How To Use Catheter To Replace Dirty Urine With Clean Urine Drug Test

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• J Pharmacol Exp Ther
• PMC3126645

J Pharmacol Exp Ther. 2011 Jul; 338(1): 31–36.

A Method to Quantify Illicit Intake of Drugs from Urine: Methamphetamine

Received 2011 Jan xi; Accepted 2011 Mar 28.

Abstract

Qualitative urinalysis can verify forbearance of drug misuse but cannot detect changes in drug intake. For drugs with slow elimination, such every bit methamphetamine (MA), a single episode of abuse tin outcome in up to 5 days of positive urine drug screens. Thus, interventions that produce substantial decreases in drug employ but do not achieve almost complete abstinence are classified equally ineffective. Using nonpharmacologic doses of deuterium-labeled fifty-methamphetamine (50-MA-d_iii) we have adult a simple, robust method that reliably estimates changes in MA intake. Twelve subjects were dosed with 5 mg of l-MA-d₃ daily and challenged with xv, 30, and 45 mg of nonlabeled d-MA (d-MA-d₀) later on reaching plasma steady condition of l-MA-d_iii. Urinary concentration ratios of d-MA-d₀ to l-MA-d₃ provided clear separation of the administered doses with as little every bit 15-mg dose increments. Administered doses could non exist resolved using d-MA-d₀ concentrations alone. In conclusion, the urinary [d-MA-d₀]:[l-MA-d_three] provides a quantitative, continuous measure of illicit MA exposure. The method reliably detects small, clinically relevant changes in illicit MA intake from random urine specimens, is acquiescent to deployment in clinical trials, and can be used to quantify patterns of MA abuse.

Introduction

Epidemics of methamphetamine (MA) abuse and habit are occurring throughout the earth (Schifano et al., 2007; Degenhardt et al., 2008; McKetin et al., 2008), fueled by the illicit synthesis of 197 to 624 metric tons of illicit amphetamine-like drugs per year, enough for more than 10 billion thirty-mg MA doses (http://www.unodc.org/documents/wdr/WDR_2010/World_Drug_Report_2010_lo-res.pdf). Some of these abusers go the addicts who create social, health, and crime consequences that impact all levels of club (Watanabe-Galloway et al., 2009). Thus, there is a pressing need to develop treatments for MA habit. Unfortunately, despite an intense endeavor over the last 20 years, no medications take been proven constructive for the handling of MA addiction (Karila et al., 2010).

Results of qualitative urine toxicology tests are the principal objective outcome measures for most antiaddiction trials, including trials for MA habit. Urine immunoassays that are sensitive (just non specific) and cheap and can be deployed in the dispensary are usually used in these trials. To eliminate faux-positive results drug identity is confirmed and a urine drug concentration measured using sensitive and specific assay methods that always include mass spectrometry (MS). Although these methods yield precise and authentic urine concentrations, several factors, including age, hydration status, urine pH, and urine flow, all make back-extrapolation from urine concentration to the quantity of drug abused difficult, if not impossible. As a issue, the results of urine drug tests are only scored as a fourth dimension series of binary outcomes of "positive" or "negative."

Abstinence is the goal of addiction treatments, and qualitative urine toxicology is exceedingly sensitive for detecting drug employ in normally abstemious individuals. Notwithstanding, it is not sensitive in detecting either reductions or cursory periods (upward to ii–three days) of abstinence in individuals. Thus, extremely large reductions in abuse (perhaps upwardly to ninety%) are needed before even a pocket-sized reduction in urinalysis-positive results will be evident and the treatment will be accepted as constructive (National Found on Drug Abuse/College on Problems of Drug Dependence, 1999). This degree of stringency may be the reason for failure of all treatments for MA addiction tested to date. If new treatments for stimulant corruption are unlikely to yield sudden, total forbearance, then qualitative methods that are unable to measure less than full forbearance are non likely to be useful in selecting drug or other treatment candidates that may subtract but not eliminate illicit intake. Considering the growing list of failed trials for MA dependence, developing methods that allow nonbinary continuous estimation of drug intake has go essential.

To determine illicit intake we have been testing the utility of giving small, pharmacologically inactive oral doses of deuterium-labeled drugs or metabolites that have a pharmacokinetic profiles similar to the abused drug of interest. We then determine urinary concentration ratios of unlabeled (illicit and self-administered) to deuterium-labeled drug (or metabolite) to arrive at an gauge of intake and exposure to the addictive drug. The method is analogous to using an internal standard in analytic chemical science.

In this article we present laboratory validation of a method for quantitatively estimating exposure to MA. When used in a clinical trial this method changes a binary to a continuous measure and will let evaluation of partial efficacy of a putative treatment. To appraise MA intake we used trideuterated l-MA with deuterium labeling on the methyl group. In prior work we have shown that this level of deuteration does non change the pharmacology of MA in humans (Harris et al., 2003). l-MA [also notated R-(−)-MA] is the less pharmacologically active isomer compared with d-MA [as well notated S-(+)-MA]. In work leading to this study we established that 5-mg oral doses of l-MA are completely absorbed, take no measurable subjective or cardiovascular effects, and are easily detected in urine (Li et al., 2010).

Materials and Methods

Subjects.

Twelve healthy, nondependent, MA-using subjects (viii men, four women; hateful age 31 ± 10 years; hateful weight 72 ± 13 kg; 83% white) participated in this written report. To be included subjects had to have used MA for at to the lowest degree 1 year with more than 20 lifetime exposures but not be MA-dependent by criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Participants were in skillful wellness as judged by medical test, laboratory tests (including hematologic, hepatic, and renal serum chemistries), urinalysis, and ECG. The written report was approved by the California Pacific Medical Center and Academy of California, San Francisco institutional review boards. The study was carried out in accord with the Proclamation of Helsinki.

Study Design.

A fixed-sequence, open-characterization design with sequential outpatient-inpatient phases was used. Oral doses of 5 mg of fifty-MA-d_three were administered for xiv days. On days 1 to 7 subjects were outpatients. During this period, a single oral dose of 5-mg l-MA-d₃ was administered every morning under direct supervision. Subjects were admitted to the inquiry ward on day 7. On report days eight, 10, and 12, a series of ascending intravenous d-MA-d₀ doses of 15, 30, and 45 mg were given. Each d-MA-d₀ dose was administered over 1 min under infusion pump control (Harvard Appliance Inc., Holliston, MA). The xv-mg dose was given equally a unmarried infusion. The xxx-mg dose was given as two 15-mg infusions with doses separated by i h. The 45-mg dose was given equally five 9-mg infusions each separated by 1 h. This pattern was designed to simulate a d-MA binge.

Earlier each outpatient l-MA-d₃ dose pharmacodynamic effects were assessed. Subjects were monitored for i h later dosing and had Visual Analog Calibration measures and vital signs measured before discharge. During the inpatient phase, vital signs and subjective-effect measures were obtained oft. During infusions subjective and cardiovascular measures were obtained before and 15 min after each infusion and at 0.5, 1, ane.5, 2, iv eight, 24, and 48 h after the last infusion.

Blood Collection.

Venous blood samples (approximately 7 ml) were obtained using sterile techniques from an indwelling intravenous catheter. During the outpatient phase trough plasma levels were obtained before dosing. On infusion days plasma samples for d-MA-d₀ and fifty-MA-d_iii levels were obtained before and at 0.25, 0.five, 1, 2, four, 8, 24, and 48 h later on dosing. For the 30- and 45-mg doses, boosted plasma samples were obtained immediately before and xv min afterwards each infusion and at 0.5, 1, 2, 4, 8, 24, and 48 h after the last dose.

Urine Collection.

During the inpatient phase subjects voided equally needed. All voided urine was collected with time, volume, and urine pH of each individual sample recorded.

Bioassay.

d-MA-d₀ and l-MA-d_three in plasma and urine were measured past combined gas chromatography (GC)-MS, using dl-MA-d_ix as the internal standard. The analytes were extracted from the respective biofluids, converted to the trifluoroacetyl amide derivatives, separated by gas chromatography on a Restek Rtx-200 MS analytical column (Restek, Bellefonte, PA), and detected by mass spectrometry operated in the chemical ionization mode, using isobutane as the reagent gas. The molecular ion species (M + H)⁺, m/z 246, 249, and 255, were monitored for the trifluoroacetyl amides of MA-d₀, MA-d_iii, and MA-d₉, respectively. Interday accuracy for the measurement of MA-d₀ and MA-d₃ in urine ranged from 108 to 109%, respectively, at the v ng/ml limit of quantitation, and from 100 and 105%, respectively, at 2500 ng/ml. The corresponding coefficients of variation were 12 and 7.v% at the limit of quantitation and 4.5 and 5.three% at 2500 ng/ml. In all cases MA-d_three could easily exist quantified against a background of MA-d₀.

Pharmacokinetic Analysis.

Pharmacokinetic data for d-MA-d₀ and l-MA-d₃ were analyzed using nonlinear mixed-effect models implemented using the programme NONMEM (version 7; NONMEM Project Grouping, University of California, San Francisco). A population pharmacokinetic model (based on complete data from 12 subjects) of oral repeated l-MA-d₃ dosing indicates that pharmacokinetic steady land reached within v days of daily oral doses of 5 mg of l-MA-d₃. The full model volition exist presented in a divide article.

Urinary Data Analysis.

The unlabeled-to-labeled MA urine concentration ratio, which we formally notate as [d-MA-d₀]:[l-MA-d_iii], was determined for each collected urinary sample. Linear discriminant analysis was used to test whether [d-MA-d₀]:[fifty-MA-d_iii]differentiated between administered doses of d-MA-d₀. Classifier accuracy was evaluated by discipline-based get out-ane-out cantankerous-validation. Each subject's data were classified based on a training set consisting of the other subject area's data. Because of the incomplete systemic distribution of MA, urine specimens nerveless within the get-go five h of d-MA-d₀ dosing were not used to railroad train the classifier but were used equally test information. A split up assay was conducted for urine specimens collected more than 24 h after dosing, because the concentration ratio is afflicted by continued daily oral 50-MA-d₃ administration at 24 h. McNemar's test was used to compare accuracy between classification methods. A linear regression model was used to depict the relationship betwixt urinary [d-MA-d₀]:[l-MA-d_iii] and the corresponding MA dose. Prediction bands of 95% were calculated to reflect the dubiety about future observations and bespeak the distribution inside which 95% of future observations are expected to autumn (Dalgaard, 2008). All computations were performed using R.

Results

Safety and Tolerability.

All MA doses tested were well tolerated, and no serious adverse events occurred. There were no measurable pharmacodynamic effects subsequently any of the l-MA-d₃ doses; d-MA produced expected increases in centre charge per unit, blood pressure, and subjective effects.

Urinary Concentration Ratio, [d-MA-d₀]:[50-MA-d₃].

A total of 589 urine samples were collected; 331 betwixt 0 and 24 h and 238 betwixt 24 and 48 h after doses of d-MA-d₀. In Fig. 1 nosotros show urine d-MA-d₀ concentrations plotted confronting time. Here, the urine concentrations after the iii doses of d-MA-d₀ (coordinating to increasing amounts of illicit intake) overlap substantially and cannot be separated by dose. This finding is consistent with a previous written report in MA addicts presenting for treatment where MA urine concentrations varied from undetectable to 300,000 ng/ml. Despite a concentration range spanning six orders of magnitude, MA urine concentrations did not let prediction of the corporeality of illicit intake (Batki et al., 2000).

Urine d-MA-d₀ concentrations after 15, 30, and 45 mg of d-MA-d₀ by individual subject.

In Fig. 2 we present the urinary [d-MA-d₀]:[50-MA-d₃] plotted against time. At present dose-dependent increases can easily be visually discriminated. Visual (and statistical) discrimination is particularly axiomatic at times more than 5 h after the first d-MA-d₀ dose. Equally described above, classification methods based on the dependent variables of time, urine [d-MA-d₀], or urine [d-MA-d₀]:[l-MA-d₃] every bit predictors were developed. The overall accuracy and sensitivity/specificity for each dose status derived from each classification method are summarized in Table ane. For urine samples collected from v h afterward d-MA-d₀ dosing through the next fifty-MA-d₃ dose, the classification accurateness was 91% using urine [d-MA-d₀]:[l-MA-d_three], which was a significant (p < 0.001) improvement over the 54% accuracy using urine [d-MA-d₀] solitary. Classification based on both urine [d-MA-d₀]:[l-MA-d₃] and time since dosing further improved accuracy to 96% (p < 0.001), and this is displayed in Fig. iii. From 24 to 48 h classifier accuracy using the urine [d-MA-d₀]:[l-MA-d₃] barbarous to 60.0% for 15-mg dose differences, only if the analysis was restricted to 30-mg dose increments accuracy remained robust at 84.6% and was a pregnant improvement over the 72.8% accuracy obtained using urine [d-MA-d₀] alone (p < 0.01). From 24 to 48 h, including fourth dimension as a predictor did not significantly meliorate classification accuracy (83.4%; p = 0.77).

Urine concentration ratio, [d-MA-d₀]:[50-MA-d_iii], later 5 mg of l-MA-d_three and fifteen, 30, and 45 mg of d-MA-d₀ past private subject.

Tabular array 1

Functioning of different classification methods

Time Menstruation	Predictors	Overall Accuracy	Sensitivity			Specificity
			15 mg	thirty mg	45 mg	15 mg	xxx mg	45 mg
h		%	%	%	%	%	%	%
five–24	[d-MA-d0]	54	76	50	36	75	66	90
5–24	[d-MA-d0]:[l-MA-d3]	91	95	87	91	96	93	97
v–24	[d-MA-d0]:[l-MA-d3], time	96	95	97	95	99	95	100
24–48	[d-MA-d0]:[l-MA-d3]	sixty	78	39	63	73	74	92
24–48 (15 vs. 45 mg)	[d-MA-d0]	73	96		46	46		96
24–48 (15 vs. 45 mg)	[d-MA-d0]:[fifty-MA-d3]	85	98		69	69		98
24–48 (xv vs. 45 mg)	[d-MA-d0]:[l-MA-diii], time	83	96		69	69		96

Classification of urine samples into different dosage conditions based on the method using [d-MA-d₀]:[l-MA-d₃] and time since dosing every bit predictors.

The ratio of d-MA-d₀ to l-MA-d_three doses in this study were 3 (15 mg of MA-d₀:5 mg of MA-d₃), vi (30 mg of MA-d₀:5 mg of MA-d_iii), and ix (45 mg of MA-d₀:5 mg of MA-d_three). When the dose ratios were treated as continuous variables instead of categorical variables, the ratios of doses were linearly related to urinary [d-MA-d₀]:[l-MA-d_iii] (Fig. iv; urinary ratio = − 0.44 + 0.62 × dose ratio; R ² = 0.8198).

Relationships between urine [d-MA-d₀]:[l-MA-d_iii] and d-MA-d₀/l-MA-d₃ dose ratio. The line inside the box is the median, the area within the box contains the 2nd and third quartiles, and whiskers include information points that fall within 1.5 times the interquartile range. The solid black line is the regression line. Dashed lines are 95% prediction bands.

Discussion

We nowadays a elementary, robust method of using pharmacologically inactive oral doses of 50-MA-d_iii to approximate the illicit MA amount consumed. With this method, useful estimates of MA exposure tin be fabricated from spontaneously voided urine specimens inside a relatively wide time window.

For both detection and confirmation, urine toxicology tests classify a sample as positive if it contains an corporeality equal to or greater than the lowest concentration of the drug that tin can be reliably detected in the urine after a single dose. This degree of sensitivity minimizes the possibility of missing an episode of drug use (Dolan et al., 2004). However, information technology also minimizes the sensitivity of these tests for detecting decreases in drug taking. For example, because of its slow emptying, low concentrations of MA can exist detected in urine for up to seven days after a unmarried oral dose of xxx mg (Valentine et al., 1995) or upward to 60 h after a single 15-mg smoked or intravenous dose (Cook et al., 1993). These data advise that the highly sensitive urine toxicology methods used in addiction trials may overdetect MA abuse, probably decreasing the ability of trials to identify effective treatments. Overdetection of abuse also exists for other abused drugs such as cocaine, amphetamine, and marijuana. For example, based on urine benzyolecgonine concentrations, Preston et al. (1997) plant that a cyclical pattern of cocaine abuse was not detected using binary effect assignments of urine results. In a written report of recently incarcerated drug abusers, amphetamine remained detectable in urine for more than than 48 h in all subjects; one subject had positive urine results for ix days (Smith-Kielland et al., 1997).

Cocky-reports of drug use are commonly used to assess the quantity of illicit intake. These measures tin can be inaccurate considering illicit drug abusers often swallow impure, diluted drugs and use dosing methods with incomplete bioavailability (oral and nasal) or where variable amounts of drug are destroyed (i.east., pyrolysis with smoked drugs). Our method estimates the bioavailable fraction of the illicit dose, the corporeality associated with pharmacologic activity and toxicity.

The detection window (the length of time in days after the last use of a drug) that sequentially collected urine samples continue to produce positive drug exam results tin be affected by many variables. Pharmacological factors include dose, road of assistants, duration of utilize (astute or chronic), and rate of elimination. Several factors affect elimination including age, organ function, urine pH, hydration condition, and polymorphisms of drug-metabolizing enzymes (http://world wide web.ndci.org/sites/default/files/ndci/DCR.VI__2.pdf). For example, urine acidification dramatically increases MA elimination. Because of the accumulation of drug in deep compartments, longer detection windows are more probable in chronic abusers, a group often targeted in clinical trials. Analytical factors such every bit the sensitivity of the test (cutoff concentration) and the method'south specificity (the actual drug and/or metabolite that is being detected) can too affect the detection window (Jaffee et al., 2008). Labeled and unlabeled MA accept identical absorption, distribution, metabolism, and emptying; thus our method controls for most of these intraindividual and interindividual factors.

In that location are two clear advantages of using urine concentration ratios of non-labeled to deuterium labeled drugs or metabolites every bit a quantitative endpoint in clinical trials. First, modest reductions in drug misuse can exist tracked, allowing better estimates of therapeutic drug efficacy or rational choice of combination therapies. In contrast to currently bachelor qualitative technologies urine concentration ratios yield a continuous outcome measure. Our data suggest than the urinary [d-MA-d₀]:[fifty-MA-d₃] can differentiate every bit little as fifteen-mg increases in exposure to d-MA-d₀ in a broad detection window. The ratio is straight related to the total d-MA-d₀ exposure without being affected by administration regimen (single or multiple) at to the lowest degree for samples obtained from 1 h later on the last unlabeled dose. These backdrop make the urinary [d-MA-d₀]:[l-MA-d_three] an attractive biomarker of disease severity and therapeutic response that can exist easily adjusted for MA treatment trials. It is noteworthy that the analytic engineering science needed to quantify the isotopes of MA (GC-MS or liquid chromatography-MS) is already widely available and currently used to confirm qualitative results. The merely change required in current analytic technologies volition be use of a differently deuterated internal standard; both MA-d_three and MA-d_nine are commercially available equally internal standards for MA assays. Second, quantitative estimates of drug exposure will allow meliorate stratification of the severity of illness. Other instruments that grade the severity of addiction, such as the Addiction Severity Index, primarily reflect slowly irresolute factors, such as employment, relationships, and legal status. Our method offers a finer temporal resolution. Logically, the severity of an addictive disorder is related to the amount of drug exposure; the ability to quantify exposure to illicit MA will permit a ameliorate assessment of the relationship between drug misuse and disease.

There are limits to our method. First, subjects need to take l-MA-d_three but may not practice then. In upcoming trials nosotros plan to coadminister l-MA-d₃ with the treatment medication. Subjects with no l-MA-d₃ in urine can exist assumed not to be adherent to the handling medication; thus our method allows evaluation of adherence likewise as event. Second, nosotros only tested intravenous MA administration, and urinary ratios may be slightly different if MA is abused past routes with slower assimilation (oral and nasal). Samples collected immediately later abuse of MA, while drug continues to be absorbed and distributed, may lead to inaccurate estimates of use. However, for samples obtained in the elimination phase urine concentration ratios should remain robust in estimating the captivated abused dose. Many participants in drug treatment nourish group or individual counseling; obtaining urine samples later on therapy visits may attenuate this limitation. Finally, our method may increase the toll of conducting trials. We approximate the costs of synthesizing deuterated MA and preparing individual dose units containing 50-MA-d₃ are $5 to 10 per dose. There should be no additional costs if confirmatory assays using mass spectrometry are used. Thus, for an 8-week trial where subjects are dosed daily with deuterated drug the additional cost would be $280 to 560 per discipline. This cost is balanced past the increased power from utilise of a continuous primary outcome variable, probably decreasing the number of subjects needed and ultimately the trial cost. In improver, the toll of rejecting potentially efficacious therapies caused by inadequate endpoints is unaffordable.

In conclusion, administration of pharmacologically inactive doses of oral l-MA-d₃ followed past quantifying the urine [d-MA-d₀]:[l-MA-d₃] permits interpretation of the amount of MA corruption from a single random urine specimen. Quantification of drug exposure from easily obtained biological specimens will be useful in developing new treatments for MA habit, understanding the patterns of corruption, and determining compliance with pharmacotherapies during clinical trials. Introduction of a continuous issue measure may be a substantial improvement from the current qualitative binary outcome measures used to appraise MA abuse. Finally, evolution of like methods for other addictive drugs is possible.

This work was supported by the National Institutes of Health National Institute of Drug Corruption [Grants P50-DA018179, DA012521, P30-DA12393]; the National Institutes of Wellness National Found of Allergy and Infectious Diseases Extramural Activities [Grant R01-AI50587]; and the National Institutes of Health National Institute of General Medical Sciences [Grant GM26696].

Article, publication date, and commendation information can exist found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.111.179176.

ABBREVIATIONS:

MA

methamphetamine

fifty-MA-d₃

deuterium-labeled fifty-methamphetamine

d-MA-d₀

nonlabeled d-MA

GC

gas chromatography

MS

mass spectrometry.

Authorship Contributions

Participated in inquiry design: Galloway and Mendelson.

Conducted experiments: Galloway, Baggott, Lopez, and Mendelson.

Contributed new reagents or analytic tools: Everhart.

Performed data assay: Li and Coyle.

Wrote or contributed to the writing of the manuscript: Li, Verotta, Baggott, and Mendelson.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126645/

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