RESUMEN
BACKGROUND AND OBJECTIVES: In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics. RESULTS: Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal. CONCLUSIONS: Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886.
Asunto(s)
Hiperoxaluria Primaria/tratamiento farmacológico , Oxalatos/orina , ARN Interferente Pequeño/farmacología , ARN Interferente Pequeño/farmacocinética , Fármacos Renales/farmacología , Fármacos Renales/farmacocinética , Adolescente , Adulto , Niño , Femenino , Glicolatos/sangre , Humanos , Hiperoxaluria Primaria/sangre , Hiperoxaluria Primaria/orina , Masculino , ARN Interferente Pequeño/efectos adversos , Fármacos Renales/efectos adversos , Método Simple Ciego , Adulto JovenRESUMEN
Fluroxypyr-meptyl and triclopyr are synthetic auxin-like herbicides that are used to control woody and broadleaf weeds. Herein, we report a case of fatal intoxication involving fluroxypyr-meptyl and triclopyr. A 61-year-old man was found dead at his farm with several suicide notes, and a white plastic bottle and a plastic cup with traces of white emulsion were found next to him. The plastic bottle was labeled as an herbicide formulation containing fluroxypyr-meptyl and triclopyr. Forensic toxicological screening of the stomach contents revealed the presence of fluroxypyr-meptyl, fluroxypyr and triclopyr. However, no fluroxypyr-meptyl was detected in blood owing to its rapid hydrolysis to fluroxypyr. In this study, fluroxypyr and triclopyr in blood were extracted using solid-phase extraction, and analyzed by liquid chromatography-tandem mass spectrometry. The analytical method was validated in terms of linearity, precision, accuracy, recovery and matrix effect, and the acceptable criteria were satisfied. Toxicological analysis showed that fluroxypyr and triclopyr concentrations were 19.7⯵g/mL and 137.4⯵g/mL in peripheral blood and 16.5⯵g/mL and 147.8⯵g/mL in heart blood, respectively. Based on these toxicological results and autopsy findings, the cause of death was determined to be acute fatal intoxication by ingestion of the pesticide containing fluroxypyr-meptyl and triclopyr. This is the first report of the determination of fluroxypyr and triclopyr in a fatal intoxication case.
Asunto(s)
Glicolatos/análisis , Herbicidas/química , Herbicidas/envenenamiento , Cromatografía Liquida , Toxicología Forense , Glicolatos/sangre , Glicolatos/envenenamiento , Humanos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Suicidio CompletoRESUMEN
Primary hyperoxalurias (PH) are inborn errors of glyoxylate metabolism characterized by an increase in endogenous oxalate production. Oxalate overproduction may cause calcium-oxalate crystal formation leading to kidney stones, nephrocalcinosis, and ultimately kidney failure. Twenty-four hour urine oxalate excretion is an inaccurate measure for endogenous oxalate production in PH patients and not applicable in those with kidney failure. Treatment efficacy cannot be assessed with this measure during clinical trials. We describe the development and validation of a gas chromatography-tandem mass spectrometry method to analyze the samples obtained following a stable isotope infusion protocol of 13C2-oxalate and 1-13C-glycolate in both healthy individuals and PH patients. Isotopic enrichments of plasma oxalate, glycolate, and glyoxylate were measured on a gas chromatography-triple quadrupole mass spectrometry system using ethylhydroxylamine and N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide (MTBSTFA) for analyte derivatization. Method precision was good for oxalate and glycolate (coefficients of variation [CV] were <6.3% and <4.2% for inter- and intraday precision, respectively) and acceptable for glyoxylate (CV <18.3% and <6.7% for inter- and intraday precision, respectively). The enrichment curves were linear over the specified range. Sensitivity was sufficient to accurately analyze enrichments. This new method allowed calculation of kinetic features of these metabolites, thus enabling a detailed analysis of the various pathways involved in glyoxylate metabolism. The method will further enhance the investigation of the metabolic PH derangements, provides a tool to accurately assess the therapeutic efficacy of new promising therapeutic interventions for PH, and could serve as a clinical tool to improve personalized therapeutic strategies.
Asunto(s)
Glicolatos/sangre , Glioxilatos/sangre , Hiperoxaluria Primaria/metabolismo , Oxalatos/sangre , Acetamidas/química , Isótopos de Carbono/química , Fluoroacetatos/química , Cromatografía de Gases y Espectrometría de Masas/métodos , Glicolatos/química , Glicolatos/metabolismo , Glioxilatos/química , Glioxilatos/metabolismo , Humanos , Hidroxilaminas/química , Hiperoxaluria Primaria/sangre , Marcaje Isotópico , Compuestos de Organosilicio/química , Oxalatos/química , Oxalatos/metabolismo , Espectrometría de Masas en Tándem/métodosRESUMEN
OBJECTIVE: To evaluate the clinical utility of glycolic acid (GA) determination in the diagnosis and prognosis of ethylene glycol (EG) intoxications. METHOD: Systematic review of serum and/or urine GA concentrations available in the literature in cases of EG poisoning. Present a clinical case in which the determination of the GA was decisive. RESULTS: In total, 137 patients were included. Serum GA concentrations (but not EG) of patients who survive are different from those who die. The optimal cut-off of serum GA to predict mortality was 990.5mg/L (sensitivity 85.2%, specificity 54.3%) with an Odds Ratio of 6.838 (2.868-16.302). In our clinical case, serum EG was negative; however, urine GA was positive (1230.7mg/L). CONCLUSIONS: In all suspected cases of EG poisoning, it is advisable to carry out the simultaneous analysis of EG and GA.
Asunto(s)
Glicol de Etileno/envenenamiento , Glicolatos/sangre , Glicolatos/orina , Biomarcadores/sangre , Biomarcadores/orina , Cromatografía de Gases y Espectrometría de Masas , Humanos , Masculino , Persona de Mediana Edad , Intoxicación/diagnóstico , Sensibilidad y EspecificidadRESUMEN
In this work, a simple device for extremely fast separation of blood plasma from diluted whole blood was developed. The device accommodates an asymmetric polysulfone membrane/supporting membrane sandwich that allows collection of 10⯵L blood plasma into a narrow glass capillary in less than 10â¯s. The composition of diluent solution was optimized in order to achieve maximum recoveries for selected metabolites of alcohol intoxication. 5% solution of [tris(hydroxymethyl)methylamino] propanesulfonic acid provided recoveries of formate, oxalate and glycolate close to 100% and only moderate erythrocyte lysis. Both charged and uncharged compounds from the whole blood samples can be analyzed in the separated blood plasma by capillary electrophoresis with contactless conductometric detection and spectrophotometry, respectively. The developed device might find wide application in on-site testing and point-of-care analysis, when only microliter volumes of whole blood are available.
Asunto(s)
Formiatos/sangre , Glicolatos/sangre , Oxalatos/sangre , Sistemas de Atención de Punto , Electroforesis Capilar/instrumentación , Humanos , Espectrofotometría/instrumentaciónRESUMEN
A rapid gas chromatographic mass spectrometric method for measuring anions associated with acute anion gap metabolic acidosis is described. The method is an extension of a previous method. The method quantifies glycolic acid, beta-hydroxybutyric acid with good linearity and pyroglutamic acid with a reproducible curvature relation between 1 and 20 mmol/L and can help the clinician distinguish effectively between ethylene glycol poisoning, alcoholic and diabetic ketoacidosis and cysteine deficiency so early that it will have clinical consequences.
Asunto(s)
Ácido 3-Hidroxibutírico/sangre , Cetoacidosis Diabética/diagnóstico , Cromatografía de Gases y Espectrometría de Masas/métodos , Glicolatos/sangre , Cetosis/diagnóstico , Ácido Pirrolidona Carboxílico/sangre , Biomarcadores/sangre , Calibración , Cisteína/deficiencia , Cetoacidosis Diabética/sangre , Diagnóstico Diferencial , Glicol de Etileno/envenenamiento , Humanos , Cetosis/sangre , Reproducibilidad de los ResultadosRESUMEN
A rapid, specific and high-throughput stable isotope-dilution LC-MS/MS method was developed and validated with high sensitivity for the quantification of R-phencynonate (a eutomer of phencynonate racemate) in rat and dog plasma. Plasma samples were deproteinized using acetonitrile and then separated on a C8 column with an isocratic mobile phase containing acetonitrile-water-formic acid mixture (60:40:0.1, v/v/v) at a flow rate of 0.2 mL/min. Each sample had a total run time of 3 min. Quantification was performed using triple quadrupole mass spectrometry in selected reaction monitoring mode with positive electrospray ionization. The method was shown to be highly linear (r2 > 0.99) and to have a wide dynamic range (0.1-100 ng/mL) with favourable accuracy and precision. No matrix effects were observed. The detailed pharmacokinetic profiles of R-phencynonate at therapeutic doses in rats and dogs were characterized by rapid oral absorption, quick clearance, high volume of distribution and poor absolute bioavailability. R-Phencynonate lacked dose proportionality over the oral dose range, based on the power model. However, the area under concentration-time curve and the maximum plasma concentration increased linearly in a dose-dependent manner in both animal models. The absolute bioavailability of R-phencynonate was 16.6 ± 2.75 and 4.78 ± 1.26% in dogs and rats, respectively.
Asunto(s)
Compuestos Aza/sangre , Compuestos Aza/farmacocinética , Cromatografía Liquida/métodos , Glicolatos/sangre , Glicolatos/farmacocinética , Espectrometría de Masas en Tándem/métodos , Administración Oral , Animales , Compuestos Aza/administración & dosificación , Disponibilidad Biológica , Antagonistas Colinérgicos/administración & dosificación , Antagonistas Colinérgicos/sangre , Antagonistas Colinérgicos/farmacocinética , Perros , Glicolatos/administración & dosificación , Masculino , Técnica de Dilución de Radioisótopos , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
A sensitive and convenient high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed to determine levophencynonate and demethyl levophencynonate levels in human plasma simultaneously. Chromatographic separation was achieved on a SHIMADZU Shim-Pack XR C8 column and mass spectrometric analysis was performed by an API5000 mass spectrometer coupled with an electro-spray ionization (ESI) source in the positive ion mode. The MRM transitions of m/z 358.4â156.4 and 344.5â144.2 were used to quantify levophencynonate and demethyl levophencynonate, respectively. This analytical method was fully validated with specificity, linearity, lower limit of quantitation (LLOQ), accuracy, precision, stability, matrix effect and recovery. The linearity of this method were developed to be within the concentration ranges of 10-4000pg/mL for levophencynonate and 25-8000pg/mL for demethyl levophencynonate in human plasma. This method was used in a clinical study which was administrated with single oral dose for Chinese healthy subjects to investigate the pharmacokinetics of levophencynonate and demethyl levophencynonate.
Asunto(s)
Compuestos Aza/sangre , Antagonistas Colinérgicos/sangre , Cromatografía Líquida de Alta Presión/métodos , Glicolatos/sangre , Espectrometría de Masas en Tándem/métodos , Compuestos Aza/metabolismo , Antagonistas Colinérgicos/metabolismo , Glicolatos/metabolismo , Humanos , Límite de Detección , Extracción Líquido-Líquido/métodos , Metilación , EstereoisomerismoRESUMEN
A simple, cost effective, and fast gas chromatography method with mass spectrometry detection (GC-MS) for simultaneous measurement of formic acid, glycolic acid, methoxyacetic acid, ethoxyacetic acid and 2-hydroxyethoxyacetic acid in serum and urine was developed and validated. This multi-analyte method is highly suitable for clinical and emergency toxicology laboratory diagnostic, allowing identification and quantification of five most common acidosis inducing organic acids present in cases of alcohol intoxication. Furthermore, when patients are admitted to emergency unit at late stage of toxic alcohol intoxication, the concentration of parent compound may be already low or not detectable. This new method employs a relatively less used class of derivatization agents - alkyl chloroformates, allowing the efficient and rapid derivatization of carboxylic acids within seconds. The entire sample preparation procedure is completed within 5 min. The optimal conditions of derivatization procedure have been found using chemometric approach (design of experiment). The calibration dependence of the method was proved to be quadratic in the range of 25-3000 mg L(-1), with adequate accuracy (97.3-108.0%) and precision (<12.8%). The method was successfully applied for identification and quantification of the selected compounds in serum of patients from emergency units.
Asunto(s)
Acidosis/diagnóstico , Intoxicación Alcohólica/sangre , Intoxicación Alcohólica/orina , Cromatografía de Gases y Espectrometría de Masas/métodos , Toxicología/métodos , Acetatos/sangre , Acetatos/orina , Análisis Químico de la Sangre/métodos , Calibración , Técnicas de Química Analítica , Femenino , Formiatos/sangre , Formiatos/orina , Glicolatos/sangre , Glicolatos/orina , Humanos , Límite de Detección , Masculino , Reproducibilidad de los Resultados , Urinálisis/métodosRESUMEN
A sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to simultaneously quantify phencynonate (PCN) and its major metabolite N-demethyl phencynonate (DM-PCN) in human plasma. Following one-step liquid-liquid extraction, the analytes were separated on a reversed-phase C18 column. Methanol and 0.02% formic acid in 10 mM ammonium acetate (62:38, v/v) was used as isocratic mobile phase at a flow-rate of 0.3 mL/min. An API 5000 tandem mass spectrometer equipped with a Turbo IonSpray ionization source was used as the detector and was operated in the positive ion mode. Multiple reaction monitoring using the transition of m/z 358.4 â m/z 156.2, m/z 344.4 â m/z 142.2, and m/z 361.3 â m/z 159.2 was performed to quantify PCN, DM-PCN, and the internal standard (D3 -PCN), respectively. This approach showed a lower limit of quantification of 10 pg/mL and 25 pg/mL for PCN and DM-PCN in plasma, respectively. This sensitivity was at least 50-fold superior to previously reported ones and thus enabled the approach well applicable to low-dose pharmacokinetic studies. The intra- and inter-day precisions were less than 14.2 % at each QC level for both PCN and DM-PCN. The inter-day relative errors ranged from -1.9% to -4.9% for PCN, and from 0.6% to 6.4% for DM-PCN. As a proof of principle, the validated method was successfully applied to simultaneous quantification of circulating PCN and DM-PCN in healthy subjects after a single oral administration of 2 mg phencynonate hydrochloride pellet.
Asunto(s)
Compuestos Aza/sangre , Compuestos Aza/metabolismo , Antagonistas Colinérgicos/sangre , Antagonistas Colinérgicos/metabolismo , Glicolatos/sangre , Glicolatos/metabolismo , Espectrometría de Masas en Tándem/métodos , Administración Oral , Compuestos Aza/administración & dosificación , Antagonistas Colinérgicos/administración & dosificación , Cromatografía Liquida/métodos , Glicolatos/administración & dosificación , Humanos , Técnicas de Dilución del Indicador , Límite de Detección , Extracción Líquido-Líquido/métodos , Masculino , MetilaciónRESUMEN
Ethylene glycol (EG) is used in antifreeze and other industrial products. It metabolizes to glycolic acid (GA) and oxalic acid (OX) that cause metabolic acidosis and are mainly responsible for the toxicity of EG. During 2010-2014, EG or GA was found in 25 postmortem cases in Finland. Of these cases, 21 were classified as fatal EG poisonings and 3 were classified as methanol (MeOH) poisonings. In this study, we report the concentrations of EG and GA in postmortem blood and urine samples of fatal EG or mixed MeOH/EG poisonings. In the fatal EG poisonings, the median EG and GA concentrations were 0.87 and 1.6 g/L in blood and 4.3 and 5.3 g/L in urine. The median urine-blood ratios were 3.8 and 3.1 for EG and GA. These results warrant the use of urine as a primary matrix for screening. In EG positive cases, the quantification of both EG and GA in blood is crucial as GA concentration appears to best indicate a fatal poisoning with an approximate threshold of 1.5 g/L. The measurement of urinary OX does not offer much additional value to toxic alcohol screening as it may originate from varying dietary conditions.
Asunto(s)
Autopsia/métodos , Glicol de Etileno/envenenamiento , Toxicología Forense/métodos , Glicolatos/sangre , Glicolatos/orina , Intoxicación por MPTP/mortalidad , Metanol/envenenamiento , Adulto , Anciano , Causas de Muerte , Glicol de Etileno/sangre , Glicol de Etileno/orina , Femenino , Finlandia , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: A simple, cost-effective, and fast gas chromatography method with mass spectrometry detection (GC-MS) for simultaneous measurement of ethylene glycol, 1,2-propylene glycol and glycolic acid was developed and validated for clinical toxicology purposes. DESIGN AND METHODS: Successful derivatization of glycolic acid with isobutyl chloroformate was achieved directly in serum/urine while glycols are simultaneously derivatized by phenylboronic acid. The entire sample preparation procedure is completed within 10 min. RESULTS: The assay was proved to be quadratic in the range of 50 to 5000 mgL(-1) with adequate accuracy (96.3-105.8%) and precision (CV ≤ 8.9%). CONCLUSION: The method was successfully applied to quantify the selected compounds in serum of patients from emergency units and the results correlated well with parallel GC-FID measurements (R(2) 0.9933 for ethylene glycol and 0.9943 for glycolic acid).
Asunto(s)
Análisis Costo-Beneficio , Glicol de Etileno/sangre , Glicol de Etileno/orina , Cromatografía de Gases y Espectrometría de Masas/economía , Cromatografía de Gases y Espectrometría de Masas/métodos , Glicolatos/sangre , Glicolatos/orina , Urgencias Médicas , Humanos , Factores de Tiempo , ToxicologíaRESUMEN
A simple, cost effective, and fast gas chromatography method with flame ionization detection (GC-FID) for simultaneous measurement of ethylene glycol, 1,2-propylene glycol and glycolic acid was developed and validated for clinical toxicology purposes. This new method employs a relatively less used class of derivatization agents - alkyl chloroformates, allowing the efficient and rapid derivatization of carboxylic acids within seconds while glycols are simultaneously derivatized by phenylboronic acid. The entire sample preparation procedure is completed within 10 min. To avoid possible interference from naturally occurring endogenous acids and quantitation errors 3-(4-chlorophenyl) propionic acid was chosen as an internal standard. The significant parameters of the derivatization have been found using chemometric procedures and these parameters were optimized using the face-centered central composite design. The calibration dependence of the method was proved to be quadratic in the range of 50-5000 mg mL(-1), with adequate accuracy (92.4-108.7%) and precision (9.4%). The method was successfully applied to quantify the selected compounds in serum of patients from emergency units.
Asunto(s)
Servicios Médicos de Urgencia , Glicol de Etileno/sangre , Glicol de Etileno/orina , Glicolatos/sangre , Glicolatos/orina , Propilenglicol/sangre , Propilenglicol/orina , Estudios de Casos y Controles , Cromatografía de Gases/métodos , Glicol de Etileno/envenenamiento , Femenino , Ionización de Llama/métodos , Glicolatos/envenenamiento , Humanos , Masculino , Propilenglicol/envenenamiento , Suero/química , Toxicología/métodosRESUMEN
BACKGROUND: Ingestion of ethylene glycol is a relatively rare event but one with potentially lethal consequences. Early diagnosis and appropriate treatment are essential. However, diagnosis of poisoning can only be confirmed definitively by the measurement of ethylene glycol and/or its metabolites, usually performed by gas chromatographic methods. These methods are complex, requiring specialized equipment and expertise, and are often not available on an emergency basis. METHODS: A quick, simple, and inexpensive enzymatic assay has been developed to detect glycolic acid, the major metabolite of ethylene glycol and the main cause of the resulting metabolic acidosis. In this assay, glycolic acid is converted to glyoxylic acid by glycolate oxidase, with the production of hydrogen peroxide, which is converted to a quinoneimine dye for spectrophotometric detection. RESULTS: The assay has a functional sensitivity of 26 mg/L and coefficients of variation less than 13% (interassay) and less than 10% (intra-assay). No significant interference was observed for a range of compounds, and a comparison with a gas chromatography-mass spectrometry method gave clinical sensitivity of 86% and clinical specificity of 92%. Stability of enzyme solutions was increased by the use of an alternative buffer, in which greater than 90% of the original activity was retained after storage at -20°C. CONCLUSIONS: As ethylene glycol poisoning is a medical emergency, there is a need for a screening test to minimize delays in diagnosis. The assay we describe is a simple and effective way to detect ethylene glycol poisoning, enabling earlier initiation of appropriate therapy and improving patient outcomes.
Asunto(s)
Glicol de Etileno/envenenamiento , Glicolatos/sangre , Espectrofotometría/métodos , Oxidorreductasas de Alcohol/metabolismo , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Glicol de Etileno/metabolismo , Cromatografía de Gases y Espectrometría de Masas/métodos , Humanos , Peróxido de Hidrógeno/análisis , Sensibilidad y EspecificidadRESUMEN
CONTEXT: Diethylene glycol (DEG) mass poisoning is a persistent public health problem. Unfortunately, there are no human biological data on DEG and its suspected metabolites in poisoning. If present and associated with poisoning, the evidence for use of traditional therapies such as fomepizole and/or hemodialysis would be much stronger. OBJECTIVE: To characterize DEG and its metabolites in stored serum, urine, and cerebrospinal fluid (CSF) specimens obtained from human DEG poisoning victims enrolled in a 2006 case-control study. METHODS: In the 2006 study, biological samples from persons enrolled in a case-control study (42 cases with new-onset, unexplained AKI and 140 age-, sex-, and admission date-matched controls without AKI) were collected and shipped to the Centers for Disease Control and Prevention (CDC) in Atlanta for various analyses and were then frozen in storage. For this study, when sufficient volume of the original specimen remained, the following analytes were quantitatively measured in serum, urine, and CSF: DEG, 2-hydroxyethoxyacetic acid (HEAA), diglycolic acid, ethylene glycol, glycolic acid, and oxalic acid. Analytes were measured using low resolution GC/MS, descriptive statistics calculated and case results compared with controls when appropriate. Specimens were de-identified so previously collected demographic, exposure, and health data were not available. The Wilcoxon Rank Sum test (with exact p-values) and bivariable exact logistic regression were used in SAS v9.2 for data analysis. RESULTS: The following samples were analyzed: serum, 20 case, and 20 controls; urine, 11 case and 22 controls; and CSF, 11 samples from 10 cases and no controls. Diglycolic acid was detected in all case serum samples (median, 40.7 mcg/mL; range, 22.6-75.2) and no controls, and in all case urine samples (median, 28.7 mcg/mL; range, 14-118.4) and only five (23%) controls (median, < Lower Limit of Quantitation (LLQ); range, < LLQ-43.3 mcg/mL). Significant differences and associations were identified between case status and the following: 1) serum oxalic acid and serum HEAA (both OR = 14.6; 95% C I = 2.8-100.9); 2) serum diglycolic acid and urine diglycolic acid (both OR > 999; exact p < 0.0001); and 3) urinary glycolic acid (OR = 0.057; 95% C I = 0.001-0.55). Two CSF sample results were excluded and two from the same case were averaged, yielding eight samples from eight cases. Diglycolic acid was detected in seven (88%) of case CSF samples (median, 2.03 mcg/mL; range, < LLQ, 7.47). DISCUSSION: Significantly elevated HEAA (serum) and diglycolic acid (serum and urine) concentrations were identified among cases, which is consistent with animal data. Low urinary glycolic acid concentrations in cases may have been due to concurrent AKI. Although serum glycolic concentrations among cases may have initially increased, further metabolism to oxalic acid may have occurred thereby explaining the similar glycolic acid concentrations in cases and controls. The increased serum oxalic acid concentration results in cases versus controls are consistent with this hypothesis. CONCLUSION: Diglycolic acid is associated with human DEG poisoning and may be a biomarker for poisoning. These findings add to animal data suggesting a possible role for traditional antidotal therapies. The detection of HEAA and diglycolic acid in the CSF of cases suggests a possible association with signs and symptoms of DEG-associated neurotoxicity. Further work characterizing the pathophysiology of DEG-associated neurotoxicity and the role of traditional toxic alcohol therapies such as fomepizole and hemodialysis is needed.
Asunto(s)
Glicoles de Etileno/sangre , Glicoles de Etileno/líquido cefalorraquídeo , Glicoles de Etileno/envenenamiento , Glicoles de Etileno/orina , Intoxicación/diagnóstico , Acetatos/líquido cefalorraquídeo , Acetatos/envenenamiento , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/orina , Estudios de Casos y Controles , Centers for Disease Control and Prevention, U.S. , Femenino , Fomepizol , Cromatografía de Gases y Espectrometría de Masas , Glicolatos/sangre , Glicolatos/líquido cefalorraquídeo , Glicolatos/envenenamiento , Glicolatos/orina , Humanos , Riñón/efectos de los fármacos , Riñón/patología , Modelos Logísticos , Masculino , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/fisiopatología , Panamá , Intoxicación/tratamiento farmacológico , Intoxicación/etiología , Pirazoles/uso terapéutico , Diálisis Renal , Manejo de Especímenes , Estados UnidosRESUMEN
BACKGROUND: Metabolites of ethylene glycol (EG) can cross-react in l-lactate assays, leading to falsely elevated serum lactate levels in case of EG intoxication. In this study, we evaluated the effects of EG and its metabolites on routinely used lactate measuring methods. METHODS: Serum aliquots were spiked with either l-lactate, EG or one of its metabolites (all 12.5 mmol/L): glyoxal, glycolate, glyoxylic acid or oxalate. An unspiked sample (l-lactate 2.6 mmol/L) served as a control. l-Lactate levels in these samples were measured in 31 national hospitals on 20 different analysers from nine manufacturers. RESULTS: The l-lactate concentrations in the control sample and in the samples spiked with l-lactate, EG, glyoxal and oxalate provided correct results by all routinely used methods. However, the glycolate and glyoxylic acid spiked samples resulted in falsely elevated l-lactate concentration with all blood gas methods and with the majority of general chemistry methods using l-lactate oxidase. CONCLUSION: The EG metabolites glycolate and glyoxylic acid were shown to falsely elevate l-lactate results with most of the currently used methods due to cross-reactivity with the oxidase enzyme. Falsely elevated l-lactate results can lead to misdiagnosis and inappropriate management of patients with EG intoxication.
Asunto(s)
Cromatografía de Gases/normas , Pruebas de Enzimas/normas , Glicol de Etileno/sangre , Glicolatos/sangre , Glioxilatos/sangre , Ácido Láctico/sangre , Errores Diagnósticos , Glicol de Etileno/envenenamiento , Reacciones Falso Positivas , Glioxal/sangre , Humanos , Oxigenasas de Función Mixta/química , Oxigenasas de Función Mixta/normas , Ácido Oxálico/sangreAsunto(s)
Glicol de Etileno/envenenamiento , Trasplante de Hígado , Lesión Renal Aguda/etiología , Adulto , Sobredosis de Droga , Glicol de Etileno/metabolismo , Glicolatos/sangre , Semivida , Humanos , Fallo Renal Crónico/etiología , Trasplante de Hígado/efectos adversos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: Fomepizole is the antidote of choice in toxic alcohol poisonings. Potential side effects from frequent use of fomepizole were studied in a patient admitted 154 times with ethylene glycol (EG) poisoning. The intra-individual correlation between the serum-ethylene glycol (serum-EG) and the osmolal gap (OG) EG-kinetics, and other laboratory parameters were also studied. METHODS: Combined pro- and retrospective collection of material from three different hospitals, and results from autopsy. RESULTS: A 26-year-old female with a dissociative disorder was admitted with EG poisoning a total of 154 times. Her admission data revealed a median pH of 7.31 (range 6.87-7.49), pCO(2): 4.2 kPa (1.2-6.7) (32 mmHg [9-50]), HCO-3: 15 mmol/L (4-26) (15 mEq/L [4-26]), base deficit (BD): 10 mmol/L (- 4 to 27) (10 mEq/L [-4 to 27]), serum-creatinine 65 µmol/L (40-133) (0.74 mg/dL [0.45-1.51]), OG 81 mOsm/kgH(2)O (25-132), and serum-EG 44 mmol/L (4-112) (250 mg/dL [25-700]). She was treated with fomepizole 99 times, ethanol 60 times (with a combination of both six times), and dialysis 73 times. The correlation between serum-EG and OG was good (r(2) = 0.76). She was finally found dead outside hospital with an EG blood concentration of 81 mmol/L (506 mg/dL). An autopsy revealed calcium oxalate crystals in the kidneys, slight liver steatosis, and slight edema of the lungs. DISCUSSION: The frequent use of fomepizole in this young patient was not associated with any detectable side effects; neither on clinical examination and lab screening, nor on the later autopsy. Regarding the sequelae from the repetitive EG-poisoning episodes, her kidney function seemed to normalize after each overdose. She was treated with buffer and antidote without hemodialysis 81 times without complications, supporting the safety of this approach in selected cases.
Asunto(s)
Glicol de Etileno/envenenamiento , Adulto , Antídotos/uso terapéutico , Trastornos Disociativos/complicaciones , Glicol de Etileno/farmacocinética , Femenino , Fomepizol , Glicolatos/sangre , Semivida , Humanos , Hiperpotasemia/sangre , Hiperpotasemia/inducido químicamente , Riñón/metabolismo , Riñón/patología , Hígado/metabolismo , Hígado/patología , Oxalatos/metabolismo , Intoxicación/diagnóstico , Intoxicación/patología , Pirazoles/uso terapéutico , Recurrencia , Diálisis Renal , SuicidioRESUMEN
A novel headspace in-tube extraction gas chromatography-mass spectrometry (ITEX-GC-MS) approach was developed for broad-scale analysis of low molecular weight organic compounds in blood and/or urine. One sample was analyzed following in-vial derivatization with dimethyl sulfate for ethylene glycol (EG), glycolic acid (GA), formic acid (FA), other hydroxylic compounds, and another sample for underivatized volatile organic compounds. Tenax adsorbent resin was used in the microtrap, and a porous layer, open tubular GC capillary column was used for separation. MS was operated in the full-scan mode, identification was based on the Automated Mass Spectral Deconvolution and Identification System, and quantification was based on extracted ions. The limits of quantification for EG, GA, and FA in blood were 10, 50, and 30 mg/L, respectively, and the expanded uncertainties of measurement were 20%, 16%, and 14%, respectively. The procedure allowed for the first time the inclusion of EG and GA as their methyl derivatives within a quantitative HS analysis. The ITEX method described here was more sensitive for analysis of volatile organic compounds than the corresponding static headspace analysis as demonstrated for 11 representative compounds.