RESUMEN
OBJECTIVE: To provide a management approach for adults with calcium channel blocker poisoning. DATA SOURCES, STUDY SELECTION, AND DATA EXTRACTION: Following the Appraisal of Guidelines for Research & Evaluation II instrument, initial voting statements were constructed based on summaries outlining the evidence, risks, and benefits. DATA SYNTHESIS: We recommend 1) for asymptomatic patients, observation and consideration of decontamination following a potentially toxic calcium channel blocker ingestion (1D); 2) as first-line therapies (prioritized based on desired effect), IV calcium (1D), high-dose insulin therapy (1D-2D), and norepinephrine and/or epinephrine (1D). We also suggest dobutamine or epinephrine in the presence of cardiogenic shock (2D) and atropine in the presence of symptomatic bradycardia or conduction disturbance (2D); 3) in patients refractory to the first-line treatments, we suggest incremental doses of high-dose insulin therapy if myocardial dysfunction is present (2D), IV lipid-emulsion therapy (2D), and using a pacemaker in the presence of unstable bradycardia or high-grade arteriovenous block without significant alteration in cardiac inotropism (2D); 4) in patients with refractory shock or who are periarrest, we recommend incremental doses of high-dose insulin (1D) and IV lipid-emulsion therapy (1D) if not already tried. We suggest venoarterial extracorporeal membrane oxygenation, if available, when refractory shock has a significant cardiogenic component (2D), and using pacemaker in the presence of unstable bradycardia or high-grade arteriovenous block in the absence of myocardial dysfunction (2D) if not already tried; 5) in patients with cardiac arrest, we recommend IV calcium in addition to the standard advanced cardiac life-support (1D), lipid-emulsion therapy (1D), and we suggest venoarterial extracorporeal membrane oxygenation if available (2D). CONCLUSION: We offer recommendations for the stepwise management of calcium channel blocker toxicity. For all interventions, the level of evidence was very low.
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Bloqueadores de los Canales de Calcio/envenenamiento , Sobredosis de Droga/terapia , Consenso , Hospitalización , HumanosRESUMEN
Animal studies and human case reports show promise in using lipid rescue to treat refractory calcium channel antagonist toxicity. However, the majority of research and clinical experience has focused on non-dihydropyridine agents. Thus, we sought to investigate the value of lipid emulsion (ILE) therapy for dihydropyridine-induced shock. This IACUC-approved study utilized seven swine that were sedated with alpha-chloralose, mechanically ventilated, and instrumented for drug delivery and hemodynamic measures. After stabilization and basal measures, nifedipine (0.01875 mg/kg/min) was infused until imminent cardiac arrest (seizure, end tidal CO2 < 10 mmHg, bradydysrhythmia, or pulseless electrical activity). Animals then received a 7 mL/kg bolus of 20% lipid emulsion via central catheter. Lipid circulation was visually confirmed by the presence of fat in peripheral arterial blood. Hemodynamics were continuously monitored until 10 min after lipid bolus. Surviving animals were euthanized. Pre- and post-lipid treatment parameters were analyzed using the Wilxocon signed rank test (p <0.05 significant). Nifedipine toxicity was characterized by vasodilatory hypotension, impaired vascular contractility, and tachycardia with terminal bradycardia. The median time to imminent cardiac arrest from start of nifedipine infusion was 218 min. Lipid treatment did not improve hemodynamics or restore circulation in any animal. There was no benefit from lipid rescue in this model of nifedipine toxicity. Further study of ILE for dihydropyridine toxicity is warranted but initial animal model results are not promising.
Asunto(s)
Bloqueadores de los Canales de Calcio/envenenamiento , Emulsiones Grasas Intravenosas/uso terapéutico , Nifedipino/envenenamiento , Choque/inducido químicamente , Choque/terapia , Animales , Glucemia/análisis , Glucemia/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Bradicardia/etiología , Bloqueadores de los Canales de Calcio/administración & dosificación , Dihidropiridinas/administración & dosificación , Dihidropiridinas/envenenamiento , Modelos Animales de Enfermedad , Femenino , Paro Cardíaco Inducido , Humanos , Metaboloma/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Nifedipino/administración & dosificación , Proyectos Piloto , Porcinos , Taquicardia/etiologíaRESUMEN
BACKGROUND: The A(3) adenosine receptor (A(3)AR) is overexpressed in the tumor and in the peripheral blood mononuclear cells of patients with hepatocellular carcinoma (HCC). The orally active drug candidate CF102, an A(3)AR agonist, induces apoptosis of HCC cells via deregulation of the Wnt signaling pathway. In this open label phase I/II trial, the safety and clinical effects of CF102 were assessed in patients with advanced unresectable HCC. METHODS: The primary objectives of this trial were to examine the safety and pharmacokinetic (PK) behavior of CF102 given orally (1, 5, and 25 mg BID) in 28-day cycles. Evaluation of anti-tumor effects and the utilization of A(3)AR as a biological predictive marker of response to CF102 were the secondary objectives. RESULTS: Eighteen patients received CF102-six at each dose level. No serious drug-related adverse events or dose-limiting toxicities were observed. CF102 demonstrated good oral bioavailability and linear PK behavior. Median overall survival in the study population, 67% of whom had received prior sorafenib, was 7.8 months, and for Child Pugh B patients (28%) it was 8.1 months. Stable disease by RECIST was observed in four patients for at least 4 months. CF102 maintained liver function over a 6-month period. A correlation between receptor overexpression levels at baseline and patients' overall survival was found. One of the patients who presented with skin nodules that were biopsy-proven to be HCC metastases prior to the trial showed complete metastasis regression during three months of treatment with CF102. CONCLUSIONS: CF102 is safe and well-tolerated, showing favorable PK characteristics in Child Pugh A and B HCC patients, justifying further clinical development.
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Adenosina/análogos & derivados , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Agonistas del Receptor Purinérgico P1/administración & dosificación , Adenosina/administración & dosificación , Adulto , Anciano , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/patología , Niño , Femenino , Humanos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Agonistas del Receptor Purinérgico P1/efectos adversos , Agonistas del Receptor Purinérgico P1/farmacocinética , Receptor de Adenosina A3/metabolismo , Sorafenib , Vía de Señalización WntAsunto(s)
Suplementos Dietéticos/envenenamiento , Enfermedades de la Uña/inducido químicamente , Uñas/efectos de los fármacos , Selenio/envenenamiento , Adulto , Niño , Preescolar , Sobredosis de Droga , Femenino , Humanos , Lactante , Enfermedades de la Uña/patología , Uñas/patología , Selenio/sangreAsunto(s)
Biomarcadores , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Endotelio Vascular/efectos de los fármacos , Enfermedades Vasculares/inducido químicamente , Animales , Biología Computacional , Evaluación Preclínica de Medicamentos , Endotelio Vascular/patología , Citometría de Flujo , Genómica , Humanos , Proteómica , Enfermedades Vasculares/metabolismo , Vasculitis/inducido químicamente , Vasculitis/metabolismoRESUMEN
The aim of this study was to assess the cardiovascular effects of a selective phosphodiesterase 5 inhibitor ER-118585, 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinecarbonitrile monohydrochloride. The present results indicated that 1) ER-118585 significantly inhibited the human ether-a-go-go related gene (HERG) tail current at 10 nM and above with an IC(50) value of 40.7 nM in human embryonic kidney 293 cells transfected with HERG cDNA; 2) ER-118585 at 100 and 1000 nM significantly increased the action potential duration (APD) at 50% and 90% repolarization in isolated papillary muscles of guinea pig; and 3) intravenous infusion of ER-118585 at 10 microg/kg/min significantly prolonged the QT interval by 10.5+/-1.6% from 281+/-2 ms to 311+/-6 ms in six anesthetized dogs subjected to atrial pacing. In consideration of both the plasma concentration of ER-118585 (984+/-78 nM, n=3) and its protein binding fraction (99.0+/-0.1%, n=5), the free plasma concentration was estimated at 9.8+/-0.8 nM, which is consistent with the minimum concentration of HERG current inhibition. In conclusion, these evaluation methods demonstrated that ER-118585 could prolong the QT interval via APD prolongation, attributable to the inhibition of the HERG potassium current.
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Evaluación Preclínica de Medicamentos , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/efectos de los fármacos , Ftalazinas/farmacología , Compuestos de Espiro/farmacología , 3',5'-GMP Cíclico Fosfodiesterasas , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Estimulación Cardíaca Artificial , Enfermedades Cardiovasculares/tratamiento farmacológico , Línea Celular , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Perros , Relación Dosis-Respuesta a Droga , Electrocardiografía , Electrofisiología , Cobayas , Humanos , Infusiones Intravenosas , Riñón/citología , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/prevención & control , Masculino , Músculos Papilares/efectos de los fármacos , Músculos Papilares/fisiología , Técnicas de Placa-Clamp , Inhibidores de Fosfodiesterasa/efectos adversos , Inhibidores de Fosfodiesterasa/sangre , Hidrolasas Diéster Fosfóricas/metabolismo , Piperidinas/farmacología , Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Canales de Potasio con Entrada de Voltaje/efectos de los fármacos , Canales de Potasio con Entrada de Voltaje/genética , Unión Proteica , Piridinas/farmacología , Transfección/métodos , Función Ventricular/efectos de los fármacos , Función Ventricular/genética , Función Ventricular/fisiología , Complejos Prematuros Ventriculares/tratamiento farmacológico , Complejos Prematuros Ventriculares/genética , Complejos Prematuros Ventriculares/prevención & controlRESUMEN
OBJECTIVE: Vomiting after activated charcoal decontamination is problematic. Acupressure (traditional Chinese medicine) is an effective treatment for emesis, but has not been tested in overdose patients. We sought to determine (1) the incidence of emesis after activated charcoal and (2) the ability of acupressure to prevent emesis due to activated charcoal. METHODS: Consecutive overdose patients were enrolled in a preliminary, prospective study to determine the incidence of emesis after activated charcoal. Awake patients, > 18 years, received 1 g/kg activated charcoal orally or via nasogastric tube, and then observedfor 1 hour. These patients served as controls forpart 2 of the study, where acupressure bands were placed on overdose patients at the Nei-Guan P-6 point of both wrists prior to activated charcoal, followed by 1 hour observation. Exclusion criteria included: ipecac decontamination, antiemetic drug ingestion, antiemetic drug therapy within 1 hour of activated charcoal, or intubation. RESULTS: Eighty-one patients were included in the control group and 106 patients in the acupressure treatment group. Demographics and ingested substances were similar in both groups. 21/81 (25.9%) in the control group vomited and 15/106 (14.2%) in the acupressure group vomited. Acupressure reduced emesis by 46% (p = 0.043; chi2). Within the acupressure group, the median duration of prophylactic acupressure was 5 minutes in those patients without vomiting compared to 4 minutes in those patients with vomiting (NS; Wilcoxon rank sum test). CONCLUSION: The incidence of emesis after activated charcoal at our institution was 26%. Prophylactic acupressure reduced activated charcoal-induced vomiting by 46%. Investigators suggest 5 minutes of acupressure prior to activated charcoal.