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Cocaine cardiovascular effects and pharmacokinetics after treatment with the acetylcholinesterase inhibitor donepezil.

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Title: Cocaine cardiovascular effects and pharmacokinetics after treatment with the acetylcholinesterase inhibitor donepezil.
Authors: Grasing, Kenneth, Mathur, Deepan, DeSouza, Cherilyn, Newton, Thomas F., Moody, David E., Sturgill, Marc
Source: American Journal on Addictions. Aug2016, Vol. 25 Issue 5, p392-399. 8p.
Subjects: Cocaine, Pharmacokinetics, Donepezil, Acetylcholinesterase, Cholinesterases, Substance abuse treatment, Substance abuse diagnosis, Bioavailability, Cardiovascular system, Cholinesterase inhibitors, Comparative studies, Crossover trials, Hydrocarbons, Research methodology, Medical cooperation, Oral drug administration, Piperidine, Preanesthetic medication, Research, Substance abuse, Evaluation research, Randomized controlled trials, Treatment effectiveness, Blind experiment
Abstract: Background: In rodents, cholinesterase inhibitors can cause sustained decreases in the reinforcing effects of cocaine. Nonetheless, cocaine is metabolized by butyrylcholinesterase (BuChE), raising concerns that cholinesterase inhibition could increase its peripheral concentrations, perhaps augmenting toxicity. Although donepezil is approved for use in patients and selective for inhibiting acetylcholinesterase over BuChE, no studies have reported cocaine bioavailability in human subjects receiving donepezil.Methods: Twelve cocaine-dependent veterans received three days of treatment with either oral placebo or 5 mg daily of donepezil, followed by cross-over to the opposite treatment. During both oral treatments, double-blind intravenous cocaine was administered at .0, .18, and .36 mg/kg in a laboratory setting, followed by determinations of heart rate, blood pressure, and plasma concentrations of cocaine and major metabolites.Results: Intravenous cocaine produced dose-related increases in systolic blood pressure that were most pronounced over the initial 30 minutes after treatment. Oral donepezil attenuated drug-induced elevations of systolic blood pressure following low-dose cocaine (.18 mg/kg). No significant difference in blood pressure following treatment with placebo or donepezil after high-dose cocaine (.36 mg/kg). Peak values of blood pressure and heart rate were unaffected by donepezil. Plasma concentrations of cocaine and metabolites did not differ in donepezil- and placebo-treated participants.Conclusions and Scientific Significance: We conclude that donepezil can attenuate drug-induced increases in systolic blood pressure following low-dose cocaine, but does not otherwise modify the cardiovascular effects of intravenous cocaine. Clinically significant changes in cocaine bioavailability and cardiovascular effects do not occur following this dose of donepezil. (Am J Addict 2016;25:392-399). [ABSTRACT FROM AUTHOR]
Copyright of American Journal on Addictions is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Cocaine cardiovascular effects and pharmacokinetics after treatment with the acetylcholinesterase inhibitor donepezil.
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  Data: <searchLink fieldCode="AR" term="%22Grasing%2C+Kenneth%22">Grasing, Kenneth</searchLink><br /><searchLink fieldCode="AR" term="%22Mathur%2C+Deepan%22">Mathur, Deepan</searchLink><br /><searchLink fieldCode="AR" term="%22DeSouza%2C+Cherilyn%22">DeSouza, Cherilyn</searchLink><br /><searchLink fieldCode="AR" term="%22Newton%2C+Thomas+F%2E%22">Newton, Thomas F.</searchLink><br /><searchLink fieldCode="AR" term="%22Moody%2C+David+E%2E%22">Moody, David E.</searchLink><br /><searchLink fieldCode="AR" term="%22Sturgill%2C+Marc%22">Sturgill, Marc</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22American+Journal+on+Addictions%22">American Journal on Addictions</searchLink>. Aug2016, Vol. 25 Issue 5, p392-399. 8p.
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  Data: <searchLink fieldCode="DE" term="%22Cocaine%22">Cocaine</searchLink><br /><searchLink fieldCode="DE" term="%22Pharmacokinetics%22">Pharmacokinetics</searchLink><br /><searchLink fieldCode="DE" term="%22Donepezil%22">Donepezil</searchLink><br /><searchLink fieldCode="DE" term="%22Acetylcholinesterase%22">Acetylcholinesterase</searchLink><br /><searchLink fieldCode="DE" term="%22Cholinesterases%22">Cholinesterases</searchLink><br /><searchLink fieldCode="DE" term="%22Substance+abuse+treatment%22">Substance abuse treatment</searchLink><br /><searchLink fieldCode="DE" term="%22Substance+abuse+diagnosis%22">Substance abuse diagnosis</searchLink><br /><searchLink fieldCode="DE" term="%22Bioavailability%22">Bioavailability</searchLink><br /><searchLink fieldCode="DE" term="%22Cardiovascular+system%22">Cardiovascular system</searchLink><br /><searchLink fieldCode="DE" term="%22Cholinesterase+inhibitors%22">Cholinesterase inhibitors</searchLink><br /><searchLink fieldCode="DE" term="%22Comparative+studies%22">Comparative studies</searchLink><br /><searchLink fieldCode="DE" term="%22Crossover+trials%22">Crossover trials</searchLink><br /><searchLink fieldCode="DE" term="%22Hydrocarbons%22">Hydrocarbons</searchLink><br /><searchLink fieldCode="DE" term="%22Research+methodology%22">Research methodology</searchLink><br /><searchLink fieldCode="DE" term="%22Medical+cooperation%22">Medical cooperation</searchLink><br /><searchLink fieldCode="DE" term="%22Oral+drug+administration%22">Oral drug administration</searchLink><br /><searchLink fieldCode="DE" term="%22Piperidine%22">Piperidine</searchLink><br /><searchLink fieldCode="DE" term="%22Preanesthetic+medication%22">Preanesthetic medication</searchLink><br /><searchLink fieldCode="DE" term="%22Research%22">Research</searchLink><br /><searchLink fieldCode="DE" term="%22Substance+abuse%22">Substance abuse</searchLink><br /><searchLink fieldCode="DE" term="%22Evaluation+research%22">Evaluation research</searchLink><br /><searchLink fieldCode="DE" term="%22Randomized+controlled+trials%22">Randomized controlled trials</searchLink><br /><searchLink fieldCode="DE" term="%22Treatment+effectiveness%22">Treatment effectiveness</searchLink><br /><searchLink fieldCode="DE" term="%22Blind+experiment%22">Blind experiment</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: <bold>Background: </bold>In rodents, cholinesterase inhibitors can cause sustained decreases in the reinforcing effects of cocaine. Nonetheless, cocaine is metabolized by butyrylcholinesterase (BuChE), raising concerns that cholinesterase inhibition could increase its peripheral concentrations, perhaps augmenting toxicity. Although donepezil is approved for use in patients and selective for inhibiting acetylcholinesterase over BuChE, no studies have reported cocaine bioavailability in human subjects receiving donepezil.<bold>Methods: </bold>Twelve cocaine-dependent veterans received three days of treatment with either oral placebo or 5 mg daily of donepezil, followed by cross-over to the opposite treatment. During both oral treatments, double-blind intravenous cocaine was administered at .0, .18, and .36 mg/kg in a laboratory setting, followed by determinations of heart rate, blood pressure, and plasma concentrations of cocaine and major metabolites.<bold>Results: </bold>Intravenous cocaine produced dose-related increases in systolic blood pressure that were most pronounced over the initial 30 minutes after treatment. Oral donepezil attenuated drug-induced elevations of systolic blood pressure following low-dose cocaine (.18 mg/kg). No significant difference in blood pressure following treatment with placebo or donepezil after high-dose cocaine (.36 mg/kg). Peak values of blood pressure and heart rate were unaffected by donepezil. Plasma concentrations of cocaine and metabolites did not differ in donepezil- and placebo-treated participants.<bold>Conclusions and Scientific Significance: </bold>We conclude that donepezil can attenuate drug-induced increases in systolic blood pressure following low-dose cocaine, but does not otherwise modify the cardiovascular effects of intravenous cocaine. Clinically significant changes in cocaine bioavailability and cardiovascular effects do not occur following this dose of donepezil. (Am J Addict 2016;25:392-399). [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Data: <i>Copyright of American Journal on Addictions is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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      – Type: doi
        Value: 10.1111/ajad.12402
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      – Code: eng
        Text: English
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        PageCount: 8
        StartPage: 392
    Subjects:
      – SubjectFull: Cocaine
        Type: general
      – SubjectFull: Pharmacokinetics
        Type: general
      – SubjectFull: Donepezil
        Type: general
      – SubjectFull: Acetylcholinesterase
        Type: general
      – SubjectFull: Cholinesterases
        Type: general
      – SubjectFull: Substance abuse treatment
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      – SubjectFull: Substance abuse diagnosis
        Type: general
      – SubjectFull: Bioavailability
        Type: general
      – SubjectFull: Cardiovascular system
        Type: general
      – SubjectFull: Cholinesterase inhibitors
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      – SubjectFull: Comparative studies
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      – SubjectFull: Crossover trials
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      – SubjectFull: Hydrocarbons
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      – SubjectFull: Piperidine
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      – SubjectFull: Randomized controlled trials
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      – TitleFull: Cocaine cardiovascular effects and pharmacokinetics after treatment with the acetylcholinesterase inhibitor donepezil.
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              Text: Aug2016
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