Isotonitazene: Fatal intoxication in three cases involving this unreported novel psychoactive substance in Switzerland.

The paper describes the first three deaths reported in Europe involved in isotonitazene consumption, a potent benzimidazole derivate opioid consumed in the recreational drug scene. Isotonitazene powder and purity determination was performed on the sample collected in the first death scene by NMR, HRMS, GC-FTIR, ATR-FTIR and GC-MS. Isotonitazene purity was determined by GC-MS analysis and proton NMR, and was defined to be above 95 % and 98 %, respectively. Quantification of isotonitazene in biological samples was performed using a targeted analysis based on SPE extraction and ultra-high performance liquid chromatography tandem mass spectrometry. The isotonitazene median concentration in femoral whole blood was 1.20ng/mL. Isotonitazene concentration in hair was similar or even lower compared to that seen in fentanyl abusers. Isotonitazene distribution in tissues converges in the brain, lungs and heart, respectively. Surprisingly, isotonitazene concentration in liver is the lowest measured for all tissues and fluids analyzed. Based on circumstantial evidence, autopsy findings and the results of the toxicological analysis, the medical examiner concluded that the cause of all three deaths was an acute intoxication with isotonitazene. Since isotonitazene toxic concentration levels are very low, the consumption of this new psychoactive drug is a real hazard for human health.

Respiratory Failure Leading to Intubation in the Setting of Flibanserin Ingestion in a Toddler.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.

Dabigatran overdose: case report of laboratory coagulation parameters and hemodialysis of an 85-year-old man.

Dabigatran is an oral direct inhibitor indicated for stroke prevention in patients with atrial fibrillation. Unlike warfarin, dabigatran's observed therapeutic window and minimal drug-to-drug interaction suggest that laboratory test and dose adjustments are not necessary; nevertheless, circumstances of excessive anticoagulation, decreased kidney function, and instances of significant bleeding and thrombosis require laboratory assessment. In order to gather experience in the management of global [activated partial thromboplastin time (APTT) and thrombin time (TT) with extended endpoint] and specific [ecarin chromogenic assay (ECA) and diluted thrombin time (dTT)] laboratory coagulation tests in patients receiving dabigatran with untoward effects, we describe a case in which hemodialysis was used in attempt to remove dabigatran in a patient with excessive anticoagulation, rectal bleeding, and severe anemia. Our experience confirmed that APTT is an unreliable method for the assessment of dabigatran in patients with acute complications because it was often normal in spite of the therapeutic drug plasma levels. Both ECA and dTT showed a linear correlation with dabigatran levels over a broad range, and identified therapeutic and supratherapeutic levels. TT assay, which is highly sensitive to dabigatran, correlated well and linearly not only with low drug levels, but also, because of the introduction of the extended endpoint (400 s), with high concentrations of the drug, and demonstrated to be a simple and reliable alternative to ECA and dTT to assess dabigatran in patients with acute complications.

An observational case series of dabigatran and rivaroxaban exposures reported to a poison control system.

OBJECTIVE: Characterize clinical presentations and outcomes of dabigatran and rivaroxaban exposures reported to a poison control system. METHODS: Data for cases of dabigatran and rivaroxaban exposures called into the California Poison Control System from January 2011 to July 2013 were collected. Data collected included patient demographics, type of exposure, medication, dosage, vital signs, laboratory values, interventions, outcomes, and disposition. Exclusion criteria included confirmed nonexposures or miscoded cases. RESULTS: A total of 56 cases were identified, with 7 excluded, leaving 37 dabigatran and 12 rivaroxaban cases. Children age 12 years or less accounted for 5 dabigatran and 2 rivaroxaban cases. Bleeding was reported in 15 dabigatran cases. There were 4 cases of acute self-harm overdose with dabigatran ranging from 1800 to 3900 mg. Mild bleeding was reported in only one of these overdose cases. There were 2 fatal hemorrhages in dabigatran cases, both in chronic therapeutic dosing. Bleeding was reported in 5 rivaroxaban cases, all in patients with chronic exposure; no deaths were reported. There were no adverse outcomes in pediatric patients. Coagulation parameters did not correlate well with bleeding. CONCLUSIONS: In our series, the greatest risk of adverse events was in patients chronically taking these agents, irrespective of excess dosing. Acute self-harm ingestions and accidental pediatric ingestions had few adverse effects, although massive overdose can lead to abnormal coagulation studies. It does not appear that single low-dose ingestions of either medication will lead to clinically significant bleeding. It may be possible to manage some pediatric exposures and most accidental ingestions with observation.

[The effects of continuous renal replacement therapy (CRRT) and intermittent haemodialysis (IHD) in the treatment of dabigatran overdose. Case report]. / CRRT e HD standard nel sovradosaggio di Dabigatran.

A 85-year-old man, with CKD (e-GFR 35 mL/min), had been given Dabigatran (a direct thrombin inhibitor) at 110 mg daily dose because of atrial fibrillation. Due to intercurrent diarrhea and dehydration, renal function worsened (e-GFR 11 mL/min) and Dabigatran excretion decreased, thereby inducing drug overload. In this case, Dabigatran must be removed by dialysis, but the most appropriate schedule is still undefined. The effects of both continuous haemodiafiltration (CVVHDF) and intermittent haemodialysis (IHD) on plasma Dabigatran (Echarin Chromogenic Assay) were reported. Dialysis clearance of Dabigatran was reported as ratio to urea clearance (Dab/Urea(Cl)). Coagulation was assessed by both DOA-aPTTratio and Thrombin Time-ratio (TTratio). Dabigatran was elevated at 597 ng/mL predialysis (bleeding threshold being 30 ng/mL), and decreased to 96 ng/mL (-84%) after 20 hours of CVVHDF (Urea(Cl) = 67 mL/min). Dab/Urea(Cl) was 0.49. Three hours after dialysis, Dabigatran rebounded to 208 ng/mL. On IHD (Urea(Cl)=238 mL/min), predialysis Dabigatran was 52 ng/mL and decreased to 8 ng/mL (-85%) after 3.5 hours of treatment. Dab/Urea(Cl) was 0.47. Fourteen hours later, Dabigatran rebounded at 19 ng/mL. There was a positive correlation between Dabigatran and TTratio (r = 0.92; p<0.0001), whereas DOA-aPTT did not increase above 2.5 times the reference values, even in face of the highest values of Dabigatran. Therefore, TTratio is more reliable than DOA-aPTT in detecting Dabigatran overdose. Post-dialysis rebound of Dabigatran occurred also with CVVHDF, thereby suggesting that accurate monitoring of both Dabigatran levels and bleeding risk are mandatory, also after long-lasting dialysis sessions.

Use of continuous veno-venous haemodiafiltration therapy in dabigatran overdose.

CONTEXT: Dabigatran etexilate is one of the newer oral anticoagulants and a direct thrombin inhibitor. Concerns regarding dabigatran's use include its lack of validated laboratory markers for measuring its anticoagulation effect, the impact of renal impairment on its clearance, and the lack of effective strategies for reversal of anticoagulation. Hemodialysis has been utilized to reverse the anticoagulant effects of dabigatran in therapeutic doses. However, hemodialysis may not be feasible in hemodynamically unstable patients. There is little data on clearance rates of dabigatran by continuous renal replacement therapies. CASE DETAILS: A 66-year-old male presented following a poly-pharmacy overdose of 9 g of dabigatran in combination with metoprolol, amlodipine, olmesartan, and moxonidine. Eleven hours post overdose extracorporeal elimination was implemented as the patient developed worsening coagulopathy with an elevated international normalized ratio of 11 IU, an activated partial thromboplastin time of 115 s, and had renal impairment with a creatinine of 158 µmol/L. As the patient was hemodynamically unstable, continuous veno-venous hemodiafiltration was preferred over intermittent hemodialysis. Renal replacement therapy was performed for 32 h in total and the patient made a full recovery with no hemorrhagic complications or end organ injury. This patient developed a peak serum dabigatran level of 1560 ng/ml, 11 h postoverdose. Clearance of dabigatran via continuous veno-venous hemodiafiltration was calculated, using both the recovery and A-V pair methods, with a mean clearance of 58.1 and 31.9 ml/h, respectively, and a calculated mean extraction ratio of 0.2. CONCLUSION: There are few case reports and little experience when dabigatran is taken in overdose. This is a case report of a large dabigatran overdose presenting data on the extraction ratio and clearance of dabigatran using continuous veno-venous hemodiafiltration.

Evaluation of dabigatran exposures reported to poison control centers.

BACKGROUND: Dabigatran is a novel oral anticoagulant for which a well-defined range of toxicity and proven antidote has not been established. OBJECTIVE: The primary objective of this study was to characterize dabigatran exposures reported to poison centers by dose ingested, clinical effects, treatments used, and managment sites to gain a better understanding of patient outcomes. METHODS: A retrospective database review was conducted for dabigatran exposures reported to the National Poison Data System for the American Association of Poison Control Centers (AAPCC) over the period October 2010 to December 2012. RESULTS: There were 802 human dabigatran exposures involving adults predominantly (91% of cases). Exposure chronicity was acute in 43%, acute-on-chronic in 46%, and chronic in 11%, with the most common reason for an exposure call being an unintentional therapeutic error (70.6%). The most common management sites were on-site in 72% of cases and within a health care facility for 26%. Bleeding events and coagulopathies were the most commonly observed clinical effects. Treatments administered included activated charcoal, blood and coagulation products, hemodialysis, and supportive measures. Confirmed outcomes included death in 13 patients (1.6%), major effects in 23 (2.9%), and moderate effects in 50 (6.2%). More severe outcomes were significantly associated with adverse drug reactions, patients ≥65 years of age, those treated with blood and coagulation products and/or dialysis, and renal dysfunction (P < .05). Children experienced few moderate effects and no major effects or deaths. CONCLUSIONS: Severe outcomes from dabigatran exposures were not common, occurring in approximately 5% of cases.

Positive outcome after intentional overdose of dabigatran.

INTRODUCTION: Dabigatran (Pradaxa™), an orally active direct thrombin inhibitor, was approved by the United States Food and Drug Administration for the prevention of stroke in patients with atrial fibrillation in October 2010. Life-threatening consequences from dabigatran therapy include hemorrhage and bleeding complications, but they typically occur after renal impairment. We describe the first case report of intentional, acute overdose with dabigatran. CASE REPORT: A 57-year-old woman with a medical history of depression and atrial fibrillation presented to the emergency department after ingesting 11.25 g of dabigatran in a suicide attempt. Despite an ecchymosis indicative of prior trauma, there was no evidence of acute bleeding. After receiving gastric lavage and activated charcoal therapy in the emergency department, she was admitted to the ICU. On presentation, dabigatran blood levels measured 970 ng/mL and thrombin clot times measured above the testable limits (>120 s) until 52 h post-arrival. The remainder of her clinical course was uncomplicated, and the patient was transferred to an inpatient psychiatric unit for depression follow-up. DISCUSSION: This case shows the clinical course of a patient with an acute, massive dabigatran overdose with no significant clinical consequences. Currently, there is no ideal method to monitor anticoagulation levels; there is no pharmacologic reversal method, and hemodialysis is an undesirable treatment option.

Fatal gastrointestinal hemorrhage after a single dose of dabigatran.

INTRODUCTION: Dabigatran (Pradaxa) is a new oral anticoagulant approved by the Food and Drug Administration (FDA), available internationally and indicated as an alternative to warfarin for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Dabigatran does not require laboratory monitoring and its kinetics allow for a more rapid onset of action with a time to peak concentration of 1.25-1.5 h. We are reporting a fatality resulting from gastrointestinal bleeding after the ingestion of a single dose of dabigatran 150 mg. CASE DETAILS: A 92-year-old man with a medical history of chronic obstructive pulmonary disease, hypothyroidism, and atrial flutter presented to the emergency department with complaints of weakness and rectal bleeding. He was seen by his Cardiologist the day before and was found to be in new atrial fibrillation. He was prescribed dabigatran 150 mg twice daily for anticoagulation therapy. He took one dose of dabigatran 150 mg at 2200 and woke up the following morning before 0900 with profuse rectal bleeding. The initial vital signs in the emergency department, approximately 11 h after ingestion, were heart rate 72 beats/min, blood pressure 62/30 mmHg, and lab work showed hemoglobin 9.9 g/dL, international normalization ratio (INR) 1.99, blood urea nitrogen (BUN) 66 mg/dL, and creatinine (SCr) 1.4 mg/dL (creatinine clearance (CrCl) 24.2 mL/min). He was resuscitated with intravenous fluids, two units of packed red blood cells, two units of fresh frozen plasma, platelets, and vitamin K 10 mg intravenously. He was also given an unknown dose of erythromycin early in his hospital stay. An actively bleeding gastric ulcer was discovered and treated with local epinephrine injections. Approximately 48 h after his exposure, he received an additional two units of blood to treat his decreasing blood pressure (98/41 mmHg). On day three, his hemoglobin and hematocrit were stable at 10 g/dL and 30%, INR 1.6, he was extubated and off vasoactive medications. Day six of hospitalization, he began having maroon stools, his hemoglobin decreased to 8.1 g/dL and his platelets to 81 × 1000/mcL. On day seven, the hemoglobin decreased to 6.4 mg/dL. Despite aggressive resuscitative efforts and supportive care, he died. DISCUSSION: This case demonstrates the potential of a single dose of dabigatran 150 mg to result in a fatal gastrointestinal hemorrhage. This patient was started on the maximum dose with a CrCl 33.9 mL/min and on admission CrCl 24.2 mL/min, suggesting underlying renal insufficiency.

Therapeutic effects of olive leaves extract on rats treated with a sublethal concentration of carbendazim.

OBJECTIVES: The present study was carried out to establish the possible protective effects of administration of olive leaves extract on carbendazim induced physiological and histopathological alterations in male rats. MATERIALS AND METHODS: The experimental rats were divided randomly into five groups and kept at ten rats per group. The first group was untreated and served as a control. The second group was orally administered with carbendazim (200 mg/kg) for one month. The third group was supplemented with olive leaves extract and exposed to carbendazim at the same dose given to the second group. Rats of the fourth group were supplemented with olive leaves extract at the same dose given to the third group. Rats of the fifth group were supplemented with only corn oil. RESULTS: Carbendazim induced statistically declines in the values of red blood corpuscles (RBC) count, hemoglobin (Hb) concentration, hematocrit (Hct) and the level of plasma and liver total protein, while the value of white blood cells (WBC) count, the levels of plasma glucose, triglycerides, cholesterol, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and liver glycogen and total lipid were elevated. Moreover, after one month of carbendazim exposure, there were severe changes in the structures of liver, kidney and testis. Pretreatment of carbendazim-exposed rats with olive leaves extract showed marked improvement in both physiological and histopathological alterations. CONCLUSIONS: We conclude that olive leaves extract is a promising chemotherapeutic agent for reducing the toxicity of carbendazim and may be for other pesticides and toxicants.

Accidental astemizole overdose in young children.

6 cases of accidental astemizole poisoning in children have been reported to the Finnish Poison Information Center. The children were aged 1 year 7 months to 3 years 4 months and had taken doses of 2.5 to 16.7 mg/kg, at least twelve times that recommended. In 2 children the overdose was verified by measurement of drug concentrations. Despite measures to prevent drug absorption prolonged QTc-interval, a sign of cardiac toxicity, was found in all 5 children on whom an electrocardiogram was available for analysis, and severe ventricular arrhythmias developed in 1. Young children with accidental astemizole overdose should be carefully monitored in hospital. Similar precautions may be justified in cases of overdose with other selective H1-histamine receptor antagonists.

[Severe antihistamine poisoning complicated by ventricular tachycardia]. / Závazná intoxikace antihistaminiky komplikovaná komorovou tachykardií.

A 26-year-old female clerk without previous heart disease ingested with suicidal intensions antihistaminic drugs--H1 blockers, astemizole (a total of 700 mg) and terfenadine (a total of 900-1200 mg). The main sign of intoxication was repeated polymorphous ventricular tachycardia type torsade de pointes, which at the onset of hospitalization changed into ventricular fibrillation. Therapeutically the impaired rhythm was controlled by electric cardioversion and atrial stimulation with a frequency of 120/min. On the third day it was possible to discontinue atrial stimulation and later the patient was discharged without any permanent sequelae.

Prolonged Q-T interval following astemizole overdose.

Astemizole overdose has been reported to cause torsades-de-pointes and in the present case it caused prolongation of the Q-T interval. Astemizole overdoses should be managed in a similar way to overdose with other cardiotoxic drugs.