The adulterated XANAX pill: a fatal intoxication with etizolam and caffeine.

A 49-year old man was found dead at home next to a glass containing a dried, white, crystalline substance and near a bag containing pills with the imprint XANAX, the trade name of alprazolam. A comprehensive screening of material collected during the autopsy revealed the presence of etizolam and caffeine in lethal concentrations (0.77 µg/mL and 190 µg/mL) but no trace of alprazolam. Benzodiazepine analogue etizolam is rarely prescribed in Germany, and as a result there are not many reports about fatal cases. It has anxiolytic, hypnotic, sedative and muscle-relaxant properties and is used for the short-term treatment of anxiety and panic attacks. The purine alkaloid caffeine, conversely, is the most widely used central nervous system stimulant. The following report outlines potentially the first reported case of a lethal combination of the downer etizolam and the upper caffeine in medical literature.

Unsuccessful Suicide Attempt With Tiapride.

To the best of our knowledge, no case has been published in the literature that reports an overdose of tiapride, either alone or in combination with other drugs. We report a self-poisoning case in an 18-year-old girl, with approximately 10 times the usual daily dose (ie, 2.5 g). Although the blood concentration was 20/30-fold higher than usually observed after therapeutic drug intakes (17,300 mcg/L), the patient remained almost asymptomatic.

[Suicidal drug overdose while receiving palliative home care: a case report]. / Suizid durch Intoxikation während einer mobilen palliativen Begleitung eines Patienten mit Bronchuskarzinom.

Suicidal thoughts are a common phenomenon in palliative care which can be seen in around 10% of the patients. There is very little knowledge about attempted and committed suicide. This article is a case report about a patient with lung cancer in a terminal state of illness who ingested drugs in a toxic dose while receiving palliative home care. This article deals with ethical issues in medical treatment and various ways of decision-making.

Double, suicidal intoxication with hydroxycarbamide--a case report.

Hydroxycarbamide (HCB), also known as hydroxyurea, is an urea derivative used mainly as antineoplastic and antisickling agent. We described a 31 yrs. female, with essential thrombocythemia, who was admitted to our clinic because of double suicidal ingestion of hydroxycarbamide. First time it was 7.5 g of HCB with coingestion of 50 mg of diazepam, and several glasses of wine, second time it was 10 g of HCB, with coingestion of 100 mg paroxetine and few glasses of vodka. Both suicidal attempts were triggered by multiple reactive factors. At the time of admissions the patient was conscious, restless, with decreased mood. Transient decrease of total leukocyte count was noted on fourth day of first overdose. The second overdose led to no significant changes in blood count. There were no other abnormalities in biochemical results. According to the best of our knowledge this is the first report of acute suicidal intoxication with hydroxy-carbamide in an adult.

[Comparison of four immunoassay screening devices for detection of benzodiazepine and its metabolites in urine: mainly detection of etizolam, thienodiazepine and its metabolites].

The immunoassay screening of benzodiazepines in urine is one of the most important methods of drug analysis in clinical and forensic laboratories. We experienced an unusual case of poisoning wherein the result of Triage DOA immunoassay screening was negative, although Depas (etizolam) was detected in the blood of the victim who had been suspected to prescribe Depas by gas chromatography-mass spectrometry. Depas has been widely used for the treatment of anxiety in Japan. Three immunoassay screening devices (AccuSign BZO, Monitect-3, and Fastect II) were evaluated for their specificity for etizolam, its 2 major metabolites M-III and M-VI, and other metabolites of benzodiazepines in urine. With AccuSign BZO, etizolam, M-III, and M-VI could be detected at concentrations of 1,000 ng/mL in urine; however, they could not be detected even at concentrations of 25,000 ng/mL with the other kits. In the case of etizolam poisoning, the result of AccuSign BZO was positive; however, Triage DOA, which is mainly used for the detection of drugs in urine at intensive care units (ICUs) or forensic laboratories, showed negative result for benzodiazepines. The concentrations of etizolam and its metabolites in urine were measured by the established high-performance liquid chromatographic method. The concentrations of M-III and M-V were 700 and 1,600 ng/mL, respectively. AccuSign BZO demonstrated higher specificity-than the other screening kits for the detection of etizolam and its metabolites in urine. Therefore, the types of drugs detected would be increased by combining Triage DOA with AccuSign BZO in ICUs or forensic laboratories.

Drug detection in decomposed cadavers confirms testimonial evidence in a case of serial homicides.

Toxicology investigation on human's buried dead bodies is a rare and challenging task in the forensic field. As requested by the Judicial Authority, this work aimed to verify testimonial evidence that emerged during a criminal investigation involving multiple murder cases. The statements indicated an improper medical administration of one or more alleged drugs (propofol, morphine, diazepam, and midazolam) which presumably caused the deaths. Since the supposed crimes took place several years before, the task of the present work was to obtain results to support the charges. The analyses involved 18 biological samples taken from four exhumed bodies, three of which were female and one male, each buried in a different date and mode. Each sample was treated with specific purification and extraction techniques (LLE - SPE) after the addition of the deuterated analogs of the searched analytes (propofol-d17, morphine-d3, diazepam-d5, midazolam-d4) as internal standards. Afterwards, the extracts were subjected to qualitative analysis by gas chromatography-mass spectrometry-Electron Impact (GC/MS - EI), both in full scan and SIM mode. Propofol, morphine, and diazepam were identified in the corpses. It supports testimonials that were administered just before the deaths occurred.

Prolonged and profound therapeutic hypothermia for the treatment of "brain death" after a suicidal intoxication. Challenging conventional wisdoms.

Therapeutic hypothermia has been reported to improve the neurologic outcome of comatose survivors of out-of-hospital cardiac arrest. The use of therapeutic hypothermia in patients who have had an acute ischemic-hypoxic brain injury after a suicidal intoxication has not been previously reported. We present the case of a young woman who presented comatose to our emergency department after attempting suicide by ingesting diazepam and a bottle of antifreeze (ethylene-glycol). Despite aggressive supportive care, the patient progressed to what appeared to be clinical brain death. At this point, the patient was managed with therapeutic hypothermia for 36 hours. The patient awoke within 48 hours of rewarming and made a complete and full neurologic recovery. In conclusion, this case has important implications in the management of patients who have had an acute ischemichypoxic brain injury. Inappropriately labeling such patients as "brain dead" will result in the failure to institute therapeutic hypothermia and other advanced neuroprotective interventions in patients who could be salvaged with a good neurologic outcome.

Alleged breaches of "standards of medical care" in a patient overdose death possibly related to chronic opioid analgesic therapy, application of the controlled substances model guidelines: case report.

OBJECTIVES: The objectives of this medicolegal case report are the following: 1) to present details of a chronic pain patient (CPP) who was placed on chronic opioid analgesic therapy (COAT), and subsequently overdosed on multiple drugs, some of which were not prescribed by his COAT physician; 2) to present both the plaintiff's and defendant's (the COAT prescriber) expert witnesses' opinions as to the allegation that COAT prescribing was the cause of death; and 3) based on these opinions, to develop some recommendations on how pain physicians can utilize the use of Controlled Substances Model Guidelines in order to protect the patient and themselves from such an occurrence. METHODS: This is a case report of a CPP treated by a pain physician. RESULTS: Differences between the plaintiff's and defendant's expert's opinions are explained utilizing the Controlled Substances Model Guidelines. CONCLUSIONS: Some CPPs may withhold information critical to their COAT treatment. Application of the Controlled Substances Model Guidelines and the newer Federation of State Medical Boards' policy on opioid prescribing can be helpful in improving patient care and may be helpful in protecting the physician medicolegally.

Designer benzodiazepines: a report of exposures recorded in the National Poison Data System, 2014-2017.

IMPORTANCE: Exposures to novel psychoactive substances are reported with increasing frequency in both the medical literature and the lay press. While the majority of reports describe synthetic cannabinoids and cathinones, a lesser understood family is the "designer benzodiazepines". The current literature describing human exposures to these compounds is comprised of case reports and small case series. OBJECTIVE: The primary objectives of this study are to describe epidemiologic trends and clinical effects of designer benzodiazepine use. METHODS: Data regarding single agent exposures to designer benzodiazepines between 1 January 2014 and 31 December 2017 was obtained from the National Poison Data System. Substances queried include: adinazolam, clonazolam, cloniprazepam, diclazepam, etizolam, flubromazepam, flubromazolam, meclonazepam, nifoxipam, norflurazepam, and pyrazolam. Data was summarized descriptively. RESULTS: 234 single agent exposures in 40 states were reported during the study period. The annual number of exposures increased each year, from 26 in 2014 to 112 in 2017, amounting to a 330% increase. The most common exposures were etizolam (n = 162) and clonazolam (n = 50). The most common clinical effects were drowsiness/lethargy (65%), and slurred speech (17%). 3% required intubation, 36% of cases required hospital admission, 22% to the intensive care unit. There was 1 death in the study population. CONCLUSIONS: The incidence of exposures to designer benzodiazepines is rising. Clinical effects are generally consistent with a sedative-hypnotic toxidrome. Severe effects, including death, seemed relatively uncommon in the study population.

Simultaneous detection and quantification of amphetamines, diazepam and its metabolites, cocaine and its metabolites, and opiates in hair by LC-ESI-MS-MS using a single extraction method.

A liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous identification and quantification of amphetamines, diazepam and its metabolites, cocaine and its metabolites, and opiates from hair using a single extraction method. As part of the method development, Gemini C18, Synergi Hydro RP, and Zorbax Stablebond-Phenyl LC columns were tested with three different mobile phases. Analyte recovery and limit of detection were evaluated for two different solid-phase extraction methods that used Bond Elut Certify and Clean Screen cartridges. Phosphate buffer (pH 5.0) was chosen as the optimum hair incubation medium because of the high stability of cocaine and 6-monoacetylmorphine using this method and faster sample preparation. The optimized method was fully validated. Linearity was established over the concentration range 0.2-10 ng/mg hair, and the correlation coefficients were all greater than 0.99. Total extraction recoveries were greater than 76%, detection limits were between 0.02 and 0.09 ng/mg, and the intra- and interday imprecisions were generally less than 20% in spiked hair. The intra- and interbatch imprecision of the method for a pooled authentic hair sample ranged from 1.4 to 23.4% relative standard deviation (RSD) and 8.3 to 25.4% RSD, respectively, for representative analytes from the different drug groups. The percent matrix effect ranged from 63.5 to 135.6%, with most analytes demonstrating ion suppression. Sixteen postmortem samples collected from suspected drug-related deaths were analyzed for the 17 drugs of abuse and metabolites included in the method. The method was sufficiently sensitive and specific for the analysis of drugs and metabolites in postmortem hair samples. There is scope for the inclusion of other target drugs and metabolites in the method.

Dual intoxication with diazepam and amphetamine: this drug interaction probably potentiates myocardial ischemia.

Drug-induced myocardial infarction is not a common phenomenon and the underlying mechanism has been related with the coronary artery spasm in the majority of cases. It is mainly related to illicit substances such as cocaine, ecstasy, LSD and amphetamine. According to the findings in the literature, it is most likely that myocardial ischemia due to amphetamine abuse is a result of combined mechanisms which include coronary artery vasospasm, and in lesser extent thrombus formation or direct myocardial toxicity. Diazepam is also usually found as a substance of abuse. Recent findings indicate that diazepam exerts an inhibitory activity on different isoforms of the enzyme cyclic nucleotide phosphodiesterase, which can be found in the heart muscle and also show that diazepam potentate the positive inotropic effect of both noradrenaline and adrenaline, which subsequently leads to increase in myocardial contractility. We propose that dual intoxication with amphetamine and benzodiazepine potentate their effects on cardiac tissue and coronary arteries which results in larger myocardial injury.

Accidental etizolam ingestion in a child.

Etizolam (ETZ) is an antidepressive thienodiazepine drug that is used worldwide. The most frequent adverse effects in adults are drowsiness and muscle weakness, and this can rarely cause paradoxical excitation; however, no information exists on intoxication in children. Furthermore, evidence bearing on its safety in children is not available. We present a case of a child who accidentally took a single dose of ETZ, approximately the same as a therapeutic dose for adults, and who showed paradoxical excitation and muscle weakness. The case presented here suggests that pediatricians and emergency physicians should be aware of the possible adverse effects in children and therapeutic approaches in intoxication of ETZ and the necessity of further investigations on a specific therapeutic guideline for overdose management especially in children.

Analysis of MT-45, a Novel Synthetic Opioid, in Human Whole Blood by LC-MS-MS and its Identification in a Drug-Related Death.

MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine) is just one of the many novel psychoactive substances (NPS) to have reached the recreational drug market in the twenty-first century; it is however, one of the first designer opioids to achieve some degree of popularity, in a market currently dominated by synthetic cannabinoids and designer stimulants. A single fatality involving MT-45 and etizolam is described. A method for the quantitation of MT-45 in whole blood using liquid chromatography-tandem mass spectrometry was developed and validated. The linear range was determined to be 1.0-100 ng/mL with a detection limit of 1.0 ng/mL, and the method met the requirements for acceptable linearity, precision and accuracy. After analyzing the sample on dilution and by standard addition, the concentration of MT-45 in the decedent's blood was determined to be 520 ng/mL, consistent with other concentrations of MT-45 reported in drug-related fatalities. Etizolam was present at a concentration of 35 ng/mL. This case illustrates the importance of considering non-traditional drugs in unexplained apparent drug-related deaths.

Benzodiazepine poisoning in elderly.

BACKGROUND/AIM: Benzodiazepines are among the most frequently ingested drugs in self-poisonings. Elderly may be at greater risk compared with younger individuals due to impaired metabolism and increased sensitivity to benzodiazepines. The aim of this study was to assess toxicity of benzodiazepines in elderly attempted suicide. METHODS: A retrospective study of consecutive presentations to hospital after self-poisoning with benzodiazepines was done. Collected data consisted of patient's characteristics (age, gender), benzodiazepine ingested with its blood concentrations at admission, clinical findings including vital signs and Glasgow coma score, routine blood chemistry, complications of poisoning, details of management, length of hospital stay and outcome. According the age, patients are classified as young (15-40-year old), middle aged (41-65-year old) and elderly (older than 65). RESULTS: During a 2-year observational period 387 patients were admitted because of pure benzodiazepine poisoning. The most frequently ingested drug was bromazepam, the second was diazepam. The incidence of coma was significantly higher, and the length of hospital stay significantly longer in elderly. Respiratory failure and aspiration pneumonia occurred more frequently in old age. Also, flumazenil was more frequently required in the group of elderly patients. CONCLUSION: Massive benzodiazepines overdose in elderly may be associated with a significant morbidity, including deep coma with aspiration pneumonia, respiratory failure, and even death. Flumazenil is indicated more often to reduce CNS depression and prevent complications of prolonged unconsciousness, but supportive treatment and proper airway management of comatose patients is the mainstay of the treatment of acute benzodiazepine poisoning.

Benzodiazepine antagonist Ro 15-1788 in self-poisoning. Diagnostic and therapeutic use.

Thirteen patients with benzodiazepine overdosage received the specific benzodiazepine antagonist Ro 15-1788. Intravenous administration of 1.5 to 10 mg reversed the central nervous system depression induced by different benzodiazepine compounds within one to two minutes of injection. These case reports indicate that Ro 15-1788 may be an effective tool in the primary management of self-poisoning.