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1.
Am J Forensic Med Pathol ; 45(2): 167-171, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38290004

RESUMEN

ABSTRACT: We report 8 children younger than 2 years who died from acute illicit fentanyl intoxications in Connecticut between 2020 and 2022.The Connecticut Office of the Chief Medical Examiner (CT OCME) investigates all unexpected, violent, and suspicious deaths in Connecticut. The CT OCME's electronic database was searched for fentanyl deaths by age. All underwent autopsies and toxicology testing.The ages ranged from 28 days to 2 years (mean age, 12 months). The causes of death involved acute fentanyl intoxications with 1 having xylazine, 1 having para-fluorofentanyl, and 1 having cocaine and morphine. All the manners of death were certified as homicide. The postmortem fentanyl blood concentrations ranged from 0.40 to 46 ng/mL. Most of the children were found unresponsive after being put to sleep. Three were co-sleeping with adults (2 in bed; 1 on a recliner). There was a known history of parental/caregiver drug abuse in 7 of 8 of the fatalities.We summarize the key investigative, autopsy, and toxicological findings. As illicit fentanyl use increases, there is a potential for infant exposure and death. The investigation and certification of these deaths and the role of intentional administration versus inadvertent exposure due to caregiver neglect in the context of the certification of the manner of death are described.


Asunto(s)
Fentanilo , Homicidio , Humanos , Fentanilo/envenenamiento , Fentanilo/análogos & derivados , Fentanilo/sangre , Lactante , Masculino , Femenino , Preescolar , Homicidio/estadística & datos numéricos , Recién Nacido , Connecticut/epidemiología , Analgésicos Opioides/envenenamiento , Analgésicos Opioides/sangre , Médicos Forenses , Narcóticos/envenenamiento , Narcóticos/sangre , Drogas Ilícitas/envenenamiento , Drogas Ilícitas/sangre
2.
Prep Biochem Biotechnol ; 51(10): 953-960, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34365899

RESUMEN

Methadone (MTD) is a synthetic analgesic drug used for treating opioid dependence and effectively used clinically for patients with severe pain. The abuse of MTD may lead to poisoning, disorder in the central nervous system and even death. The regular monitoring of MTD in biological matrices including serum, plasma and urine samples is an effective way to control abuse of MTD. In this manner, the selection of analytical monitoring of MTD in biological matrices is of paramount importance. This study was conducted to review high-performance liquid chromatography (HPLC) techniques carried out on MTD and its main metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in the biological samples during 2015-June 2021.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Metadona/sangre , Metadona/orina , Narcóticos/sangre , Narcóticos/orina , Monitoreo de Drogas/métodos , Cabello/química , Humanos , Metadona/análisis , Metadona/metabolismo , Uñas/química , Narcóticos/análisis , Narcóticos/metabolismo , Detección de Abuso de Sustancias/métodos
3.
Sud Med Ekspert ; 62(5): 43-46, 2019.
Artículo en Ruso | MEDLINE | ID: mdl-31626194

RESUMEN

The purpose of the work is the development of mathematical models in the forensic diagnosis of poisonings by the main groups of toxicologically important substances, on the basis of biochemical characteristics of blood. The most informative forensic and biochemical indicators of cadaveric blood used to detect lethal poisoning are the urea content, total protein content, and the ratio of urea to creatinine. Mathematical models of poisoning can be used to diagnose poisoning with narcotic drugs, psychotropic substances and substitutes of ethyl alcohol.


Asunto(s)
Etanol/sangre , Medicina Legal/métodos , Narcóticos/sangre , Intoxicación/diagnóstico , Psicotrópicos/sangre , Cadáver , Etanol/envenenamiento , Humanos , Modelos Teóricos , Narcóticos/envenenamiento , Intoxicación/sangre , Psicotrópicos/envenenamiento
4.
Forensic Sci Med Pathol ; 14(3): 295-300, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29713941

RESUMEN

Determining the manner of death in cases involving multiple stab injuries from a knife is generally straightforward. The medico-legal investigation of a stabbing death caused by a single stab injury from a knife comprises a smaller but potentially more problematic subset of forensic cases. We reviewed our institute's experience with single stab injuries and endeavored to identify features identified at the post-mortem examination which may aid in the differentiation between cases of homicide, suicide and accidental death. The single stab injury was to the left chest in the majority of deaths from homicide and from suicide. Clothing was nearly always involved in cases of homicide, but was also seen in cases of suicide. The knife was found in situ in 9 of the 11 cases of suicide involving a chest injury, but was not seen in any of the cases of homicide. There were no cases of an accidental single stab death from a knife in our records. Clinical data on accidental stab injuries was sought via a search of the medical records of a major tertiary referral hospital. A single non-fatal case of an accidental single stab injury from a knife was identified after the conclusion of our study period. Accidental stab injuries from a knife causing injury or death are rare.


Asunto(s)
Homicidio/estadística & datos numéricos , Suicidio/estadística & datos numéricos , Heridas Punzantes/mortalidad , Heridas Punzantes/patología , Traumatismos Abdominales/mortalidad , Traumatismos Abdominales/patología , Accidentes/estadística & datos numéricos , Adolescente , Adulto , Distribución por Edad , Anciano , Australia/epidemiología , Nivel de Alcohol en Sangre , Vestuario , Femenino , Patologia Forense , Humanos , Masculino , Persona de Mediana Edad , Narcóticos/sangre , Traumatismos del Cuello/mortalidad , Traumatismos del Cuello/patología , Psicotrópicos/sangre , Estudios Retrospectivos , Distribución por Sexo , Traumatismos Torácicos/mortalidad , Traumatismos Torácicos/patología , Adulto Joven
5.
Int J Legal Med ; 131(5): 1253-1260, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28509940

RESUMEN

Medico-legal experts are increasingly enlisted to assess the methamphetamine and amphetamine serum concentrations after a criminal offense. However, since criminal users rarely provide useful information to medico-legal experts regarding the substances abused, when the substance(s) was/were used, dose of ingestion tools are needed to interpret the analytical data, which can be used as objective evidence in such cases. A comparative series of methamphetamine and amphetamine serum concentrations were used to analyze the frequency of concentrations, to determine methamphetamine/amphetamine concentration ratios, and prove them as a tool to distinguish pure methamphetamine from mixed amphetamine/methamphetamine ingestion. Additionally, two cases of survived accidental methamphetamine intoxication, resulting from ingestion smuggling which was longitudinally monitored, and pharmacokinetic parameters were assessed. In a series of 628 samples where the most frequent concentration of methamphetamine exceeded the therapeutic level, there was a strong correlation suggesting pure methamphetamine consumption, when the ratios of methamphetamine/amphetamine concentrations were within the range between 3 and 10. In the two cases of methamphetamine bodypacking, the relevant serum concentrations of methamphetamine and amphetamine, which could be measured up to 9 days after ingestion, indicated a decrease of the methamphetamine/amphetamine ratios in an exponential manner. However, the ratios were not always within the range between 3 and 10. Lastly, the course of the serum concentrations suggested an increase of the apparent elimination half-life of methamphetamine. In terms of the objective evidence required in criminal law, calculating methamphetamine/amphetamine concentration ratio is not a suitable to means to distinguish pure methamphetamine intake and that of mixed amphetamine/methamphetamine abuse in an individual case. Instead, methamphetamine high serum concentrations and the possible increase in apparent elimination half-life suggest that an extended detection period may be used to distinguish between "illicit use" as compared to "therapeutic use" of methamphetamine.


Asunto(s)
Anfetamina/sangre , Metanfetamina/sangre , Narcóticos/sangre , Adulto , Anfetamina/farmacocinética , Transporte Intracorporal de Contrabando , Conducir bajo la Influencia , Sobredosis de Droga , Cromatografía de Gases y Espectrometría de Masas , Semivida , Humanos , Masculino , Metanfetamina/farmacocinética , Persona de Mediana Edad , Narcóticos/farmacocinética , Detección de Abuso de Sustancias
6.
Int J Legal Med ; 131(2): 379-389, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27915431

RESUMEN

Interpretation of postmortem morphine concentrations in forensic toxicology provides several pitfalls such as missing information on tolerance, analyte stability, or postmortem redistribution (PMR). Recently, it had been shown that computed tomography (CT)-guided collection of biopsies using a robotic arm (virtobot) provides a valuable strategy for systematic studies on time-dependent PMR. Using this technique, time-dependent PMR of morphine and its metabolites was investigated in 12 cases. At admission to the institute (t1), femoral and heart blood (right ventricle) as well as biopsies from the right lung, the right kidney, liver, spleen, and muscle tissue were collected. At autopsy approximately 24 h later (t2), samples from the same body regions were collected again. Additionally, gastric contents, urine, brain tissue, and heart blood from the left ventricle was collected. Morphine, normorphine, hydromorphone, morphine-3-glucuronide, morphine-6-glucuronide, and morphine-sulfate were quantified with LC-MS/MS. In femoral blood, significant increase of morphine concentrations was observed, although ultimately not relevant for forensic interpretation. In the alternative matrices, increases as well as decreases were observed without a clear trend. The morphine metabolites did not exhibit relevant concentration changes. Investigation of underlying redistribution mechanisms indicated that concentration change (i.e., increase) of morphine in femoral blood rather resulted from diffusion processes than from release of morphine from its conjugates. Concentration changes in heart blood might have been caused by redistribution from lung tissue or gastric content. This study also proved that CT-guided collection of biopsies using a virtobot arm is an invaluable tool for future studies on PMR redistribution of other substance groups.


Asunto(s)
Derivados de la Morfina/sangre , Morfina/sangre , Narcóticos/sangre , Cambios Post Mortem , Biopsia con Aguja Fina , Encéfalo/diagnóstico por imagen , Química Encefálica , Cromatografía Liquida , Contenido Digestivo/diagnóstico por imagen , Corazón/diagnóstico por imagen , Humanos , Riñón/química , Riñón/diagnóstico por imagen , Hígado/química , Hígado/diagnóstico por imagen , Pulmón/química , Pulmón/diagnóstico por imagen , Espectrometría de Masas , Morfina/farmacocinética , Derivados de la Morfina/farmacocinética , Músculo Esquelético/química , Músculo Esquelético/diagnóstico por imagen , Miocardio/química , Narcóticos/farmacocinética , Radiografía Intervencional , Bazo/química , Bazo/diagnóstico por imagen , Factores de Tiempo , Tomografía Computarizada por Rayos X
7.
Ther Drug Monit ; 39(6): 640-647, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28937537

RESUMEN

BACKGROUND: Opioid and cocaine antenatal substance use can result in significant obstetric and pediatric health implications. Accurate detection of in utero-exposed neonates can improve patient care and health outcomes. Therefore, the effectiveness of mother-infant biological and diagnostic indicators collected at labor and delivery to provide accurate detection of in utero opiate and cocaine exposure was assessed. METHODS: A retrospective medical chart review included 335 mother-infant dyads exposed to antenatal substances who were delivered between January 2009 and March 2014. Mother-infant dyads were a subset of a larger retrospective cohort of 560 substance-using mothers, who had a valid meconium drug screen (MDS) and anesthesia before delivery. Alternative biological and diagnostic indicators of maternal urine drug screens (UDS), maternal substance use International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes, and neonatal exposure diagnostic ICD-9-CM codes were compared against MDS. Data were analyzed using classification accuracy measures. RESULTS: Compared with MDS, maternal UDS had the highest sensitivity [0.52, 95% confidence interval (CI), 0.39-0.65] and specificity (0.88, 95% CI, 0.79-0.97) to detect intrauterine opiate exposure. Maternal substance use diagnosis had the highest sensitivity (0.39, 95% CI, 0.16-0.61) and maternal UDS had the highest specificity (1.00, 95% CI, 0.99-1.00) to detect intrauterine cocaine exposure. Cocaine exposure had significantly higher accuracy scores across detection methods compared with opiate exposure. CONCLUSIONS: Alternative indicators collected at delivery were ineffective at identifying in utero substance exposure, especially neonatal-exposed ICD-9-CM codes. Low sensitivity scores indicate that many exposed neonates could be misdiagnosed or left untreated. Accurate antenatal exposure identification at delivery is an important form of tertiary assessment that warrants the development of improved screening methodology and standardization of hospital biological drug testing.


Asunto(s)
Cocaína , Narcóticos/sangre , Complicaciones del Embarazo/diagnóstico , Detección de Abuso de Sustancias/métodos , Trastornos Relacionados con Sustancias/diagnóstico , Bioensayo , Cocaína/análisis , Cocaína/orina , Estudios de Cohortes , Femenino , Humanos , Lactante , Recién Nacido , Intercambio Materno-Fetal , Meconio/química , Alcaloides Opiáceos/sangre , Embarazo , Efectos Tardíos de la Exposición Prenatal , Estudios Retrospectivos , Sensibilidad y Especificidad , Trastornos Relacionados con Sustancias/sangre , Trastornos Relacionados con Sustancias/orina
8.
Am J Forensic Med Pathol ; 36(2): 84-7, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25881815

RESUMEN

Chronic renal failure results in reduced elimination of a variety of substances within the blood, including numerous drugs and their metabolites. This report describes a case of a man who died in jail, after less than 48 hours of being incarcerated, wherein postmortem toxicology testing revealed a blood benzoylecgonine level of 0.25 mg/L with no cocaine detected, suggesting possible recent cocaine use in jail. Autopsy and investigation revealed severe underlying cardiovascular disease and dialysis-dependent CRF, thus accounting for the elevated benzoylecgonine levels and allaying concerns that the man obtained and used cocaine in jail.


Asunto(s)
Cocaína/análogos & derivados , Fallo Renal Crónico/complicaciones , Narcóticos/sangre , Adulto , Cocaína/sangre , Cocaína/farmacocinética , Trastornos Relacionados con Cocaína/sangre , Enfermedad de la Arteria Coronaria/patología , Toxicología Forense , Humanos , Hipertensión/patología , Masculino , Narcóticos/farmacocinética , Prisioneros
9.
Forensic Sci Med Pathol ; 11(2): 193-201, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25801127

RESUMEN

PURPOSE: Deaths among drug addicts are frequently caused by intoxication with methadone and/or morphine. These drugs are often used in combination with other drugs, such as buprenorphine. In addition, methadone is generally used as a mixture of R- and S-enantiomers. To date, a method for separation and quantitation of these specific drugs has not been developed. The aim of this study was to develop a sensitive enantioselective method for quantitation of morphine, its active metabolite morphine 6-glucuronide, buprenorphine, and R- and S-methadone, in a single analytical run. METHODS: Whole blood samples were diluted with 0.5 mol/L ammonium carbonate buffer and extracted on a Bond Elut C18 solid-phase extraction column with an automatic solid-phase extraction system. Chromatographic separation was performed on a chiral alpha-1-acid glycoprotein column with an acetonitrile/ammonium acetate buffer (10 mmol/L, pH 7.0, 22:78 v/v) mobile phase. The whole blood concentrations of the drugs were quantified by mass spectrometry using their stable isotope-labeled compounds as internal standards. RESULTS: The method was validated with respect to specificity, linearity, precision, limits of detection, and quantification and matrix effects. The precision (coefficient of variation) was below 15%, and the accuracy was between 90 and 115%. CONCLUSIONS: This method will be useful for routine analyses in forensic laboratories where blood samples are frequently analyzed for drugs of abuse. In some cases, sudden death from methadone overdose is caused by the enantiomeric form of the methadone, which makes the enantiomer separation capability of this method important.


Asunto(s)
Buprenorfina/sangre , Metadona/sangre , Derivados de la Morfina/sangre , Morfina/sangre , Narcóticos/sangre , Buprenorfina/química , Cromatografía Liquida , Toxicología Forense , Humanos , Espectrometría de Masas , Metadona/química , Estructura Molecular , Morfina/química , Derivados de la Morfina/química , Narcóticos/química , Extracción en Fase Sólida , Estereoisomerismo , Trastornos Relacionados con Sustancias/sangre
10.
J Pharmacol Exp Ther ; 348(2): 311-5, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24307200

RESUMEN

The change in frequency of cocaine self-administration as a function of the unit dose is widely assumed to represent a graded pharmacodynamic response. Alternatively, a pharmacological theory states that during maintained self-administration, a quantal response occurs at a minimum maintained cocaine concentration (satiety threshold). Rats self-administered cocaine at unit doses spanning an 8-fold range from 0.75 to 6 µmol/kg. Despite an approximately 7-fold difference in the interinjection intervals, there were no differences in the plasma cocaine concentration at the time of lever press across this range of unit doses, consistent with the satiety threshold representing an equiactive cocaine concentration. Because self-administration always occurs when cocaine concentrations decline back to the satiety threshold, this behavior represents a process of automatic back titration of equiactive agonist concentrations. Therefore, the lower frequency of self-administration at higher unit doses is caused by an increase in the duration of the cocaine-induced satiety response, and the graded dose-frequency relationship is due to cocaine pharmacokinetics. After the interinjection intervals at a particular unit dose were stable, rats were injected with the competitive D1-like dopamine receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390; 15 nmol/kg intravenously) and the session continued. At all cocaine unit doses, SCH23390 accelerated self-administration with a concomitant increase in the calculated satiety threshold, and these equiactive cocaine concentration ratios were independent of the cocaine unit dose. Therefore, the measurement of antagonist potency requires only a single unit dose of cocaine, selected on the basis of convenience, and using multiple cocaine unit doses is redundant.


Asunto(s)
Benzazepinas/uso terapéutico , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Cocaína/administración & dosificación , Modelos Animales de Enfermedad , Antagonistas de Dopamina/uso terapéutico , Inhibidores de Captación de Dopamina/administración & dosificación , Respuesta de Saciedad/efectos de los fármacos , Administración Intravenosa , Animales , Conducta Animal/efectos de los fármacos , Benzazepinas/administración & dosificación , Cocaína/sangre , Cocaína/farmacocinética , Cocaína/toxicidad , Trastornos Relacionados con Cocaína/sangre , Antagonistas de Dopamina/administración & dosificación , Inhibidores de Captación de Dopamina/sangre , Inhibidores de Captación de Dopamina/farmacocinética , Inhibidores de Captación de Dopamina/toxicidad , Relación Dosis-Respuesta a Droga , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Masculino , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/uso terapéutico , Narcóticos/administración & dosificación , Narcóticos/sangre , Narcóticos/farmacocinética , Narcóticos/toxicidad , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/antagonistas & inhibidores , Autoadministración , Factores de Tiempo
11.
Int J Legal Med ; 128(5): 771-8, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24997532

RESUMEN

A rapid and sensitive liquid chromatography/tandem mass spectrometric (LC-MS/MS) method for simultaneous quantification of fentanyl (F), norfentanyl (NF), despropionylfentanyl (DPF), and hydroxynorfentanyl (OHNF) in human plasma and urine specimens has been developed and validated according to international guidelines. Analytes were extracted from 250-µL plasma or urine by liquid-liquid extraction. OHNF in urine affords a second extraction step and analysis with a different column. Calibration curves in plasma were linear from 0.05-10 ng/mL for F, 0.07-0.5 ng/mL for NF, 0.02-1.0 ng/ml for DPF, and 0.67-3.0 ng/mL for OHNF; in urine, from 0.09-10.0, 0.17-50, 0.08-1.0, and 1.0-5.0 ng/mL for F, NF, DPF, and OHNF, respectively. Analytical bias and intra- and inter-assay imprecision were within ± 15 % of target, except for OHNF in plasma and DPF in urine at the respective lower quality control level. All analytes were stable in processed samples when stored for 24 h at room temperature. Recoveries and process efficiencies were above 82.9 and 75.1 % for all analytes in plasma and urine. The low level of DPF in plasma indicated with a matrix effect of 71.3 % moderate ion suppression, all other analytes in plasma and urine showed no matrix effects. The lower limit of quantification (LOQ) in plasma was 0.05, 0.07, 0.02 and 0.67 ng/mL for F, NF, DPF, and OHNF, respectively. In urine, the LOQ of F, NF, DPF, and OHNF were 0.09, 0.17, 0.08, and 1.28 ng/mL, respectively. This assay has been applied to human specimens collected during a clinical drug-drug interaction study.


Asunto(s)
Cromatografía Liquida , Fentanilo/sangre , Fentanilo/orina , Narcóticos/sangre , Narcóticos/orina , Espectrometría de Masas en Tándem , Fentanilo/análogos & derivados , Toxicología Forense/métodos , Humanos , Límite de Detección
12.
Anal Bioanal Chem ; 406(5): 1339-54, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23912828

RESUMEN

The metabolic profiles of urine and blood plasma in drug-addicted rat models based on morphine (MOR), methamphetamine (MA), and cocaine (COC)-induced conditioned place preference (CPP) were investigated. Rewarding effects induced by each drug were assessed by use of the CPP model. A mass spectrometry (MS)-based metabolomics approach was applied to urine and plasma of MOR, MA, and COC-addicted rats. In total, 57 metabolites in plasma and 70 metabolites in urine were identified by gas chromatography-MS. The metabolomics approach revealed that amounts of some metabolites, including tricarboxylic acid cycle intermediates, significantly changed in the urine of MOR-addicted rats. This result indicated that disruption of energy metabolism is deeply relevant to MOR addiction. In addition, 3-hydroxybutyric acid, L-tryptophan, cystine, and n-propylamine levels were significantly changed in the plasma of MOR-addicted rats. Lactose, spermidine, and stearic acid levels were significantly changed in the urine of MA-addicted rats. Threonine, cystine, and spermidine levels were significantly increased in the plasma of COC-addicted rats. In conclusion, differences in the metabolic profiles were suggestive of different biological states of MOR, MA, and COC addiction; these may be attributed to the different actions of the drugs on the brain reward circuitry and the resulting adaptation. In addition, the results showed possibility of predict the extent of MOR addiction by metabolic profiling. This is the first study to apply metabolomics to CPP models of drug addiction, and we demonstrated that metabolomics can be a multilateral approach to investigating the mechanism of drug addiction.


Asunto(s)
Cocaína/administración & dosificación , Metaboloma/efectos de los fármacos , Metanfetamina/administración & dosificación , Narcóticos/administración & dosificación , Trastornos Relacionados con Sustancias , Animales , Cocaína/sangre , Cocaína/orina , Condicionamiento Operante , Modelos Animales de Enfermedad , Cromatografía de Gases y Espectrometría de Masas , Masculino , Redes y Vías Metabólicas/efectos de los fármacos , Metanfetamina/sangre , Metanfetamina/orina , Morfina/administración & dosificación , Morfina/sangre , Morfina/orina , Narcóticos/sangre , Narcóticos/orina , Ratas , Ratas Sprague-Dawley , Recompensa , Trastornos Relacionados con Sustancias/sangre , Trastornos Relacionados con Sustancias/orina
13.
Sud Med Ekspert ; 57(6): 37-9, 2014.
Artículo en Ruso | MEDLINE | ID: mdl-25764901

RESUMEN

The objective of the present study was the comparative analysis of the concentrations of the low and medium molecular weight substances in the blood serum in the cases of lethal poisoning with narcotic drugs, alcoholic intoxication, and endogenous intoxication associated with various diseases. The spectrogram profile of the low and medium molecular weight substances present in the blood serum obtained in the case of lethal poisoning with narcotic drugs exhibited a peak at 260-274 nm that was not found in an analogous profile in the case of alcoholic intoxication or a disease. It is concluded that the proposed analysis can be used as an additional diagnostic criterion for the documentation of poisoning with narcotic drugs and/or other potent agents.


Asunto(s)
Etanol/sangre , Etanol/envenenamiento , Toxicología Forense/métodos , Narcóticos/sangre , Narcóticos/envenenamiento , Intoxicación Alcohólica/sangre , Intoxicación Alcohólica/mortalidad , Biomarcadores/sangre , Cadáver , Humanos , Peso Molecular , Intoxicación/sangre , Intoxicación/mortalidad
14.
J Anal Toxicol ; 48(5): 343-349, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38491986

RESUMEN

Available literature demonstrates that methadone is prone to moderate postmortem redistribution, but subject to high interindividual variability in the central to peripheral blood concentration ratios (C/P). In this case series, 10 cases of chronic methadone users displaying C/P < 1 (range 0.26-0.82) are described. Femoral, cardiac and ante-mortem blood concentrations of methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) are reported for all cases, as well as sex, age, case history, results of the pathological investigation, other toxicological findings and cause and manner of death. EDDP blood concentrations, similar in both central and peripheral blood, as well as antemortem blood concentration results in Case 4, demonstrate that this atypical C/P < 1 finding is attributable to postmortem changes and not analytical or pre-analytical artifacts. Case 4 is a particularly instructive example, with femoral blood concentration (966 ng/mL) approximately twice as high as cardiac blood (499 ng/mL) and ante-mortem blood (418 ng/mL, collected 38 min prior to death)-clearly demonstrating that cardiac blood methadone concentration is more representative of the antemortem blood concentration in this case. In Case 4 and four others, toxicological interpretation based on femoral blood concentration alone would have been misleading. Based on these results and evidence from the literature, it is hypothesized that methadone bioaccumulates in the tissues of chronic users and redistributes from thigh tissues into femoral blood, increasing the concentration postmortem. This case series highlights how femoral blood is not always preserved from postmortem changes and that the analysis of multiple blood sources is necessary to avoid a misleading toxicological interpretation-particularly for cases of chronic methadone users.


Asunto(s)
Metadona , Cambios Post Mortem , Humanos , Metadona/sangre , Masculino , Femenino , Adulto , Persona de Mediana Edad , Autopsia , Toxicología Forense , Pirrolidinas/sangre , Detección de Abuso de Sustancias/métodos , Trastornos Relacionados con Opioides/sangre , Narcóticos/sangre
15.
Antimicrob Agents Chemother ; 57(5): 2304-9, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23478952

RESUMEN

Hepatitis C virus (HCV) antibody is present in most patients enrolled in methadone maintenance programs. Therefore, interactions between the HCV protease inhibitor telaprevir and methadone were investigated. The pharmacokinetics of R- and S-methadone were measured after administration of methadone alone and after 7 days of telaprevir (750 mg every 8 h [q8h]) coadministration in HCV-negative subjects on stable, individualized methadone therapy. Unbound R-methadone was measured in predose plasma samples before and during telaprevir coadministration. Safety and symptoms of opioid withdrawal were evaluated throughout the study. In total, 18 subjects were enrolled; 2 discontinued prior to receiving telaprevir. The minimum plasma concentration in the dosing interval (C(min)), the maximum plasma concentration (Cmax), and the area under the plasma concentration-time curve from h 0 (time of administration) to 24 h postdose (AUC(0-24)) for R-methadone were reduced by 31%, 29%, and 29%, respectively, in the presence of telaprevir. The AUC0-24 ratio of S-methadone/R-methadone was not altered. The median unbound percentage of R-methadone increased by 26% in the presence of telaprevir. The R-methadone median (absolute) unbound C(min) values in the absence (10.63 ng/ml) and presence (10.45 ng/ml) of telaprevir were similar. There were no symptoms of opioid withdrawal and no discontinuations due to adverse events. In summary, exposure to total R-methadone was reduced by approximately 30% in the presence of telaprevir, while the exposure to unbound R-methadone was unchanged. No symptoms of opioid withdrawal were observed. These results suggest that dose adjustment of methadone is not required when initiating telaprevir treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT00933283.).


Asunto(s)
Antivirales/farmacología , Metadona/farmacología , Narcóticos/farmacología , Oligopéptidos/farmacología , Adolescente , Adulto , Antivirales/sangre , Antivirales/farmacocinética , Área Bajo la Curva , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Metadona/sangre , Metadona/farmacocinética , Persona de Mediana Edad , Narcóticos/sangre , Narcóticos/farmacocinética , Oligopéptidos/sangre , Oligopéptidos/farmacocinética , Tratamiento de Sustitución de Opiáceos , Estereoisomerismo , Síndrome de Abstinencia a Sustancias/prevención & control
16.
Antimicrob Agents Chemother ; 57(12): 6154-7, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24080665

RESUMEN

Interactions between HIV and opioid dependence therapies are known to occur. We sought to determine if such interactions occurred between methadone and elvitegravir boosted with cobicistat (EVG/COBI). We performed a within-subject open-label pharmacokinetic and pharmacodynamic study of 11 HIV-seronegative subjects stabilized on at least 2 weeks of methadone. Subjects underwent baseline and steady-state evaluation of the effect of elvitegravir 150 mg once a day (QD) boosted with 150 mg QD of cobicistat (EVG/COBI) on methadone pharmacokinetic parameters. Safety and pharmacodynamics were monitored throughout the study. Compared to baseline values, the R-methadone mean area under the concentration-time curve to the end of the dosing period (AUCtau) (5,550 versus 6,210 h · ng/ml) and mean maximum concentration of drug in serum (Cmax) (316 versus 337 ng/ml) did not significantly increase in the presence of EVG/COBI. Compared to baseline values, the S-methadone mean AUCtau (7,040 versus 7,540 h · ng/ml) and mean Cmax (446 versus 452 ng/ml) did not significantly increase in the presence of EVG/COBI. The AUCtau, Cmax, and Ctau of elvitegravir and cobicistat did not significantly differ from those of historical controls. Opioid withdrawal or overdose was not observed among subjects in this study. The addition of EVG/COBI to stabilized patients receiving methadone did not affect methadone pharmacokinetics and pharmacodynamics. These two agents can be safely coadministered.


Asunto(s)
Fármacos Anti-VIH/farmacocinética , Carbamatos/farmacocinética , Metadona/farmacocinética , Narcóticos/farmacocinética , Quinolonas/farmacocinética , Tiazoles/farmacocinética , Adulto , Fármacos Anti-VIH/sangre , Área Bajo la Curva , Carbamatos/sangre , Cobicistat , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Metadona/sangre , Persona de Mediana Edad , Narcóticos/sangre , Tratamiento de Sustitución de Opiáceos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Quinolonas/sangre , Tiazoles/sangre
17.
Int J Legal Med ; 127(2): 395-404, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22899355

RESUMEN

Genetic polymorphisms in cytochrome P 450 (CYP) enzymes could lead to a phenotype with altered enzyme activity. In pharmacotherapy, genotype-based dose recommendations achieved great importance for several drugs. In our pilot study, we ask if these genetic tests should be applied to forensic problems as a matter of routine. Starting from 2004 through 2008, we screened routine cases for samples where the relation of parent compound to metabolite(s) (P/M ratio), particularly morphine to codeine ratios and diazepam to its metabolites, was noticeable or not consistent with the information provided by the defendants. We found 11 samples with conspicuous results. These were analyzed for polymorphisms of the CYP 2D6 and 2C19 genes using the Roche AmpliChip Cytochrome P450 Genotyping test. If not previously conducted, a general unknown analysis by gas chromatography/mass spectrometry (GC/MS) was additionally carried out. For CYP 2D6, we found two cases with the genotype poor metabolizer (PM), three cases with heterozygote extensive metabolizer genotype classified as an intermediate metabolizer (IM) with probably reduced enzyme activities, but no ultrarapid metabolizer genotype. For CYP 2C19, two cases were characterized as IM phenotypes, with no PM found. Once we achieved no appropriate amounts of DNA, one case was excluded after GC/MS analysis. Only in one case could the polymorphism clearly explain the changes in drug metabolism. More frequently, a drug-drug interaction was thought to have a stronger impact. Additionally, our results suggest that IM genotypes may be more relevant than previously suspected. With respect to the small number of cases in which we thought a genotyping would be helpful, we conclude that the overall relevance of toxicogenetics in forensic problems is moderate. However, in some individual cases, a genotyping may provide new insight.


Asunto(s)
Codeína/sangre , Sistema Enzimático del Citocromo P-450/genética , Diazepam/sangre , Genotipo , Morfina/sangre , Narcóticos/sangre , Toxicología Forense , Cromatografía de Gases y Espectrometría de Masas , Heterocigoto , Humanos , Hipnóticos y Sedantes/sangre , Análisis por Micromatrices , Farmacogenética , Proyectos Piloto , Polimorfismo Genético
18.
Addict Biol ; 18(1): 1-7, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21481103

RESUMEN

High blood-brain permeability and effective delivery of morphine to the brain have been considered as explanations for the high potency of heroin. Results from Andersen et al. indicate that 6-monoacetylmorphine (6-MAM), and not morphine, is the active metabolite responsible for the acute effects observed for heroin. Here, we use pharmacokinetic modeling on data from the aforementioned study to calculate parameters of the distribution of heroin, 6-MAM and morphine in blood and brain tissue after subcutaneous heroin administration in mice. The estimated pharmacokinetic parameters imply that the very low heroin and the high 6-MAM levels observed both in blood and brain in the original experiment are likely to be caused by a very high metabolic rate of heroin in blood. The estimated metabolic rate of heroin in brain was much lower and cannot account for the low heroin and high 6-MAM levels in the brain, which would primarily reflect the concentrations of these compounds in blood. The very different metabolic rates for heroin in blood and brain calculated by the model were confirmed by in vitro experiments. These results show that heroin's fast metabolism in blood renders high concentrations of 6-MAM which, due to its relatively good blood-brain permeability, results in high levels of this metabolite in the brain. Thus, it is the high blood metabolism rate of heroin and the blood-brain permeability to 6-MAM, and not to heroin, which could account for the highly efficient delivery of active metabolites to the brain after heroin administration.


Asunto(s)
Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Heroína/farmacocinética , Modelos Biológicos , Morfina/farmacocinética , Narcóticos/farmacocinética , Animales , Área Bajo la Curva , Heroína/sangre , Humanos , Inyecciones Subcutáneas , Ratones , Morfina/sangre , Derivados de la Morfina/sangre , Derivados de la Morfina/farmacocinética , Narcóticos/sangre , Manejo de Especímenes/métodos , Distribución Tisular
19.
Am J Forensic Med Pathol ; 34(3): 237-41, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23361082

RESUMEN

OBJECTIVE: The objective of this study was to show that, in a medical examiner population, ethanol intoxication is associated with an increase in the occurrence of subdural hematoma (SDH), whereas the presence of cocaine is not associated with an increase in the occurrence of SDH. DESIGN: This was a retrospective evaluation of 967 SDH including the investigative information, autopsy, and toxicological findings derived from 18,314 medical examiner cases over 8 years. RESULTS: Subdural hematoma is found in 7% to 9% of cases with either no ethanol or less than 100 mg/dL of ethanol. Subdural hematoma is found in 18% of cases with ethanol levels of greater than 100 mg/dL. Subdural hematoma is found in 11% of cases negative for cocaine, whereas SDH is found in 9% of cases with any form of cocaine present at death.


Asunto(s)
Depresores del Sistema Nervioso Central/sangre , Cocaína/sangre , Etanol/sangre , Hematoma Subdural/patología , Narcóticos/sangre , Accidentes de Tránsito/estadística & datos numéricos , Adulto , Intoxicación Alcohólica/sangre , Femenino , Patologia Forense , Homicidio/estadística & datos numéricos , Humanos , Masculino , Estudios Retrospectivos , Suicidio/estadística & datos numéricos
20.
Am J Forensic Med Pathol ; 34(3): 248-52, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23629396

RESUMEN

We have conducted a retrospective study of all gunshot deaths that occurred in Geneva, Switzerland, over a 10-year period (2001-2010). The 133 cases reviewed were classified according to the manner of death, that is, suicide (106 cases), homicide (25 cases), and accident (2 cases). Various data from police authorities and the medicolegal examinations of the bodies were studied, including the age and sex of the victims, location of the event, type of firearm used, concomitant use or nonuse of alcohol and/or other drugs, seasonality, and entry site. These various elements were compared with data found in the literature.


Asunto(s)
Heridas por Arma de Fuego/mortalidad , Accidentes/mortalidad , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Benzodiazepinas/sangre , Depresores del Sistema Nervioso Central/sangre , Niño , Etanol/sangre , Femenino , Medicina Legal , Traumatismos Penetrantes de la Cabeza/mortalidad , Traumatismos Penetrantes de la Cabeza/patología , Lesiones Cardíacas/mortalidad , Lesiones Cardíacas/patología , Homicidio/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Narcóticos/sangre , Estudios Retrospectivos , Estaciones del Año , Distribución por Sexo , Suicidio/estadística & datos numéricos , Suiza , Adulto Joven
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