Sandbox Reserved 987: Difference between revisions

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== Medical Relevance ==

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.~~(10)~~ 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. Emergency room visits due to cocaine abuse is greater than any other drug with nearly 50% of emergency room visits involving an illicit drug.<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.

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. Emergency room visits due to cocaine abuse is greater than any other drug with nearly 50% of emergency room visits involving an illicit drug.<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.

Finding a therapeutic agent to combat cocaine, such as small molecules has proven difficult. For this reason, the focus has been switched to cocaine esterases. For over a decade, cocaine esterases have been studied and numerous findings strongly suggest that bacterial cocaine esterases should provide a safe and effective method to rapidly eliminate the symptoms of acute cocaine intoxication in humans, as well as reducing addictiveness to the drug.

As an example, there was a test done involving rhesus-monkeys and the effects of CocE on the brain after cocaine uptake.<ref>A thermostable bacterial cocaine esterase rapidly eliminates cocaine from brain in nonhuman primates.LL Howell, JA Nye, JS Stehouwer, RJ Voll, J Mun, D Narasimhan, J Nichols, R Sunahara, MM Goodman, FI Carroll and JH Woods</ref> The study was the first to evaluate the effects of CocE on cocaine brain levels. Positron emission tomography (PET) neuroimaging was used to evaluate the time course of cocaine elimination from the brain of rhesus-monkeys in the presence and absence of CocE.

(add picture)

PET scans of the rhesus-monkey brain show that just after 15 minutes of being exposed to CocE almost all the brain activity caused by cocaine has diminished; much more so opposed to saline solution. This data further supports the development of CocE for the treatment of acute cocaine toxicity.

== References ==

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 == Medical Relevance ==
-Cocaine is a tropane alkaloid produced by the South American plant Erythroxylon coca.<sup><ref>Benowitz NL. Clinical pharmacology and toxicology of cocaine. Pharmacol. Toxicol. 1993; 72(1): 3–12. [PubMed: 8441738]</ref></sup> 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.<sup><ref>Johanson CE, Fischman MW. The pharmacology of cocaine related to its abuse. Pharmacol. Rev. 1989; 41(1):3–52. [PubMed: 2682679]</ref></sup> 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.(10) 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.<sup><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></sup> Cocaine also binds cardiac and neuronal sodium channels leading to profound cardiovascular and central nervous system alterations that are frequently lethal.<sup><ref>Zimmerman JL. Cocaine intoxication. Crit Care Clin 2012; 28: 517–526</ref></sup> Cocaine abuse is a serious public health problem. Emergency room visits due to cocaine abuse is greater than any other drug with nearly 50% of emergency room visits involving an illicit drug.<sup><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></sup> 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.
+Cocaine is a tropane alkaloid produced by the South American plant Erythroxylon coca.<sup><ref>Benowitz NL. Clinical pharmacology and toxicology of cocaine. Pharmacol. Toxicol. 1993; 72(1): 3–12. [PubMed: 8441738]</ref></sup> 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.<sup><ref>Johanson CE, Fischman MW. The pharmacology of cocaine related to its abuse. Pharmacol. Rev. 1989; 41(1):3–52. [PubMed: 2682679]</ref></sup> 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.<sup><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></sup> Cocaine also binds cardiac and neuronal sodium channels leading to profound cardiovascular and central nervous system alterations that are frequently lethal.<sup><ref>Zimmerman JL. Cocaine intoxication. Crit Care Clin 2012; 28: 517–526</ref></sup> Cocaine abuse is a serious public health problem. Emergency room visits due to cocaine abuse is greater than any other drug with nearly 50% of emergency room visits involving an illicit drug.<sup><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></sup> 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.
 Finding a therapeutic agent to combat cocaine, such as small molecules has proven difficult. For this reason, the focus has been switched to cocaine esterases. For over a decade, cocaine esterases have been studied and numerous findings strongly suggest that bacterial cocaine esterases should provide a safe and effective method to rapidly eliminate the symptoms of acute cocaine intoxication in humans, as well as reducing addictiveness to the drug.
 As an example, there was a test done involving rhesus-monkeys and the effects of CocE on the brain after cocaine uptake.<sup><ref>A thermostable bacterial cocaine esterase rapidly eliminates cocaine from brain in nonhuman primates.LL Howell, JA Nye, JS Stehouwer, RJ Voll, J Mun, D Narasimhan, J Nichols, R Sunahara, MM Goodman, FI Carroll and JH Woods</ref></sup> The study was the first to evaluate the effects of CocE on cocaine brain levels. Positron emission tomography (PET) neuroimaging was used to evaluate the time course of cocaine elimination from the brain of rhesus-monkeys in the presence and absence of CocE.
 (add picture)
 PET scans of the rhesus-monkey brain show that just after 15 minutes of being exposed to CocE almost all the brain activity caused by cocaine has diminished; much more so opposed to saline solution. This data further supports the development of CocE for the treatment of acute cocaine toxicity.
 == References ==
 <references/>