence for cocaine cardiotoxicity in cat. Can. J. Physiol. Pharmacol. 1990; 68(5):622–625. [PubMed: 2340451]</ref>} Cocaine also binds cardiac and neuronal sodium channels leading to profound cardiovascular and central nervous system alterations that are frequently lethal.^{<ref>Zimmerman JL. Cocaine intoxication. Crit Care Clin 2012; 28: 517–526</ref>} Cocaine abuse is a serious public health problem. 50% of emergency room visits are due to illicit drug use, cocaine accounts for the majority of those cases.^{<ref>Ball, JK.; Albright, V. National Estimates of Drug-Related Emergency Department Visits. Rockville, MD, USA: Substance Abuse and Mental Health Services Administration, Office of Applied Studies; 2008</ref>} Interestingly, despite cocaine’s broad use and high addictiveness, there is no US FDA-approved medication for the treatment of cocaine abuse or toxicity. Physicians treat patients enduring cocaine toxicity with standard emergency room agents that control arrhythmias, convulsions and high blood pressure but not with drugs that directly address the toxic levels of cocaine present in the patient.