Establishment of a High-Resolution Liquid Chromatography-Mass Spectrometry Spectral Library for Screening Toxic Natural Products.

Many natural products have biological effects on humans and animals. Poisoning caused by natural products is common in clinical toxicology cases. Liquid chromatography-high-resolution mass spectrometry (LC-HRMS) has recently emerged as a powerful analytical tool for large-scale target screening, and the application of LC-HRMS can be expanded to evaluate potential natural product poisoning in clinical cases. We report the construction of an LC-HRMS spectral library of 95 natural products commonly implicated in poisoning, and an LC-HRMS assay was validated for definitive detection of natural products in urine and serum samples. For each compound, the limit of detection was determined in the analytical range of 1.0-1,000 ng/mL for urine samples and 0.50-500 ng/mL for serum samples. The mean (SD) values of matrix effects for urine samples and that for serum samples were both -21% (22%), and the mean (SD) value of recovery for serum samples was 89% (26%). The LC-HRMS assay was successfully applied to identify natural products in clinical cases. The spectral library parameters of each compound are provided in the supplementary material to aid other laboratories in identification of unknown natural toxins and development of similar methods on different mass spectrometry platforms.

Lacosamide induced Brugada I morphology in the setting of septicemia: A case report.

INTRODUCTION: Brugada syndrome may be unmasked by non-antiarrhythmic pharmaceuticals or drugs. Lacosamide is an antiepileptic agent with a novel mechanism of sodium channel inhibition and has the potential to cause cardiac sodium channel blockade. PATIENT CONCERNS: In this report, we describe the case of patient with a history of a seizure disorder who presented with Brugada I electrocardiogram morphology in the setting of septicemia. DIAGNOSIS: Brugada I electrocardiogram morphology was unmasked by lacosamide antiepileptic monotherapy. INTERVENTIONS: Lacosamide therapy was discontinued. OUTCOMES: Normalization of the electrocardiogram and resolution of Brugada morphology occurred on hospital day 1. CONCLUSION: Caution should be exercised in the use of lacosamide in those at risk for conduction delay, or in combination therapy with medications that impair renal clearance, metabolism of lacosamide, or that display inherent sodium channel blocking properties.

Gamma-Butyrolactone Overdose Potentially Complicated by Co-Ingestion of Industrial Solvent N-Methyl-2-Pyrrolidone.

Gamma-hydroxybutyrate (GHB) is misused as an intoxicant, either alone or concurrently with other substances. Because GHB is illegal, the precursor chemicals 1,4-butanediol and gamma-butyrolactone are also misused for the same effect, either through pre-ingestion alteration or endogenous metabolism to GHB. We describe a case of a 50-year-old man with a history of polysubstance misuse who experienced an overdose of GHB from gamma-butyrolactone ingestion. The patient also co-ingested a common industrial solvent, N-methyl-2-pyrrolidone (NMP). This co-ingested substance raised theoretical concern of metabolism to a GHB congener, underscoring that the emergence of new psychoactive substance use patterns requires ongoing vigilance and toxicologic confirmation.

A case of unexplained duodenal ulcer and massive gastrointestinal bleed.

A 73-year-old man was displaying symptoms of massive gastrointestinal (GI) bleed. Surgical actions were performed to control the bleed caused by an erosive duodenal ulcer with duodenal perforation. When investigating the culprit of this case, the pain medications prescribed two weeks prior by a traditional Chinese medicine doctor raised attention. The patient's admission serum sample and the pain medications from unknown sources were analyzed using a clinically validated liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method. The NSAIDs diclofenac, piroxicam, and indomethacin were identified, as well as some other synthetic drugs and natural products. The patient's concurrent exposure to multiple NSAIDs significantly increased the risk of upper GI complications. It is reasonable to argue that the high-dose use of the NSAIDs was a major cause of the duodenal ulcer and GI bleed. In addition, the identified natural products such as atropine and ephedrine have well-documented toxicities. It is important to increase the visibility of unregulated medications, and the capability to perform untargeted mass spectrometry analysis provides a unique diagnostic advantage in cases where exposure to toxic substances is possible.

Real-time comprehensive toxicology testing in the clinical management of accidental pediatric capecitabine ingestion.

INTRODUCTION: Capecitabine is an orally bioavailable prodrug of the chemotherapeutic agent, fluorouracil. Fluorouracil is converted to several active metabolites that induce a cytotoxic effect. Capecitabine toxicity can be life-threatening with a delayed presentation from ingestion. An oral antidote, uridine triacetate, exists but requires the administration of 20 total doses over a course of five days. CASE REPORT: In this report, we describe a case where timely coordination with a clinical toxicology laboratory was utilized to drive clinical decision making and management. Two children were brought to the emergency department shortly after suspected capecitabine ingestion. MANAGEMENT AND OUTCOME: Patients were admitted to the hospital and started on uridine triacetate. Real-time comprehensive toxicology testing of the children's blood was used to rule out capecitabine toxicity and prevent several unnecessary days of hospitalization and doses of antidote. Patients were discharged safely. DISCUSSION: Real-time comprehensive toxicology testing on a patient's blood may be a valuable resource in ruling out or confirming toxic exposure in accidental pediatric ingestion of chemotherapeutic agents like capecitabine when performed in a timely manner.

Mass spectrometry in emergency toxicology: Current state and future applications.

This manuscript offers a broad overview of the state of emergency toxicology testing in clinical laboratories. We summarize the specific challenges of performing emergency toxicology testing, introduce a variety of currently used methods including mass spectrometry, and compare and contrast the utility of different types of mass spectrometers for this purpose. Finally, we examine evidence on the utility of toxicological testing in the treatment of poisoned patients, with special emphasis on the demonstrated utility of mass spectrometry-based tests. This review included primary literature indexed in the NCBI PubMed Database. Search terms included "emergency toxicology", "emergency mass spectrometry", "mass spectrometry toxicology", "utility of toxicology testing", and "toxicology surveillance". There are relatively few clinical trials on the utility of toxicology testing in overdosed or poisoned patients, and those studies that exist have a number of limitations. One of the most significant is that nearly all were conducted with immunoassay-based tests, which can only detect a limited number of compounds and are known to have a high false-positive rate. In addition, few are prospective. The overwhelming majority of studies of immunoassay-based tests concluded that results rarely changed patient management, regardless of the patient's clinical presentation. Many of these studies suggest that results could still be useful in other contexts, including identification of opportunities to refer a patient to substance abuse treatment or avoidance of drug-drug interactions. Mass spectrometry-based testing has several advantages over immunoassays, including the breadth of compounds that can be detected and substantially higher specificity, yet many questions remain about utility in emergency toxicology. The utility of mass spectrometry-based testing has not been assessed in a prospective clinical trial, rather the literature is overwhelmingly case-based, and a small number of laboratories are responsible for the majority of the case reports. The limited evidence that exists suggests that mass spectrometry can be useful in emergency situations, provided that results are available rapidly, interpreted by a knowledgeable physician, and that the scope of the method includes the compound implicated in the poisoning. Like results from immunoassays, many authors report using mass spectrometry-based testing for purposes other than direct patient care, namely surveillance of emerging drugs and trends in local drug use. A number of case reports and larger case series present evidence in support of this use. Despite the potential advantages of mass spectrometry, the quantity and quality of published evidence are not sufficient to adequately assess the utility of mass spectrometry-based emergency toxicology results. This is a field that is ripe for investigation, particularly as mass spectrometers become less expensive and the technology is adopted by an increasing number of clinical laboratories. There is a strong need for prospective studies on implementation of STAT mass spectrometry-based tests in emergency toxicology and larger scale assessments of impact on acute patient care as well as public health.