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The testing of biological specimens has become a major component in the identification and the treatment of drug misuse. Testing has been performed under the auspices of the military, the criminal justice system, the public sector, and the private sector. Urine remains the primary specimen for drug abuse testing, but other specimens such as oral fluid, sweat, and hair have also been used. Each testing program is different, but there are common components throughout the programs. Specimens are collected under a chain of custody that documents the location of the specimen from collection to disposal. No single test is used to identify a positive specimen; positive results are reported only after a positive initial test and a positive confirmation test. Concentration cutoffs are employed to distinguish negative from positive specimens. The analytical methods used must be validated prior to use on donor specimens. Moreover, a quality assurance program must be in place for all aspects of the process, from specimen collection to specimen testing to reporting of results. Some programs, such as the Department of Health and Human Services Program, require specimen validity tests to ensure the integrity of the specimen prior to receipt in the laboratory. To ensure continued acceptable laboratory performance, proficiency testing programs and laboratory accreditation are also components of the forensic drug-testing process.

Hallucinogens are drugs that alter perception of reality. In high-enough doses, these psychedelic or psychomimetic drugs can induce illusions, hallucinations, or delusions. The hallucinogenic state is characterized by heightened awareness of sensory input, a sense of a divided self, and feelings not experienced outside of dreams or religious experiences. Most hallucinogens are plant alkaloids and function as 5-HT2A receptor agonists. Hallucinogens can be divided into indolylalkylamines and phenylalkylamines. This chapter encompasses the history, synthesis, drug abuse patterns, pharmacology, metabolism, detection and analysis, and toxicological interpretation of classic hallucinogenic compounds, including phencyclidine (PCP), lysergic acid diethylamide (LSD), mescaline, psilocybin, and ketamine. More recently, synthetic analogs have also emerged in the illicit drug market as novel psychoactive substances, including analogs of PCP, mescaline (2C and NBOMe types), and ketamine. While PCP may be considered a dissociative anesthetic and ketamine is used as another anesthetic, they are abused for their hallucinogenic properties and are therefore discussed in detail in this chapter.

To determine the incidence of positive drug screens in children undergoing a multiple sleep latency test (MSLT) for evaluation of excessive daytime sleepiness (EDS).A retrospective analysis was performed in children evaluated at the Boston Children's Hospital Sleep Center between 1998 and 2013 who underwent MSLT for EDS with a concurrent urine and/or serum drug screen.A total of 210 MSLTs were accompanied by drug testing. Children were 12.7 ± 3.7 years old (mean ± SD), 43% were female, and 24% had narcolepsy. Positive tests were obtained in 32% for caffeine, 5% for prescription medications, and 4% for over-the-counter drugs. No drugs of abuse were identified. Children testing positive for caffeine were older (13.8 ± 3.5 vs. 12.4 ± 3.7) and more likely female (59% vs. 36%), but did not differ in MSLT or overnight polysomnographic parameters compared to children without caffeine detected. Overall, only 14% had specific documentation regarding caffeine intake, though 90% were referred from a sleep clinic. Of the children testing positive for caffeine, 5% acknowledged use, 3% denied use, and 92% did not have a documented caffeine intake history during their sleep clinic visit.Routine drug testing for drugs of abuse during an MSLT for EDS yielded no positive results over a 15-year period, indicating that this routine practice is unnecessary in our pediatric population without specific concerns. However, objective evidence for caffeine exposure was found in 32% of tested children undergoing an MSLT. Sleep physicians rarely documented the caffeine intake history during clinic visits for EDS.

The extraction of drugs from biological matrices is an essential specimen preparation step in current forensic postmortem laboratories. Traditionally, liquid/liquid extractions (LLE) were developed and employed to screen for the general unknown. However, solid-phase extractions (SPE) are becoming more popular as the availability of columns with suitable stationary phases increased. The purpose of this work was to determine if switching from an existing LLE to SPE was feasible. The limits of detection (LOD) for 122 drugs and metabolites were determined in blood following SPE and compared to previously determined LOD's by LLE, if available. There were 41 drugs that had LOD's in blood established by both methods; LLE had a lower LOD for 8 drugs (19.5%), SPE had a lower LOD for 16 (39%), and the LOD's were comparable in the remaining drugs. Although SPE cartridges were more expensive than LLE, SPE was determined to be a faster technique and doubled the number of specimens that could be extracted by one analyst within a specific timeframe. The SPE method utilized enabled the detection of several drugs not detectable after LLE (most notably, morphine and benzoylecgonine) and allowed the extraction of weakly acidic and neutral drugs with only one extra step.

At The Office of the Cuyahoga County Coroner (CCCO), Cleveland, Ohio, it is customary to perform an autopsy and conduct toxicological testing on decedents less than 19 years of age. This study provides a retrospective evaluation of drugs detected in a pediatric postmortem population between the years 1998 and 2002 (n = 730). Demographic information, cause and manner of death, and toxicological results were examined. Blacks comprised 54% of cases, males 59%, and 48% were less than one year of age or stillborn. Forty-two percent of deaths were ruled natural, 27% accident, 13% undetermined, 5% suicide, and 2% homicide. Of the 640 cases subjected to comprehensive testing, 38% of the cases were positive for at least one compound. Resuscitative/treatment drugs were detected most frequently (56% of positive results), followed by illicit drugs (26%), ethanol (11%), carbon monoxide (8%), and antihistamines (6%). Eighty-seven cases contained more than one drug. The deaths of 47 individuals were drug related (6%). In this population, it is recommended that illicit drugs and ethanol are targeted for testing, especially when limited specimens are available for analysis. Language: en

The concentration of drugs and metabolites in cerebrospinal fluid (CSF) and blood were determined in 282 autopsied cases using liquid-liquid extraction techniques and gas chromatographic analyses. All drugs were confirmed in one matrix by gas chromatography-mass spectrometry. CSF/blood ratios were used to compare the two biological fluids. Classes of drugs evaluated in this study included: benzodiazepines, anticonvulsants, sedatives, opioids, antidepressants, anesthetics, and antihistamines. The majority of the drugs tested were readily detected in CSF specimens. The average CSF/blood ratio for most drugs was in the range of 0.05-0.50. Interpretation of these results is difficult because protein binding, half-life, hydrophobic properties, and pKa of a drug, in addition to survival time after drug use, influence the CSF/blood ratio. While CSF specimens do provide a viable alternative testing matrix when blood specimens are not available, they should not be used to estimate blood drug concentrations.

Understanding cocaine and metabolites urinary excretion following smoking is important for interpretation of urine test results in judicial, workplace and treatment settings. In National Institute on Drug Abuse approved studies on a secure research unit, six subjects smoked placebo, 10, 20, and 40 mg cocaine with a precise dose delivery device and six different subjects smoked 42 mg cocaine in a glass pipe. Urine specimens (n = 700) were collected for up to seven days and analyzed for cocaine (COC), benzoylecgonine (BE), ecgonine methylester (EME), m-hydroxybenzoylecgonine (mOHBE), p-hydroxybenzoylecgonine (pOHBE), norbenzoylecgonine (NBE), and ecgonine (EC) by gas chromatography–mass spectrometry. Results (mean ± SE) for the 40-mg precise delivery doses are as follows: COCBEEMEmOHBEpOHBENBEECCutoff(ng/mL)10201025252550Cmax(ng/mL)4085±23039196±15694638±1548222±69540±227614±347852±211Tmax(h)2.2±0.36.6±0.95.6±1.47.8±0.54.4±1.56.0±2.09.3 ±1.3Lastpositive(h)5510616455553280 Mean Cmax for all analytes linearly increased with increasing dose. Tmax was not dose-dependent. All metabolites were detected in some subjects within 2 h. EC concentrations were significantly higher after smoked cocaine in a precise delivery coil compared to a glass “crack” pipe.

Carbon monoxide (CO) poisoning as a cause of death is well documented in industrialized countries. The objective of this study was to compare demographic data in deaths due to accidents (in fires) and suicides in the same population between 1988 and 1998. Furthermore, the potential effect of a community wide education effort regarding safety in the home was assessed. Postmortem reports were reviewed for all deaths examined at the Office of the Cuyahoga County Coroner in Cleveland, OH, USA. During the study period, there were 209 accidental deaths due to fires in the home (6.5% of all accidents in the home) and 182 CO deaths by suicide (9.8% of all suicides). Demographic characteristics of the two groups differed: while males represented the majority of cases in both groups (55% of accidents, 70% suicides), race specific death rates were higher for whites than blacks (18/100,000 white, 3/100,000 black) in suicides compared with 29/100,000 deaths for blacks and 11/100,000 for whites in accidental cases. Fire deaths were prevalent in the young (0-9 years) and old (>60) whereas in the suicide group the age specific death rate was highest for those over 70 years. The majority of fire deaths occurred in the city of Cleveland but suicides were prevalent in the suburbs. More fire deaths occurred in December than any other month whereas more suicides occurred in April. In 1992, there was a community wide effort to provide free smoke detectors to residents in Cleveland. In 1992, there were 4.2/100,000 fire deaths in the city. This decreased to 0.6/100,000 in 1996, increased to 1.2/100,000 in 1997 followed by a decrease to 0.8/100,000 in 1998. This suggested that the program may have aided in decreasing these types of deaths. Deaths due to fires in the suburbs were

The ability to differentiate illicit from legitimate drug use in a drug-testing program would decrease costs by reducing the number of screening specimens requiring confirmation and also reduce the stigma attached to positive preliminary test results. Because many screening tests for drug detection use immunoassays, increasing the specificity of these tests has been a goal of manufacturers. In this study we evaluated the utility of one such assay, the Cedia heroin metabolite (6-acetylmorphine, 6-AM) assay to reliably detect heroin use. Specimens (N = 525) from a criminal justice drug-testing program were screened with this assay (cutoff concentration = 10 ng/mL 6-AM) and any positive samples were confirmed by gas chromatographic-mass spectrometric analysis (lower reporting limit for 6-AM = 5 ng/mL). The confirmation rate for the enzyme immunoassay (EIA) was 98% (517/525). Specimens contained 6-AM at concentrations ranging from 5 to 16,923 ng/mL (mean = 1251; median = 317). All confirmed specimens also contained morphine (range: 8-222,427 ng/mL; mean = 11,203 ; median = 4134). When challenged with standard drug solutions, the EIA correctly identified drug-free urine and produced positive results (lowest concentration, in ng/mL, that produced a positive result) with morphine at 10,000; oxycodone at 61,000; codeine at 60,000; hydromorphone at 10,000; hydrocodone at 60,000, 6-AM at 10, and pentazocine at 35,000 ng/mL. The Cedia heroin metabolite (6-AM) assay produced a high confirmation rate when challenged with urine specimens and therefore should be a useful tool in forensic toxicology. Potential users should be aware that high concentrations of other opioids (e.g., morphine, oxycodone) and structurally related compounds (e.g., pentazocine) may produce positive results.

Quetiapine is a new atypical antipsychotic that was approved in 1997 by the U.S. Food and Drug Administration for the treatment of schizophrenia. It possesses a high affinity for 5-HT2 receptors and a low affinity for D1 and D2 dopamine receptors. Because quetiapine has only been released recently to the U.S. market, little information exists regarding therapeutic, toxic, and lethal concentrations. This study reports the detection of quetiapine in 13 postmortem cases. Following a basic liquid-liquid extraction, quetiapine was identified and quantitated by capillary gas chromatography with nitrogen phosphorus detection. Confirmation was accomplished by full scan electron impact gas chromatography/mass spectrometry. Heart blood quetiapine concentrations ranged from 0.07 to 18.37 mg/L (N = 12, mean +/- SD = 3.42 +/- 5.67, median 0.62) and femoral blood concentrations ranged from 0.06 to 19.25 mg/L (N = 10. mean +/- SD = 3.89 +/- 6.12, median 0.81). The average heart blood/femoral blood ratio was 1.31 (range 0.55 to 2.57, N = 10). Urine, bile, and gastric contents were assayed in all cases in which they were submitted. In three cases, the cause of death was determined to be quetiapine toxicity. In these cases heart blood concentrations ranged from 0.72 to 18.37 mg/L (N = 3). These data may provide a basis for establishing levels associated with quetiapine toxicity as well as therapeutic concentrations in postmortem specimens.

An unusual fatality secondary to oxycodone in a child is reported. A 2-year-old female child was conveyed to a local hospital after exhibiting signs of rubbing of the mouth and staggering. A hospital toxicological immunoassay screen for drugs of abuse and tricyclic antidepressants was performed on a urine sample and reported as negative. She was discharged and found unresponsive the next morning. She was conveyed to a second hospital in full cardiopulmonary arrest and despite resuscitative efforts, was pronounced dead upon arrival. An autopsy was performed and postmortem specimens were submitted and screened for drugs using mainly chromatographic techniques. Quantitation was achieved by gas chromatography with nitrogen phosphorus detection. Confirmation was performed by gas chromatography/mass spectrometry. Oxycodone was the only drug detected in the following concentrations: heart blood, 1.36 mg/L; gastric contents, 7.33 mg in 33 mL (222.34 mg/L); liver, 0.2 mg/kg; and urine, 47.23 mg/L (47,230 ng/mL). In addition, immunoassay testing of the urine was positive for the opiate class of drugs. This case report demonstrates an unusual cause of death in a young child with emphasis on potential limitation in hospital urine screening tests and the importance of complete forensic toxicological testing in all child deaths.

It is well known that United States paper currency in general circulation is contaminated with trace amounts of illicit substances such as cocaine, heroin and marijuana. As is the case with cocaine, differentiating "background levels" of the various cannabinoid constituents of Cannabis sativa L., namely, Delta(9)-tetrahydrocannabinol (THC), cannabinol (CBN), and cannabidiol (CBD) contaminating currency found in the general circulation from currency associated with illegal drug activity is imperative if a legal nexus is to be established with the latter. We analyzed 165 randomly collected paper currency notes from 12 U.S. cities (N = 125) and 4 foreign countries (N = 40) for THC, CBD, CBN, 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol, and 11-hydroxy-Delta(9)-tetrahydrocannabinol. Uncirculated US 1 dollar notes were added as negative controls. Drug residues were washed from individual bills, extracted using a liquid-liquid extraction protocol, derivatized, and quantitated by gas chromatography-mass spectrometry by selected ion monitoring. For the US 1 dollar currency, THC was present in 1.6% (2 notes), CBN 10.31% (13 notes), CBD 1.6% (2 notes). The following concentrations were determined: 0.085 microg/bill and 0.146 microg/bill for THC; 0.014-0.774 microg/bill (mean 0.166 microg/bill) for CBN; and 0.032 microg/bill and 0.086 microg/bill for CBD. For the foreign currency (Colombia, Qatar, India, and New Zealand), THC and CBN were present in 22.5% (9 notes). The following concentration ranges were determined: THC 0.026-0.065 microg/bill (mean 0.049 microg/bill), CBN 0.061-0.197 microg/bill (mean 0.115 microg/bill). All of the positive THC and CBN were found in the New Zealand polypropylene notes. This study demonstrated that marijuana (cannabinoids) may contaminate both paper and plastic currency.

In forensic toxicology general alkaline drug screens typically utilize liquid liquid [LLE] or solid phase extraction [SPE] sample preparation techniques. It is expected that different drugs will be detected when a laboratory changes techniques. In this study, when the authors switched from LLE to SPE they were able to detect benzoylecgonine [BE]. Benzoylecgonine isopropyl ester [BEIE] was also detected. Further investigation demonstrated that the BEIE was formed during sample elution with methylene chloride/isopropanol/ammonium hydroxide. BEIE was not detected if methanol/ammonium hydroxide was used as the elution solvent. Analysts should be aware that BEIE is formed in the presence of BE if elution solvents comprise isopropanol and a strong base. Therefore, use of BEIE as an internal standard in such assays will result in inaccurate quantitation of BE.

Postmortem fingernail and toenail specimens were utilized for the detection of cocaine analytes and opiates. Nail clippings were obtained from suspected overdoses and/or drug users. Nail clippings were washed with methanol and then solubilized in 0.1M potassium phosphate (pH 5.0). Analytes were isolated from the solubilized nails and methanolic washes by solid-phase or liquid-liquid extraction techniques. Quantitation was performed by gas chromatography-mass spectrometry. Clippings from each hand and foot were analyzed separately for comparison purposes. Concentrations of all the analytes were significantly higher in fingernails than in toenails. Cocaine analytes were detected in the nails of 15 cases with the following concentration ranges (ng/mg): cocaine (n = 15) 1.2-414.1; benzoylecgonine (n = 15) 1.4-170.3; ecgonine methyl ester (n = 14) 0.19-27.0; norcocaine (n = 12) 0.11-32.7; cocaethylene (n = 2) 0.08-2.93. Opiates were detected in 17 cases with the following concentration ranges (ng/mg): morphine (n = 15) 0.05-407.9; 6-acetylmorphine (n = 15) 0.04-504.0; codeine (n = 9) 0.06-8.84; hydromorphone (n = 4) 0.02-0.45. Oxycodone and hydrocodone were each detected in one case. The extent of drug incorporation due to external contamination was evaluated by comparing the differences in the amount of drugs detected in fingernails and toenails, along with the corresponding washes of those nails. These results demonstrate the usefulness of nails as postmortem specimens in detecting drugs of abuse.

The disposable QED saliva alcohol test provides a very simple, fast, and reliable means for quantitative onsite alcohol detection. The purpose of this study was to determine if the QED test would be a useful tool for the determination of postmortem ethanol levels in cases where a rapid result was needed. QED results were compared with ethanol levels determined by headspace GC analysis. Both saliva and vitreous humor specimens were used for the evaluation. QED tests were initially attempted using the oral fluid from 50 individuals. Of these cases, 17 of the tests were valid with 8 positive results. For 23 cases the oral fluid was not attainable, and for 10 cases, the sample was contaminated with blood making the tests invalid. The correlation between the oral fluid results and the blood headspace GC analysis was poor (r = 0.8345) over the range of 0.01-0.29 g/dL. Vitreous specimens were found to be the matrix of choice for analyzing postmortem cases using the QED. Only 6 of 171 specimens were found to be unsuitable. The QED results correlated well with the headspace GC analysis (r = 0.9931, n = 165). When using ethanol levels0.02 g/dL (n = 126), an average vitreous (GC)/blood ratio of 1.16 correlated well with the average QED/blood ratio of 1.22. Although the QED saliva alcohol test does not appear to be useful in determining postmortem saliva ethanol levels, it does provide accurate results when using postmortem vitreous humor as the testing matrix.

It is known that US paper currency in the general circulation is contaminated with cocaine. Several mechanisms have been offered to explain this finding, including contamination due to handling during drug deals and the use of rolled up bills for snorting. Drug is then transferred from one contaminated bill to others during counting in financial institutions. The possibility of contamination of currency with other drugs has not been reported. In this study, the author reports the analysis of 10 randomly collected US$ 1 bills from five cities, for cocaine, heroin, 6-acetylmorphine (6-AM), morphine, codeine, methamphetamine, amphetamine and phencyclidine (PCP). Bills were immersed in acetonitrile for 2h prior to extraction and GC-MS analysis. Results showed that 92% of the bills were positive for cocaine with a mean amount of 28.75+/-139.07 microg per bill, a median of 1.37 microg per bill, and a range of 0.01-922.72 microg per bill. Heroin was detected in seven bills in amounts ranging from 0.03 to 168.50 microg per bill: 6-AM and morphine were detected in three bills; methamphetamine and amphetamine in three and one bills, respectively, and PCP was detected in two bills in amounts of 0.78 and 1.87 microg per bill. Codeine was not detected in any of the US$ 1 bills analyzed. This study demonstrated that although paper currency was most often contaminated with cocaine, other drugs of abuse may be detected in bills.

Heroin is one of the major target drugs in workplace drug-testing programs because of its history of abuse, liability, and continued negative social impact. This study was a comprehensive examination of pharmacokinetics, pharmacodynamics, detection times, opiate immunoassay performance, and urine excretion profiles following single doses of heroin administered to human subjects via smoking and intravenous routes. Studies of the first four components of this investigation were previously published. This article describes the urine excretion profiles. Total morphine (Tmor), free morphine (Fmor), and 6-acetylmorphine (6-AM) were measured by gas chromatography-mass spectrometry (GC-MS) in 920 urine samples collected from 11 male human subjects following single doses of heroin. Eight received intravenous doses of 3, 6, and 12 mg heroin HCI and four smoked 3.5-, 5.2-, 7-, 10.5-, or 13.9-mg doses of heroin (base). In addition, 183 urine-based blind quality-control samples were added to the study set to assess assay performance. Creatinine was also measured in each sample by a colorimetric technique. The parameters studied were not significantly dependent on route of administration. Excretion half-life mean +/- SD for Tmor was 3.11 +/- 0.30 h. Range (median) of peak urine concentrations, time to peak, time to last positive sample for low cutoff (300 ng/mL) and high cutoff (2000 ng/mL) for Tmor following lower doses (or = 7 mg) were, respectively, 1392-9250 (3620) ng/mL, 1.2-6.2 (2.3) h, 7.4-31.9 (7.4) h, and 0-10.1 (4.3) h. Following higher doses (10 mg) they were 2065-29,030 (16,470) ng/mL, 2.3-9.3 (4.5) h, 10.7-53.5 (34.4) h, 2.3-22.3 (8.3) h. Fmor peaked in the same sample as Tmor. Range (median) of peak Fmor concentrations and time to last positive using a cutoff of 100 ng/mL for low and high doses were, respectively, 117-1160 (415) ng/mL, 1.2-10.1 (4.5) h and 150-2580 (1400) ng/mL, 2.3-29.1 (9.3) h. The range (median) of peak urine concentrations for 6-AM was 6.1-568 (124) ng/mL. In general, the first urine void had the peak 6-AM concentration and was the only specimen positive at a 10-ng/mL cutoff. As previously reported urine concentrations varied greatly between subjects and within subjects with time after dosing but were much more predictable when values were reported as amount of drug per unit of creatinine. The range (median) values for percent of heroin excreted into urine as Tmor was 12.8-88.5% (51.0).

Olanzapine is a relatively new antipsychotic drug used in the United States for the treatment of schizophrenia. Since its release in the United States market in 1996, few cases of fatal acute intoxication have been reported in the literature. This article describes the case of a 25-year-old man found dead at home who had been prescribed olanzapine for schizophrenia. This case is unique because of the measurement of olanzapine in brain tissue obtained from seven regions in addition to the commonly collected biologic matrices. Olanzapine was detected and quantitated by basic liquid-liquid extraction followed by dual-column gas chromatographic analysis with nitrogen phosphorus detection. The assay had a limit of detection of 0.05 mg/L and an upper limit of linearity of 2 mg/L. The presence of olanzapine was confirmed by gas chromatography-mass spectrometry by use of electron impact ionization. The concentrations of olanzapine measured in this case were as follows (mg/L or mg/kg): 0.40 (heart blood), 0.27 (carotid blood), 0.35 (urine), 0.61 (liver), negative (cerebrospinal fluid), 0.33 mg in 50 ml (gastric contents). In the brain, the following distribution of olanzapine was determined (mg/kg): negative (cerebellum), 0.22 (hippocampus), 0.86 (midbrain), 0.16 (amygdala), 0.39 (caudate/putamen), 0.17 (left frontal cortex), and 0.37 (right frontal cortex). The cause of death was determined to be acute intoxication by olanzapine, and the manner of death was accidental.

The Federal Workplace Drug Testing Program changed urine screening and confirmation cutoff concentrations for opiate testing from 300 to 2000 ng/mL in 1998. Morphine was the designated target compound. An additional heroin metabolite, 6-acetylmorphine (6-AM), was added to the testing procedure with a cutoff concentration > or = 10 ng/mL. Testing of 6-AM was required if morphine was positive to assist in medical review. A comparison of the new opiate cutoff concentrations was made with the older cutoff concentration at 300 ng/mL. Six commercial opiate immunoassays, four with a 300-ng/mL cutoff, ONLINE, EMIT, CEDIA and AxSym, and two with 2000-ng/mL cutoffs, ONLINE and EMIT, were selected to test 920 urine samples collected from 11 male human subjects following single doses of heroin. Eight received intravenous doses of 3, 6, and 12 mg heroin HCl and four smoked 3.5-, 5.2-, 10.5-, or 13.9-mg doses of heroin (base). In addition, 183 urine-based blind quality-control specimens were added to the study set to assess linearity, cross-reactivity, and interference. Total morphine, free morphine, and 6-AM were measured in each sample by gas chromatography-mass spectrometry (GC-MS). Linearity, cross-reactivity, and interference results for each immunoassay are described. Detection times, sensitivity, specificity, and efficiency of each assay were determined using data from the specimens collected after heroin administration. Detection times for morphine using the 300-ng/mL cutoff assays was approximately 12 h for low dose and 24 to 48 h for higher doses of heroin. For the two 2000-ng/mL cutoff concentration assays detection time was about 12 h. This was also the detection time for 6-AM by GC-MS. ONLINE had the lowest sensitivity, 60-74%, highest specificity, 98.8-100%, and least interference from a selection of common over-the-counter drugs and opioids. Increasing the cutoff to 2000 ng/mL from 300 ng/mL increased efficiencies of the assays from 72.7 to 82.6% to over 97%.

Vitreous humor (VH) is routinely collected at autopsy for the testing of electrolytes and ethanol. In recent years drugs of abuse have been detected in this specimen. In this study the authors assayed 30 VH samples for phencyclidine (PCP) and 50 specimens for cannabinoids. Specimens were screened by immunoassay and then assayed for PCP by GC-FID and cannabinoids by GC/MS. Eighteen (60%) specimens screened positive for PCP using a cutoff of 25ng/mL. Quantitative analysis showed PCP concentrations in VH that screened positive ranged 30–290ng/mL. Corresponding blood concentrations were 50–600ng/mL. VH PCP concentrations in the 12 cases which screened negative were 40–470ng/mL. False negative results were probably due to matrix effects. All VH specimens screened for cannabinoids were negative. Ten negative screening specimens assayed by GC/MS yielded 1 11-nor-9-carboxy-delta-9-tetrahydrocannabinol positive result at 2ng/mL. These data indicated that VH maybe a useful specimen for the detection of PCP but not for cannabinoids.

Olanzapine, a new antipsychotic agent, was approved by the U.S. Food and Drug Administration in 1996 for use in the treatment of schizophrenia. It is structurally similar to clozapine, has a low incidence of extrapyramidal effects, and is effective in treating both the positive and negative symptoms of schizophrenia. This paper describes the determination of olanzapine in biological specimens obtained from the autopsy of a 35-year-old white male found dead in bed at a psychiatric facility. In the months prior to his death, the deceased was prescribed multiple medications, including olanzapine. Olanzapine was identified qualitatively by full scan gas chromatography-mass spectrometry, with quantitative analysis performed by liquid-liquid extraction followed by dual-column gas chromatography. The following concentrations were determined in the specimens analyzed: heart blood, 550 ng/mL; bile, 6346 ng/mL; and gastric contents, 157 ng/mL. Vitreous humor, cerebrospinal fluid, and urine specimens were negative. Although steady-state plasma concentrations of 10-25 ng/mL olanzapine have been reported, effective levels are known to be highly variable and a plasma concentration of 300 ng/mL has been tolerated without adverse effects. Based upon the autopsy, toxicological findings, and case investigation, the cause of death was determined to be intramyocardial arteriosclerosis with severe stenosis of the nodal artery due to hypertensive cardiovascular disease, and the manner was natural.

A 40-year-old white male was found dead in bed in a group home for mentally ill adults. The decedent had been diagnosed a paranoid schizophrenic. An autopsy was performed at the Office of the Cuyahoga County Coroner in Cleveland, Ohio. Toxicological testing detected olanzapine and citalopram in post mortem specimens. Multiple fluids and tissues were assayed by liquid-liquid extraction followed by gas chromatography with nitrogen phosphorus detection, and qualitative confirmation by electron impact gas chromatography/mass spectrometry. Drug concentrations [olanzapine: citalopram; mg/L or mg/Kg] determined in this case are the highest reported to date involving these drugs- 1.38:3.35 heart blood, 1.11:1.65 femoral blood, 60.24:32.43 urine, 6.47:10:71 liver, and 38.36:49.16 lung, respectively. Drug concentrations in tissues were found to be the highest in lung for both drugs and lowest in the heart. Citalopram but not olanzapine was detected in bone. The cause of death was ruled acute intoxication by the combined effects of olanzapine and citalopram and the manner, accident.

Self-contained drug-testing kits are currently being marketed for a variety of drugs of abuse. These tests are designed to provide rapid access to test results without the need for laboratory facilities. This report describes a validity study of the accuPINCH THC test, a self-contained test for cannabinoids in urine. Three healthy male volunteers with a history of marijuana use participated in the clinical study. Each subject smoked one, two, or four marijuana cigarettes (2.6% THC) on each test day. Urine samples were collected and incorporated into a specimen set consisting of 178 clinical samples, 72 urine samples containing known amounts of drug, and 50 drug-free urine samples. The specimen set was randomized and analyzed under blind conditions by the accuPINCH test and by gas chromatography-mass spectrometry (GC-MS) for 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (THCCOOH). AccuPINCH results were interpreted independently by three readers as positive at either two calibration points (positive A100 ng/mL THCCOOH; positive Bor = 100 ng/mL THCCOOH) or negative. Concordance analysis was performed by comparison of the accuPINCH results with GC-MS. In addition, the effects of changes in sample turbidity, temperature, and assay reading time on test outcome were assessed. For the clinical samples, positive B results were associated exclusively with THCCOOH concentrations greater than or equal to 15 ng/mL, whereas positive A and negative results were obtained at all concentrations. All drug-free urine samples were interpreted as either negative or positive A. The test demonstrated relatively low cross-reactivity with THC and other cannabinoids.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective To investigate the intraindividual pharmacokinetics (PKs) of total (protein bound plus unbound) and unbound lopinavir/ritonavir (LPV/RTV) and to assess whether the pediatric formulation (100 mg/25 mg) can overcome any pregnancy-associated changes. Design Prospective longitudinal PK study. Methods HIV-infected pregnant antiretroviral therapy-naive and experienced women receiving LPV/RTV 400 mg/100 mg tablets twice daily. Intensive PK evaluations were performed at 20-24 weeks (PK1), 30 weeks (PK2) followed by empiric dose increase using the pediatric formulation (100 mg/25 mg twice daily), 32 weeks (PK3), and 8 weeks postpartum (PK4). Results Twelve women completed prespecified PK evaluations. Median (range) age was 28 (18-35) years and baseline BMI was 32 (19-41) kg/m. During pregnancy, total area under the time concentration (AUC0-12h) for LPV was significantly lower than postpartum (PK1, PK2, or PK3 vs. PK4, P = 0.005). Protein-unbound LPV AUC0-12h remained unchanged during pregnancy [PK1: 1.6 (1.3-1.9) vs. PK2: 1.6 (1.3-1.9) μg·h/mL, P = 0.4] despite a 25% dose increase [PK2 vs. PK3: 1.8 (1.3-2.1) μg·h/mL, P = 0.5]. Protein-unbound LPV predose concentrations (C12h) did not significantly change despite dose increase [PK2: 0.10 (0.08-0.15) vs. PK3: 0.12 (0.10-0.15) μg/mL, P = 0.09]. Albumin and LPV AUC0-12h fraction unbound were correlated (rs = 0.3, P = 0.03). Conclusions Total LPV exposure was significantly decreased throughout pregnancy despite the increased dose. However, the exposure of unbound LPV did not change significantly regardless of trimester or dose. Predose concentrations of unbound LPV were not affected by the additional dose and were 70-fold greater than the minimum efficacy concentration. These findings suggest dose adjustments may not be necessary in all HIV-infected pregnant women.

Despite the current popularity of smoking as a route of drug self-administration, there have been few human studies characterizing the pharmacokinetics and pharmacodynamics of smoked drugs of abuse. A variety of technological difficulties are encountered in the design of smoking studies, such as delivering reproducible doses and limiting the amount of pyrolysis of parent drug. As part of a concerted research effort to deliver precise, smoked doses of drug, a computer-assisted smoking device was utilized that delivered single puffs of heroin vapor to human subjects under controlled clinical conditions. Recovery studies indicated that the smoking device delivered approximately 89% of parent heroin to subjects. Although only two qualified heroin smokers could be identified as eligible volunteers, their participation provided the unique opportunity to study the pharmacokinetics and pharmacodynamics of smoked heroin. The two subjects were administered four smoked heroin doses in ascending order. In addition, four intravenous doses of heroin were administered for comparison of effects and estimation of bioavailability. Concurrent physiological, behavioral, and performance measures were collected along with blood samples. Blood was analyzed for heroin, 6-acetylmorphine, and morphine by solid-phase extraction gas chromatography-mass spectrometry. Heroin appeared rapidly in blood after administration and peaked 1-5 minutes after smoking, which is similar to that observed following intravenous administration. Heroin concentrations declined rapidly to the limit of detection (1.0 ng/mL) by 30 minutes. 6-Acetylmorphine blood concentrations also peaked and declined rapidly after smoked heroin with peak concentrations occurring at 1-2 minutes after smoking. Morphine levels rose and decayed more slowly. Mean elimination half-lives for heroin, 6-acetylmorphine, and morphine were 3.3 min, 5.4 min, and 18.8 min, respectively, by the smoked route. The bioavailability of smoked heroin was highly variable. Physiological measures such as pupil diameter demonstrated a counterclockwise hysteresis compared with heroin blood levels. The rapid onset of pharmacological effects together with the early appearance of heroin and metabolites in blood following smoked heroin demonstrated the effectiveness of this route of drug administration. It is evident that the smoking route enables individuals to obtain similar pharmacological effects as are produced by intravenous administration of heroin.

A mainstay of strategies to prevent HIV-1 transmission is to use antiretroviral therapy (ART) for pre-exposure prophylaxis (PrEP). Critical to the design and interpretation of PrEP prevention trials is the ability to make accurate pharmacological measurements of ART drugs in human genital and colorectal mucosal tissues, the principal route of HIV transmission. Here, we evaluated two drugs that are preferentially used for PrEP: tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC). A single oral dose of TDF/FTC (Truvada) was administered to 15 healthy individuals. Over the next 14 days, TFV and FTC were measured in blood plasma and genital secretions using a sensitive assay (lower level of quantification, 0.1 ng/ml). The active intracellular phosphorylated metabolites of these drugs [TFV diphospate (TFV-DP) and FTC triphosphate (FTC-TP)] were measured in homogenates prepared from rectal, vaginal, and cervical tissues. TFV and FTC were detected in blood plasma 14 days after administration of a single dose. The area under the concentration-time curve from 24 hours to 14 days (AUC(1-14d)) for FTC in genital secretions was 27-fold greater than in blood plasma, whereas the AUC(1-14d) for TFV was only 2.5-fold greater in genital secretions than in blood plasma. In rectal tissue, TFV and TFV-DP concentrations were detectable for 14 days and were 100-fold higher than the concentrations in vaginal and cervical tissues. Vaginal and cervical tissue concentrations of FTC were 10- to 15-fold higher than in rectal tissue. Despite high concentrations of FTC in vaginal and cervical tissue, FTC-TP concentrations in all tissue types were detected for only 2 days after dose. The exposure to TFV, TFV-DP, FTC, and FTC-TP was wide ranging depending on the type of mucosal tissue. These results demonstrate the need for detailed pharmacological studies to improve the application of ART for PrEP to prevent transmission of HIV.

The misuse/abuse of drugs is a serious problem in our community. In 2006, the Drug Abuse Warning Network (DAWN) estimated that 1,742,887 emergency room visits in the USA were drug related and that 958,164 were due to the use of an illicit drug [1]. Drugs are classified by the US Controlled Substance Act into categories based on abuse potential and acceptable medical use. Schedule I drugs have a high abuse potential with no currently approved medical uses. The remaining schedules are lesser variations with the abuse potential decreasing with acceptable medical uses. Drugs are abused based on their pharmacological properties which may include euphoria, increase in mood or energy. The use of some drugs causes an activation of the dopamine reward pathway which increases the likelihood of abuse.

Standard addition (SA) has occasionally been utilized as an analytical tool in forensic toxicology. It is recommended for difficult matrices such as tissue or decomposed specimens in which the accurate quantitation of drug may be problematic. However, the additional preparation time and increased use of specimen may limit its general applicability. In this study, the authors compared SA with direct extraction (DE) and quantitation against a blood calibration curve to assess whether the quantitative results were significantly different. Twenty-two postmortem cases were assayed for drugs such as cocaine and metabolites, opioids, and antidepressants by solid-phase extraction followed by gas chromatography―mass spectrometry operated in the selected ion monitoring mode. A two-tailed, homoscedastic Student's t-test demonstrated that the two sets of data were not statistically different (p = 0.81). In addition, SAs were more likely to demonstrate nonlinearity (r 2 < 0.98).

Recently, a number of "quick tests" became available for use in on-site drug testing. These tests offer advantages in simplicity, ease of performance, and rapid access to test results. However, there is a paucity of data on the validity of these tests for the detection of drugs of abuse. This report describes a validity study of the EZ-SCREEN cannabinoid test for the detection of cannabinoids in urine. Three healthy, male volunteers with a history of marijuana use participated in the study. Each subject smoked 1, 2, or 4 marijuana cigarettes (2.6% THC) on each test day. Urine samples were collected and incorporated into a specimen set consisting of 178 clinical urine samples, 72 urine samples containing known amounts of drug, and 50 drug-free urine samples. The specimen set was randomized and analyzed under blind conditions by the EZ-SCREEN test and by GC/MS for 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (THCCOOH). Results were interpreted independently by three readers. Concordance analysis was performed by comparison of results of the EZ-SCREEN test with GC/MS. The EZ-SCREEN test was highly sensitive and produced positive results at a standard THCCOOH concentration of 5 ng/mL. While showing high sensitivity to THCCOOH, the assay demonstrated low cross-reactivity with delta 9-tetrahydrocannabinol (THC) and other cannabinoids. No false-positive results were recorded with 50 drug-free urine samples, but one reader recorded eight undecided results. Overall agreement between the three readers for the EZ-Screen results was approximately 80%. Delayed readings and photocopy readings tended to be less accurate than readings obtained at 3 min.(ABSTRACT TRUNCATED AT 250 WORDS)

There is a paucity of literature detailing the disposition of drugs in bone and bone marrow. Infrequently, in deaths involving skeletonized remains, fragmentation, decomposition, and exsanguination, traditional specimens may be unavailable for toxicological testing. This study examined the utility of bone for the detection of benzodiazepines, opiates, cocaine and metabolites, and basic drugs in 39 cases. Cases were identified on the basis of a positive blood result. After specimen preparation, samples were assayed by liquid-liquid or solid phase extraction with gas chromatographic and gas chromatographic mass spectrometric detection. The majority of decedents were white males with 28% of individuals between the ages of 41 to 50 years. The cause of death was drug intoxication in 22 cases. The most prevalent drugs detected in the blood males and females were opiates and bases. Morphine, codeine, and oxycodone were detected in bone, whereas 6-acetylmorphine and hydrocodone were absent. For alkaline extractable drugs, in only 57% of blood positive specimens, the corresponding bone was also positive. These included antidepressants and antihistamines. Diazepam and nordiazepam were detected in the bone of all blood positive cases. Bone concentrations were higher than blood levels. Benzoylecgonine was the most common cocaine analyte detected in bone. These data demonstrated that drugs may be detected in bone using current technologies and that in general concentrations were higher than those observed in corresponding blood specimens. A negative result in bone, however, should be interpreted with caution because multiple factors determine the deposition of a drug in this matrix.

Testing for the presence of cocaine (COC) is common in postmortem and clinical laboratories. COC use may be detected by screening urine specimens for COC metabolite. In the forensic arena, screening positive results are confirmed by a more specific and sensitive technique, such as gas chromatography-mass spectrometry. This article reports the case of an individual who died of COC intoxication but whose immunoassay screen (EMIT) for COC metabolite was negative. Gas chromatography-mass spectrometry analysis of the urine detected benzoylecgonine (BE) at a concentration of 75 ng/mL and COC at 55 ng/mL. These concentrations explain the negative screening result since the cutoff concentration of the assay was 300 ng/mL for BE. The reported cross reactivity with COC was 25,000 ng/mL. However, heart blood concentrations of COC and BE were 18,330 and 8640 ng/mL, respectively. The results from this case provide evidence that an EMIT test alone may fail to detect COC use. Individuals utilizing results of drug screening by immunoassay must be aware of the limitations of this testing methodology.

Increases in methadone and oxycodone related deaths have been recently documented in the United States. In response to these reports, the authors investigated cases over a six-year period in which postmortem toxicological analyses revealed the presence of methadone, hydrocodone, and oxycodone. The study was designed to determine whether regional methadone-associated mortality in Cuyahoga County reflected national trends and more specifically, to distinguish methadone mortality from other commonly used opioid analgesics. All records of decedents that were found to be positive for methadone, hydrocodone, and/or oxycodone in 1998-2003 were reviewed. The cause and manner of death and demographic information was compiled. The cases were divided into lethal intoxications and cases where a positive result was determined to be an incidental finding. Lethal intoxications as a result of only methadone, hydrocodone, or oxycodone were separated from polydrug intoxications. Thoroughout the study, an increase was observed in the number of positive cases. In contrast to recent national data, although the number of methadone-positive cases increased from 4 in 1998 to 18 in 2003, this did not result in an increase in methadone overdoses [1 death in 1998 (25%) to 4 deaths in 2003 (22%)]. Although the pharmacokinetic profiles differ, methadone, hydrocodone, and oxycodone lethal intoxications equally comprised 28-29% of cases in which these drugs were detected. There was an overlap in the range of blood concentrations observed for the drug-related death groups and the incidental finding groups. However, mean and median concentrations in oxycodone and hydrocodone related deaths were more than two times greater than those in non-drug-related deaths.

Hydrocodone (HC) has received renewed interest in the US due to reported increases in opiate related deaths involving psychotherapeutic drugs. The relative contribution of dihydrocodeine (DHC) in these deaths is unknown since little testing of this compound is performed. The objective of the study was to determine the prevalence of DHC in HC positive decedents and report the range of concentrations detected in these cases in order to evaluate the potential role of DHC in the deaths and determine the usefulness of including this analyte in opioid testing protocols. Specimens were assayed by liquid-liquid or solid phase extraction followed by gas chromatography/mass spectrometry operated in the selected ion monitoring mode. A multipoint calibration was utilized in the linear range 2-600ng/mL. Accuracy for HC, DHC and hydromorphone (HM) was 101-106% and between day precision at 160ng/mL between 7% and 11%. One hundred and thirty six cases were identified with the majority male (62%) and white (83%). A search of HC positive cases identified 64 with DHC (47%). The range of HC concentrations was 9-3039ng/mL heart blood (n=43) and 42-12353ng/mL urine (n=21). DHC concentrations in these cases ranged 3-243ng/mL in heart blood and 5-1842ng/mL in urine. DHC/HC ratios ranged 0.00(7)-2.90 in blood (n=43), and 0.01-5.04 in urine (n=21) with 16% and 24% of these cases with ratios >0.50, respectively. HM was detected in only 9 HC cases with the majority positive in urine.

Contents Foreword by Yale Caplan Preface Contributors CHAPTER 1 Specimens of Maternal Origin: Amniotic Fluid and Breast Milk Sarah Kerrigan, Ph.D., and Bruce A. Goldberger, Ph.D., DABFT CHAPTER 2 Drugs of Abuse in Meconium Specimens Christine M. Moore, PhD., DABCC CHAPTER 3 Nails: Utility in Drugs-of-Abuse Testing Diana Garside, Ph.D., DABFT CHAPTER 4 Drug Testing in Hair Pascal Kintz Ph.D. CHAPTER 5 Drugs-Of-Abuse Testing in Saliva or Oral Fluid Vina Spiehler, Ph.D., DABFT and Gail Cooper, PhD, CChem MRSC CHAPTER 6 The Detection of Drugs in Sweat Neil A. Fortner, MS, FTS-ABFT, TC-NRCC CHAPTER 7 Drugs of Abuse Testing in Vitreous Humor Barry S. Levine, Ph.D. DABFT, DABCC and Rebecca Jufer, Ph.D. DABFT CHAPTER 8 Drugs in Bone and Bone Marrow Olaf H. Drummer, Ph.D. CHAPTER 9 Drugs-of-Abuse in Liver Graham R. Jones, Ph.D., DABFT and Peter P. Singer, Ph.D. CHAPTER 10 Drugs-of-Abuse Testing in Brain Thomas Stimpfl, Mag.pharm., Dr.rer.nat.

The objective of this study was to review demographic characteristics and drugs detected in carbon monoxide (CO)-related deaths from cases received by the Office of the Cuyahoga County Coroner in Cleveland, Ohio, from 2000-2003. Postmortem reports were reviewed, and decedents for which CO was listed as the cause of death were included. The data were compiled into 3 groups according to the official coroner's verdict as to the manner of death: accident, suicide, and homicide. Included in this study were 122 cases: 84 (69%) accidental, 31 (25%) suicide, and 7 (6%) homicide. Accident decedents were typically white males, aged 40-59 years, residing in Cleveland. Suicide decedents were also middle-aged, white males but residing in the suburbs. Homicide decedents under the age of 6 were characteristically black (N=2), while decedents over the age of 39 were predominately white (N=3). Carboxyhemoglobin (COHb) levels in suicide cases were higher than concentrations measured in accidental deaths. The highest percentage of suicide decedents (36%) had a COHb level>70% saturation, accident decedents (36%) between 50% and 69% saturation, and homicide decedents (71%) below 50% saturation. Ethanol (N=34) was detected in 28% of deaths, and therapeutic and/or abused drugs (N=50) were detected in 41% of deaths. Illicit drugs were detected in 11% of cases (cocaine/metabolites; THC/metabolites), other drug positives were therapeutic medications. The most common drugs detected were antidepressants and antihistamines in suicides and pain medications and antihistamines in accidents.

We report a case of a 75-year-old hypertensive, diabetic man who presented to the emergency room with symptoms and signs of nausea, acute intoxication, significant alteration in mental status with rapid neurologic deterioration, and blunt impact injuries sustained during a recent altercation with a 36-year-old female companion-caretaker. He denied a history of ethanol abuse or other recent toxic ingestion and had not been diagnosed with or treated for depression. Hospital laboratory tests revealed a metabolic acidosis and a negative urine toxicology screen. He was diagnosed with toxic encephalopathy with metabolic acidosis secondary to metformin. Despite treatments including hemodialysis, he expired after approximately 28 hours of hospitalization. A postmortem anatomic examination revealed recent blunt-impact injuries and cardiac and renal pathology. A subsequent histologic examination revealed the presence of calcium oxalate crystals in the kidneys and brain, in addition to cardiac and renal pathology. Comprehensive forensic toxicologic testing was performed on antemortem and postmortem samples and revealed lethal levels of ethylene glycol. The cause of death was as a result of acute intoxication by ethylene glycol with another condition of multiple blunt impacts to the head, trunk, and extremities. The manner of death was ruled as homicide. A trial by jury, involving the female companion-caretaker, resulted in her conviction, and she was sentenced to 23 years to life in prison. In this report, we present an unusual case of homicidal ethylene glycol intoxication in which legal proceedings have occurred.

During a death investigation at the Office of the Cuyahoga County Coroner in Cleveland, OH, doxacurium became a drug of interest. The Coroner's Office enlisted the aid of the Federal Bureau of Investigation Laboratory for the doxacurium analysis. Following the request, a method for the extraction and qualitative analysis of the drug in biological fluids was developed. The procedure relies on a simple solid-phase extraction procedure followed by qualitative analysis with liquid chromatography-tandem mass spectrometry. During the development of the new analytical procedure, two breakdown products of doxacurium were detected. Structures for these breakdown products are proposed. This procedure was used to analyze heart blood, cerebrospinal fluid, and bile specimens from the decedent. Doxacurium and its breakdown products were identified in all three specimens.

Previous studies have shown that up to 50% of adult drownings are related to the consumption of alcohol. Little information is available in the literature regarding the possible contribution of ethanol and other drugs to drownings. All records of deaths occurring in Cuyahoga County, Ohio, from 1994-2003, in which drowning was listed as the cause of death, were reviewed. Toxicology analysis was performed on cases where specimens were submitted. Review of the 187 cases showed that the majority (78%) of drowning deaths were ruled as accidents, 26 (14%) as suicide, 5 (3%) as homicide, and 11 (6%) as undetermined. Among the accidental deaths (n = 141), 97 (69%) were negative for all drugs, including ethanol, and 30 cases (21%) were positive for ethanol only. Illicit drugs were detected in 4 of the cases (3%). In the suicides (n = 26), 16 (62%) were negative for all drugs, including ethanol, and 7 cases (27%) were positive for ethanol only (mean blood alcohol concentration [BAC] 0.03 g/dL). Illicit drugs were detected in 3 of the cases (12%). Two of the 5 homicide cases (40%) were positive for ethanol. There were no cases in which the victim tested positive for illicit drugs.Of the 11 cases ruled as undetermined, 64% (n = 7) were negative for all drugs, including ethanol. The remainder of the cases tested positive for ethanol only. There were no cases in which illicit drugs were detected. This study demonstrates that the majority of drowning deaths in Cuyahoga County, Ohio, were not drug related. Deaths in which drugs were detected were typically accidental deaths, with ethanol the most common drug detected.

The relationship between plasma and oral fluid concentrations of nicotine after infusion at varying times was investigated. Five healthy human volunteers were administered 0, 0.75, and 1.5 mg nicotine as 0.5-, 1.0-, 2.5-, and 5-minute infusions. Blood and oral fluid were collected before drug administration and for 4 hours thereafter. Nicotine concentrations were determined by HPLC using a limit of quantification of 1 ng/mL. Plasma nicotine concentrations were dose related. Peak plasma concentrations (mean+/-SD) at the 4 infusion times were 14.1+/-5.5, 11.8+/-5.3, 12.8+/-1.9, and 11.5+/-4.0 ng/mL (N=5) after the 0.75-mg dose and 26.3+/-11.7, 19.3+/-12.8, 24.54+/-10.4, and 19.02+/-6.5 ng/mL after the 1.5-mg dose. In general, the highest peak concentration occurred at the shortest infusion time at each dose. Peak nicotine oral fluid concentrations (mean+/-SD) at the 4 infusion times of 22.4+/-29.1, 22.64+/-29.9, 19.1+/-13.5, and 49.1+/-31.7 ng/mL (n=5) after the low dose and 35.8+/-21.1, 26.0+/-7.7, 33.3+/-28.8, and 104.0+/-68.9 ng/mL, after the 1.5 mg dose. The highest oral fluid concentration of nicotine occurred at the longest infusion time at each dose. Oral fluid/plasma were >1 for up to 60 minutes after the low dose and 120 minutes after the high dose. There was no correlation between plasma and oral fluid nicotine concentrations.

Quetiapine is a new atypical antipsychotic that was approved in 1997 by the U.S. Food and Drug Administration for the treatment of schizophrenia. It possesses a high affinity for 5-HT2 receptors and a low affinity for D1 and D2 dopamine receptors. Because quetiapine has only been released recently to the U.S. market, little information exists regarding therapeutic, toxic, and lethal concentrations. This study reports the detection of quetiapine in 13 postmortem cases. Following a basic liquid-liquid extraction, quetiapine was identified and quantitated by capillary gas chromatography with nitrogen phosphorus detection. Confirmation was accomplished by full scan electron impact gas chromatography/mass spectrometry. Heart blood quetiapine concentrations ranged from 0.07 to 18.37 mg/L (N = 12, mean +/- SD = 3.42 +/- 5.67, median 0.62) and femoral blood concentrations ranged from 0.06 to 19.25 mg/L (N = 10. mean +/- SD = 3.89 +/- 6.12, median 0.81). The average heart blood/femoral blood ratio was 1.31 (range 0.55 to 2.57, N = 10). Urine, bile, and gastric contents were assayed in all cases in which they were submitted. In three cases, the cause of death was determined to be quetiapine toxicity. In these cases heart blood concentrations ranged from 0.72 to 18.37 mg/L (N = 3). These data may provide a basis for establishing levels associated with quetiapine toxicity as well as therapeutic concentrations in postmortem specimens.

The relationship between blood cocaine concentrations and pharmacological effects is of both theoretical and practical interest. This study utilized a computer-assisted smoking device for the delivery of three active doses (10, 20, and 40 mg) of cocaine base to seven human volunteers. Doses were administered in an ascending dose design with random placement of placebo. Physiological, subjective, and performance measures were collected concurrently with blood samples. Mean peak plasma cocaine concentrations were achieved at 2 min after the 20-mg and 40-mg doses and at 5 min after the 10-mg dose. Maximal responses in systolic and diastolic blood pressure, "feel", "good" drug, and drug "liking" subjective effects were also achieved immediately after drug administration. Pupil diameter and heart rate increases demonstrated a modest counter-clockwise hysteresis in relation to plasma cocaine concentrations shortly after dosing. Systolic and diastolic blood pressure, heart rate, and some subjective and performance measures of drug effect demonstrated a biphasic response after smoked cocaine. Initial increases above baseline levels were followed by an apparent compensatory decrease below baseline levels at a later time after smoked cocaine. Despite evidence of hysteresis and biphasic responses for some measures, linear correlation was obtained between mean plasma cocaine concentrations and several pharmacological effects over a period of 4 h after dosing. Several subjective and cardiovascular measures returned to baseline levels in the presence of detectable concentrations of cocaine.

Citalopram is a bicyclic phthalate compound approved in 1998 by the U.S. Food and Drug Administration for the treatment of depression. It is a highly selective serotonin reuptake inhibitor that appears to have little effect on noradrenaline or dopamine reuptake. Since this drug has only recently been released on the U.S. market, information regarding therapeutic, toxic, and lethal concentrations is sparse. This study reports the detection of citalopram in 22 postmortem cases. Citalopram was identified and quantitated by capillary column gas chromatography with nitrogen phosphorus detection after basic liquid-liquid extraction. Confirmation was achieved by full scan electron impact gas chromatography/mass spectrometry. In the 22 cases studied, heart blood citalopram concentrations ranged from 0.09 to 1.64 mg/L (n = 22, mean +/- SD = 0.51+/-0.43, median = 0.34); femoral blood concentrations ranged from 0.09 to 0.76 mg/L (n = 14, mean +/- SD = 0.34+/-0.23, median = 0.28); and urine concentrations ranged from 0.05 to 276.00 mg/L (n = 13). Liver was analyzed in three cases with citalopram concentrations ranging from 2.22 to 8.08 mg/kg. The average heart blood/femoral blood ratio was 1.26 (range 0.75 to 1.98, n = 14). In each case, the cause of death was not considered to be related to citalopram toxicity. These data may therefore provide a basis for establishing post mortem citalopram concentrations following therapeutic doses.

Chapter 1 Clinical Point-of-Care Testing for Drugs of Abuse Jimmie L. Valentine 1 General Considerations 2 Pediatric Clinical Considerations 3 Adolescent Clinical Considerations 4 Adult Clinical Considerations 5 Physiological Considerations for Clinical Testing 6 Conclusions References Chapter 2: On-Site Tests for Therapeutic Drugs Alan H. B. Wu 1 Rationale for Therapeutic Monitoring and Need for On-Site Drug Testing 2 On-Site and Point-of-Care (POC) Drug Testing 3 Direct On-Site Testing Instruments and Devices for Therapeutic Drugs 4 Indirect On-Site Testing for Therapeutic Drugs 4.1 Monitoring of Lipid Lowering Medications 4.2 Monitoring of Antithrombotic Medications 4.2.1 Heparin 4.2.2 Oral Antithrombotic Therapy 4.2.3 On-Site Testing for Anticoagulant Drugs 5 Conclusion References Chapter 3: On-Site Workplace Drug Testing David Armbruster 1 Background 2 Conducting On-Site Workplace Drug Testing 3 The Future of On-Site Workplace Drug Testing References Chapter 4: Program Requirements, Standards, and Legal Considerations for On-Site Drug Testing Devices in Workplace Testing Programs Theodore F. Shults and Yale H. Caplan 1 Introduction 2 What Is 'On-Site' Testing from a Standards Perspective? 3 Establishing Federal Standards for On-Site Drug Testing 3.1 Drug Testing Advisory Board (DTAB) 3.1.1 Collection Site 3.1.2 Collector/Tester 3.1.3 Collection Device/Test Device 3.1.4 Specimen 3.1.5 Collection Procedure 3.1.6 On-Site Testing 3.1.7 Laboratory Testing 3.1.8 Quality Control/Quality Assurance (QC/QA) 3.1.9 Reporting 3.1.10 Medical Review Officer 3.2 The DTAB End Game 4 The Legal Requirements for Confirmatory Testing in Private Sector On-Site Testing 5 The Legal Requirements for a Medical Review Officer in Private Sector On-Site Testing 6 New Liability Risks of Drug Testing Providers and On-Site Drug Testing-Another Factor in Establishing Standards 7 Conclusion Notes Chapter 5: On-Site Testing Devices in the Criminal Justice System Leo J. Kadehjian and James Baer 1 Drug Testing in the Criminal Justice Arena 1.1 Introduction 1.2 On-Site Testing 1.3 Use of Noninstrument Drug Testing Devices 2 Legal Admissibility, Evidentiary Weight, and Due Process 2.1 Standards for Admissibility of Scientific Evidence 2.2 Cases Addressing the Use of Noninstument Drug Testing Devices 2.3 Requirements for Repeat and/or Confirmation Testing 3 Conclusions References Chapter 6: On-Site Testing Devices and Driving-Under-the-Influence Cases J. Michael Walsh 1 Introduction 2 On-Site Testing in DUI Cases 3 Summary References Chapter 7 Analysis of Ethanol in Saliva Kurt M. Dubowski 1 Introduction 2 Saliva as a Specimen Saliva Collection Relationship of Saliva and Blood-Alchohol 2.1 Saliva Collection 2.2 Relation of Saliva-Alcohol to Alcohol in Other Body Fluids 3 Saliva-Alcohol Testing Principles and Procedures 4 Commercial Saliva-Alcohol Screening Test Devices 5 Quality Assurance 5.1Testing Personnel 6 Interpretation and Use of Results References Chapter 8: Analysis of Drugs in Saliva Vina Spiehler, Dene Baldwin, and Christopher Hand 1 Roadside or On-Site Saliva Drug Testing 1.1 Introduction 1.2 Saliva Collection 1.3 Cutoff Concentrations in Saliva 1.4 Amphetamines 1.5 Benzodiazepines 1.6 Cannabinoids 1.7 Cocaine 1.8 Opiates 1.9 Conclusion 2 Cozart RapiScan Saliva Drug Test System 2.1 Introduction 2.2 Testing Principle 2.3 Quality Control 2.4 Interpretation 2.5 Performance 2.6 Adulteration

Mixed drug reactions are frequently encountered in emergency department overdose cases and also in fatal intoxications. Assessment of the relative contribution of each drug in producing adverse effects is often compounded by lack of case history and the paucity of cases reported in the literature. This report describes a fatal intoxication with three common over-the-counter medications: guaifenesin, diphenhydramine, and chlorpheniramine. A 48-year-old woman was found dead in the attic bedroom of her residence. Specimens obtained at autopsy for toxicologic analysis included heart blood, urine, bile, gastric contents, vitreous humor, and cerebrospinal fluid. The over-the-counter drugs were identified and quantitated by acid/neutral or basic liquid-liquid extraction followed by gas chromatographic analysis with nitrogen phosphorus detection. Concentrations of guaifenesin, diphenhydramine, and chlorpheniramine detected in the heart blood were 27.4, 8.8, and 0.2 mg/L, respectively. The cause of death was determined to be acute intoxication by the combined effects of guaifenesin, diphenhydramine, and chlorpheniramine, and the manner of death was determined to be suicide. To our knowledge, the blood guaifenesin concentration in this case is the highest reported concentration to date associated with an acute intoxication.

This study examined cocaine and benzoylecgonine concentrations in 100 consecutive deaths where either compound was identified in blood or urine specimens to determine whether any relationship between these concentrations and cause of death can be found. Forty-seven of the 100 cases were deaths attributed to cocaine, narcotic or combined cocaine and narcotic intoxication. There were 13 cases of cocaine intoxication where no psychoactive substance other than ethanol was detected. The mean cocaine concentration in these deaths was 908 ng/ml; three cases had cocaine concentrations greater than 2000 ng/ml, while the other ten cases had cocaine concentrations less than or equal to 700 ng/ml. The mean cocaine concentration in non-cocaine deaths where no psychoactive substance other than ethanol was detected was 146 ng/ml. This difference was not statistically significant. However, the average blood benzoylecgonine concentration in the 13 cocaine deaths was significantly higher than in the 19 non-cocaine deaths. A review of combined cocaine and narcotic deaths suggest that the narcotic is the main causative agent in these deaths.

The case of a 34-year-old, mentally challenged, Caucasian female found dead in a group home is presented. Empty containers of perphenazine and valproic acid were found next to her bed. The perphenazine had been prescribed to another patient. No anatomic cause of death was determined at autopsy. Comprehensive testing of the heart blood for ethanol and drugs identified perphenazine at a concentration of 4.4 mg/L and valproic acid at a concentration of 950 mg/L. The distribution of perphenazine in other specimens was consistent with previously reported phenothiazine cases. The medical examiner ruled that the cause of death in this case was multiple drug intoxication and the manner of death was suicide.