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Scheidweiler K.B.,U.S. National Institutes of Health | Kolbrich Spargo E.A.,U.S. National Institutes of Health | Kolbrich Spargo E.A.,Southwestern Institute of Forensic science | Kelly T.L.,University of Canberra | And 2 more authors.
Therapeutic Drug Monitoring | Year: 2010

Oral fluid is an attractive alternative matrix for drug testing with a noninvasive and directly observed collection, but there are few controlled cocaine administration studies to guide interpretation. MATERIALS AND METHODS: While residing on a closed research unit for up to 10 weeks under constant medical supervision, 19 participants were administered 75 mg/70 kg subcutaneous cocaine and 14 received 150 mg/70 kg. The disposition of cocaine, benzoylecgonine (BE), and ecgonine methyl ester (EME) into oral fluid was determined by gas chromatography-mass spectrometry for 0.08 to 48 hours after administration. RESULTS: In oral fluid collected by citric acid candy-stimulated expectoration, cocaine first appeared in oral fluid 0.08 to 0.32 hours after dosing and was rapidly eliminated with half-lives of 1.1 to 3.8 hours. BE and EME were first detected 0.08 to 1.0 hours after dosing with longer half-lives of 3.4 to 13.8 (BE) and 2.4 to 15.5 hours (EME) (P < 0.05). Oral fluid and plasma concentrations were significantly correlated for cocaine, BE, and EME (P < 0.0001). There were no significant differences (P > 0.05) in first and last detection times with the 8-μg/L cutoff proposed by the Substance Abuse and Mental Health Services Administration or the 10-μg/L cutoff from the European initiative, Driving Under the Influence of Drugs, Alcohol and Medicines. Metabolite:cocaine ratios increased after cocaine administration, potentially helpful for interpreting time of last use. Comparison of oral fluid collection through citric acid candy-stimulated expectoration, citric acid-treated Salivette, and neutral cotton Salivette devices did not reveal significant differences between devices for areas under the curve for cocaine, BE, or EME (P > 0.05). DISCUSSION AND CONCLUSION: These results provide additional evidence for interpreting cocaine and metabolite concentrations in oral fluid and oral fluid's usefulness as an alternative matrix for drug testing. Copyright © 2010 by Lippincott Williams & Wilkins.


Thompson M.P.,University of Texas Southwestern Medical Center | Pinckard J.K.,University of Texas Southwestern Medical Center | Pinckard J.K.,Southwestern Institute of Forensic science
American Journal of Forensic Medicine and Pathology | Year: 2011

Thyrotoxic periodic paralysis is a rare and dramatic complication of hyperthyroidism. Thyrotoxic periodic paralysis classically presents with proximal lower limb weakness in the setting of hypokalemia and thyrotoxicosis. Thyrotoxic periodic paralysis represents an endocrine emergency with a rapidly ascending paralysis that can result in respiratory insufficiency, cardiac arrhythmias, and death if not accurately and rapidly diagnosed. We report a case of undiagnosed fatal thyrotoxic periodic paralysis presenting to the medical examiner. The diagnosis was made primarily by review of the clinical history. © 2011 by Lippincott Williams & Wilkins.


Schwaninger A.E.,Saarland University | Meyer M.R.,Saarland University | Barnes A.J.,U.S. National Institute on Drug Abuse | Kolbrich-Spargo E.A.,U.S. National Institute on Drug Abuse | And 5 more authors.
Biochemical Pharmacology | Year: 2012

The R-and S-enantiomers of racemic 3,4-methylenedioxymethamphetamine (MDMA) exhibit different dose-concentration curves. In plasma, S-MDMA was eliminated at a higher rate, most likely due to stereoselective metabolism. Similar data were shown in various in vitro experiments. The aim of the present study was the in vivo investigation of stereoselective elimination of MDMA's phase I and phase II metabolites in human urine following controlled oral MDMA administration. Urine samples from 10 participants receiving 1.0 and 1.6 mg/kg MDMA separated by at least one week were analyzed blind by liquid chromatography-high resolution-mass spectrometry and gas chromatography-mass spectrometry after chiral derivatization with S-heptafluorobutyrylprolyl chloride. R/S ratios at C max were comparable after low and high doses with ratios >1 for MDMA, free DHMA, and HMMA sulfate, and with ratios <1 for MDA, free HMMA, DHMA sulfate and HMMA glucuronide. In the five days after the high MDMA dose, a median of 21% of all evaluated compounds were excreted as R-stereoisomers and 17% as S-stereoisomers. Significantly greater MDMA, DHMA, and HMMA sulfate R-enantiomers and HMMA and HMMA glucuronide S-stereoisomers were excreted. No significant differences were observed for MDA and DHMA sulfate stereoisomers. Changes in R/S ratios could be observed over time for all analytes, with steady increases in the first 48 h. R/S ratios could help to roughly estimate time of MDMA ingestion and therefore, improve interpretation of MDMA and metabolite urinary concentrations in clinical and forensic toxicology. © 2011 Elsevier Inc.


Schwaninger A.E.,Saarland University | Meyer M.R.,Saarland University | Barnes A.J.,U.S. National Institute on Drug Abuse | Kolbrich-Spargo E.A.,U.S. National Institute on Drug Abuse | And 5 more authors.
Clinical Chemistry | Year: 2011

BACKGROUND: 3,4-Methylendioxymethamphetamine (MDMA) is excreted in human urine as unchanged drug and phase I and II metabolites. Previous urinary excretion studies after controlled oral MDMA administration have been performed only after conjugate cleavage. Therefore, we investigated intact MDMA glucuronide and sulfate metabolite excretion. METHODS: We used LC-high-resolution MS and GC-MS to reanalyze blind urine samples from 10 participants receiving 1.0 or 1.6 mg/kg MDMA orally. We determined median C max, t max, first and last detection times, and total urinary recovery; calculated ratios of sulfates and glucuronides; and performed in vitro-in vivo correlations. RESULTS: Phase II metabolites of 3,4-dihydroxymethamphetamine (DHMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-dihydroxyamphetamine (DHA), and 4-hydroxy-3-methoxyamphetamine were identified, although only DHMA sulfates, HMMA sulfate, and HMMA glucuronide had substantial abundance. Good correlation was observed for HMMA measured after acid hydrolysis and the sum of unconjugated HMMA, HMMA glucuronide, and HMMA sulfate (R 2 = 0.87). More than 90% of total DHMA and HMMA were excreted as conjugates. The analyte with the longest detection time was HMMA sulfate. Median HMMA sulfate/glucuronide and DHMA 3-sulfate/4-sulfate ratios for the first 24 h were 2.0 and 5.3, respectively, in accordance with previous in vitro calculations from human liver microsomes and cytosol experiments. CONCLUSIONS: Human MDMA urinary metabolites are primarily sulfates and glucuronides, with sulfates present in higher concentrations than glucuronides. This new knowledge may lead to improvements in urine MDMA and metabolite analysis in clinical and forensic toxicology, particularly for the performance of direct urine analysis. © 2011 American Association for Clinical Chemistry.


Deisch J.,University of Texas Southwestern Medical Center | Quinton R.,Southwestern Institute of Forensic science | Gruszecki A.C.,American Forensics
Journal of Forensic Sciences | Year: 2011

Accidents and inflicted trauma account for 33% and 5-8% of childhood deaths, respectively. Injuries secondary to falling televisions have been reported in the clinical literature. However, descriptions of such injuries at autopsy are limited. The severity and patterns of injury may mimic those considered ''typical'' of inflicted trauma. Thus, integration of data from clinical, scene investigation, and autopsy is necessary for determination of the cause and manner of death. We present autopsy findings from two cases which illustrate injuries sustained from falling televisions. Findings common to both cases include subscalpular hemorrhages, skull fractures, subdural hemorrhages, brain injuries, and optic nerve sheath hemorrhages. The first case showed postsurgical changes secondary to evacuation of a posterior fossa hematoma; three-dimensional reconstruction of the admission computed tomography scan demonstrated the extent of the preintervention skull fractures. In addition, the second case showed a right epidural hematoma. Only case two showed retinal hemorrhage. © 2011 American Academy of Forensic Sciences.


Lann M.A.,University of Colorado at Denver | Lovell M.A.,Childrens Hospital | Lovell M.A.,Southwestern Institute of Forensic science | Kleinschmidt-Demasters B.K.,University of Colorado at Denver
American Journal of Forensic Medicine and Pathology | Year: 2010

Acute hemorrhagic leukoencephalopathy (AHLE) is a rare, acute disorder characterized by perivenular demyelination and diffuse hemorrhagic necrosis of the central nervous system. AHLE is thought to represent a hyperacute form of acute disseminated encephalomyelitis. AHLE is associated with a greater morbidity and mortality and, fortunately, is much less common than acute disseminated encephalomyelitis. Since most cases of AHLE result in patient demise, forensic pathologists should be cognizant of this entity and consider it in their differential diagnosis.Here we describe an interesting case of a previously healthy 11-year-old boy who initially complained of vague gastroenteritis-like symptoms while visiting a mountain lake. The boy's symptoms evolved to include severe headache and dizziness, necessitating a visit to a rural emergency department. He presented with focal neurologic findings, and head computed tomography (CT) scan confirmed thalamic edema. Cerebrospinal fluid analysis was suggestive of infectious etiology, and multiple empiric therapies were initiated. He was transferred to our institution, and his clinical status continued to worsen. Given the poor prognosis, the family requested withdrawal of supportive care. On day 14 of symptoms the boy succumbed to his illness. An autopsy was requested to further characterize the proximate cause of death.AHLE often presents with abrupt onset of fever, neck stiffness, seizure, and/or focal neurologic signs several days following a viral illness or vaccination. Thus, AHLE can clinically mimic a direct central nervous system infection or a toxic ingestion. AHLE has a very poor prognosis, with rapid deterioration and death usually occurring within days to one week after onset of symptoms. The cause for AHLE is unclear. An autoimmune pathophysiology is likely, with immune cross-reactivity between myelin basic protein moieties and various infectious agent antigens. Treatment for AHLE is not well-established; some authors describe in recent literature that a combination of immunosuppressant medications and/or therapeutic plasma exchange may be of benefit in treating AHLE. Copyright © 2010 by Lippincott Williams & Wilkins.


Lann M.A.,Southwestern Institute of Forensic science | Martin A.,Denver Office of the Medical Examiner
Journal of Forensic Sciences | Year: 2010

Deaths involving sensory deprivation tanks are very rare. We describe a unique case in which a previously healthy 50-year-old woman apparently died while floating in a sensory deprivation tank at her residence. Autopsy failed to reveal definitive anatomical abnormalities pointing to the cause of death. A thorough scene investigation, full medicolegal autopsy to include toxicological analyses, and a complete investigation into the equipment at the scene, were conducted. Blood toxicologic studies were significant for the presence of ethanol (0.27%) and a mixture of over-the-counter sedating medications and prescription drugs. The cause of death was ruled as acute mixed drug and ethanol toxicity combined with probable environmental hyperthermia; manner was accident. This case report will help the forensic community understand the intended use of flotation tanks, as well as possible risks associated with improper use. © 2010 American Academy of Forensic Sciences.


Hartman R.L.,U.S. National Institute on Drug Abuse | Hartman R.L.,University of Maryland, Baltimore | Desrosiers N.A.,U.S. National Institute on Drug Abuse | Desrosiers N.A.,University of Maryland, Baltimore | And 9 more authors.
Analytical and Bioanalytical Chemistry | Year: 2014

3,4-Methylenedioxymethamphetamine (MDMA) is an illicit phenethylamine ingested for entactogenic and euphoric effects. Although blood is more commonly submitted for forensic analysis, previous human MDMA pharmacokinetics research focused on plasma data; no direct blood-plasma comparisons were drawn. Blood and plasma specimens from 50 healthy adult volunteers (33 males, 17 females, 36 African-American) who ingested recreational 1.0 and 1.6 mg/kg MDMA doses were quantified for MDMA and metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-methylenedioxyamphetamine (MDA), and 4-hydroxy-3-methoxyamphetamine (HMA) by two-dimensional gas chromatography-mass spectrometry. Specimens were collected up to 3 h post-dose and evaluated for maximum concentration (Cmax), first detection time (tfirst), time of Cmax (t max), and 3-h area under the curve (AUC0-3 h); as well as blood metabolite ratios and blood/plasma ratios. Median blood MDMA and MDA C max were significantly greater (p <0.0005) than in plasma, but HMMAwas significantly less (p <0.0005). HMA was detected in few blood specimens, at low concentrations. Nonlinear pharmacokinetics were not observed for MDMA or MDA in this absorptive phase, but HMMA Cmax and AUC0-3 h were similar for both doses despite the 1.6-fold dose difference. BloodMDA/ MDMA and MDA/HMMA significantly increased (p <0.0001) over the 3-h time course, and HMMA/MDMA significantly decreased (p <0.0001). Blood MDMA Cmax was significantly greater in females (p =0.010) after the low dose only. Low-dose HMMAAUC0-3 h was significantly decreased in females' blood and plasma (p =0.027) and in African-Americans' plasma (p =0.035). These data provide valuable insight into MDMA blood-plasma relationships for forensic interpretation and evidence of sex-and race-based differential metabolism and risk profiles. © Springer-Verlag Berlin Heidelberg 2013.


Desrosiers N.A.,Clinical Pharmacology and Therapeutic Research Branch | Desrosiers N.A.,University of Maryland, Baltimore | Barnes A.J.,Clinical Pharmacology and Therapeutic Research Branch | Hartman R.L.,Clinical Pharmacology and Therapeutic Research Branch | And 6 more authors.
Analytical and Bioanalytical Chemistry | Year: 2013

Oral fluid (OF) offers a noninvasive sample collection for drug testing. However, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) in OF has not been adequately characterized in comparison to plasma. We administered oral low-dose (1.0 mg/kg) and high-dose (1.6 mg/kg) MDMA to 26 participants and collected simultaneous OF and plasma specimens for up to 143 h after dosing. We compared OF/plasma (OF/P) ratios, time of initial detection (tfirst), maximal concentrations (Cmax), time of peak concentrations (tmax), time of last detection (tlast), clearance, and 3,4-methylenedioxyamphetamine (MDA)-to- MDMA ratios over time. For OF MDMA and MDA, Cmax was higher, tlast was later, and clearance was slower compared to plasma. For OF MDA only, tfirst was later compared to plasma. Median (range) OF/P ratios were 5.6 (0.1-52.3) for MDMA and 3.7 (0.7-24.3) for MDA. OF and plasma concentrations were weakly but significantly correlated (MDMA: R2=0.438, MDA: R2=0.197, p<0.0001). Median OF/P ratios were significantly higher following high dose administration: MDMA low=5.2 (0.1-40.4), high=6.0 (0.4-52.3, p<0.05); MDA low=3.3 (0.7-17.1), high=4.1 (0.9-24.3, p<0.001). There was a large intersubject variation in OF/P ratios. The MDA/MDMA ratios in plasma were higher than those in OF (p<0.001), and the MDA/MDMA ratios significantly increased over time in OF and plasma. The MDMA and MDA concentrations were higher in OF than in plasma. OF and plasma concentrations were correlated, but large inter-subject variability precludes the estimation of plasma concentrations from OF. © Springer-Verlag Berlin Heidelberg 2012.


PubMed | U.S. National Institute on Drug Abuse, Southwestern Institute of Forensic science and 00 Ingleside Avenue
Type: Journal Article | Journal: Analytical and bioanalytical chemistry | Year: 2016

3,4-Methylenedioxymethamphetamine (MDMA) is an illicit phenethylamine ingested for entactogenic and euphoric effects. Although blood is more commonly submitted for forensic analysis, previous human MDMA pharmacokinetics research focused on plasma data; no direct blood-plasma comparisons were drawn. Blood and plasma specimens from 50 healthy adult volunteers (33 males, 17 females, 36 African-American) who ingested recreational 1.0 and 1.6mg/kg MDMA doses were quantified for MDMA and metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-methylenedioxyamphetamine (MDA), and 4-hydroxy-3-methoxyamphetamine (HMA) by two-dimensional gas chromatography-mass spectrometry. Specimens were collected up to 3h post-dose and evaluated for maximum concentration (C max), first detection time (t first), time of C max (t max), and 3-h area under the curve (AUC0-3h); as well as blood metabolite ratios and blood/plasma ratios. Median blood MDMA and MDA C max were significantly greater (p<0.0005) than in plasma, but HMMA was significantly less (p<0.0005). HMA was detected in few blood specimens, at low concentrations. Nonlinear pharmacokinetics were not observed for MDMA or MDA in this absorptive phase, but HMMA C max and AUC0-3h were similar for both doses despite the 1.6-fold dose difference. Blood MDA/MDMA and MDA/HMMA significantly increased (p<0.0001) over the 3-h time course, and HMMA/MDMA significantly decreased (p<0.0001). Blood MDMA C max was significantly greater in females (p=0.010) after the low dose only. Low-dose HMMA AUC0-3h was significantly decreased in females blood and plasma (p=0.027) and in African-Americans plasma (p=0.035). These data provide valuable insight into MDMA blood-plasma relationships for forensic interpretation and evidence of sex- and race-based differential metabolism and risk profiles. Figure Median (interquartile range) blood/plasma 3,4-methylenedioxymethamphetamine (MDMA) (a), 4-hydroxy-3-methoxymethamphetamine (HMMA) (b), and 3,4-methylenedioxyamphetamine (MDA) (c) ratios for 3h after controlled MDMA administration. Changes over time were significant after the 1.6 mg/kg dose for HMMA and MDA (p=0.013 and p=0.021), but not for MDMA. No changes over time were significant after the 1.0 mg/kg dose. Note: y-axes do not begin at 0. *p <0.05 (low vs. high).

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