RESUMO
The presence of ecgonine in urine has been proposed as an appropriate marker of cocaine use. Only a few methods have been published for their determination along with cocaine and the rest of its metabolites. Due to their high polarity and consequent solubility in water, these have low recoveries, which is why it is necessary to increase the sensitivity, by the formation of hydrochloric salts or multiderivatization of the analytes or by performing two solid-phase extractions (SPEs), considerably increasing the time and cost of the analysis. This work describes a fast and fully validated procedure for the simultaneous detection and quantification of ecgonine, ecgonine-methyl-ester, benzoylecgonine, nor-benzoylecgonine, m-hydroxybenzoylecgonine, cocaethylene, cocaine, norcocaine, and norcocaethylene in human urine (500 µL) using one SPE and simple derivatization. Separation and quantification were achieved by gas chromatography-electron ionization-mass spectrometry (GC-EI-MS) in selected-ion monitoring mode. Quantification was performed by the addition of deuterated analogs as internal standards. Calibration curves were linear in the adopted ranges, with determination coefficients higher than 0.99. The lower limits of quantification ranged from 2.5 to 10 ng/mL. The intra- and inter-day precision, calculated in terms of relative standard deviation, were 1.2%-14.9% and 1.8%-17.9%, respectively. The accuracy, in terms of relative error, was within a ± 16.4% interval. Extraction efficiency ranged from 84% to 103%. Compared with existing methods, the procedure described herein is fast, since only one SPE is required, and cost-effective. In addition, this method provides a high recovery for ecgonine, resulting in a better alternative to the previously published methods.
Assuntos
Cocaína/análogos & derivados , Cocaína/metabolismo , Cocaína/urina , Extração em Fase Sólida/métodos , Detecção do Abuso de Substâncias/métodos , Confiabilidade dos Dados , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Limite de DetecçãoRESUMO
OBJECTIVE: To evaluate frequency and risk factors for dextropropoxypheneinduced QT-interval prolongation in the clinical setting. DESIGN: Prospective, noninterventional, observational, longitudinal cohort approach. Electrocardiograms were blindly evaluated by independent professionals. SETTING: General ward of a public hospital of metropolitan Buenos Aires. PATIENTS, PARTICIPANTS: Ninety-two patients with indication of receiving dextropropoxyphene for analgesic purposes were included consecutively. All patients finished the study. INTERVENTIONS: All patients were monitored with electrocardiographic controls (previous to drug administration and during steady state) to diagnose and quantify changes in the duration of the QTc interval. MAIN OUTCOME MEASURE: Frequency of drug-induced QTc interval prolongation, QTc interval correlation with plasma drug, and metabolite levels. RESULTS: Ninety-two patients were studied (50 percent males). All patients received a (mean ± SD [range]) dextropropoxyphene dose of 125 ± 25[100-150] mg/d. Dextropropoxyphene and norpropoxyphene concentrations were 112 ± 38[45-199] and 65 ± 33[13-129] ng/mL, respectively. The intra-treatment QTc interval was >450 ms in only one patient (only with the Hodge correction). There were no cases of QTc > 500 ms, and there were no significant differences in the results considering different correction formulas (Bazzet, Fridericia, Framingham, Hodges). Dextropropoxyphene concentrations correlated with QTc (R > 0.45) interval and ΔQTc (R 0.52-0.87), whereas norpropoxyphene correlation was even greater for QTc (R > 0.40-0.64) and ΔQTc (R > 0.47-0.92). Depending on the QTc correction formula, eight patients presented ΔQTc > 30 ms and one patient with ΔQTc > 60 ms. No patient presented arrhythmia during the study. CONCLUSIONS: The authors did not observe a relationship between dextropropoxyphene and QTc interval prolongation at the therapeutic doses used in Argentina.
Assuntos
Analgésicos Opioides/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Dextropropoxifeno/efeitos adversos , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Potenciais de Ação , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/sangue , Argentina , Arritmias Cardíacas/sangue , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatologia , Dextropropoxifeno/administração & dosagem , Dextropropoxifeno/sangue , Monitoramento de Medicamentos , Eletrocardiografia , Feminino , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
RATIONALE: Several opioid analgesics have been related to the prolongation of cardiac repolarization, a condition which can be fatal. In order to establish a correct estimation of the risk/benefit balance of therapeutic doses of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene, it was necessary to develop an analytical method to determinate plasma concentrations of these opioids. METHODS: Here we describe a method which incorporates strong alkaline treatment to obtain norpropoxyphene amide followed by a one-elution step solid-phase extraction, and without further derivatization. Separation and quantification were achieved by gas chromatography/electron ionization mass spectrometry (GC/EI-MS) in selected-ion monitoring mode. Quantification was performed with 500 µL of plasma by the addition of deuterated analogues as internal standards. RESULTS: The proposed method has been validated in the linearity range of 25-1000 ng/mL for all the analytes, with correlation coefficients higher than 0.990. The lower limit of quantification was 25 ng/mL. The intra- and inter-day precision, calculated in terms of relative standard deviation, were 2.0-12.0% and 6.0-15.0%, respectively. The accuracy, in terms of relative error, was within a ± 10% interval. The absolute recovery and extraction efficiency ranged from 81.0 to 111.0% and 81.0 to 105.0%, respectively. CONCLUSIONS: A GC/MS method for the rapid and simultaneous determination of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene in human plasma was developed, optimized and validated. This procedure was shown to be sensitive and specific using small specimen amounts, suitable for application in routine analysis for forensic purposes and therapeutic monitoring. To our knowledge, this is the first full validation of the simultaneous determination of these opioids and their metabolites in plasma samples.
Assuntos
Analgésicos Opioides/sangue , Dextropropoxifeno/análogos & derivados , Dextropropoxifeno/sangue , Cromatografia Gasosa-Espectrometria de Massas/métodos , Meperidina/análogos & derivados , Meperidina/sangue , Extração em Fase Sólida/métodos , Tramadol/sangue , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/isolamento & purificação , Dextropropoxifeno/efeitos adversos , Dextropropoxifeno/isolamento & purificação , Monitoramento de Medicamentos , Coração/efeitos dos fármacos , Humanos , Meperidina/efeitos adversos , Meperidina/isolamento & purificação , Tramadol/efeitos adversos , Tramadol/isolamento & purificaçãoRESUMO
A prolongation of the QTc-interval has been described for several opioids, including pethidine (meperidine). OBJECTIVE: To evaluate in the clinical setting the frequency and risk factors associated with the QT-interval prolongation induced by meperidine. RESEARCH DESIGN AND METHODS: We recruited patients requiring meperidine administration and recorded their medical history and comorbidities predisposing to QT-interval prolongation. Ionograms and electrocardiograms (ECGs) were performed at baseline and during treatment; QT was corrected using the Bazzet, Fridericia, Framinghan, and Hogdes formulas. We measured meperidine and normeperidine by gas chromatography. Values are expressed as mean ± SD (range). RESULTS: 58 patients were studied (43.1% males). All patients received meperidine at a dose of 304 ± 133 (120 - 480) mg/day. Meperidine and normeperidine concentrations were 369 ± 60 (265 - 519) and 49 ± 17 (15 - 78) ng/mL, respectively. Intratreatment control found QTcB 370 ± 30 (305 - 433), QTcFri 353 ± 35 (281 - 429), QTcFra 360 ± 30 (299 - 429), QTcH 359 ± 27 (304 - 427), ΔQTcB +9 ± 42 (-90 to +136), ΔQTcFri +4 ± 45 (-86 to +137), ΔQTcFra +5 ± 40 (-77 to +129), and ΔQTcH +7 ± 40 (-76 to +129) ms. Meperidine concentration correlated with QTc-interval (R > 0.36) and ΔQTc (R > 0.69) but the correlation was even better for normeperidine concentration, QTc (R > 0.52) and ΔQTc (R > 0.81). Depending on the QTc correction formula used, 13 - 15 patients (22.41 - 25.86%) presented ΔQTc values > 30 ms, and 7 - 8 patients (12.07- 13.79%) showed ΔQTc values > 60 ms. Renal failure was associated with risk for ΔQTc > 30 ms of 3.74 (IC95% 1.73 - 8.10) and for ΔQTc > 60 ms of 4.27 (IC 95% 1.26 - 14.48). No patient developed arrhythmias during the study. CONCLUSIONS: Meperidine treatment causes ECG changes (QTc-interval prolongation) in high correlation with normeperidine plasma concentration. Renal failure increases the risk.â©.
Assuntos
Analgésicos Opioides/efeitos adversos , Sistema de Condução Cardíaco/efeitos dos fármacos , Síndrome do QT Longo/induzido quimicamente , Meperidina/efeitos adversos , Potenciais de Ação/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/sangue , Analgésicos Opioides/farmacocinética , Argentina/epidemiologia , Biotransformação , Eletrocardiografia , Feminino , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/epidemiologia , Síndrome do QT Longo/fisiopatologia , Estudos Longitudinais , Masculino , Meperidina/análogos & derivados , Meperidina/sangue , Meperidina/farmacocinética , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Insuficiência Renal/epidemiologia , Medição de Risco , Fatores de RiscoRESUMO
La contaminación de agua provocada por arsénico (As) es un serio problema de salud pública de importancia a nivel mundial debido al poder carcinógeno y neurotóxico del elemento. El arsénico no solo está presente en las aguas subterráneas sino también en las aguas superficiales y su origen varia de acuerdo a la zona que se considere. Se define como Hidroarsenicismo Crónico Regional Endémico (HACRE), a la enfermedad producida por el consumo de arsénico a través del agua y los alimentos. Esta enfermedad se caracteriza por presentar lesiones en piel y alteraciones sistémicas cancerosas y no cancerosas, luego de un periodo variable de exposición a concentraciones mayores de 50 ppb en agua de consumo diario. A pesar de las investigaciones realizadas hasta la fecha en nuestro país, no existe aun una base de datos única con información detallada (áreas y población expuesta; localización y propiedad de los pozos; año de construcción; etc.) de la extensión y magnitud del problema de las aguas arsenicales, tanto a nivel nacional como local. Esta falta de información ha demorado las medidas dirigidas a solucionar el problema en las áreas afectadas. Los resultados de los monitoreos que se realizan actualmente sobre el estado físico químico de las aguas de todo el país, deberían conformar una base de datos única que sirva para el análisis tanto local como central y colabore en la toma de decisiones y las evaluaciones financieras pertinentes. Asimismo se hace necesario unificar la metodología de recolección, procesamiento y análisis de muestras ambientales para obtener resultados confiables y comparables. La escasez de información de morbimortalidad por la exposición crónica al As, se debe en parte, a la falta de capacitación del equipo de salud de áreas de riesgo sobre los efectos del arsénico, su diagnóstico precoz y tratamiento oportuno y las pautas para disminuir la exposición. Por lo que se hace imperativo la ejecución y evaluación de programas de formación y capacitación sobre la temática, así como la promoción de evaluaciones económico sanitarias Uni