Search

Objective Validation of a non-targeted method for urine drug screening (UDS) by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF), and comparison to an established GC–MS method in a hospital setting. Methods 217 UDS specimens sent to a quaternary hospital pathology department, were analysed by a CEDIA® immunoassay screen (six drug panels; amphetamines , barbiturates, benzodiazepines , cocaine metabolites, cannabinoids and opiates) on an Abbott Architect instrument. Specimens were subsequently analysed by an established non-targeted qualitative GC–MS method and results compared with a general unknown screening method by LC-QTOF that was under evaluation as a replacement method. Results 42 selected drugs were evaluated; limits of identification ranged from 2 to 100 µg/L and most drugs (n = 39) were stabile for 24 h after preparation. Matrix effects greater than 25% were observed in seven of the selected drugs. 87% of the specimens tested positive to 1 or more drug panels in a CEDIA® screen. A total of 537 positive drug findings were identified by GC–MS compared to 1,267 positive findings by LC-QTOF. On average, each GC–MS screen identified 2.5 ± 1.8 drugs and the LC-QTOF screen identified 5.8 ± 3.2 drugs. No drugs were identified in 11.3% of the GC–MS screens, whereas drugs were detected in 99% of these by the LC-QTOF. In almost all instances, the LC-QTOF screen could provide mass spectrometric confirmatory results of positive immunoassay screens and was able to identify a wider range of additional drugs and drug metabolites . Conclusions The described general unknown screening (non-targeted, qualitative) LC-QTOF method can detect a larger range of drugs encountered in a hospital setting. The method has been shown to be suitable for comprehensive toxicology screening in a clinical toxicology laboratory.

Background Many clinical toxicology laboratories receive urine specimens in urine cups that contain point of care (POC) drug testing strips. We conducted this study to evaluate the effect on the stability of commonly measured drugs in the clinical toxicology laboratory when urine is exposed to POC urine drug testing cups. Methods Drug free urine was spiked with 85 drugs that were measured by a validated liquid chromatography mass spectrometry (LCMS) method after exposure to POC urine drug testing cups at ambient and 2–6 °C temperatures. Alterations ≥20% were defined as significant changes in the drugs concentration. Results Concentrations of amitriptyline, cyclobenzaprine, fentanyl, fluoxetine, flunitrazepam, nortriptyline, paroxetine, and sertraline were significantly reduced when urine specimens were stored inside POC urine drug testing cups for 24 h at ambient temperature. Storage of urine in urine chemistry dipsticks reduced the concentration of several drugs. When spiked urine was exposed to an increasing number of POC urine drug testing strips, the concentrations of some drugs were reduced in a dose-dependent manner. The drugs that were absorbed by POC urine drug testing strips were partially back extracted from the strips. Conclusion Exposure of urine specimens to POC urine drug testing strips reduces the concentration of several drugs measured by LCMS method.

Cocaine (COC) is one of the most widely abused drugs in the world and its sensitive and its reliable measurement in blood is of great importance in the field of forensic and clinical toxicology. Additionally, the determination of COC metabolites such as benzoylecgonine (BZE), cocaethylene (CE), ecgonine methyl ester (EME), and norcocaine (NCOC) are also of complementary diagnostic value. The quantification of COC and metabolites in dried blood spots (DBS) may be an alternative to conventional collection methods with several advantages, including easier, on-site, collection, transportation and storage. In this study, we present a simple and comprehensively validated UPLC–MS/MS assay to measured COC, BZE, EME, NCOC and CE in DBS. The evaluated assay was linear from 5–500 ng mL−1. Precision assays presented CV% of 1.27–6.82, and accuracy in the range of 97–113.78%. Low haematocrit values had a negative impact in the assay accuracy. COC, BE, NCOC and CE measurements can be made reliably in DBS stored for 14 days at room temperature, as well as at −20 °C and 45 °C. All evaluated compounds can be measured in DBS maintained at −20 °C for 14 days. DBS sampling can be used for the clinical evaluation of the exposure to COC, being an alternative for collection, short-term storage and transportation of blood at room and high temperatures.

Use of intravenous lipid emulsion (ILE) as an antidote for severe cardiotoxicity and neurotoxicity has expanded in the veterinary world in the past decade. Despite advances in understanding of potential mechanisms of action of antidotal ILE, knowledge gaps remain in efficacy, appropriate dosing rates for various toxicants, and potential adverse reactions. Use of ILE in management of toxicoses of veterinary patients should be considered investigational, and should not be first-line treatment of most toxicoses, especially where established treatment protocols have good likelihood of positive outcomes. Use of ILE in veterinary toxicology cases requires judicious assessment of individual cases and proper informed consent of clients.

In the last few years an increasing number of new psychoactive substances (NPS), with different chemical structures (of which 37% are stimulants), have been released into the illicit drug market. Their detection and identification in biological samples is hence of great concern. The aim of this work was to develop a high-throughput and rapid method for the determination of different classes of stimulants (amphetamine-type stimulants, cathinones, phenethylamines and ketamine analogues) from blood and urine samples using GC–MS. The proposed method allows the almost simultaneous derivatization and extraction of analytes from biological samples in a very short time, by using hexyl chloroformate as derivatization agent. The extraction of analytes was performed by Dispersive Liquid Liquid Microextraction (DLLME), a very rapid, cheap and efficient extraction technique that employs microliter amounts of organic solvents. The chromatographic method allowed for the separation of 26 stimulants including positional isomers (3-MMC and 4-MMC). The method was validated on urine and blood samples with the ability to detect and quantify all analytes with satisfactory limits of detection (LODs) ranging between 1 and 10 ng/mL, limits of quantification (LOQs) between 2 and 50 ng/mL, selectivity and linearity (5–1000 ng/mL). The method was then applied to real samples from forensic cases, demonstrating its suitability for the screening of a wide number of stimulants in biological specimens.

Background and aim Aim of this review is to describe the role of clinical toxicology in the context of acute medicine. A special focus is put on antidotes and important aspects of diagnosis and therapy of acute intoxications. The data of the annual report of GIZ-Nord Poisons Centre is analyzed concerning the following aspects: what intoxications are relevant in acute medicine, are there special aspects in therapy, e.g. antidotes, and what antidotes are relevant? More over intoxication-related fatalities are analyzed. Results and conclusion In 2015 the poisons centre was consulted in 33,000 cases of acute intoxications. The most important groups are drugs (e.g. antidepressants, beta blockers and calcium channel blockers), chemical products (e.g. products containing surfactant, corrosive substances and toxic alcohols like methanol), plants and recreational drugs. Intoxications are relevant in acute medicine. Some substances can cause fatal intoxications. Important antidotes are naloxone for opiods, acetylcystein for paracetamol, fomepizole and ethanol for toxic alcohols and diazepam for intoxications caused by chloroquine.

Highly sensitive detection of Pb2+ is very necessary for water quality control, clinical toxicology, and industrial monitoring. In this work, a simple and novel DNAzyme-based SERS quadratic amplification method is developed for the detection of Pb2+. This strategy possesses some remarkable features compared to the conventional DNAzyme-based SERS methods, which are as follows: (i) Coupled DNAzyme-activated hybridization chain reaction (HCR) with bio barcodes; a quadratic amplification method is designed using the unique catalytic selectivity of DNAzyme. The SERS signal is significantly amplified. This method is rapid with a detection time of 2 h. (ii) The problem of high background induced by excess bio barcodes is circumvented by using magnetic beads (MBs) as the carrier of signal-output products, and this sensing system is simple in design and can easily be carried out by simple mixing and incubation. Given the unique and attractive characteristics, a simple and universal strategy is designed to accomplish sensitive detection of Pb2+. The detection limit of Pb2+ via SERS detection is 70 fM, with the linear range from 1.0×10–13 M to 1.0×10−7 M. The method can be further extended to the quantitative detection of a variety of targets by replacing the lead-responsive DNAzyme with other functional DNA.

A liquid chromatography–high resolution mass spectrometry (LC-HRMS) method for the simultaneous screening in hair samples of drugs of abuse and medicaments was developed. Target analytes screened using a single extraction and analytical run were opiates, cocaine, amphetamines and amphetamine-like substances, ketamine and analogues, cannabinoids, both natural and synthetic, cathinones, piperazines, ephedrines and others new psychoactive substances not pertaining to these classes; pharmaceutical drugs such as antipsychotics, antiepileptics, antidepressants, benzodiazepines and analogues, anorectics, stimulants, drugs for the erectile dysfunction. The multiresidual method involved methanolic incubation of 30 mg of decontaminated hair and analysis of the extract in HPLC using a C18 column. The mass detector, a benchtop Orbitrap Exactive, with nominal resolving power of 100,000, operated in full scan mode in positive ESI. Analytes were identified by exact mass, correspondence of isotopic cluster and retention times using a home-made database. The database contained the protonated exact masses of each monoisotopic compound, the retention time and the molecular formula of each studied analyte. At the moment the database contains 177 analytes. The screening method was validated for selectivity, limit of detection (LOD), matrix effect and carryover. The limits of detection obtained varied from 2 to 30 pg/mg, and the matrix effect was negligible. This method was then applied to three hundred authentic samples, resulting in the identification of various drugs of abuse and therapeutic drugs. The analyte identity was subsequently confirmed by in-source fragmentation. Thanks to the scan acquisition, this method also enables retrospective re-analysis of the acquired datafile in case a further analyte needs to be screened.

Poisoning is commonly encountered in acute medical practice and can involve toxicity arising from exposure to any one of a large number of different drugs or chemicals. Clinical toxidromes can help to define particular toxicological mechanisms so that appropriate treatments can be considered. The electrocardiogram and arterial blood gas are particularly important assessing poisoned patients, and laboratory drug confirmation plays a role in some situations. Oral activated charcoal is capable of reducing the gastrointestinal absorption of a number of drugs and chemicals. A wide range of specific antidotes are available, including acetylcysteine. Generalized strategies that minimize toxicity include haemodialysis and intravenous lipid administration for selected poisonings. Poisons units provide access to specialist expertise and poisoning management advice.

Although both the prevalence of asthma and the prescription drug use, notably the opiate analgesic class, epidemics are increasing, there is a complex interplay between both disorders, with both protective and exacerbating factors involved in the effect of opiates on asthma pathogenesis and clinical severity. This review examines the airway effects, both immunologic and neurologic, of opiates, which may interact and result in protection or exacerbation of asthma.

Pain management is an evolving discipline. New formulations mature with promises of improved pain control, better dosing, and fewer side effects. These agents also have an equal risk for abuse. Street chemists are adept at manipulating drugs to more potent versions and creating new compositions of matter. The clinical assessment of the patient is paramount to developing an index of suspicion of overdose, toxicity, or illicit drug use; the clinical laboratory can be a resource to support investigations and guide therapy. The clinical toxicology laboratory needs to keep in step, adapting technology and methodology to facilitate detection of such substances.

Liquid chromatography coupled to mass spectrometry (LC-MS) is nowadays an indispensable tool in the clinical toxicology laboratory. It allows the identification of a very high number of compounds for confirmation of positive immunoassay results as well as the detection of yet unknown compounds present in an intoxicated patient. In clinical toxicological laboratories ion traps and triple stage quadrupole instruments are widely used, whereas high-resolution instruments are only used in specialized laboratories. As every analytical method also LC-MS has its limitations; the most important drawbacks are matrix effects which can lead to ionization enhancement or suppression. For the identification of a compound, 3 to 4 identification points are necessary, regardless if a high-resolution instrument is used or not.

The current implementation of LC-MS/MS in drug development presents distinct challenges in the clinical setting for real-time sample analysis in clinical toxicology and therapeutic drug monitoring. Realization of STAT sample analysis using a single instrument within a single shift is the evolutionary goal of the technology. The constraint of performing many different measurements on a diverse array of analytes also confounds this paradigm. In the absence of an approved platform to resolve these issues, we developed a solution using commercially available multiplexing systems to facilitate rapid testing of >100 analytes as sub-panels (3–10 analytes per panel). Each panel is developed with consistent dilution (10–20 fold aqueous internal standard solutions) and incorporates assay specific online extraction/LC gradient motifs with generic column and solvent combinations. This paper discusses developmental considerations to ameliorate known MS detection issues such as phospholipids, provides a rational burden of proof for precision based recovery and demonstrates throughput in excess of 1440 samples per day per system. Additional capabilities are shown such as historical calibration and open channel access utility while conforming to the highest standards of analytical validity. Importantly, the concepts described within this manuscript have been reduced to clinical practice in the analysis of >500000 patients over the last 8 years.

Introduction Local cryotherapy induces vasoconstriction, which leads to a reduction in the inflammatory process. However, the effectiveness of local cryotherapy as a coadjuvant in the treatment of snakebite with F(ab’)2 antivenom is unknown. Objective To describe the clinical effectiveness of local cryotherapy as a coadjuvant in patients with snakebite treated with F(ab’)2 antivenom therapy at the Hospital Juarez de Mexico. Material and methods Patients with grade II snakebite envenomation according to the Christopher-Rodning classification system were enrolled from the Clinical Toxicology Service of the Hospital Juarez de Mexico. One group of patients received F(ab’)2 antivenom therapy (Antivipmyn®) plus local cryotherapy, and the other group received only F(ab’)2 antivenom therapy. Results Thirty-eight patients were included, of whom 86.8 % were male (n = 33). Approximately 81.5 % of the subjects were injured in an upper extremity, while 18.5 % were injured in a lower extremities; 47.3 % of the subjects reported treatment of the snakebite prior to hospitalization (suction, the application of a tourniquet, incision of the bite site, or the application of traditional medicine). No differences were found concerning edema, swelling, and pain between the groups. The group that received local cryotherapy as a coadjuvant to F(ab’)2 antivenom therapy had a shorter hospital stay (Cohen's d = 1.33; 95 % confidence interval [95 % CI] = 0.74–1.62; p Conclusions The use of adequate local cryotherapy as a coadjuvant to F(ab’)2 antivenom therapy reduces the length of hospital stay and the number of doses of F(ab’)2 antivenom therapy used.

The field of new psychoactive substances (NPS) is highly dynamic and the situation changes from year to year. Therefore, the current review provides a timely update about the latest developments to help analysts keep the pace with NPS distribution. It covers PubMed-listed studies published between January 2014 and January 2016 dealing with the application of liquid chromatography (LC) coupled low- and high-resolution mass spectrometry (MS) for broad screenings for NPS in clinical (CT) and forensic (FT) toxicology. Latest developments and applications are highlighted and selected papers critically discussed. Comprehensive tables summarizing all discussed articles complete the overview. Finally, an outlook on the future of LC coupled MS in CT and FT is provided and readers will learn why low-resolution mass spectrometry might remain the standard for the next couple of years at least for easy-to-use quantitative screening procedures.

Robust computational approaches are needed to characterize systems-level responses to chemical perturbations in environmental and clinical toxicology applications. Appropriate characterization of response presents a methodological challenge when dealing with diverse phenotypic endpoints measured using in vivo systems. In this article, we propose an information-theoretic method named Aggregate Entropy (AggE) and apply it to scoring multiplexed, phenotypic endpoints measured in developing zebrafish (Danio rerio) across a broad concentration-response profile for a diverse set of 1060 chemicals. AggE accurately identified chemicals with significant morphological effects, including single-endpoint effects and multi-endpoint responses that would have been missed by univariate methods, while avoiding putative false-positives that confound traditional methods due to irregular correlation structure. By testing AggE in a variety of high-dimensional real and simulated datasets, we have characterized its performance and suggested implementation parameters that can guide its application across a wide range of experimental scenarios.

The COVID-19 outbreak emerged in December 2019 and has rapidly become a global pandemic. A great deal of effort has been made to find effective drugs against this disease. Chloroquine (CQ) and hydroxychloroquine (HCQ) were widely adopted in treating COVID-19, but the results were contradictive. CQ/HCQ have been used to prevent and treat malaria and are efficacious anti-inflammatory agents in rheumatoid arthritis and systemic lupus erythematosus. These drugs have potential broad-spectrum antiviral properties, but the underlying mechanisms are speculative. In this review, we re-evaluated the treatment outcomes and current hypothesis for the working mechanisms of CQ/HCQ as COVID-19 therapy with a special focus on disruption of Ca2+ signaling. In so doing, we attempt to show how the different hypotheses for CQ/HCQ action on coronavirus may interact and reinforce each other. The potential toxicity is also noted due to its action on Ca2+ and hyperpolarization-activated cyclic nucleotide-gated channels in cardiac myocytes and neuronal cells. We propose that intracellular calcium homeostasis is an alternative mechanism for CQ/HCQ pharmacology, which should be considered when evaluating the risks and benefits of therapy in these patients and other perspective applications., Chloroquine, Hydroxychloroquine, Calcium, HCN, SARS-CoV-2; Cardiology; Pathology; Infectious disease; Neurology; Pharmacology; Immunology; Clinical toxicology; Toxicology; Eye-ear-nose-throat; Internal medicine

Macrotyloma uniflorum Linn. (Fabaceae) seeds are widely used for their diuretic and urolithiatic effects in India. The present study investigated the effect of aqueous extract of Macrotyloma uniflorum seeds (AEMU) on ethylene glycol induced urolithiasis in rats. To induce urolithiasis, 0.75% v/v ethylene glycol was administered orally for 14 days. The curative doses of 400 and 800 mg/kg were administered from 15th to 28th day. On the 28th day, 24 h urine, serum was collected and various biochemical parameters were estimated in urine, serum and kidney homogenate along with histology of kidney. Co-administration of AEMU with ethylene glycol has significantly (p < 0.001) increased the urine volume and the level of calculus inhibitors like magnesium, citrate and decreased the level of calculus promoters like calcium, oxalate, uric acid and urea also decreased in crystalluria in urine. AEMU supplement also prevented the pathological changes in the kidney and increased the glomerulus activity of the kidney. These results indicate that AEMU showed significant activity in urolithiasis which might be due to its diuretic, calcium oxalate crystal formation inhibitory effects and its ability to increase the levels of inhibitors and decrease the level of promoters of urolithiasis.

Recent studies have shown that statins and Metformin may have beneficial effects on seizure through different mechanisms. In the current study, we investigated whether Metformin, Atorvastatin, and concomitant uses of them have beneficial effects on pentylenetetrazole (PTZ)-induced kindling. Adult male C57BL/6 mice were randomly divided into four experimental groups with seven mice in each group. Group 1, control group; group 2, received Metformin (200 mg/kg, i.p); group 3, received Atorvastatin (10 mg/kg, i.p.); group 4, received Atorvastatin (10 mg/kg, i.p.) plus Metformin (200 mg/kg, i.p.). Twenty minutes after injection of the mentioned drugs, the experimented mice received 37/5 mg/kg of PTZ intraperitoneally on alternating days. Then the convulsive behavior signs were evaluated for 20 min after each PTZ injection. There were significant differences in the stage 2 latency parameter among group 2 (p = 0.033, F = 8.46)/group 3 (p = 0.032, F = 10.42)/group 4 (p = 0.008, F = 24.57) as compared to the control group, while no significant differences were found comparing only group 2,3, and 4 with eachother excluding the control group. Pretreatment with Atorvastatin (p = 0.002, F = 33), Atorvastatin + Metformin (p = 0.006, F = 20.77), and Metformin alone increased stage 5 latency as compared to the PTZ group, significantly. Also, our results have shown that pretreatment with Atorvastatin (p = 0.013, F = 14.48), Metformin (p = 0.015, F = 16.67), and concomitant usage of them significantly decreased stage 5 duration as compared to the control group. Our findings clearly demonstrate that concomitant use of Metformin and Atorvastatin has no more protective effect against the development of kindling as compare to these drugs alone. Thus, we concluded that, these drugs may inhibit kindling via a similar mechanism and we suggested that it is probably through regulation of autophagy., Biochemistry; Toxicology; Pharmacology; Clinical Toxicology; Medical Ethics; Atorvastatin; Metformin; Pentylenetetrazole kindling; seizure

The aim of these investigations was to study vitamin E supplement effect in male albino rats after 30 days of repeated treatment. Four groups of six male rats were orally administered distilled water (control), 500, 1000 and 2000 mg/kg body weight vitamin E daily for 30 days. The impact of the treatment on percent body weight and mortality was determined and compared to the control group. Some hematological analysis, biochemical parameters and histological examination of different body organs were assessed. The rats treated with different doses of vitamin E supplement showed no deaths recorded in 30 days. The treatment with higher dose Vitamin E supplementation" caused significant alteration at the hematological, biochemical and histological level. Therefore, oral administration of vitamin E supplement in rats for 30 days was not safe for the liver and kidney and in the other hand, safe for the testes therefore that side effect on the liver and kidney should be considered when recommended vitamin E for therapeutic purpose. Care should be taken in taking high doses of vitamin E., Biochemistry; Toxicology; Clinical toxicology; Health sciences; Organ system; Vitamin E supplement; Liver; Kidney; Testes

The increasing number of new psychoactive substances (NPS) present in the illicit market render their identification in biological fluids/tissues of great concern for clinical and forensic toxicology. Analytical methods able to detect the huge number of substances that can be used are sought, considering also that many NPS are not detected by the standard immunoassays generally used for routine drug screening. The aim of this work was to develop a method for the screening of different classes of NPS (a total of 78 analytes including cathinones, synthetic cannabinoids, phenethylamines, piperazines, ketamine and analogues, benzofurans, tryptamines) from blood samples. The simultaneous extraction of analytes was performed by Dispersive Liquid/Liquid Microextraction DLLME, a very rapid, cheap and efficient extraction technique that employs microliters amounts of organic solvents. Analyses were performed by a target Ultrahigh Performance Liquid Chromatography tandem Mass Spectrometry (UHPLC-MS/MS) method in multiple reaction monitoring (MRM). The method allowed the detection of the studied analytes with limits of detection (LODs) ranging from 0.2 to 2ng/mL. The proposed DLLME method can be used as an alternative to classical liquid/liquid or solid-phase extraction techniques due to its rapidity, necessity to use only microliters amounts of organic solvents, cheapness, and to its ability to extract simultaneously a huge number of analytes also from different chemical classes. The method was then applied to 60 authentic real samples from forensic cases, demonstrating its suitability for the screening of a wide number of NPS.

SummaryIdiosyncratic drug-induced liver injury (DILI) is a common cause for drug withdrawal from the market and although infrequent, DILI can result in serious clinical outcomes including acute liver failure and the need for liver transplantation. Eliminating the iatrogenic “harm” caused by a therapeutic intent is a priority in patient care. However, identifying culprit drugs and individuals at risk for DILI remains challenging. Apart from genetic factors predisposing individuals at risk, the role of the drugs’ physicochemical and toxicological properties and their interactions with host and environmental factors need to be considered. The influence of these factors on mechanisms involved in DILI is multi-layered. In this review, we summarize current knowledge on 1) drug properties associated with hepatotoxicity, 2) host factors considered to modify an individuals’ risk for DILI and clinical phenotypes, and 3) drug-host interactions. We aim at clarifying knowledge gaps needed to be filled in as to improve risk stratification in patient care. We therefore broadly discuss relevant areas of future research. Emerging insight will stimulate new investigational approaches to facilitate the discovery of clinical DILI risk modifiers in the context of disease complexity and associated interactions with drug properties, and hence will be able to move towards safety personalized medicine.

Some nurses have chosen to work The skills acquired through their professional experience in the field, combined with specific training in clinical toxicology, equip them to fulfil their role in innovative missions. Their main activity consists in manning the emergency helpline with additional toxicovigilance missions.

Resume Dans le cadre d’une etude en milieu ambulatoire ayant pour objectif de montrer l’efficacite du baclofene sur la consommation d’alcool, il est propose lors de la visite de sortie de realiser le dosage de l’ethyl glucuronide (EtG) dans les urines. Les inclusions de cette etude etant multicentriques, le probleme de conservation des prelevements urinaires avant acheminement apparait comme une limite au dosage de ce marqueur. Nous avons donc envisage une etude de stabilite complete sur trois semaines chez differents types de consommateurs pour apprecier la faisabilite de ce dosage dans les conditions de cette etude. Les dosages urinaires lors d’une consommation controlee d’alcool chez deux temoins permettent egalement de decrire l’elimination urinaire de ce marqueur. Des urines de temoins consideres comme buveurs sociaux ou alcooliques chroniques sont recueillies le matin. Les dosages d’EtG (DRI, Thermo Fisher Scientific, seuil de positivite 0,5 mg/L), d’ethanol et de creatinine urinaires, ainsi qu’une analyse cytobacteriologique sont realises au moment du recueil. Le dosage d’EtG est teste sur des tubes contenant de l’acide borique et sur des flacons type ECBU sans conservateur. Dans un premier temps, on realise l’etude de stabilite pour chaque urine pendant 3 semaines dans des conditions differentes de temperature (4 °C, temperature ambiante), d’oxydation et de lumiere et pendant 3 mois a −20 °C. Puis, on etudie le suivi de l’elimination urinaire de l’EtG chez deux temoins apres consommation controlee de 10 et 30 g d’alcool. Les prelevements urinaires realises sur des tubes contenant de l’acide borique (pour eviter la proliferation bacterienne pouvant fausser le dosage de l’EtG) ont tous donne des resultats faussement negatifs. Les concentrations mesurees dans les flacons type ECBU varient de 0,50 a 17,83 mg/g de creatinine (entre H12 et H18) pour la categorie des « buveurs sociaux » ( n = 7) et beaucoup plus elevees de 88,32 et de 125,24 mg/g de creatinine pour deux « alcooliques chroniques ». L’etude menee sur une periode de trois semaines et l’etude de congelation sur trois mois montrent une excellente stabilite pour l’ensemble des conditions etudiees (CV entre 3,1 % et 13,9 %). Des concentrations mesurees a differents temps pour deux temoins pour des consommations controlees de 10 et 30 g d’alcool montrent des resultats tres variables. Les estimations de la surface sous la courbe des cinetiques d’elimination urinaire en fonction du temps, des demi-vies d’elimination (entre 2,75 et 3,50 h) permettent de realiser une approche de la fenetre de detection de l’EtG dans les urines (entre 12,1 h pour une dose de 10 g et 30,1 h pour une dose de 30 g). Les resultats sur les tubes contenant de l’acide borique ne sont pas utilisables. Pour l’etude en ambulatoire, nos resultats de stabilite montrent qu’il n’y a aucune precaution particuliere a prendre et que des pots sans conservateur peuvent etre utilises. Les variabilites observees pour les temoins dont l’EtG dans les urines a ete mesure pour differentes quantites d’alcool consomme, peuvent etre expliquees par une saturation des voies oxydatives principales de l’alcool (ADH) a l’origine d’une surexpression de la voie minoritaire de l’UDP-glucuronosyltransferase (UGT) pour laquelle on decrit un polymorphisme genetique.

Bruton's Tyrosine Kinase (BTK) is a member of the TEC family and plays a central role in B-cell signaling, activation, proliferation and differentiation. Here we evaluated the impact of BTK inhibitor Ibrutinib on a panel of HL models in vitro and in vivo. Ibrutinib suppressed viability and induced apoptosis in 4 HL cell lines in a dose and time dependent manner. Molecular analysis showed induction of both apoptotic and autophagy markers. Ibrutinib treatment resulted in suppression of BTK and other downstream targets including PI3K, mTOR and RICTOR. Ibrutinib given at 50 mg/kg p.o daily for three weeks caused statistically significant inhibition of HL cell line derived subcutaneous xenografts (p < 0.01) in ICR-SCID mice. Molecular analysis of residual tumor tissue revealed down-regulation of BTK; its related markers and autophagy markers. Our studies are the first showing in vitro and in vivo action of BTK inhibition in classical HL. A phase II study examining the activity of ibrutinib in relapsed or refractory HL is currently enrolling (NCT02824029).

An epidemic of prescription drug abuse in the United States has increased the burden on clinical toxicology testing laboratories. Urine drug testing provides objective evidence for compliance and aberrant drug behavior in patients on chronic (non-cancer) pain management. This article describes the testing menu, drug testing assays including tandem mass spectrometry and their limitations, interpretation of opiate results and clinical considerations.

Clinical toxicology laboratories and forensic toxicology laboratories operate in a highly regulated environment. This article outlines major US legal/regulatory issues and requirements relevant to accreditation of toxicology laboratories (state and local regulations are not covered in any depth). The most fundamental regulatory distinction involves the purposes for which the laboratory operates: clinical versus nonclinical. The applicable regulations and the requirements and options for operations depend most basically on this consideration, with clinical toxicology laboratories being directly subject to federal law including mandated options for accreditation and forensic toxicology laboratories being subject to degrees of voluntary or state government–required accreditation.

Ethylene glycol poisoning is a medical emergency that presents challenges both for clinicians and clinical laboratories. Untreated, it may cause morbidly or death, but effective therapy is available, if administered timely. However, the diagnosis of ethylene glycol poisoning is not always straightforward. Thus, measurement of serum ethylene glycol, and ideally glycolic acid, its major toxic metabolite in serum, is definitive. Yet measurement of these structurally rather simple compounds is but simple. This review encompasses an assessment of analytical methods for the analytes relevant for the diagnosis and prognosis of ethylene glycol poisoning and of the role of the ethylene glycol metabolites, glycolic and oxalic acids, in its toxicity.

Mass spectrometry is rapidly expanding its role in clinical chemistry. To date, this growth has primarily been in the area of small molecule analysis, though the field now seems set for a rapid growth of protein and peptide analysis. Small molecule analysis applications can be grouped roughly into the analysis of endogenous compounds and the analysis of exogenous compounds. The analysis of exogenous compounds is largely the domain of toxicology, and this is the focus of this article. To limit the scope and, therefore, the length of this article, we focus primarily on 2 general topics within clinical toxicology: therapeutic drug monitoring and trace element analysis. While these 2 topics do not cover the full breadth of mass spectrometry applications in clinical toxicology, omitting, for example, clinical drugsof-abuse testing and applications supporting poison control programs, we feel that they, nevertheless, provide a fairly representative overview of mass spectrometry in the clinical toxicology lab.

Over the past decade great progress has been made in metals and metalloids analysis. This analysis is a basic stage in toxicity assessment and is indispensable in achieving a realistic evaluation of substance toxicity. A recently introduced technique, inductively coupled plasma mass spectrometry (ICP-MS) is progressively replacing atomic absorption. This analysis permits multi-elementary determinations, approximately 30 elements, with an optimal gain in sensitivity in many biological matrices: i.e. whole blood, plasma, urine, hair, nail, biopsy samples. Moreover, this method allows semiquantitative determination with an additional 30 supplementary elements, which enables the toxicologist to sufficiently estimate the toxic levels and metal exposure. The authors demonstrate that the ICP-MS could be very useful for a wide range of clinical applications. Furthermore, this procedure offers new exploration possibilities in various fields such as clinical toxicology, forensic toxicology as well as work place testing or environmental exposure and permits epidemiologic studies. This analytical method in fact also provides a new scientific approach. To our knowledge we are the first to propose: the metallic profile.

patients with acute myocardial infarction☆ Ja-Liang Lin ⁎, Pao-Hsien Chu , Dan-Tzu Lin-Tan , Ching-Wei Hsu , Wen-Hung Huang , Kuan-Hsing Chen , Tzung-Hai Yen a,1 a Division of Nephrology and Clinical Toxicology, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Chang Gung University and School of Medicine, Taipei, Taiwan, ROC b Division of Cardiology, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Chang Gung University and School of Medicine, Taipei, Taiwan, ROC

The relationship between basic research and its potential clinical applications is often a difficult subject. Clinical toxicology has always been very dependent on experimental research whose usefulness has been impaired by the existence of huge differences in the toxicity expression of different substances, inter- and intra-species which make it difficult to predict clinical effects in humans. The new methods in molecular biology developed in the last decades are furnishing very useful tools to study some of the more relevant molecules implied in toxicokinetic and toxicodynamic processes. We aim to show some meaningful examples of how recent research developments with genes and proteins have clear applications to understand significant clinical matters, such as inter-individual variations in susceptibility to chemicals, and other phenomena related to the way some substances act to induce variations in the expression and functionality of these targets.

The following is a list of 68 questions formulated as a ember benefit for the American Academy of Clinical oxicology (AACT). One question/answer is e-mailed daily o members under the title “AACT Tox Question of the ay.” Each answer is appropriately referenced. As the eader can see from the scope of these questions, the field of linical Toxicology is extremely diverse and encompasses irtually every medical specialty. Other AACT member benefits include discounts to the nnual scientific meeting, journal/abstracts subscription, pecialty section membership, and enhanced networking apabilities. Interested prospective members are encouraged o contact AACT via phone at (717) 558-7847 or through ur Web site at http://www.clintox.org.

During the past decade, tandem mass spectrometry hyphenated to liquid chromatography separation systems (HPLC-MS/MS) has developed to an important technology in clinical chemistry - not only for research purposes but also for routine use. At present, most important application fields are target analyses in therapeutic drug monitoring (TDM) and metabolic disorders diagnosis. The essential strengths of HPLC-MS/MS include potentially high analytical specificity, wide range of applicability to small and large molecules, capability of multi- and mega-parametric tests, and the opportunity to develop powerful assays with a high degree of flexibility within a short time frame. The technique has overcome important limitations of GC-MS and is characterized by short analytical runtimes, applicability to thermo labile, polar and large molecules, and straightforward sample preparation. However, implementation of HPLC-MS/MS assays still requires substantial expertise and know-how. At the present, its application is limited to a rather small number of clinical routine laboratories. Nonetheless, HPLC-MS/MS has the potential to be further developed to a commonly applied high-throughput technique in clinical chemistry, complementary to present standard techniques as photometry and ligand binding methods. This review intends to characterize working characteristics of present day HPLC-MS/MS instrumentations used in clinical routine laboratories. Limitations of currently available systems and applications will be critically discussed. Required instrument improvements supporting the successful spreading of HPLC-MS/MS in laboratory medicine within the next decade will be outlined.

The various techniques that can be used to achieve gastrointestinal decontamination have been reviewed in position statements sponsored by the American Academy of Clinical Toxicology and the European Association of Poison Centres and Clinical Toxicologists. Although the indications have been presented, clinicians still have some latitude as to whether they should use them or not in a particular case. The aim of this article is to present an approach that clinicians may use to help them decide to decontaminate a patient or not after an oral exposure. After a review of the position statements, we will discuss how the risk assessment of the exposure can be made and suggest an approach, the gastrointestinal triangle, to balance the potential risks against the foreseeable benefits of decontamination.

Scientific case studies in clinical toxicology on single cases or series of similar cases should document sufficient information on the clinical methodology and observations, the medical laboratory methodology and results, the toxicological analyses methodology and results, the source of used reference values for drug/poison concentrations and kinetics with critical discussion of such values, a description and discussion of the toxicodynamic, the toxicological and the kinetic properties of the detected drugs and/or poisons. The data management, statistical analysis and finally the clinical and/or analytical outcomes must also be described and discussed in correlation to already published data. Statistical methods used for evaluation of clinical as well as for analytical data should be described in detail. When possible, quantitative findings should be presented with appropriate indicators of measurement error or uncertainty. Requirements for such studies are discussed.

The unique geographic isolation of Australia has resulted in the evolution of a distinctive range of Australian arachnid fauna. Through the pioneering work of a number of Australian arachnologists, toxinologists, and clinicians, the taxonomy and distribution of new species, the effective clinical treatment of envenomation, and the isolation and characterisation of the many distinctive neurotoxins, has been achieved. In particular, work has focussed on several Australian arachnids, including red-back and funnel-web spiders, paralysis ticks, and buthid scorpions that contain neurotoxins capable of causing death or serious systemic envenomation. In the case of spiders, species-specific antivenoms have been developed to treat envenomed patients that show considerable cross-reactivity. Both in vitro and clinical case studies have shown they are particularly efficacious in the treatment of envenomation by spiders even from unrelated families. Despite their notorious reputation, the high selectivity and potency of a unique range of toxins from the venom of Australian arachnids will make them invaluable molecular tools for studies of neurotransmitter release and vesicle exocytosis as well as ion channel structure and function. The venoms of funnel-web spiders, and more recently Australian scorpions, have also provided a previously untapped rich source of insect-selective neurotoxins for the future development of biopesticides and the characterisation of previously unvalidated insecticide targets. This review provides a historical viewpoint of the work of many toxinologists to isolate and characterise just some of the toxins produced by such a unique group of arachnids and examines the potential applications of these novel peptides. © 2006 Elsevier Ltd. All rights reserved.

The sarin gas attack in the Tokyo subway system is reviewed from a clinical toxicology perspective. Based on the lessons learned from this attack, the following areas should be addressed on a global scale. First, an adequate supply of protective equipment is required, including level B protective equipment with a pressure demand breathing apparatus. In addition, a system should be established that enables a possible cause to be determined based on symptoms, physical findings, general laboratory tests, and a simple qualitative analysis for poisonous substances. If an antidote is needed, the system should enable it to be administered to the victims as quickly as possible. Preparation for a large-scale chemical attack by terrorists requires the prior establishment of a detailed decontamination plan that utilizes not only mass decontamination facilities but also public facilities in the area. A system should be established for summarizing, evaluating, and disseminating information on poisonous substances. Finally, a large-scale scientific investigation of the Tokyo sarin attack should be conducted to examine its long-term and subclinical effects and the effects of exposure to asymptomatic low levels of sarin.

Resume Les dix centres antipoison (CAP) francais ont pour principale mission l’information telephonique toxicologique en urgence pour le public et les professionnels de sante. Cette tâche est assuree 24 heures sur 24 par des medecins specialement formes, et permet de realiser d’importantes economies de sante en limitant les consultations abusives dans les services hospitaliers d’urgences. D’autres missions connexes sont parallelement effectuees au cours du travail de telemedecine des CAP : education sanitaire de la population, prevention des accidents, expertise toxicologique, toxicovigilance, enseignement et recherche en toxicologie clinique et contribution a d’autres vigilances par exemple en collaborant avec les centres regionaux de pharmacovigilance ou les centres d’evaluation et d’information sur les pharmacodependances (CEIP). Les missions et moyens des CAP francais sont definis par le decret 96-833 du 17 septembre 1996.

A quantitative method using high-performance liquid chromatography–mass spectrometry (LC–MS, ion trap) after matrix supported liquid–liquid extraction is described for the simultaneous determination in whole blood of 33 benzodiazepines including metabolites and benzodiazepine-like substances. The limits of detection (LOD) range from 0.0001 to 0.0126 mg/l. Linearity is satisfactory for all compounds. The extraction recoveries for the benzodiazepines in whole blood are between 60 and 91%, desmethyldiazepam, OH-bromazepam and brotizolam excepted. Selectivity, accuracy and precision are satisfactory for clinical and forensic purposes.

The multi-elementary quantitation method using inductively coupled plasma mass spectrometry has been widely developed for use with biological fluids. Many elements can be quantified simultaneously in biological fluids, including: Li, Be, B, Al, Mn, Co, Ni, Cu, Zn, Ga, Ge, As, Se, Rb, Sr, Mo, Pd, Cd, Sn, Sb, Te, Ba, W, Pt, Hg, Tl, Pb, Bi, U. The validation procedure is described by the French Society of Clinical Biology. Results for urine are corrected after creatinine determination. We report applications in clinical toxicology and forensic toxicology. Advances in inductively coupled plasma mass spectrometry in the field of clinical biology are particularly important for toxicological analysis. This powerful tool is helpful for better patient care and for the search for cause of death.

Introduction The diagnosis in clinical toxicology is based on the collection of information on: – the substance, the dose, and the route of administration; – signs and symptoms that have to fit the supposed ingested drug (SID), and; – toxicological analysis (TA) which is expected to provide the definitive diagnosis. However, in the past, the development of methods based on immuno-enzymology provided information on the class rather the substance by itself with questionable ability to quantify exposure. Consequently, routinely used TA was progressively disgarded. TA was recommended in only a few number of toxicants and in conditions were SID does not explain major signs and symptoms. However, over the past decade, modern TA using various modes of mass spectrometry was developed meanwhile analysts claimed they were able to address all toxicological concerns of attending physicians. From a theoretical viewpoint this assumption was sounded. However, the translational to practice has not been assessed to our knowledge. The aim of this retrospective study performed in a medical polyvalent intensive care unit (MPICU) was to test the hypothesis more especially as the MPICU has unlimited access to facilities provided by three University Toxicology Laboratory (Tox Lab). Patients and methods Patients: included patients were adult patients admitted for suspicion of poisoning ranging from moderate to severe in our MPICU from the 1st of January 2014 until April 2015. This period of time corresponded to the period of time at which the MPICU has unlimited access to the three Tox Lab. Toxicology analyses: according to our current practice blood and urine specimens were collected at the time of admission and sent to the different ToxLab owing to the facilities provided by each, including the local hospital for a limited of toxicants, the ToxLab on duty in our institution allowing screening and dosing, and The ToxLab of the forensic department of our Institution. The two latters have facilities of modern apparatus including mass spectrometry in various modes as well as separative process (gas and liquid). The ToxLab were blinded regarding the aim of the study. Expression of results: in each patient's results from the different laboratory were gathered one positive detection/quantitification of an SID was considered SID+,TA+; lack of SID with positive TA: SID-,TA+, a SID+ with negative TA was considered SID+,TA-. Unfortunately there was no SID6,TA- as there were no need to ask for the presence of a drug to Toxlab knowing is was absent in a study done in current practice. Assessment of severity of exposure: severity of exposure as assessed only for drugs and alcohol using the maximum daily recommended for drugs (a therapeutic index > 1 deontes an intoxication) and a blood alcohol level (BAL) of 0.4 g/lg (a BAL > 0.4 g/L was considered toxic). Results Over the study period there were 224 occurrences concerning 90 SID (a number of multiple occurrences of the same drug) in 70 patients (a number of patients reported multiple drug ingestions). An SID+, TA+ was recorded in only 33% of the 224 occurrences; however, the TI was > 1 in 45% of the dosed drugs. In addition, in the group of SSI-, TA+, the TA added in 15% of patients with SID-. However, in 79% of the SID-, TA+, the TI was less than 1. This finding suggests the detection was that of drugs prescribed or used by the patient therapeutically or recreatively in this class of patients SID6, TA+. Discussion In the sixties, toxicological analysis was considered the gold standard to definitively assume the role of a substance in a poisoning. Suprisingly, while the methods used in analytical toxicology resulted in a manifold increase in sensitivity and specificity allowing to screen hundreds of substances in 10 microliter of whole blood, the added value of analytical toxicology is fairly low as shown by evidencing the SID in only 33% of the occurrences. We can question about the accuracy of the SID. However, until the toxicological analysis does not currently assume the substance is not present, the analytical result is subject to caution. The question is open to know whether high-resolution mass spectrometer can actually increase the added value of TA. Furthermore, closer collaboration regarding the actual needs of the clinicic and may help analysts in defining the lists of toxicants of interest, providing an regular update of this list of toxicants. Conclusion Gathering facilities provided by three University Tox Lab using modern technology resulted in a low added value of toxicological analysis in acute poisonings daily presenting in ICU. Improving the gap might be helped by high-resolution mass spectrometry. However, a close collaboration between toxicologists and analysts should result in filling the gap.