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1.
Blood Coagul Fibrinolysis ; 26(2): 225-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25629417

RESUMO

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.


Assuntos
Antitrombinas/envenenamento , Benzimidazóis/envenenamento , Coagulação Sanguínea/efeitos dos fármacos , Overdose de Drogas/terapia , Diálise Renal/métodos , beta-Alanina/análogos & derivados , Idoso de 80 Anos ou mais , Dabigatrana , Overdose de Drogas/sangue , Humanos , Masculino , beta-Alanina/envenenamento
2.
Am J Emerg Med ; 32(9): 1077-84, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24908445

RESUMO

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.


Assuntos
Anticoagulantes/envenenamento , Benzimidazóis/envenenamento , Morfolinas/envenenamento , Tiofenos/envenenamento , beta-Alanina/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , California/epidemiologia , Criança , Pré-Escolar , Dabigatrana , Overdose de Drogas/epidemiologia , Overdose de Drogas/terapia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Centros de Controle de Intoxicações/estatística & dados numéricos , Estudos Prospectivos , Estudos Retrospectivos , Rivaroxabana , Adulto Jovem , beta-Alanina/envenenamento
3.
G Ital Nefrol ; 31(2)2014.
Artigo em Italiano | MEDLINE | ID: mdl-24777926

RESUMO

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.


Assuntos
Antitrombinas/envenenamento , Benzimidazóis/envenenamento , Overdose de Drogas/terapia , Terapia de Substituição Renal , beta-Alanina/análogos & derivados , Idoso de 80 Anos ou mais , Dabigatrana , Humanos , Masculino , Diálise Renal , beta-Alanina/envenenamento
4.
Ann Pharmacother ; 48(3): 354-60, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24301686

RESUMO

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.


Assuntos
Anticoagulantes/efeitos adversos , Benzimidazóis/efeitos adversos , Centros de Controle de Intoxicações , beta-Alanina/análogos & derivados , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos , Idoso , Anticoagulantes/envenenamento , Benzimidazóis/envenenamento , Coagulação Sanguínea/efeitos dos fármacos , Criança , Dabigatrana , Bases de Dados Factuais , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Estudos Retrospectivos , beta-Alanina/efeitos adversos , beta-Alanina/envenenamento
6.
J Med Toxicol ; 9(2): 192-5, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23212788

RESUMO

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.


Assuntos
Antitrombinas/envenenamento , Benzimidazóis/envenenamento , Overdose de Drogas/terapia , beta-Alanina/análogos & derivados , Antitrombinas/sangue , Antitrombinas/farmacocinética , Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Carvão Vegetal/uso terapêutico , Quelantes/uso terapêutico , Dabigatrana , Overdose de Drogas/sangue , Serviço Hospitalar de Emergência , Feminino , Lavagem Gástrica , Humanos , Pessoa de Meia-Idade , Tentativa de Suicídio , Resultado do Tratamento , beta-Alanina/sangue , beta-Alanina/farmacocinética , beta-Alanina/envenenamento
7.
Clin Toxicol (Phila) ; 50(7): 571-3, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22800505

RESUMO

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.


Assuntos
Anticoagulantes/envenenamento , Benzimidazóis/envenenamento , Hemorragia Gastrointestinal/induzido quimicamente , beta-Alanina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Dabigatrana , Evolução Fatal , Humanos , Masculino , beta-Alanina/envenenamento
9.
Forensic Sci Int ; 116(1): 59-61, 2001 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-11118755

RESUMO

We describe four fatal cases due to ingestion of carbofuran, a carbamate insecticide. Carbofuran was detected in the gastric contents using thin layer chromatography (TLC) and gas chromatography/mass spectrophotometry (GC/MS), and quantified in the blood using a gas chromatograph equipped with nitrogen-phosphorus detector (NPD). Fatal concentrations of carbofuran in blood ranged from 0.32 to 11.6 microg/ml.


Assuntos
Carbofurano/sangue , Carbofurano/envenenamento , Medicina Legal , Inseticidas/sangue , Inseticidas/envenenamento , Suicídio , beta-Alanina/análogos & derivados , Adulto , Benzofuranos/análise , Benzofuranos/sangue , Benzofuranos/química , Benzofuranos/envenenamento , Carbofurano/análise , Carbofurano/química , Cromatografia em Camada Delgada , Evolução Fatal , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Conteúdo Gastrointestinal/química , Humanos , Inseticidas/análise , Inseticidas/química , Masculino , Sobrevida , beta-Alanina/análise , beta-Alanina/sangue , beta-Alanina/química , beta-Alanina/envenenamento
10.
Int J Legal Med ; 112(4): 268-70, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10433038

RESUMO

We describe here three cases involving acute fatalities due to benfuracarb ingestion and the forensic toxicological implications. Benfuracarb, a carbamate insecticide and its main metabolite carbofuran, were detected using thin layer chromatography (TLC) and gas chromatography/mass spectrophotometry (GC/MS) after extraction with ethyl acetate and then quantified using gas chromatography (GC) equipped with NPD. The blood levels of benfuracarb and carbofuran were in the range of 0.30-2.32 microg/ml and 1.45-1.47 microg/ml, respectively. Benfuracarb was not detected in urine, but carbofuran was detected in the range of 0.53-2.66 microg/ml.


Assuntos
Benzofuranos/envenenamento , Inseticidas/envenenamento , Envenenamento/diagnóstico , Suicídio/legislação & jurisprudência , beta-Alanina/análogos & derivados , Adulto , Benzofuranos/análise , Carbofurano/análise , Cromatografia Gasosa , Cromatografia em Camada Delgada , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Inseticidas/análise , Masculino , beta-Alanina/análise , beta-Alanina/envenenamento
12.
Acta Neuropathol ; 81(1): 66-73, 1990.
Artigo em Inglês | MEDLINE | ID: mdl-2128162

RESUMO

Two metabolites of 5-fluorouracil (FU), monofluoroacetic acid (FA) and alpha-fluoro-beta-alanine (FBAL), were continuously administered into the left ventricle of the brain in cats for up to 1 month to investigate the mechanism of neurotoxicity of FU and its derivatives. The cumulative doses of FU and FBAL over a 1-month period were 1.5-45 mg (20 cats) and 0.2-4.8 mg (21 cats), respectively. As controls for each experimental group, acetic acid (AA) and beta-alanine (BAL) were administered. In terms of survival time in relation to the cumulative dose and molecular weight, FBAL was more toxic than FA. Neuropathologically, two types of change, vacuoles and necrosis/softening-like change, were found. The vacuoles were 20-50 microns in diameter, and distributed mainly in the cerebellar nuclei, white matter and the tectum and tegmentum of the brain stem in both experimental groups. Electron microscopically, these vacuoles were due to splitting of the myelin intraperiod line or separation between the axon and the innermost layer of myelin. Necrosis/softening-like change occurred preferentially in the FBAL group and was located symmetrically in the superior and inferior colliculi, oculomotor nuclei and thalamus. Both types of neuropathological change, especially those in the FBAL group, were similar to those found in cats orally administered with FU and its derivatives.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Encéfalo/patologia , Fluoracetatos/toxicidade , Fluoruracila/toxicidade , Neurotoxinas , beta-Alanina/análogos & derivados , Animais , Axônios/efeitos dos fármacos , Axônios/ultraestrutura , Encéfalo/efeitos dos fármacos , Encéfalo/ultraestrutura , Gatos , Fluoracetatos/envenenamento , Fluoruracila/metabolismo , Fluoruracila/envenenamento , Microscopia Eletrônica , Especificidade de Órgãos , Vacúolos/efeitos dos fármacos , Vacúolos/ultraestrutura , beta-Alanina/envenenamento , beta-Alanina/toxicidade
13.
Ciba Found Symp ; 126: 221-38, 1987.
Artigo em Inglês | MEDLINE | ID: mdl-3107939

RESUMO

beta-N-Oxalylamino-L-alanine (BOAA) and beta-N-methylamino-L-alanine (BMAA) are chemically related excitant amino acids isolated from the seed of Lathyrus sativus (BOAA) and Cycas circinalis (BMAA), consumption of which has been linked to lathyrism (an upper motor neuron disorder) and Guam amyotrophic lateral sclerosis (ALS), respectively. Both diseases are associated with degeneration of motor neurons. Experimentally, single doses of BOAA or BMAA induce seizures in neonatal mice and postsynaptic neuronal oedema and degeneration in explants of mouse spinal cord and frontal cortex. Preliminary studies show that these behavioural and pathological effects are differentially blocked by glutamate-receptor antagonists. In macaques, several weeks of daily oral doses of BOAA produce clinical and electrophysiological signs of corticospinal dysfunction identical to those seen in comparably well-nourished animals receiving a fortified diet based on seed of Lathyrus sativus. By contrast, comparable oral dosing with BMAA precipitates tremor and weakness, bradykinesia and behavioural changes, with conduction deficits in the principal motor pathway. BOAA and BMAA (or a metabolite thereof) are the first members of the excitotoxin family to have been shown to possess chronic motor-system toxic potential. These observations provide a rational basis for searching for comparable endogenous neurotoxins in sporadic and inherited forms of human motor neuron disease.


Assuntos
Alanina/análogos & derivados , Diamino Aminoácidos/envenenamento , Neurônios Motores , Junção Neuromuscular/efeitos dos fármacos , Neurônios/efeitos dos fármacos , beta-Alanina/análogos & derivados , Animais , Humanos , Latirismo/etiologia , Macaca , Doenças Neuromusculares/etiologia , beta-Alanina/envenenamento
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