Mixed Drug Toxicity Research Articles

A study on improving drug–drug interactions prediction using convolutional neural networks

Appropriate studies on drug–drug interactions (DDIs) can evade possible adverse side effects due to the ingestion of multiple drugs. This paper proposes a novel framework called Similarity Network Fusion and Hybrid Convolutional Neural Network (SNF–HCNN) to predict the DDIs better. The proposed framework leverages data from DrugBank, PubChem, and SIDER. Seven critical drug features are extracted: Target, Transporter, Enzymes, Chemical substructure, Carrier, Offside, and Side effects. The Jaccard Similarity measure evaluates the similarity of drug features to construct a comprehensive similarity matrix that effectively captures potential drug relationships and patterns. The similarity selection process identifies the most relevant features, reduces redundancy, and enhances identifying potential drug interactions. Integrating Similarity Network Fusion (SNF) with the selected similarity matrix ensures a comprehensive representation of drug features and leads to superior accuracy compared to conventional methods. Our experimental results demonstrate the effectiveness of the proposed hybrid convolutional neural network (HCNN) architectures, such as CNN+LR (CNN+Logistic Regression), CNN+RF (CNN+Random Forest), and CNN+SVM (CNN+Support Vector Machine), showing impressive accuracies of 95.19%, 94.45%, and 93.65%, respectively. Moreover, CNN+LR outperforms other approaches regarding precision, sensitivity, F1-score, and AUC score, which implicate better outcomes for ensuring medication safety aspects in clinical settings in the future.

Fentanyl-Related Deaths in Ontario, Canada: Toxicological Findings and Circumstances of Death in 4395 Cases (2020-2022).

Over the last 20 years there has been a significant increase in fentanyl related deaths in Ontario, Canada. This report examines toxicological findings in a series of death investigations in which fentanyl was quantitated to identify the prevalence, trends and demographic data associated with fentanyl in Ontario, Canada, and to highlight the changes in these trends since fentanyl began appearing in casework in Ontario in the early 2000s. A retrospective study of all cases in which fentanyl was quantitated in blood, using liquid chromatography-tandem mass spectrometry, was conducted for the time period between January 1, 2020, and December 31, 2022. A total of 4395 cases were included, 77% of the decedents were male and 23% were female with ages ranging from 0 to 95. The most frequently classified cause of death was mixed drug toxicity (69%) followed by fentanyl intoxication at 19%. Less than 10% of cases where fentanyl was quantitated were classified as non-drug related deaths. Fentanyl concentrations in all cases ranged from 1.3 to > 2000 ng/mL. Other drugs were frequently detected with fentanyl. In mixed drug toxicity cases, stimulants were the most frequently encountered class of drugs: cocaine was identified in 51.8% and methamphetamine was observed in 43.0% of cases, respectively. Detailed reports for select cases were included to provide additional insight into the different case types and to show the difficulty in interpreting blood concentrations without additional detailed case histories. This study provides valuable information for the scientific and medical community regarding the continued use of fentanyl and how patterns of fentanyl use have evolved since it began to appear in forensic casework.

Intoxication cases in the Emergency Department at a Norwegian University Hospital 2019-20.

Acute intoxication is a common chief complaint in emergency medicine, but there is a lack of up-to-date studies from the emergency departments in Norway on the incidence and prevalence of various toxic substances. The aim of this study was to survey acute intoxications at the emergency department of St Olav's Hospital, Trondheim. In this review of patient records, we used data from the emergency department at St Olav's Hospital in Trondheim in the period 1 January 2019-31 December 2020. All cases with 'acute intoxication' as the reason for the emergency department visit were included. In a patient population of 836 unique patients, there were a total of 1423 intoxications, of which 168/836 patients (20.0%) had more than one intoxication episode in the period. The median age was 31 years (interquartile range 22-47), and 395/836 (47.2%) of the patients were women. Combined drug intoxication constituted 666/1423 (46.8%) of the cases, and the most frequent intoxications were from ethanol: 802/1423 (56.4%); benzodiazepines 314/1423 (24.0%); and opioids 243/1423 (17.1%). Altogether, 1146/1423 (80.5%) incidents resulted in hospital admission. There were no deaths during their hospital stay. Emergency departments must be prepared to manage patients who have taken various poisoning agents. The antidotes must be available, and it must be possible to perform interventions.

Difficulties associated with the interpretation of postmortem toxicology.

While postmortem (PM) toxicology results provide valuable information towards ascertaining both the cause and manner of death in coronial cases, there are also significant difficulties associated with the interpretation of PM drug levels. Such difficulties are influenced by several pharmacokinetic and pharmacodynamic factors including PM redistribution, diffusion, site-to-site variability in drug levels, different drug properties and metabolism, bacterial activity, genetic polymorphisms, tolerance, resuscitation efforts, underlying conditions, and the toxicity profile of cases (i.e. single- or mixed-drug toxicity). A large body of research has been dedicated for better understanding and even quantifying the influence of these factors on PM drug levels. For example, several investigative matrices have been developed as potential indicators of PM redistribution, but they have limited practical value. Reference tables of clinically relevant therapeutic, toxic, and potentially fatal drug concentrations have also been compiled, but these unfortunately do not provide reliable reference values for PM toxicology. More recent research has focused on developing databases of peripheral PM drug levels for a variety of case-types to increase transferability to real-life cases and improve interpretations. Changes to drug levels after death are inevitable and unavoidable. As such, guidelines and practices will continue to evolve as we further our understanding of such phenomena.

Evaluation of Poisoning Cases Presenting to the Pediatric Emergency Department

Aim: Poisoning in the pediatric population often results in numerous visits to emergency services. The purpose of our study is to conduct a retrospective analysis of the demographic and epidemiological characteristics, clinical progression, laboratory findings, and prognosis of patients who presented to the pediatric emergency outpatient clinic due to poisoning. Material and Methods: The clinical and laboratory features of patients who presented to our hospital's emergency department due to poisoning between March 2019 and March 2020 were retrospectively examined. Statistical analyses were carried out using IBM SPSS Statistics for Windows 22.0 software. Results: The mean age of the 624 cases who presented to the pediatric emergency department due to poisoning over a one-year period was 7.9±6.2 (1.0-18.0) years, with 49.8% of them being female (n=311). It was found that the cause of poisoning in 14.6% (n=91) of the cases was a suicide attempt. Drug intoxications accounted for 54.3% (n=339) of all cases, of which 77% (n=261) involved a single drug and 23% (n=78) involved multiple drug consumption. 79.3% (n=495) of the patients, who had an admission time to hospital of 1.3±0.6 (1.0-4.0) hours, were asymptomatic upon arrival, and 71.5% (n=446) were admitted for hospitalization. 28.5% (n=178) were treated on an outpatient basis. 35.3% (n=157) of the hospitalized patients required monitoring in the intensive care unit. The mean hospital stay was determined to be 2.4±1.1 (1.0-11.0) days. Conclusion: Drugs, especially analgesics, are the most frequent cause of poisoning in childhood. The most appropriate strategy for poisoning will be to enact preventive measures, increase societal awareness, and ensure that diagnosis and treatment are swiftly and effectively implemented.

Increased incidence of mixed drug toxicity deaths involving tapentadol - A forensic study.

Tapentadol is a relatively new synthetic opioid analgesic prescribed for the management of moderate to severe pain. While tapentadol has been shown to be more effective than traditional opioid analgesics, it still carries the risk of addiction, abuse, and misuse. In Australia, tapentadol has become one of the top five most commonly prescribed opioid drugs, with prescriptions increasing by approximately 150,000 each year since it first became available. The rapid increase in tapentadol prescriptions has occurred in parallel to an increasing number of post-mortem tapentadol detections in South Australia (SA). While the number of deaths in SA related to tapentadol use was low in the current study, findings suggest that an increasing trend of deaths involving tapentadol will continue in parallel to a rapidly increasing number of prescriptions, mirroring trends associated with traditional opioids in SA. As a comparatively new opioid analgesic, monitoring future trends will be important to determine if additional prescribing education, intervention, or restrictions are required.

Adverse Drug Reaction Reporting in Geriatric Oncology in India: An Understudied Topic that Needs Attention

AbstractIn the elderly, polypharmacy is a common problem, and drug interactions and adverse drug reactions (ADR) have been linked to considerable harm in several population-based studies. However, when compared with other medical disciplines, studies with elderly cancer patients are lacking in oncology and India in particular. Additionally, intake of multiple drugs and, at times, potentially inappropriate medications (PIMs) are also common in older cancer patients. Physiologically, the body's metabolic functions are reduced in the elderly, resulting in altered medication pharmacokinetics and pharmacodynamic characteristics. There is also a high risk of aging-related disorders, and an increase in pharmaceutical use. Because cancer can affect the physiological milieu, patients are more likely to experience negative drug responses, drug–disease interactions, and drug–drug interactions, thereby making the elderly more vulnerable to the ill effects. Considering this, there is a need for greater knowledge and measures that try to lessen exposure to and the risks connected to drug combinations that might be detrimental. As the geriatric population grows, the need to address medical issues among aging cancer patients becomes more pressing, particularly in India. As far as the authors are aware, there is no review that addresses the drug–drug interactions and adverse drug responses brought on by polypharmacy in older cancer patients. It is expected that this endeavor will help the fraternity and the patients, and will serve as a valuable academic material for the health care students.

Human Digital Twin for Personalized Elderly Type 2 Diabetes Management.

Managing Elderly type 2 diabetes (E-T2D) is challenging due to geriatric conditions (e.g., co-morbidity, multiple drug intake, etc.), and personalization becomes paramount for precision medicine. This paper presents a human digital twin (HDT) framework to manage E-T2D that exploits various patient-specific data and builds a suite of models exploiting the data for prediction and management to personalize diabetes treatment in E-T2D patients. These models include mathematical and deep-learning ones that capture different patient aspects. Consequently, the HDT virtualizes the patient from different viewpoints using an HDT that mimics the patient and has interfaces to update the virtual models simultaneously from measurements. Using these models the HDT obtains deeper insights about the patient. Further, an adaptive patient model fusing this information and a learning-based model predictive control (LB-MPC) algorithm are proposed. The geriatric conditions are captured as model parameters and constraints while solving the LB-MPC to personalize the insulin infusion for E-T2D management. The HDT is deployed on and illustrated with 15 patients using clinical trials and simulations. Our results show that HDT helps improve the time-in-range from 3-75% to 86-97% and reduces insulin infusion by 14-29%.

Deliberate Self-Poisoning: Real-Time Characterization of Suicidal Habits and Toxidromes in the Food and Drug Administration Adverse Event Reporting System.

Deliberate self-poisoning (DSP) using drugs is the preferred method of suicide at a global level. Its investigation is hampered by limited sample sizes and data reliability. We investigate the role of the US FDA Adverse Event Reporting System (FAERS), a consolidated pharmacovigilance database, in outlining DSP habits and toxidromes. We retrieved cases of 'intentional overdose' and 'poisoning deliberate' from the FAERS (January 2004-December 2021). Using descriptive and disproportionality analyses, we estimated temporal trends, potential risk factors, toxidromes, case-fatality rates and lethal doses (LDs) for the most frequently reported drugs. We retrieved 42,103 DSP cases (17% fatal). Most cases were submitted in winter. Reports of DSP involved younger people, psychiatric conditions, and alcohol use, compared with non-DSP, and fatality was higher in men and older patients. Suspected drugs were mainly antidepressants, analgesics, and antipsychotics. Multiple drug intake was recorded in more than 50% of the reports, especially analgesics, psychotropics, and cardiovascular agents. The most frequently reported drugs were paracetamol, promethazine, amlodipine, quetiapine, and metformin. We estimated LD25 for paracetamol (150g). Worldwide coverage of the FAERS complements existing knowledge about DSP and may drive tailored prevention measures to timely address the DSP phenomenon and prevent intentional suicides.

Clinical features of children with drug poisoning in a single emergency department in Goyang, Korea

Purpose: Pediatric drug poisoning is a frequent reason for emergency department (ED) visits. Considering the increasing number of mental illnesses in adolescents, it has become a serious public health problem. We aimed to investigate the drug poisoning in the ED.Methods: We retrospectively analyzed children aged 1-17 years with diagnostic codes related to drug poisoning who visited the ED from January 1, 2010 through October 7, 2022. Exclusion criteria were non-pharmaceutical poisoning, insufficient data, and poisoning via respiratory, dermal or ocular route. Baseline characteristics, clinical manifestations, and outcomes of drug poisoning were analyzed in the study population, according to intention of poisoning and drug category.Results: A total of 197 cases of 161 children were analyzed. Compared with non-intentional poisoning, intentional poisoning was associated a higher age, a longer time from ingestion to visit, and higher proportions of girls, antipyretics/analgesics or psychotropic drugs, symptoms related to the gastrointestinal, neurologic or cardiopulmonary systems (P = 0.034), psychiatric comorbidity, multiple drug ingestion, suicide attempt, decontamination (P = 0.017), the use of antidote, history of drug poisoning, and hospitalization (P = 0.004; all other Ps < 0.001). Acetaminophen, a representative of antipyretics/analgesics, was associated with a longer time from ingestion to visit and higher proportions of girls (P = 0.004), the presence of initial gastrointestinal symptoms, suicide attempt (P = 0.001), the use of antidote, and hospitalization (all other Ps < 0.001). Psychotropic drug was associated with higher proportions of psychiatric comorbidity (P < 0.001) and multiple drug ingestion (P = 0.012).Conclusion: This study will enable pediatricians or emergency physicians to obtain an overview of the management of drug poisoning in EDs.

Evaluation of the demographic, etiological & the costs of drug intoxication

Cases of intoxication are among the common medical emergencies. Cases of suicidal drug intoxication are more common among young people. Based on this information, our study aimed to identify the demographic and etiological characteristics of cases of drug intoxication and their costs to the social security institution. The files of patients diagnosed with drug intoxication in the adult emergency department of Kahramanmaraş Sutcu Imam University Medical Faculty Hospital between 01.01.2022 and 31.12.2022 were reviewed retrospectively from the automation system. In our study, the data of 110 patients admitted to the emergency department with a clinical picture of drug-related intoxication were evaluated. 75.5% of the patients were female and 40% of them were in the 18-24 age group. It was determined that 92.7% of the patients took the drug that caused intoxication for suicidal purposes and that psychiatric agents constituted a significant part of the drugs taken. Treatment costs increased significantly in cases of suicidal drug intake and multiple drug intake. The length of hospital stay and the cost of treatment increased as the time between the time of drug intake and the hospital arrival time increased. Most of the drug-related intoxications occurred due to suicidal intake. Most of the drugs used for this purpose were analgesics and psychiatric drugs. Emergency departments are the first places where patients with drug intoxication are evaluated, and all physicians working in the emergency department should know the approach to intoxication very well.

Synthesis of Alginate/Hydroxyapatite Beads for Acetaminophen Delivery

Conventional drug delivery systems usually involve the intake of multiple drugs, which could amplify the risk of overdosing. Acetaminophen is a widely used pain relief substance that is prone to accidental overdosing. Hence, a controlled drug delivery system is needed to ensure its efficacy. A nanocomposite hydroxyapatite/alginate system that was used as a drug carrier for acetaminophen was synthesized through the sol-gel method, and the mechanism underlying its controlled drug delivery was investigated. Spherical nanocomposite bead samples were synthesized by incorporating 5 wt%, 10 wt%, and 15 wt% hydroxyapatite into mixtures containing alginate. The mixtures were then dropped into calcium chloride solution. The phase purity of the hydroxyapatite sample was confirmed through X-ray diffraction, and the functional groups that confirmed the presence of alginate and hydroxyapatite in the nanocomposite samples were analyzed by using Fourier transform infrared spectroscopy. The release of acetaminophen can be controlled for 48 h, and the Korsmeyer–Peppas kinetics model showed the best correlation for all samples. The kinetics of Al/HAp5, Al/HAp10, and Al/HAp15 were governed by quasi-Fickian diffusion with the n values of 0.199, 0.238, and 0.225, respectively. The composite beads show potential for application as a controlled drug delivery vehicle.

Detection of novel benzodiazepines in post-mortem cases

The global prevalence of novel benzodiazepines (BZDs) has increased significantly in recent years with the predominant BZDs constantly changing to evade bans pertaining to specific chemical structures. As of 2020 the European Union Early Warning System (EWS) was monitoring 30 novel BZDs, 16 of which have been reported since 2016. Evidence of novel BZD-associated harms is growing and there is concern regarding their prevalence in drug-related deaths. We therefore analysed deaths in England, Wales, and Northern Ireland where novel BZDs, i.e., those that are not available on prescription via the National Health Service (NHS) in the United Kingdom, were detected at post-mortem in order to determine the circumstances surrounding novel BZD-associated fatalities. The National Programme on Substance Abuse Deaths (NPSAD) receives voluntary reports on drug-related deaths from coroners across England, Wales, and Northern Ireland that covers approximately 80% of all coronial jurisdictions. Deaths that occurred between 1999-2020 and were reported to NPSAD by the 1st of November 2021 where a novel BZD was detected at post-mortem were extracted for analysis. Qualifying cases contained toxicological evidence of novel BZDs and/or their metabolites in post-mortem tissue(s). Analysis and statistical tests were performed using the IBM® SPSS software (Version 26). 971 deaths were extracted from NPSAD where a novel BZD was detected at post-mortem, with the first post-mortem detection occurring in 1999 with flunitrazepam. A sharp increase in deaths has been reported since 2016 and a total of 16 different novel BZDs detected in submitted toxicology reports. Five of these novel BZDs were detected for the first time in 2019 and 2020 (flualprazolam, delorazepam, flubroalprazolam, cinolazepam, meclonazepam), but nevertheless represent 20% of total novel BZD detections ( n = 211/1,064 [note: in some cases multiple novel BZDs were detected]). The most commonly detected novel BZDs were alprazolam and phenazepam until 2018, after which etizolam, flubromazolam and flualprazolam detections prevail. The cause of death in 95% of cases ( n = 926/971) was due to drug toxicity in which novel BZDs were directly implicated in causing death in 34% ( n = 319/926). Polydrug use was evident in 99% of cases ( n = 964/971) and the majority involved the co-administration of at least one additional central nervous system (CNS) depressant (98%, n = 943/964), namely opioids (84%, n = 812/964). Most deaths were deemed to be accidental in nature (92%, n = 894/971), with small proportions due to suicide (4%, n = 42/971), natural causes (1%, n = 12/971), and those where intent could not be determined (2%, n = 23/971). Decedents were mainly male (83% of cases, n = 801/971), had a known history of illicit substance use (71%, n = 687/971) and lived in the most deprived areas of the country (deciles 1-3, 59% of cases; n = 541/971). The results of this study document a startling increase in novel BZD detections in post-mortem toxicology, with a shift in the predominant novel BZDs over time. As novel BZDs are sold on the Internet as ‘research chemicals’ or the illicit market at a low cost, there is greater access and less oversight which can lead to dosing errors and unintended adverse effects. The concomitant use with other CNS depressants furthers the likelihood of a fatal outcome through increased sedation and respiratory depression, as shown here with the majority of fatalities resulting from mixed drug toxicity. To our knowledge this is the largest dataset on novel BZD-related fatalities to date. Reporting of novel BZD deaths has increased considerably in England, Wales, and Northern Ireland with specific concerns relating to polydrug use. The wide availability of novel BZDs combined with the lack of complete understanding regarding their pharmacology is likely contributing to the exponential rise in novel BZD-associated fatalities.

Control Poly-Pharmacy: Elderly Patients’ Practices

Background: Poly-pharmacy is an area of concern for the elderly. Poly-pharmacy was initially coined to refer to specific problems linked to multiple drug intake and excessive drug usage. Aim of the study: The study aims to assess practices used by old-age patients to control Poly-pharmacy. Design: Descriptive cross-sectional study design was used to answer the research questions. Subjects & Setting: sample size was 114 elderly patients from elderly patients visiting outpatient clinics monthly. Tools: A checklist to assess poly pharmacies’ practices. Results: the majority of the study sample wasn’t reading the labels of the medications nor adhering to the immunization system of the old age (79.8% and 78%, respectively). The highest satisfactory level (66.6%) of practice was for the university education, followed by the urban area residents (60%), and finally, in the third level were the secondary level of education 59.1%. Conclusion: The prevalence of polypharmacy and its consequences among the elderly is significantly affected by the level of education. University education was the highest satisfactory adherence to the alternative practices that control poly-pharmacy, followed by secondary education, then primary then illiterate. Recommended: Designing an educational program for the elderly to increase their awareness and knowledge about the phenomenon of drug abuse and its consequences.

A case of fatal multidrug intoxication involving flualprazolam: distribution in body fluids and solid tissues

PurposeDesigner benzodiazepines (DBZDs) increasingly emerged on the novel psychoactive substance (NPS) market in the last few years. They are usually sold as readily available alternatives to prescription benzodiazepines (BZDs) or added to counterfeit medicines. BZDs are generally considered relatively safe drugs due to the low risk of serious acute adverse effects in mono-intoxication, though e.g., alprazolam seems to display an elevated risk of respiratory depression. Here we report on a fatal intoxication involving the novel DBZD flualprazolam.MethodsA complete postmortem examination was performed. General unknown screenings and analysis of drugs of abuse were performed on postmortem samples by immunoassay, gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry. The standard addition method was employed to quantify flualprazolam in postmortem blood and tissues. Finally, a toxicological significance score (TSS) was assigned.ResultsFlualprazolam was detected in heart serum (25.4 ng/mL) and peripheral blood (21.9 ng/mL) as well as in urine, stomach contents, brain, liver and kidney (65.2–323 ng/g). The cause of death was deemed as central nervous system (CNS) and respiratory depression with agonal aspiration of stomach contents, in the setting of a multiple drug intake. Given the concentration levels of the co-consumed CNS depressants, the contribution of flualprazolam to the death was considered likely (TSS of 3).ConclusionsOur results support that highly potent DBZDs like flualprazolam carry an elevated risk for unintended toxicity, especially in association with other CNS depressants. A multidisciplinary evaluation of fatalities remains mandatory, especially when pharmacological/toxicological data on intoxicating compounds are lacking. To our knowledge this is the first report of flualprazolam concentrations in solid tissues in human.

Causes, Nature and Toxicology of Fentanyl-Analogues Associated Fatalities: A Systematic Review of Case Reports and Case Series.

ObjectiveMortalities due to fentanyl derivatives are on the rise with novel fentanyl analogues and still emerging on the global illicit drug market. They are highly potent and very fatal in low doses, yet there has been a lack of systematic research surrounding this subject. This review aims to assess the causes, nature, and toxicology of fatalities associated with fentanyl analogues.MethodsFive databases: Scopus, Embase, Medline, PubMed and Google Scholar were searched from inception to October 2020 to identify case studies and case series reporting fentanyl analogue-related fatalities. Two independent reviewers screened and selected the articles followed by the data extraction from each article, which included demography, route of administration, causes and nature of death, and the fentanyl analogue implicated. All articles were then subject to quality assessment tools developed by the Joanna Briggs Institute (JBI). A narrative synthesis was undertaken.ResultsThe initial data search yielded 834 articles, only 14 of which met the inclusion criteria – this included nine case reports and five case series. Of the 1079 fentanyl-analogue related deaths reported, the majority of them occurred in the US (n=1044, 96.8%). The majority of fatalities were male (n=766, 71%), white (n=884, 87%) and in the age ranges 25–34 and 35–44 years (30.5% and 29.6%, respectively). The most common route of administration was intravenous (n=319, 66%) and the manner of death was almost exclusively accidental (99.7%). The predominant cause of death was fentanyl-analogue toxicity (n=292, 85.4%) and involved mixed drug toxicity (n=47, 13.7%). The mean post-mortem fentanyl analogue concentration was 31.6 ng/mL.ConclusionMost fatalities were reported in the US involving young white males. Overdose through intravenous administration and by mixed drug toxicities with other opioids were the major causes of death. Deaths reported in peer-reviewed literature were relatively less than those reported by real-world data.

Strategic Decision-Making by a Forensic Toxicology Laboratory in Response to an Emerging NPS: Detection, Quantitation and Interpretation of Carfentanil in Death Investigations in Ontario, Canada, July 2017 to June 2018.

The proliferation of novel psychoactive substances (NPS) and the current opioid epidemic creates challenges for a toxicology laboratory. Methods capable of detecting and quantitating emerging compounds must be established despite limited information on toxicologically relevant concentrations. This paper will (i) describe how a publicly funded forensic laboratory reacted to the emergence of carfentanil as a public safety concern and (ii) contribute to the existing forensic literature by presenting a series of deaths involving carfentanil between July 2017 and June 2018. The Centre of Forensic Sciences is the primary provider of forensic toxicology testing in medicolegal death investigations in the province of Ontario. When carfentanil was first identified in the illicit drug supply, routine screening methods used by this laboratory were not sufficiently sensitive to detect the drug at concentrations expected in blood samples. Previously validated, multi-target liquid chromatography-tandem mass spectrometry (LC-MS-MS) quantitative methods already in use by the laboratory did show improved detectability for carfentanil. Thus, an existing LC-MS-MS method was adapted to include carfentanil, achieving improved sensitivity while also providing quantitation in suspected drug-related deaths. This approach had the added benefit that the LC-MS-MS method selected for modification was used in all death investigations requiring toxicology analysis in Ontario, thereby providing an opportunity for surveillance. Using this method, 4,953 cases were analyzed with carfentanil detected at a concentration greater than the limit of detection (0.05 ng/mL) in 160 decedents. Postmortem blood carfentanil concentrations ranged from less than 0.1 to 9.2 ng/mL. Of the 160 carfentanil-positive cases, 156 were classified as either mixed drug toxicity or carfentanil overdose. The approach described enabled this laboratory to efficiently implement a quantitative test for carfentanil in all death investigations, providing a useful template for modifying existing methods when a new psychoactive substance becomes available in the population.

Drug-induced hypersomnia

Daytime somnolence may be a symptom of different somatic, neurological and psychiatric diseases and develop due to abuse and/or discontinuation of various medications. Drug- induced hypersomnia (DIH) is defined as hypersomnolence caused by the intake of multiple drugs. DIH is one of the most frequently reported effects and/or side effects of drugs. DIH prevalence varies widely and can be as high as 75% in patients receiving specific medications. DIH risk factors include elderly and senile age, impaired drug metabolism, serum drug concentration, method and frequency of drug administration, single and daily doses of drugs, etc., as in many other drug- induced diseases and syndromes. DIH can occur both due to sedative agents administration and withdrawal of psychostimulants and other activating psychotropic medications. Most often, the development of DIH is associated with the use of levodopa-carbidopa, antipsychotics, antidepressants. The pathogenesis of DIH is complex and multifactorial and is associated with the mechanism of action of individual drugs and the presence of concomitant diseases. The article discusses the risk assessment of DIH development due to various medications, diagnosis and management tactics of patients with DIH.

A Case Series of Etizolam in Opioid-Related Deaths.

Etizolam is a novel psychoactive substance and novel benzodiazepine of the thienotriazolodiazepine class, which has recently seen an increasing trend in use worldwide. We report a case series of 10 decedents with etizolam and opioids in their systems. Death investigation, expanded toxicology and medical investigation information were included for contextualization of etizolam in death. Etizolam was detected and confirmed within peripheral and cardiac blood, urine, vitreous humor and, in one case, gastric fluid, by liquid chromatography-tandem mass spectrometry and liquid chromatography-quadrupole time of flight mass spectrometry methodologies. Death investigation indicated nonmedical use of most drugs. Medical investigation commonly noted pulmonary edema, cardiomegaly and cerebral swelling. The majority of the decedents appeared to be unaware of the presence of etizolam and succumbed to the mixed drug toxicity of their routine depressant and narcotic analgesic drug of abuse in combination with etizolam. Etizolam use continues to be observed and poses as a potentially lethal contribution to multiple drug toxicity, especially in the age of the opioid crisis. Assessment of analytes like etizolam requires up-to-date methodologies and vigilance in testing to better characterize the toxicology and interpret the contribution to death.

Fatal poisoning case involving drug interaction due to the inhibition of cytochrome P450

Introduction. Cytochrome P450 (CYP) enzymes are responsible for the metabolism of various drugs and chemicals. The forensic pathologist should consider not only pharmacodynamic interactions by multiple drugs but also the pharmacokinetic drug interactions of each drug in the case of multiple drug ingestion. Case report. A female in her forties, receiving therapy for alcohol dependence, was found dead in her house. The medicolegal autopsy revealed no findings suggestive of natural cause of death. Quantitative toxicological analysis showed that levomepromazine, promethazine, dextromethorphan, estazolam, clomipramine, risperidone, and flunitrazepam concentrations in femoral blood were 0.750 ?g/mL, 0.701 ?g/mL, 0.332 ?g/mL, 0.390 ?g/mL, 0.216 ?g/mL, 0.031 ?g/mL, and 0.002 ?g/mL, respectively, along with a blood ethanol level of 377 mg/dL. Conclusion. We concluded that the cause of death was the interaction between ethanol and multiple psychotropic drugs. Pharmacokinetic drug interactions due to the CYPs inhibition should be considered in the evaluation of toxicity in poisoning cases involving multiple drugs.