Alain Verstraete

Detection Times of Drugs of Abuse in Blood, Urine, and Oral Fluid

Abstract: Data on the detection times of drugs of abuse are based on studies of controlled administration to volunteers or on the analysis of biologic samples of subjects who are forced to stop their (often chronic) use of drugs of abuse, eg, because of imprisonment or detoxification. The detection times depend mainly on the dose and sensitivity of the method used and also on the preparation and route of administration, the duration of use (acute or chronic), the matrix that is analyzed, the molecule or metabolite that is looked for, the pH and concentration of the matrix (urine, oral fluid), and the interindividual variation in metabolic and renal clearance. In general, the detection time is longest in hair, followed by urine, sweat, oral fluid, and blood. In blood or plasma, most drugs of abuse can be detected at the low nanogram per milliliter level for 1 or 2 days. In urine the detection time of a single dose is 1.5 to 4 days. In chronic users, drugs of abuse can be detected in urine for approximately 1 week after last use, and in extreme cases even longer in cocaine and cannabis users. In oral fluid, drugs of abuse can be detected for 5–48 hours at a low nanogram per milliliter level. The duration of detection of GHB is much shorter. After a single dose of 1 or 2 ng of flunitrazepam, the most sensitive methods can detect 7-aminoflunitrazepam for up to 4 weeks in urine.

Drugs and driving

The authors present a global overview on the issue of drugs and driving covering four major areas: (1) Epidemiology and Prevalence—which reviews epidemiological research, summarizes available information, discusses the methodological shortcomings of extant studies, and makes recommendations for future research to better define prevalence and epidemiology; (2) Effects of Medicinal and Illegal Drugs on Driving Performance—focuses on the six classes of drugs most often found in impaired and injured drivers, draws conclusions regarding the risk of these drugs to traffic safety and discusses the need for additional research; (3) Toxicological Issues—discusses ways to identify drug users via behavioral testing and analytical techniques, reviews the approaches used by different countries, screening and confirmation techniques, alternative specimens (e.g., urine, oral fluid, sweat), and how rapid roadside testing could be coupled with behavioral and laboratory testing in an effective approach to identifying and prosecuting drugged drivers; (4) Driving Under the Influence of Drugs [DUID] Laws—provides an overview of DUID laws in the United States and Europe, discusses the basic tenets of these laws, the various types of DUID statutes, the reasons why many existing laws hinder the prosecution of drugged drivers and the rationale for developing per se legislation as a strategy to more effectively manage the drugged driver problem.

Relationship Between Oral Fluid and Blood Concentrations of Drugs of Abuse in Drivers Suspected of Driving Under the Influence of Drugs

In recent years, the interest in the use of oral fluid as a biological matrix has increased significantly, particularly for detecting driving under the influence of drugs (DUID). In this study, the relationship between the oral fluid and the blood concentrations of drugs of abuse in drivers suspected of DUID is discussed. Blood and oral fluid samples were collected from drivers suspected of DUID or stopped during random controls by the police in Belgium, Germany, Finland, and Norway for the ROSITA-2 project. The blood samples were analyzed by gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS), sometimes preceded by immunoassay screening of blood or urine samples. The oral fluid samples were analyzed by GC-MS or LC-MS(/MS). Scatter plots and trend lines of the blood and oral fluid concentrations and the median, mean, range, and SD of the oral fluid to blood (OF:B) ratios were calculated for amphetamines, benzodiazepines, cocaine, opiates, and ▵9-2 tetrahydrocannabinol. The ratios found in this study were comparable with those that were published previously, but the range was wider. The OF:B ratios of basic drugs such as amphetamines, cocaine, and opiates were >1 [amphetamine: median (range) 13 (0.5-182), methylenedioxyamphetamine: 4 (1-15), methylenedioxymethamphetamine: 6 (0.9-88), methamphetamine: 5 (2-23), cocaine: 22 (4-119), benzoylecgonine: 1 (0.2-11), morphine: 2 (0.8-6), and codeine: 10 (0.8-39)]. The ratios for benzodiazepines were very low, as could be expected as they are highly protein bound and weakly acidic, leading to low oral fluid concentrations [diazepam: 0.02 (0.01-0.15), nordiazepam: 0.04 (0.01-0.23), oxazepam: 0.05 (0.03-0.14), and temazepam: 0.1 (0.06-0.54)]. For tetrahydrocannabinol, an OF:B ratio of 15 was found (range 0.01-569). In this study, the time of last administration, the dose, and the route of administration were unknown. Nevertheless, the data reflect the variability of the OF:B ratios in drivers thought to be under the influence of drugs. The wide range of the ratios, however, does not allow reliable calculation of the blood concentrations from oral fluid concentrations.

The use of oral fluid and sweat wipes for the detection of drugs of abuse in drivers.

Blood, urine, oral fluid (by spitting or with a Salivette), and sweat samples (by wiping the forehead with a fleece moistened with isopropanol) were obtained from 180 drivers who failed the field sobriety tests at police roadblocks. With quantitative GC-MS, the positive predictive value of oral fluid was 98, 92, and 90% for amphetamines, cocaine, and cannabis respectively. The prevalence of opiate positives was low. The proposed SAMHSA cut-off values for oral fluid testing at the workplace, proved their usefulness in this study. The positive predictive value of sweat wipe analysis with GC-MS was over 90% for cocaine and amphetamines and 80% for cannabis. The accuracy of Drugwipe was assessed by comparing the electronic read-out values obtained on-site after wiping the tongue and the forehead, with the corresponding GC-MS results in plasma, oral fluid, and sweat. The accuracy was always less than 90% except for the amphetamine-group in sweat.

Meropenem and piperacillin/tazobactam prescribing in critically ill patients: Does augmented renal clearance affect pharmacokinetic/pharmacodynamic target attainment when extended infusions are used?

BackgroundCorrect antibiotic dosing remains a challenge for the clinician. The aim of this study was to assess the influence of augmented renal clearance on pharmacokinetic/pharmacodynamic target attainment in critically ill patients receiving meropenem or piperacillin/tazobactam, administered as an extended infusion.MethodsThis was a prospective, observational, pharmacokinetic study executed at the medical and surgical intensive care unit at a large academic medical center. Elegible patients were adult patients without renal dysfunction receiving meropenem or piperacillin/tazobactam as an extended infusion. Serial blood samples were collected to describe the antibiotic pharmacokinetics. Urine samples were taken from a 24-hour collection to measure creatinine clearance. Relevant data were drawn from the electronic patient file and the intensive care information system.ResultsWe obtained data from 61 patients and observed extensive pharmacokinetic variability. Forty-eight percent of the patients did not achieve the desired pharmacokinetic/pharmacodynamic target (100% f T>MIC), of which almost 80% had a measured creatinine clearance >130 mL/min. Multivariate logistic regression demonstrated that high creatinine clearance was an independent predictor of not achieving the pharmacokinetic/pharmacodynamic target. Seven out of nineteen patients (37%) displaying a creatinine clearance >130 mL/min did not achieve the minimum pharmacokinetic/pharmacodynamic target of 50% f T>MIC.ConclusionsIn this large patient cohort, we observed significant variability in pharmacokinetic/pharmacodynamic target attainment in critically ill patients. A large proportion of the patients without renal dysfunction, most of whom displayed a creatinine clearance >130 mL/min, did not achieve the desired pharmacokinetic/pharmacodynamic target, even with the use of alternative administration methods. Consequently, these patients may be at risk for treatment failure without dose up-titration.

Innovative development and validation of an HPLC/DAD method for the qualitative and quantitative determination of major cannabinoids in cannabis plant material

GC is commonly used for the analysis of cannabis samples, e.g. in forensic chemistry. However, as this method is based on heating of the sample, acidic forms of cannabinoids are decarboxylated into their neutral counterparts. Conversely, HPLC permits the determination of the original composition of plant cannabinoids by direct analysis. Several HPLC methods have been described in the literature, but most of them failed to separate efficiently all the cannabinoids or were not validated according to general guidelines. By use of an innovative methodology for modelling chromatographic responses, a simple and accurate HPLC/DAD method was developed for the quantification of major neutral and acidic cannabinoids present in cannabis plant material: Delta9-tetrahydrocannabinol (THC), THC acid (THCA), cannabidiol (CBD), CBD acid (CBDA), cannabigerol (CBG), CBG acid (CBGA) and cannabinol (CBN). Delta8-Tetrahydrocannabinol (Delta8-THC) was determined qualitatively. Following the practice of design of experiments, predictive multilinear models were developed and used in order to find optimal chromatographic analytical conditions. The method was validated following an approach using accuracy profiles based on beta-expectation tolerance intervals for the total error measurement, and assessing the measurements uncertainty. This analytical method can be used for diverse applications, e.g. plant phenotype determination, evaluation of psychoactive potency and control of material quality.

Cholinesterase reactivation in organophosphorus poisoned patients depends on the plasma concentrations of the oxime pralidoxime methylsulphate and of the organophosphate.

We measured in nine patients, poisoned by organophosphorus agents (ethyl parathion, ethyl and methyl parathion, dimethoate, or brompphos), erythrocyte and serum cholinesterase activities, and plasma concentrations of the organophosphorus agent. These patients were treated with pralidoxime methylsulphate (ContrathionR), administered as a bolus injection of 4.42 mg.kg−1 followed by a continuous infusion of 2.14 mg.kg−1/h, a dose regimen calculated to obtain the presumed “therapeutic” plasma level of 4 mg.l−1, or by a multiple of this infusion rate. Oxime plasma concentrations were also measured. The organophosphorus agent was still detectable in some patients after several days or weeks. In the patients with ethyl and methyl parathion poisoning, enzyme reactivation could be obtained in some at oxime concentrations as low as 2.88 mg.l−1; in others, however, oxime concentrations as high as 14.6 mg.l−1 remained without effect. The therapeutic effect of the oxime seemed to depend on the plasma concentrations of ethyl and methyl parathion, enzyme reactivation being absent as long as these concentrations remained above 30 μg.l−1. The bromophos poisoning was rather mild, cholinesterases were moderately inhibited and increased under oxime therapy. The omethoate inhibited enzyme could not be reactivated.

Detection time of drugs of abuse in urine

Abstract Estimating the detection time of a drug in urine is complex because of many different influencing factors and the lack of experimental data. Detection times vary depending on dose and route of administration, metabolism and characteristics of the screening and confirmation assays. Using a cut-off value of 1000 ng/mL, urinary samples can be positive for amphetamine for up to 5 days after intake of the drug. At the lower 300 ng/mL cut-off, amphetamine will be detectable one day longer. Very few data are available for designer amphetamines. After smoking one marijuana cigarette, THCCOOH (9-carboxy-Δ9 tetrahydrocannabinol) is detectable (using a screening cut-off of 50 ng/mL) for 2-4 days. More frequent use will be detectable for almost 1 month, exceptionally 3 months. Immunoassays to detect cocaine are targeted against the metabolite benzoylecgonine and use a cut-off of 300 ng/mL. An intravenous dose of 20 mg cocaine can be detected for 1.5 days. Street doses (administered via different routes) are detectable up to 1 week, and extremely high doses up to 3 weeks. Heroin rapidly metabolises to 6-acetylmorphine and morphine. Immunoassays for heroin are calibrated with morphine but important cross-reactivity occurs and positive results must be confirmed by GC-MS. Experimental data for total morphine using a cut-off of 300 ng/mL suggest a detection time of 1 to 1.5 days for relatively low doses of heroin (3-12 mg) administered via IV, IN or IM route.

Cortisol in violent suicidal behaviour: association with personality and monoaminergic activity

BACKGROUND According to recent theories, suicidal behaviour is associated with depressive disorders that are commonly induced by social stressors in persons with a trait-dependent vulnerability. Stressor-induced increased cortisol secretion may interfere with this vulnerability that can be defined in terms of (possibly inter-related) biological and psychological or personality-related characteristics. Delineation of such trait-like characteristics may increase the specificity in the prediction of suicidal behaviour and thus lead to new approaches to the treatment and prevention of suicidal behaviour. METHODS Psychiatric symptomatology, personality dimensions (Cloningers Temperament and Character), peripheral markers of serotonergic (whole blood serotonin, platelet MAO activity) and noradrenergic (plasma MHPG) activity, and urinary cortisol were measured in a random sample of patients with a history of violent suicidal behaviour and compared to those of patients without such a history. RESULTS When compared to patients without a history of violent suicidal behaviour (n=23), patients with such a history (n=17) were characterised by higher urinary cortisol levels, a significantly lower mean score on Reward Dependence, a borderline significantly increased score on Novelty Seeking and a significantly lower mean plasma MHPG level. Urinary cortisol level correlated significantly with Reward Dependence and Novelty Seeking scores. There were no differences between patient groups regarding severity of anxiety or depressive symptomatology. No differences with regard to the biological parameters were found between patients who recently attempted suicide and those with a history of suicidal behaviour. LIMITATIONS Limitations of this study included a relatively small number of study subjects and the use of peripheral markers to assess central neurotransmission functions. CONCLUSIONS Violent suicidal behaviour is associated with increased cortisol secretion, a personality profile defined by low Reward Dependence (reflecting the degree of sensitivity to social stressors) and a tendency of increased Novelty Seeking (related to impulsivity and the regulation of anger), and reduced noradrenergic functioning (possibly reflecting an inability to adapt to stressors).

A Sudden Awakening from a Near Coma After Combined Intake of Gamma-Hydroxybutyric Acid (GHB) and Ethanol

OBJECTIVE A case of a sudden awakening from a near coma after combined intake or gamma-hydroxybutyric acid (GHB) (125 micrograms/mL), ethanol (134 mg/dL), and cannabinoids is described. METHODS GHB was determined by gas chromatography-mass spectrometry after acetonitrile precipitation and derivation with N-methyl-N-trimethylsilyltrifluoroacetamide, using valproic acid as the internal standard. CONCLUSION The described case illustrates the consequences of GHB overdose. GHB overdose should be considered in every case of unexplained sudden coma, i.e., without any evidence of head injury, intake of coma-inducing drugs, or increasing intracranial pressure. GHB overdose will be missed by routine toxicological screening.