Clinical Toxicology Research Articles

Advances in Chemical Constituents, Clinical Applications, Pharmacology, Pharmacokinetics and Toxicology of Erigeron breviscapus.

Dengzhanxixin (DZXX), the dried whole plant of Erigeron breviscapus (Vaniot) Hand.-Mazz., belonging to Compositae and first published in Materia Medica of South Yunnan by Lan Mao in the Ming Dynasty (1368 AD–1644 AD), is included in Medicinal Materials and Decoction Pieces of the 2020 edition of the Pharmacopeia of the People’s Republic of China. Its main chemical components are flavonoids that mainly include flavonoid, flavonols, dihydroflavones, flavonol glycosides, flavonoid glycosides, coffee acyl compounds, and other substances, such as volatile oil compounds, coumarins, aromatic acids, pentacyclic terpenoids, phytosterols, and xanthones. Among them, scutellarin and 1,5-dicoffeoylquininic acid are the main active components of DZXX. DZXX has pharmacological effects, such as improving cerebral and cerebrovascular ischemia, increasing blood flow, inhibiting platelet aggregation, promoting antithrombotic formation, improving microcirculation, reducing blood viscosity, protecting optic nerves, exhibiting anti-inflammatory properties, scavenging free radicals, and eliciting antioxidant activities. It is widely used in the treatment of cardiovascular and cerebrovascular ischemic diseases, kidney diseases, liver diseases, diabetic complications, and glaucoma. Pharmacokinetic studies have shown that the active components of DZXX have a low bioavailability and a high elimination rate in vivo. Nevertheless, its utilization can be improved through liposome preparation and combination with other drugs. Acute and subacute toxicity studies have shown that DZXX is a safe medicinal material widely used in clinical settings. However, its target and drug action mechanism are unclear because of the complexity of its composition. In this paper, the clinical application and pharmacological toxicology of DZXX are reviewed to provide a reference for further studying its active components and action mechanism.

A survey of health professionals' opinion about web and smartphone application in clinical toxicology training

A survey of health professionals' opinion about web and smartphone application in clinical toxicology training

Clinical toxicology of immune checkpoint blockers

Clinical toxicology of immune checkpoint blockers

The Effects of Succimer and Penicillamine on Acute Lead Poisoning Patients

Background: Lead poisoning was on the rise in recent years. There exists a lack of easy access to some of the main chelator drugs in developing countries. Thus, this study aimed to explore the comparative effects of Succimer and D-Penicillamine on acute lead poisoning patients from 2013 to 2018. Methods: This descriptive study was conducted in the Clinical Toxicology Department of Khorshid Hospital in Isfahan City, Iran. Adult patients with acute lead poisoning were included in the study. Patients in the 3 treatment groups of D-Penicillamine, D-Penicillamine with succimer, and succimer were compared concerning demographic characteristics as well as clinical and laboratory findings at admission time and two weeks later. Results: In total, 163 patients were evaluated in this research. There was no significant difference between the treatment groups respecting improvement in clinical symptoms. The mean blood lead levels during hospitalization and two weeks after the treatment did not significantly differ between the three groups; however, there was a significant reduction in all study groups after two weeks of treatment (P<0.05). The mean white blood cell count was significantly lower only in the D-Penicillamine group two weeks after hospitalization (P<0.05). In the D-Penicillamine group, the mean platelet, hematocrit, and hemoglobin levels were significantly lower two weeks after hospitalization, although within the healthy range. Conclusion: D-Penicillamine may be an acceptable chelator drug for treating patients with acute lead poisoning, especially in communities without access to drugs, like succimer.

Marijuana use, fetal growth, and uterine artery Dopplers

Objective Marijuana (MJ) use is associated with adverse effects on fetal growth. We aimed to investigate the timing of suboptimal fetal growth onset in MJ-exposed pregnancies. In addition, we aimed to explore the relationship between MJ-exposure and both abnormal uterine artery (UtA) Doppler parameters and small for gestational age (SGA). Study design This was a secondary analysis of a prospective multicenter cohort that enrolled nulliparous individuals delivering non-anomalous fetuses beyond 20 weeks’ gestation. Marijuana exposure was ascertained by self-report or clinical urine toxicology testing. Ultrasound estimated fetal weights (EFWs) were assessed in participants at both 16w0d–21w6d and 22w0d–29w6d. EFWs and birth weight (BW) were converted to weight percentiles (wPCT). EFW and BW wPCTs were calculated using population-based standards. Additionally, a customized standard designed to be applicable to both EFWs and BWs within the same model was also used to allow for EFW to BW percentile trajectories. The primary outcome, longitudinal wPCT, was compared between individuals with and without MJ use in a linear mixed-effects regression model adjusting for tobacco. For modeling, wPCT was smoothed across gestational age; MJ was estimated as an intercept and linear difference in the slope of gestational age. UtA Doppler notching, resistance index (RI), and pulsatility index (PI) at 16w0d–21w6d were compared using t-test and χ 2. SGA at delivery was also compared. Results Nine thousand one hundred and sixty-three individuals met inclusion criteria; 136 (1.5%) used MJ during pregnancy. Individuals who used MJ were more likely to be younger, identify as non-Hispanic Black, and have had less education. Fetuses exposed to MJ had lower wPCT beginning at 28 weeks using population-based and customized standards, when compared to those without exposure. UtA notching, PI, and RI were similar between groups. SGA was more frequent in neonates exposed to MJ using both population-based (22 vs. 9%, p<.001) and customized (25 vs. 14%, p<.001) curves. Conclusions MJ-exposed fetuses were estimated to be smaller than unexposed fetuses starting at 28 weeks’ gestation across both growth standards without a difference in UtA Doppler parameters.

Just say no to postmortem drug dose calculations.

For years, a number of professional groups have warned forensic and clinical toxicologists against calculating an administered dose of a drug based on postmortem blood drug concentrations. But to date, there has been limited information as to how unreliable these dose calculations may actually be. Using amitriptyline as a model drug, this study used empirically determined pharmacokinetic variables for amitriptyline from clinical studies coupled with clinical overdoses (where the individual survived), and death case studies (ascribed to amitriptyline toxicity) in which the dose of amitriptyline was known. Using these data, standard pharmacokinetic equations, and general error propagation, it was possible to estimate the accuracy of calculated doses of amitriptyline, compared with the doses that were consumed. As was expected in postmortem cases, depending on the pharmacokinetic equation used, the accuracy (mean +128% to +2347%) and precision (SD±383% to 3698%) were too large to allow reliable estimations of the dose of amitriptyline consumed prior to death based on postmortem blood drug concentrations. This work again reinforces that dose calculations from postmortem blood drug concentrations are unreliable.

Polyphenols as anticancer agents: Toxicological concern to healthy cells.

Polyphenols are a group of diverse chemical compounds present in a wide range of plants. Various biological properties such as antiallergic, antiviral, antibacterial, anticarcinogenic, antiinflammatory, antithrombotic, vasodilatory, and hepatoprotective effect of different polyphenols have been reported in the scientific literature. The major classes of polyphenols are flavonoids, stilbenoids, lignans, and polyphenolic acids. Flavonoids are a large class of food constituents comprising flavones, isoflavanones, flavanones, flavonols, catechins, and anthocyanins sub-classes. Even with seemingly broad biological activities, their use is minimal clinically. Among the other concurrent problems such as limited bioavailability, rapid metabolism, untargeted delivery, the toxicity associated with these polyphenols has been a topic of concern lately. These polyphenols have been reported to result in different forms of toxicity that include organ toxicity, genotoxicity, mutagenicity, cytotoxicity, etc. In the present article, we have tried to unravel the toxicological aspect of these polyphenols to healthy cells. Further high-quality studies are needed to establish the clinical efficacy and toxicology concern leading to further exploration of these polyphenols.

Potential Clinical and Laboratory Prognostic Factors for Prediction of Need for ICU admission in Acute Aluminum Phosphide Poisoning

Background: Aluminum phosphide (AlP) is a type of fumigant which became a leading factor for suicidal poisoning in developing countries. In the absence of specific antidote, acute aluminum phosphide poisoning is considered a major public health problem. Determination of prognosis is a major concern for clinical toxicologists. Prognostic factors facilitate appropriate disposition to limited intensive care unit (ICU) beds. Aim: The aim of this study was to determine the impact of clinical and laboratory findings for prediction of need for intensive care unit admission in acute aluminum phosphide poisoning. Patients and methods: This cross sectional study was conducted on 114 acute aluminum phosphide poisoned patients admitted to Tanta University Poison Control Center (TUPCC) from May 2017 to November 2019. For these patients characteristic clinical manifestations, laboratory investigations and outcome were recorded. Results: Acute aluminum phosphide poisoned patients who required ICU admission represented 69.3% of cases and 91.1% of all cases died. A significant difference was recorded between patients who needed and those who didn’t need ICU admission as regard Glasgow Coma Scale (GCS), pulse, random blood sugar, pH, HCO3 and serum potassium. Moreover, respiratory rate, oxygen saturation, systolic blood pressure and serum Na were found to be good predictors for ICU admission need in acute aluminum phosphide poisoned patients. Conclusion: Respiratory rate, oxygen saturation, systolic blood pressure and serum Na can predict need for ICU admission in acute aluminum phosphide poisoned patients.

Consensus Recommendations on the Treatment of Opioid Use Disorder in the Emergency Department

The treatment of opioid use disorder with buprenorphine and methadone reduces morbidity and mortality in patients with opioid use disorder. The initiation of buprenorphine in the emergency department (ED) has been associated with increased rates of outpatient treatment linkage and decreased drug use when compared to patients randomized to receive standard ED referral. As such, the ED has been increasingly recognized as a venue for the identification and initiation of treatment for opioid use disorder, but no formal American College of Emergency Physicians (ACEP) recommendations on the topic have previously been published. The ACEP convened a group of emergency physicians with expertise in clinical research, addiction, toxicology, and administration to review literature and develop consensus recommendations on the treatment of opioid use disorder in the ED. Based on literature review, clinical experience, and expert consensus, the group recommends that emergency physicians offer to initiate opioid use disorder treatment with buprenorphine in appropriate patients and provide direct linkage to ongoing treatment for patients with untreated opioid use disorder. These consensus recommendations include strategies for opioid use disorder treatment initiation and ED program implementation. They were approved by the ACEP board of directors in January2021.

Unintentional paediatric iron poisoning: A retrospective case series.

Iron poisoning is a historically important cause of paediatric morbidity and mortality. In recent decades, public health measures have considerably reduced paediatric iron exposures. We investigated unintentional paediatric iron poisoning in children with the aim of developing an assessment approach specific for this group. This was a retrospective observational study of unintentional iron poisoning in children (<7 years old) referred to either a state-wide poisons information service or a tertiary clinical toxicology unit from 1 January 2015 to 16 February 2020. Patients were identified from prospective databases maintained by both services, and data were extracted from these in addition to the medical record. There were 54 children included in the study (29 [54%] male; median age 2 years (range 8months to 4 years). The median suspected dose of elemental iron ingested was 72 mg/kg (IQR 41-140 mg/kg). Seventeen (31%) children were symptomatic. There were no cases of severe toxicity. Children symptomatic with gastrointestinal toxicity had a median suspected dose ingested of 60 mg/kg (IQR 38-150 mg/kg) that was similar to asymptomatic children (81 mg/kg [IQR 41-143 mg/kg], P= 0.809). The median peak iron concentration was 49 μmol/L (IQR 13.5-67.5μmol/L, range 4-75 μmol/L). Symptomatic children had a significantly higher median peak serum iron concentration of 66 μmol/L (IQR 54-68 μmol/L) compared to 12 μmol/L (IQR 9-15 μmol/L) in asymptomatic children (P< 0.001). Unintentional paediatric iron poisoning is uncommon and largely benign. Suspected dose ingested is a poor predictor of toxicity. Targeting investigations and interventions to symptomatic children should reduce unnecessary assessment and management while still safely managing the exposure.

Can the Intake of a Synthetic Tryptamine be Detected Only by Blood Plasma Analysis? A Clinical Toxicology Case Involving 4-HO-MET.

Tryptamines represent a group of hallucinogenic new psychoactive substances with increasing prevalence. Unfortunately, only limited data concerning their toxicology and bioanalysis are available as tryptamines are not included in routine screening procedures in many laboratories. In order to expand the current knowledge, we report a non-fatal clinical toxicology case involving the synthetic tryptamine 4-HO-MET (4-hydroxy-N-methyl-N-ethyl-tryptamine, 3-{2-[ethyl(methyl)amino]ethyl}-1H-indol-4-ol, metocin or methylcybin). As only blood of the intoxicated patient was available, our systematic blood plasma screening approaches based on gas chromatography-mass spectrometry (GC-MS) and liquid chromatography (LC) coupled to low-resolution linear ion trap mass spectrometry (ITMSn) or high-resolution tandem mass spectrometry (HRMS-MS) were conducted. The ingestion of the synthetic tryptamine 4-HO-MET could be revealed by blood plasma analysis using both LC-based systematic screening approaches. However, 4-HO-MET was not detected by GC-MS. Furthermore, the detection of metabolites, which may be used to confirm an intake of the parent compound 4-HO-MET, was only successful using LC-HRMS-MS most probably due to its increased sensitivity compared to LC-ITMSn. A total of four metabolites were detected in blood, including N-demethyl-, oxo- and hydroxy-4-HO-MET, as well as the N-oxide. Finally, LC-HRMS-MS analysis revealed a plasma concentration of 193 ng/mL for 4-HO-MET using the standard addition method. The presented data may help clinical and forensic toxicologists with the interpretation of future cases involving synthetic tryptamines, especially if only blood samples are available.

Low Temperature Dynamic Chromatography for the Separation of the Interconverting Conformational Enantiomers of the Benzodiazepines Clonazolam, Flubromazolam, Diclazepam and Flurazepam

Benzodiazepines (BZDs) are an important class of psychoactive drugs with hypnotic-sedative, myorelaxant, anxiolytic and anticonvulsant properties due to interaction with the GABAa receptor in the central nervous system of mammals. BZDs are interesting both in clinical and forensic toxicology for their pharmacological characteristics and potential of abuse. The presence of a non-planar diazepine ring generates chiral conformational stereoisomers, even in the absence of stereogenic centers. A conformational enrichment of BZD at the binding sites has been reported in the literature, thus making interesting a stereodynamic screening of a wide range of BZDs. Herein, we report the investigation of three stereolabile 1,4-benzodiazepine included in the class of “designer benzodiazepines” (e.g., diclazepam, a chloro-derivative of diazepam, and two triazolo-benzodiazepines, flubromazolam and clonazolam) and a commercially available BZD known as flurazepam, in order to study the kinetic of the “ring-flip” process that allows two conformational enantiomers to interconvert at high rate at room temperature. A combination of low temperature enantioselective dynamic chromatography on chiral stationary phase and computer simulations of the experimental chromatograms allowed us to measure activation energies of enantiomerization (ΔG‡) lower than 18.5 kcal/mol. The differences between compounds have been correlated to the pattern of substitutions on the 1,4-benzodiazepinic core.

Determination of 19 Psychoactive Substances in Premortem and Postmortem Whole Blood Samples Using Ultra-High-Performance Liquid Chromatography–Tandem Mass Spectrometry

An ever-increasing need exists within the forensic laboratories to develop analytical processes for the qualitative and quantitative determination of a broad spectrum of new psychoactive substances. Phenylethylamine derivatives are among the major classes of psychoactive substances available on the global market and include both amphetamine analogues and synthetic cathinones. In this work, an ultra-high-performance liquid chromatography-positive ion electrospray ionization tandem mass spectrometric method (UHPLC-ESI-MS/MS) has been developed and fully validated for the determination of 19 psychoactive substances, including nine amphetamine-type stimulants and 10 synthetic cathinone derivatives, in premortem and postmortem whole blood. The assay was based on the use of 1 mL premortem or postmortem whole blood, following solid phase extraction prior to the analysis. The separation was achieved on a Poroshell 120 EC-C18 analytical column with a gradient mobile phase of 0.1% formic acid in acetonitrile and 0.1% formic acid in water in 9 min. The dynamic multiple reaction monitoring used in this work allowed for limit of detection (LOD) and lower limit of quantitation (LOQ) values of 0.5 and 2 ng mL−1, respectively, for all analytes both in premortem and postmortem whole blood samples. A quadratic calibration model was used for the 12 quantitative analytes over the concentration range of 20–2000 ng mL−1, and the method was shown to be precise and accurate both in premortem and postmortem whole blood. The method was applied to the analysis of real cases and proved to be a valuable tool in forensic and clinical toxicology.

An Overview on Patient-Centered Clinical Services

Drug-related problems (DRPs) had often been a concern in the system that needed to be detected, avoided, and addressed as soon as possible. The need for a clinical pharmacist becomes even more important. He is the one who can not only share the load but also be an important part of the system by providing required advice. They fill out the patient's pharmacotherapy reporting form and notify the medical team's head off any drug-related issues. General practitioners register severe adverse drug reactions (ADRs) yearly. As a result of all of this, a clinical pharmacist working in and around the healthcare system is expected to advance the pharmacy industry. Its therapy and drugs can improve one's health quality of life by curing, preventing, or diagnosing a disease, sign, or symptom. The sideshows, on the other hand, do much harm. Because of the services they offer, clinical pharmacy has grown in popularity. To determine the overall effect and benefits of the emergency department (ED) clinical pharmacist, a systematic review of clinical practice and patient outcomes will be needed. A clinical pharmacist's anatomy, toxicology, pharmacology, and medicinal chemistry expertise significantly improves a patient's therapy enforcement. It is now important to examine the failure points of healthcare systems as well as the individuals involved.

Ambient ionization mass spectrometry applied to new psychoactive substance analysis.

In the past decade a plethora of drugs with similar effects to controlled psychoactive drugs, like cannabis, amfetamine (amphetamine), or lysergic acid diethylamide, have been synthesized. These drugs can collectively be classified under the term new psychoactive substances (NPS) and are used for recreational purposes. The novelty of the substances, alongside the rapid rate of emergence and structural variability, makes their detection as well as their legal control highly challenging, increasing the demand for rapid and easy-to-use analytical techniques for their detection and identification. Therefore, interest in ambient ionization mass spectrometryapplied to NPS has grown in recent years, which is largely because it is relatively fast and simple to use and has a low operating cost. This review aims to provide a critique of the suitability of current ambient ionization techniques for the analysis of NPS in the forensic and clinical toxicology fields. Consideration is given to analytical performance and ease of implementation, including ionization efficiency, selectivity, sensitivity, quantification, analyte chemistry, molecular coverage, validation, and practicality.

Urine toxicology screening by liquid chromatography time-of-flight mass spectrometry in a quaternary hospital setting

ObjectiveValidation 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. Methods217 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. Results42 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. ConclusionsThe 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.

Hair Testing for Classic Drugs of Abuse to Monitor Cocaine Use Disorder in Patients Following Transcranial Magnetic Stimulation Protocol Treatment.

Simple SummaryHair testing for classic drugs of abuse offers the possibility of longer detection times (for drug substances) when compared to urine analysis. Hair analysis is routinely used to detect drug abuse in forensic cases and clinical toxicology, whereas it is rarely used at addiction clinics to monitor the clinical efficacy of therapeutic interventions. Here, we explore for the first time whether hair analysis might represent a valid tool to track the clinical improvements in a population of patients with cocaine use disorder (CocUD) who underwent a repetitive transcranial magnetic stimulation (rTMS) treatment.In recent years, hair has become an alternative biological specimen for drug testing in the fields of forensic and clinical toxicology. The advantages of hair testing include larger detection windows (months/years), depending on the length of the hair shaft, compared to those of urine/blood (hours to 2–4 days for most drugs). Segmental hair analysis can disclose a month-to-month (considering 1 cm segment cuts) information of drug exposure (single or repeated) and potentially identify patterns of drug use/administration. Repetitive transcranial magnetic stimulation (rTMS) was recently proposed as a valid tool for therapeutic purposes in addictions, including cocaine use disorder (CocUD). Here, we proposed hair testing analyses of classic drugs of abuse in a clinical setting to monitor the clinical changes in treatment-seeker CocUD patients undergoing protocol treatments with rTMS stimulating the left dorsolateral prefrontal cortex (l-DLPFC). We collected hair samples from nine CocUD patients at different stages from the beginning of treatments. Hair sample analyses revealed significant changes in the patterns of cocaine use, according to the negativity of urine screening tests and the clinical reductions of craving. These data, albeit preliminary, suggest that hair testing analysis of classic drugs of abuse could be extended to clinical settings to monitor the clinical efficacy of innovative therapeutic interventions, such as rTMS.

Formation, development and activities of the Department of Clinical Toxicology of the Russian Medical Academy of Continuous Professional Education

The creation of an emergency clinical toxicology service in our country led to the need to train clinical toxicologists and to create a specialized Department for this purpose, which was opened in 1985 at the Central Institute of Advanced Medical Training. The staff of the Department carried out a lot of methodological, educational and scientific work, which allowed to achieve a high level of teaching. Successful activity of the Department was promoted by: work on the clinical basis of a multidisciplinary research medical institution – N.V. Sklifosovsky Research Institute for Emergency Medicine; admission to the Institute a large number of patients with various intoxications ensuring thematic completeness of teaching; the unity of command in the leadership of the Toxicological Department of the N.V. Sklifosovsky Research Institute for Emergency Medicine and the Department of Clinical Toxicology of the Russian Medical Academy of Continuous Professional Education in the person of E.A. Luzhnikov, who used his experience in scientific, practical and teaching activities of the Department; due to the existence of the scientific school of academician E.A. Luzhnikov – the development of new technologies for screening, treatment and rehabilitation of acute poisonings; the use of modern teaching methods, including field cycles and distance learning technologies; close interaction with scientific societies, contributing to a significant expansion of the possibilities of new teaching methods.

Optimization of statistical processing of clinical and laboratory data in acute poisoning

The article describes a specialized software application developed by the authors that summarizes the long-term experience of analyzing clinical and laboratory data in clinical toxicology using Microsoft’s Visual Basic for Applications object-oriented programming tools in Excel. The main purpose of the application is a significant (5-10 times) acceleration of the implementation of the complex of the most commonly used statistical algorithms. The application calculates descriptive sample characteristics, identifies deviations of sample distributions from the normal law by several generally accepted criteria, performs statistical comparison of data matrices by several criteria, and automatically generates a number of tables ready for placement in scientific texts for various purposes in Microsoft Word format. The presentation of the output data makes it easy to verify the results of calculations by comparing them with the output forms of the Statistica application software package. The acceleration of obtaining the final result is achieved: 1 – due to the absence of the need to move data from Excel to the package of applied statistical programs; 2 – as a result of automating the determination of task parameters by means of special color markup; 3 – by combining a limited number of the most commonly used statistical methods into one immutable complex; 4 – as a result of the software implementation of statistical comparison of all possible combinations of data matrices involved in the study for a set of indicators as a single operation that does not require user intervention; 5 – due to the application’s use of syntactic transformations of output data and automatic table formation by filling in ready-made templates with calculation results.

41st International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 25-28 May 2021, Virtual Meeting

41st International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 25-28 May 2021, Virtual Meeting