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Try out PMC Labs and tell us what you think. Learn More. All addictive drugs produce tolerance and addicts compensate by increasing drug exposure. Thus, the quantity of illicit drug ingested is related to the severity of addiction. Unfortunately, there are no objective methods to estimate intake for most addictive drugs. This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of single oral doses of R-MA in healthy adults to select a dose of R-MA-d3 to be used as a biomarker for estimation the amount of methamphetamine abuse.
This was a five-session randomized, double-blind, placebo-controlled, balanced crossover study in eight subjects. Pharmacokinetic and pharmacodynamic measures were obtained. No serious adverse events occurred during the study and all doses of R-MA were well tolerated. Linear pharmacokinetics was observed within our oral dose range of 1 to 10 mg.
Complete bioavailability and pharmacologic inactivity were found for all oral doses. Knowledge of the quantity Crystal meth dosage methamphetamine intake may allow better estimation of disease severity and treatment efficacy. Experience gained from this study also can be applied to the management of other drug dependence problems such as cocaine, cannabinoid, and opiate addiction.
Methamphetamine MA addiction is a worldwide public health crisis. There is a pressing need to develop treatments to manage this addictive disease with diminishing abused, illicit drug use as a primary goal. The amount of illicit drug use is usually estimated by self-report, an often noisy measure that lacks objective validation. To address the need for a quantitative method to estimate the dose of illicit MA consumed by addicts, we have developed a method to provide a continuous and objective evaluation of the efficacy of the tested treatment.
Addicts generally prefer and abuse the S isomer. Eight subjects participated in this study. The subjects Crystal meth dosage not dependent on any psychoactive drug except nicotine or caffeine according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Revised criteria.
Inclusion criteria were age 18 to 50 years, no recent less than 3 months use of MA, and ability to give informed consent. Exclusion criteria included use of medications containing MA eg, the Vicks Crystal meth dosage or medications that are metabolized to MA eg, selegiline within the last month and ificant medical or psychiatric illnesses. The study was carried out in accordance with the Declaration of Helsinki.
All doses were given at least 1 hour after and at least 2 hours before food. Intravenous doses were slowly administered over 30 minutes by an infusion pump starting 1.
The oral placebo was lactose; the intravenous placebo was 0. Because deuterium labeling does not alter the pharmacology of MA, we used unlabeled MA as the oral dose and labeled MA only for the intravenous dosing condition; in clinical trials, we will use deuterium-labeled MA. Plasma samples were collected at 15 minutes before and 0. All urine was collected in hour Crystal meth dosage with separate aliquots saved from each void.
The p-methyl analogs of each analyte are used as internal standards. Pharmacokinetic parameters were calculated by the noncompartmental trapezoidal method using the software package WinNonlin Professional Version 5. The area under the plasma concentration—time curve AUC was calculated from time 0 hour to time of the last plasma sample and with extrapolation to infinity using the terminal rate constant k.
Other parameters included terminal half-life, the maximal plasma concentration C maxand the time to maximal concentration. Blood pressure, heart rate, skin and tympanic temperature, respiratory rate, and pulse oxygen saturation were monitored noninvasively at 15 minutes before and 0.
Analysis of variance will be done on log-transformed PK parameters to test for differences between dose levels. Heart rate, systolic blood Crystal meth dosage, and diastolic blood pressure in each dose condition did not differ from placebo. No clinical ificant changes in core temperature, respiratory rate, oxygen saturation, electrocardiography, physical examination, biochemical tests, or hematologic parameters were evident. No ificant difference in corrected AUC and C max were seen compared with the 1-mg session, suggesting linear PKs within our experimental dose range.
To estimate absolute bioavailability, we gave 2. Major PK parameters for each subject are summarized in Table 2. The half-life is similar between the intravenous and oral routes. Pharmacokinetic PK Parameters for 2. of subjective measures were similar with no differences from placebo on visual analog scales or clinical parameters Fig. Crystal meth dosage, methamphetamine; po, orally; iv, intravenously. Based on these data, we have selected 5 mg as the preferred biomarker dose because it is the lowest dose that met all the requirements.
One puzzling outcome was the unexpected bioavailability of more than one for most subjects. This unexpected finding may be partly the result of the following reasons. First, some portion of the intravenous dose may have been lost during administration. A dead space in the intravenous tubing of approximately 2 mL was inherent in the de of the infusion system.
Second, we cannot rule out possible carryover effects from oral dose sessions or self-administered illicit MA use during the trial. Although AUC 0—t was adjusted to them by subtracting the area contributed by the predose level to get closer to the actual value, data manipulation in such a manner will still introduce some variation.
In conclusion, this is the first study supporting development of a semiquantitative method for estimating abused drug exposure. We plan to apply Crystal meth dosage method in clinical trials, allowing continuous estimates of MA abuse during the trial. Using a known dose of a reference compound will help us to better control a variety of factors affecting the disposition of MA. This is the first step for a potentially important change in the evaluation of MA treatments efficacy. Knowledge of the quantity of Crystal meth dosage intake may allow better estimation of disease severity and treatment efficacy.
Knowledge gained from this study also can be applied to the management and assessment of disease severity in other addictions; cocaine, opiate, and cannabinoid addictions are natural targets. National Center for Biotechnology InformationU. Ther Drug Monit. Author manuscript; available in PMC Feb Gantt P. Matthew J. Author information Copyright and information Disclaimer. Copyright notice.
The publisher's final edited version of this article is available at Ther Drug Monit. See other articles in PMC that cite the published article. Abstract All addictive drugs produce tolerance and addicts compensate by increasing drug exposure. Keywords: methamphetamine, abuse, biomarker.
Pharmacokinetic Measures Sample Collection Plasma samples were collected at 15 minutes before and 0. Pharmacokinetic Analysis Pharmacokinetic parameters were calculated by the noncompartmental trapezoidal method using the software package Crystal meth dosage Professional Version 5. Pharmacodynamic Measures Physiological Measures Blood pressure, heart rate, skin and tympanic temperature, respiratory rate, and pulse oxygen saturation were monitored noninvasively at 15 minutes before and 0. Open in a separate window.
Parameters 1 mg R-MA 2.
References 1. Ann Ist Super Sanita. Pharmacotherapy for methamphetamine dependence: Crystal meth dosage review of the pathophysiology of methamphetamine addiction and the theoretical basis and efficacy of pharmacotherapeutic interventions. Ann Clin Psychiatry. Available at: www. Human pharmacology of the methamphetamine stereoisomers. Clin Pharmacol Ther. Gas chromatographic determination of methamphetamine and its metabolite amphetamine in human plasma and urine following conversion to N-propyl derivatives.
J Chromatogr. The bioavailability of intranasal and smoked methamphetamine. Exploratory assessment of dose proportionality: review of current approaches and proposal for a practical criterion. Pharm Stat. Formation of the para-hydroxy methamphetamine metabolite is not enantiomer specific.
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