RESUMEN
Cisplatin (CDDP) stands out as an effective chemotherapeutic agent; however, its application is linked to the development of significant adverse effects, notably nephro- and ototoxicity. The human organic cation transporter 2 (hOCT2), found in abundance in the basolateral membrane domain of renal proximal tubules and the Corti organ, plays a crucial role in the initiation of nephro- and ototoxicity associated with CDDP by facilitating its uptake in kidney and ear cells. Given its limited presence in cancer cells, hOCT2 emerges as a potential druggable target for mitigating unwanted toxicities associated with CDDP. Potential strategies for mitigating CDDP toxicities include competing with the uptake of CDDP by hOCT2 or inhibiting hOCT2 activity through rapid regulation mediated by specific signaling pathways. This study investigated the interaction between the already approved cationic drugs disopyramide, imipramine, and orphenadrine with hOCT2 that is stably expressed in human embryonic kidney cells. Regarding disopyramide, its influence on CDDP cellular transport by hOCT2 was further characterized through inductively coupled plasma isotope dilution mass spectrometry. Additionally, its potential protective effects against cellular toxicity induced by CDDP were assessed using a cytotoxicity test. Given that hOCT2 is typically expressed in the basolateral membrane of polarized cells, with specific regulatory mechanisms, this work studied the regulation of hOCT2 that is stably expressed in Madin-Darby Canine Kidney (MDCK) cells. These cells were cultured in a matrix to induce the formation of cysts, exposing hOCT2 in the basolateral plasma membrane domain, which was freely accessible to experimental solutions. The study specifically tested the regulation of ASP+ uptake by hOCT2 in MDCK cysts through the inhibition of casein kinase II (CKII), calmodulin, or p56lck tyrosine kinase. Furthermore, the impact of this manipulation on the cellular toxicity induced by CDDP was examined using a cytotoxicity test. All three drugs-disopyramide, imipramine, and orphenadrine-demonstrated inhibition of ASP+ uptake, with IC50 values in the micromolar (µM) range. Notably, disopyramide produced a significant reduction in the CDDP cellular toxicity and platinum cellular accumulation when co-incubated with CDDP. The activity of hOCT2 in MDCK cysts experienced a significant down-regulation under inhibition of CKII, calmodulin, or p56lck tyrosine kinase. Interestingly, only the inhibition of p56lck tyrosine kinase demonstrated the capability to protect the cells against CDDP toxicity. In conclusion, certain interventions targeting hOCT2 have demonstrated the ability to reduce CDDP cytotoxicity, at least in vitro. Further investigations in in vivo systems are warranted to ascertain their potential applicability as co-treatments for mitigating undesired toxicities associated with CDDP in patients.
Asunto(s)
Quistes , Ototoxicidad , Humanos , Animales , Perros , Transportador 2 de Cátion Orgánico , Proteínas de Transporte de Catión Orgánico/metabolismo , Cisplatino/metabolismo , Disopiramida , Calmodulina/metabolismo , Imipramina , Orfenadrina , Células de Riñón Canino Madin Darby , Proteínas Tirosina Quinasas/metabolismoRESUMEN
Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of the AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action po-tential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmaco-logical effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax), and decreased AP duration (APD), conduction velocity (CV), and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that disopyramide may be more effective against Pitx2-induced AF than propafenone and quinidine by prolonging WL.
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Arritmias Cardíacas/tratamiento farmacológico , Fibrilación Atrial/tratamiento farmacológico , Proteínas de Homeodominio/genética , Factores de Transcripción/genética , Animales , Antiarrítmicos/química , Antiarrítmicos/farmacología , Arritmias Cardíacas/genética , Arritmias Cardíacas/patología , Fibrilación Atrial/genética , Fibrilación Atrial/patología , Simulación por Computador , Disopiramida/química , Disopiramida/farmacología , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/patología , Humanos , Ratones , Propafenona/química , Propafenona/uso terapéutico , Quinidina/química , Quinidina/farmacología , Proteína del Homeodomínio PITX2RESUMEN
A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments.
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Acetamidas/uso terapéutico , Anticonvulsivantes/uso terapéutico , Disopiramida/uso terapéutico , Convulsiones/tratamiento farmacológico , Acetamidas/administración & dosificación , Acetamidas/química , Animales , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/química , Disopiramida/administración & dosificación , Disopiramida/química , Relación Dosis-Respuesta a Droga , Electrochoque , Femenino , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Masculino , Ratones , Estructura Molecular , Pentilenotetrazol/administración & dosificación , Ratas , Ratas Wistar , Convulsiones/inducido químicamente , Relación Estructura-ActividadRESUMEN
Early repolarization (ER) has been associated with an increased risk of sudden cardiac arrest. Interestingly, ventricular arrhythmias seem to be triggered by parasympathetic stimulation. In the present case report, we describe complete control of highly frequent malignant ventricular arrhythmias after adding theophylline to ineffective oral hydroquinidine and high-rate pacing in a patient suffering from malignant ER. We hypothesize that the theophylline-mediated enhanced beta-adrenergic stimulation could reduce the transmural myocardial voltage discrepancy by increasing the inward ICa,L current.
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Desfibriladores Implantables , Taquicardia Ventricular/tratamiento farmacológico , Teofilina/uso terapéutico , Vasodilatadores/uso terapéutico , Antiarrítmicos/uso terapéutico , Niño , Disopiramida/uso terapéutico , Humanos , Masculino , Quinidina/análogos & derivados , Quinidina/uso terapéutico , Recurrencia , Taquicardia Ventricular/fisiopatologíaRESUMEN
Hypertrophic cardiomyopathy has a range of clinical severity in children. Treatment options are limited, mainly on account of small patient size. Disopyramide is a sodium channel blocker with negative inotropic properties that effectively reduces left ventricular outflow tract gradients in adults with hypertrophic cardiomyopathy, but its efficacy in children is uncertain. A retrospective chart review of patients ⩽21 years of age with hypertrophic cardiomyopathy at our institution and treated with disopyramide was performed. Left ventricular outflow tract Doppler gradients before and after disopyramide initiation were compared as the primary outcome measure. Nine patients received disopyramide, with a median age of 5.6 years (range 6 days-12.9 years). The median left ventricular outflow tract Doppler gradient before initiation of disopyramide was 81 mmHg (range 30-132 mmHg); eight patients had post-initiation echocardiograms, in which the median lowest recorded Doppler gradient was 43 mmHg (range 15-100 mmHg), for a median % reduction of 58.2% (p=0.002). With median follow-up of 2.5 years, eight of nine patients were still alive, although disopyramide had been discontinued in six of the nine patients. Reasons for discontinuation included septal myomectomy (four patients), heart transplantation (one patient), and side effects (one patient). Disopyramide was effective for the relief of left ventricular outflow tract obstruction in children with hypertrophic cardiomyopathy, although longer-term data suggest that its efficacy is not sustained. In general, it was well tolerated. Further study in larger patient populations is warranted.
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Cardiomiopatía Hipertrófica/tratamiento farmacológico , Disopiramida/administración & dosificación , Ventrículos Cardíacos/diagnóstico por imagen , Función Ventricular Izquierda/fisiología , Adolescente , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/fisiopatología , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Ecocardiografía Doppler , Electrocardiografía , Femenino , Ventrículos Cardíacos/fisiopatología , Humanos , Lactante , Recién Nacido , Masculino , Pronóstico , Estudios Retrospectivos , Bloqueadores del Canal de Sodio Activado por Voltaje/administración & dosificación , Adulto JovenRESUMEN
It remains unclear whether flecainide, a Class I antiarrhythmic drug, improves left ventricular pressure gradient (LVPG) or symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM). Our study evaluated the long-term efficacy of flecainide, compared to disopyramide, when administered orally, on LVPG and symptoms in obstructive HCM patients. Among 164 obstructive HCM patients, 15 were administered oral flecainide therapy and 33 administered oral disopyramide therapy. LVPG declined from 79.8 ± 36.6 to 39.2 ± 36.7 mmHg (p = 0.003) after flecainide therapy and from 74.5 ± 26.4 to 31.4 ± 24.8 mmHg (p < 0.001) after disopyramide therapy. The percent reduction in LVPG was -47.9 ± 43.2 % in patients treated with flecainide, comparable to the results for those treated with disopyramide (-57.1 ± 33.0 %; p = 0.425). We found no significant differences in improvement in NYHA functional class between patients treated with flecainide and those treated with disopyramide (p = 0.331). Patients treated with flecainide exhibited no significant adverse side effects, and there was no need for myectomy or alcohol septal ablation to reduce LVPG and symptoms. Improvements in LVPG and symptoms were similar in patients treated with flecainide and patients treated with disopyramide, suggesting that flecainide is a potentially useful alternative for symptomatic obstructive HCM patients, particularly those with disopyramide-induced vagolytic side effects, narrow angle glaucoma, or prostatic hyperplasia and pre-existing urination difficulties. Our data must be viewed with caution, however, in view of the small number of study patients. Flecainide therapy will require further proof of safety before it can be routinely recommended in patients with symptomatic obstructive HCM.
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Cardiomiopatía Hipertrófica/tratamiento farmacológico , Disopiramida/administración & dosificación , Flecainida/administración & dosificación , Ventrículos Cardíacos/fisiopatología , Obstrucción del Flujo Ventricular Externo/tratamiento farmacológico , Presión Ventricular/efectos de los fármacos , Administración Oral , Antiarrítmicos/administración & dosificación , Cardiomiopatía Hipertrófica/etiología , Cardiomiopatía Hipertrófica/fisiopatología , Relación Dosis-Respuesta a Droga , Ecocardiografía , Femenino , Estudios de Seguimiento , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Obstrucción del Flujo Ventricular Externo/complicaciones , Obstrucción del Flujo Ventricular Externo/fisiopatología , Presión Ventricular/fisiologíaRESUMEN
A 67-year-old man who had cardiopulmonary arrest (CPA) at home was admitted to our institution. His spontaneous circulation was restored by bystander cardiopulmonary resuscitation (CPR) performed by his wife and an automated external defibrillator (AED). J waves were observed in the inferior leads of an electrocardiogram. We performed an implantable cardioverter defibrillator (ICD) implantation. After the ICD implantation, appropriate shocks due to ventricular fibrillation (VF) were observed on interrogation of the ICD at a frequency of twice a month. Most VF events occurred in the early morning between 1:00 to 6:00, and ventricular premature contractions (VPCs) were detected just before the occurrence of VF. Since the VF events always occurred in the early morning, we started long-acting disopyramide (150 mg/day, before bedtime), which has a muscarinic receptor blocking action. As a result, he has not received any appropriate ICD shocks for more than two years.
Asunto(s)
Disopiramida/administración & dosificación , Cardioversión Eléctrica/métodos , Paro Cardíaco , Fibrilación Ventricular , Anciano , Antiarrítmicos/administración & dosificación , Reanimación Cardiopulmonar/métodos , Desfibriladores Implantables , Cardioversión Eléctrica/instrumentación , Electrocardiografía/métodos , Paro Cardíaco/etiología , Paro Cardíaco/terapia , Humanos , Masculino , Periodicidad , Recurrencia , Resultado del Tratamiento , Fibrilación Ventricular/complicaciones , Fibrilación Ventricular/diagnóstico , Fibrilación Ventricular/fisiopatología , Fibrilación Ventricular/terapiaRESUMEN
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic disorder for which first-line treatments for obstructive HCM (oHCM) include beta-blockers, non-dihydropyridine calcium channel blockers, and disopyramide for refractory cases. Mavacamten, a selective cardiac myosin inhibitor, is indicated for symptomatic oHCM to improve functional capacity and symptoms. Use of disopyramide and mavacamten together is not recommended due to concerns of additive negative inotropic effects. Transitioning from disopyramide to mavacamten may be preferred to avoid adverse effects and frequent administration, however, the best approach for making the transition has not been established. CASES: We present a series of seven patients with oHCM who transitioned from disopyramide to mavacamten and underwent echocardiograms mandated by a Risk Evaluation and Mitigations Strategies program. Two methods were employed. The first approach, involving washout of disopyramide before starting mavacamten, resulted in worsening of heart failure symptoms in the first two cases. The second approach, involving tapering disopyramide when starting mavacamten, was successfully implemented in the last five cases, with no adverse effects or worsening of systolic dysfunction. CONCLUSION: Our method of tapering disopyramide when starting mavacamten using a stepwise approach is feasible and safe. Our report fulfills an unmet need by serving as a guide for other clinicians who seek to transition their patients from disopyramide to mavacamten.
Asunto(s)
Cardiomiopatía Hipertrófica , Disopiramida , Humanos , Disopiramida/uso terapéutico , Cardiomiopatía Hipertrófica/tratamiento farmacológico , Cardiomiopatía Hipertrófica/inducido químicamente , Bencilaminas/efectos adversos , Antagonistas Adrenérgicos betaRESUMEN
BACKGROUND: Left ventricular outflow tract obstruction (LVOTO) is present in 1/3 of children with Hypertrophic Cardiomyopathy (HCM). Disopyramide improves symptoms associated with LVOTO and delays surgical intervention in adults, but it is not licensed in children. AIM: To describe a single-centre thirty-year experience of using disopyramide to treat LVOTO-related symptoms in a paediatric HCM cohort. METHODS: Clinical data were collected for all patients meeting diagnostic criteria for HCM (<18 years) at the time of initiation, 6 months after, and last follow-up or end of disopyramide treatment. It included demographics, clinical history, 12lead electrocardiography, and echocardiography. Comparisons between baseline and 6 month follow up, and end of follow up respectively were performed. RESULTS: Fifty-one patients with HCM were started on disopyramide at a mean age 10.2±5.3 years. At 6 months, of those previously symptomatic, 33(86.8%) reported an improvement of symptoms and 12(31.6%) were asymptomatic. PR interval, corrected QT interval and maximal LVOT gradient had not significantly changed, but fewer participants were noted to have systolic anterior motion of the mitral valve 31 (72.1%) vs. 26 (57.80%). Patients were followed up for a median of 1.9 years (IQR 0.83-4.5). Nine patients (17.6%) reported side effects, and eleven patients (33.3%) with initial improvement in symptoms reported a return or worsening of symptoms requiring a change in medication (n = 4, 12.1%) or left ventricular septal myomectomy (n = 7, 21.2%) during follow up. CONCLUSION: Disopyramide is a safe and effective treatment for LVOTO-related symptoms in childhood obstructive HCM. Any delay in the need for invasive intervention, particularly during childhood, is of clear clinical benefit.
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Cardiomiopatía Hipertrófica , Obstrucción del Flujo Ventricular Externo , Adulto , Humanos , Niño , Preescolar , Adolescente , Disopiramida/uso terapéutico , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Cardiomiopatía Hipertrófica/tratamiento farmacológico , Cardiomiopatía Hipertrófica/complicaciones , Ecocardiografía , Ventrículos Cardíacos/diagnóstico por imagenRESUMEN
The Class Ia antiarrhythmic drug disopyramide (DISO) causes QT interval prolongation that is potentially dangerous in acquired Long QT Syndrome but beneficial in short QT syndrome, through inhibition of the hERG-encoded channels responsible for rapid delayed rectifier K(+) current (I(Kr)). In this study, alanine mutants of hERG S6 and pore helix residues and MthK-based homology modelling and ligand docking were used to investigate molecular determinants of DISO binding to hERG. Whole-cell hERG current (I(hERG)) recordings were made at 37°C from HEK-293 cells expressing WT or mutant hERG channels. WT outward I(hERG) tails were inhibited with an IC(50) of 7.3µM, whilst inward I(hERG) tails in a high [K(+)](e) of 94mM were blocked with an IC(50) of 25.7µM. The IC(50) for the Y652A mutation was ~55-fold that of WT I(hERG); this mutation also abolished a leftward shift in voltage-dependent I(hERG) activation present for WT hERG. The IC(50) for F656A I(hERG) was ~51 fold its corresponding WT control. In contrast to previously studied methanesulphonanilide hERG inhibitors, neither the G648A S6 nor the T623A and S624A pore helical mutations modified DISO IC(50). Computational docking with the hERG model showed that DISO did not exhibit a single unique binding pose; instead several low energy binding poses at the lower end of the pore cavity favoured interactions with Y652 and F656. In the WT hERG model DISO did not interact directly with residues at the base of the pore helix, consistent with the minimal effect of mutation of these residues on drug block.
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Antiarrítmicos/farmacología , Disopiramida/farmacología , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/genética , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Secuencia de Aminoácidos , Relación Dosis-Respuesta a Droga , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/química , Células HEK293 , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , Conformación ProteicaRESUMEN
Human α(1)-acid glycoprotein (hAGP) in serum functions as a carrier of basic drugs. In most individuals, hAGP exists as a mixture of two genetic variants, the F1*S and A variants, which bind drugs with different selectivities. We prepared a mutant of the A variant, C149R, and showed that its drug-binding properties were indistinguishable from those of the wild type. In this study, we determined the crystal structures of this mutant hAGP alone and complexed with disopyramide (DSP), amitriptyline (AMT), and the nonspecific drug chlorpromazine (CPZ). The crystal structures revealed that the drug-binding pocket on the A variant is located within an eight-stranded ß-barrel, similar to that found in the F1*S variant and other lipocalin family proteins. However, the binding region of the A variant is narrower than that of the F1*S variant. In the crystal structures of complexes with DSP and AMT, the two aromatic rings of each drug interact with Phe-49 and Phe-112 at the bottom of the binding pocket. Although the structure of CPZ is similar to those of DSP and AMT, its fused aromatic ring system, which is extended in length by the addition of a chlorine atom, appears to dictate an alternative mode of binding, which explains its nonselective binding to the F1*S and A variant hAGPs. Modeling experiments based on the co-crystal structures suggest that, in complexes of DSP, AMT, or CPZ with the F1*S variant, Phe-114 sterically hinders interactions with DSP and AMT, but not CPZ.
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Orosomucoide/química , Orosomucoide/genética , Amitriptilina/química , Clorpromazina/farmacología , Simulación por Computador , Cristalografía por Rayos X/métodos , Disopiramida/química , Variación Genética , Humanos , Lipocalinas/química , Modelos Biológicos , Mutación , Unión Proteica , Conformación Proteica , Estructura Terciaria de ProteínaRESUMEN
AIMS: Patients undergo ablation for focal atrial fibrillation (AF) as a result of failure of anti-arrhythmic drugs. Our basic studies have implicated cholinergic and adrenergic neurotransmitter release as the underlying mechanism for focal AF. Therefore, we tested the efficacy of a combination of sodium channel-blocking agents with additional vagolytic properties and a ß-blocker to terminate and prevent focal AF. METHODS AND RESULTS: In 18 Na-pentobarbital-anaesthetized dogs, after a right or left thoracotomy, acetylcholine (Ach, 0.5 cc, 100 mM) was injected into a fat pad containing ganglionated plexi (GP) or applied on an atrial appendage (AA) to induce focal firing at the pulmonary veins (PVs) or AA, respectively. Disopyramide (2-4 mg/kg, n= 6) or quinidine (3-6 mg/kg, n= 12) combined with esmolol or propranolol (1 mg/kg, n= 13 and 5, respectively) were slowly injected to terminate (Group I, n= 12) or prevent (Group II, n= 6) Ach-induced sustained focal AF. In another four dogs, only the sodium channel-blocking agents with additional vagolytic properties or only the ß-blocker was injected prior to or after the initiation of focal AF. At baseline, the mean duration of AF induced by Ach was 26 ± 4 min. Group I: After drugs, Ach-induced AF duration was 3 ± 1 min (P< 0.001). Group II: Prior to drugs, Ach-induced AF lasted for 19 ± 3 min. With the drug combination the duration of Ach-induced AF, decreased to 6 ± 1/min, P< 0.001. Either quinidine or propranolol alone did not change the duration of Ach-induced AF, mean 25 ± 10 min compared with Ach alone, 28 ± 16 min, P= 0.2. CONCLUSIONS: Type IA (cholinergic antagonist) plus Type II (ß-adrenergic antagonist) provides significant prevention and suppression of focal AF arising at PV and non-PV sites.
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Antiarrítmicos/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/prevención & control , Acetilcolina/administración & dosificación , Antagonistas Adrenérgicos beta/uso terapéutico , Animales , Apéndice Atrial/efectos de los fármacos , Disopiramida/uso terapéutico , Perros , Quimioterapia Combinada , Venas Pulmonares/efectos de los fármacos , Quinidina/uso terapéutico , Bloqueadores de los Canales de Sodio/uso terapéuticoRESUMEN
Nurses can decrease the risk of adverse drug problems with medication review and prompt interventions. The Beers Criteria lists medications to avoid using among elderly clients. The origin of the Beers Criteria, its 2002 modification, and application in acute care settings are explained.
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Quimioterapia/enfermería , Prescripción Inadecuada , Anciano , Antiarrítmicos/efectos adversos , Disopiramida/efectos adversos , Enfermería Geriátrica , Humanos , Medicamentos sin Prescripción/efectos adversos , Polifarmacia , Psicotrópicos/efectos adversosRESUMEN
The management of syncope is clinically important for heart failure (HF) patients. We herein describe a case on the efficacy of disopyramide for refractory syncope in HF with preserved ejection fraction (HFpEF). An 82-year-old man was hospitalized for respiratory distress and lower limb edema and was subsequently diagnosed with HFpEF. The use of diuretics improved HF symptoms; however, on day 10 after hospitalization, a rapid decrease in blood pressure and transient loss of consciousness developed. After neurologic examination, he was diagnosed with pure autonomic failure. Although he was administered midodrine 8 mg/d, fludrocortisone 0.1 mg/d, and droxidopa 300 mg/d, syncope was observed once a day on average. According to the Holter electrocardiogram, the patient's heart rate and coefficient of variation of R-R intervals (CVRR) during the day were unstable. In addition, high frequency power (parasympathetic nerve activity) was significantly higher than low frequency power (both sympathetic and parasympathetic nerves activity), suggesting that the parasympathetic nerves may have been highly active while the sympathetic nerves would have been blocked. On day 29, a pharmacist proposed disopyramide 300 mg/d, which blocks parasympathetic nerves and improves neural-mediated syncope, to the attending doctor. After the initiation of disopyramide, transient loss of consciousness was not observed. Furthermore, the diurnal variation in the heart rate and CVRR completely disappeared. In conclusion, disopyramide would be effective for refractory syncope in patients with HFpEF, and the Holter electrocardiogram may be a useful tool for the assessment of drug efficacy by pharmacists.
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Disopiramida , Insuficiencia Cardíaca , Anciano de 80 o más Años , Electrocardiografía Ambulatoria/efectos adversos , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Masculino , Volumen Sistólico , Síncope/tratamiento farmacológico , Síncope/etiologíaRESUMEN
AIMS: To evaluate the role of bisoprolol to control symptoms and left ventricular outflow tract obstruction (LVOTO) in a consecutive cohort of adults with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: In this retrospective study, patients with HCM with an LVOT gradient ≥50 mmHg after Valsalva manoeuvre and New York Heart Association (NYHA) class II-III symptoms were assigned to receive bisoprolol (starting at 1.25 mg daily). The initial dose was increased every two weeks to achieve the target in LVOT gradient <30 mmHg or the maximum tolerated dose. The primary endpoint was the achievement of a LVOT gradient <30 mmHg and ≥ 1 NYHA class improvement. The secondary endpoints were proportion of patients with LVOT gradient <30 mmHg or < 50 mmHg, proportion of patients with ≥1 NYHA class improvement, and change from baseline in LVOT gradient. Between December 2001 and December 2020, 92 patients were enrolled into the study. Sixteen (17%) patients on bisoprolol met the primary endpoint. Bisoprolol reduced the LVOT gradient to less than 30 mmHg in 33 (36%) patients, to less than 50 mmHg in 57 (62%), and improved NYHA class in 30 (33%). The mean reduction of LVOT gradient on bisoprolol was 28 (±14) mmHg and the percentage reduction was 42 (±21) %. In 35 (38%) patients, bisoprolol did not reduce the gradient to less than 50 mmHg requiring disopyramide and/or myectomy to achieve this goal. CONCLUSION: Treatment with bisoprolol was well-tolerated and effective in relieving obstruction and improving symptoms in a significant proportion of patients with symptomatic obstructive HCM.
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Cardiomiopatía Hipertrófica , Obstrucción del Flujo Ventricular Externo , Adulto , Bisoprolol/uso terapéutico , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Cardiomiopatía Hipertrófica/tratamiento farmacológico , Disopiramida/uso terapéutico , Humanos , Estudios Retrospectivos , Obstrucción del Flujo Ventricular Externo/diagnóstico por imagen , Obstrucción del Flujo Ventricular Externo/tratamiento farmacológicoRESUMEN
Disopyramide, an antiarrhythmic drug, has been reported to cause hypoglycemia; however, its mechanism of action remains unclear. Pre-existing factors that increase the concentration of the drug in the blood increase the risk of hypoglycemia. Furthermore, other factors can also increase the risk of hypoglycemia even when disopyramide levels are in the therapeutic range. It has been proposed that disopyramide-induced hypoglycemia is caused by stimulation of insulin secretion due to the inhibition of the pancreatic beta-cell ATP-sensitive K+ channels. We report a case of severe disopyramide-induced hypoglycemia in a nondiabetic 72-year-old woman on hemodialysis. Concentrations of counter-regulatory hormones, serum insulin, and C-peptide were measured. From these data, it appears that disopyramide-induced hypoglycemia results from sustained endogenous insulin secretion, with a concomitant inadequate counter-regulatory response. Although hypoglycemia occurs infrequently in patients treated with disopyramide, this adverse effect is clinically important and potentially life-threatening. Evidence suggests that disopyramide-induced hypoglycemia results from endogenous insulin secretion and can occur in patients with therapeutic blood concentrations of the drug. Patients at risk include those with renal impairment, advanced age, and malnutrition, and blood glucose levels should be monitored carefully in such patients.
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Antiarrítmicos/efectos adversos , Fibrilación Atrial/tratamiento farmacológico , Disopiramida/efectos adversos , Hipoglucemia/inducido químicamente , Diálisis Renal , Anciano , Femenino , Humanos , PolifarmaciaRESUMEN
A micellar liquid chromatography (MLC) method using a C18 column was developed to determine three antiarrhythmic drugs--disopyramide, lidocaine, and quinidine--that are most usually monitored in serum samples. After the application of an interpretative strategy for optimization of sodium dodecyl sulfate (SDS) and modifier concentrations in order to ensure the minimum analysis time, maximum sensitivity, and good resolution, the optimum chromatographic conditions for the determination of the three antiarrhythmics were flow rate, 1 mL/min; injection volume, 20 microL; separation temperature, 25 degrees C; mobile phase, 150 mmol/L SDS-7% (v/v) butanol-phosphate buffer, 10 mmol/L, pH 7-0.9% (w/v) NaCl; and detection at 214 nm. The calibration curves for the drugs were linear (r2 > 0.999). The intraday and interday precisions were lower than 3.9% (CV). Recoveries were 100 +/- 0.6% when the method was applied to both serum samples spiked with the antiarrhythmics (n = 10) and real serum samples. In all cases, the results were similar to those obtained using the reference method (fluorescence polarization immunoassay) usually used in the Spanish hospital. The proposed method is useful for hospital monitoring of the antiarrhythmics by direct injection into the chromatograph.
Asunto(s)
Cromatografía Liquida/métodos , Disopiramida/sangre , Lidocaína/sangre , Quinidina/sangre , Antiarrítmicos/sangre , Disopiramida/análisis , Humanos , Lidocaína/análisis , Quinidina/análisis , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Negative ionotropic agents are established treatments for left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM). However, their benefit in those with LVOTO without typical HCM is unclear. We evaluated if negative ionotropic agents are beneficial in treatment of LVOTO in patients without typical HCM. METHOD: In this retrospective cohort study, we evaluated echocardiograms and reviewed records of 15 patients with resting LVOT obstruction due to sigmoid septum (SS, n=9) and mild concentric left ventricular hypertrophy (LVH, n=6). Patients received treatment with sequential negative ionotropic agents (ß-blockers and disopyramide). Initial symptoms, presentation characteristics and echocardiographic characteristics pre and post treatment were evaluated. RESULTS: Fifteen patients (mean age 66.2 years, 46.7% male) were included. Dyspnoea (NYHA Class II/III) was reported as the initial symptom in all patients with four patients reporting chest pain. All patients had hypercontractile LV function at baseline (fractional shortening 46.29±8.77%) but had normal LVS/PW ratio (1.03±0.10). The mean resting LVOT gradient was 74.4±55.2 mmHg. Fourteen patients received initial ß-blocker therapy with a mean reduction in peak LVOT gradient of 40.9 mmHg seen in 11 patients that responded to therapy (p=0.02). Nine patients received disopyramide with a further 24.2±25.8 mmHg reduction in peak LVOT gradient observed in eight patients who tolerated treatment (p=0.04). Symptomatic improvement occurred in 80% of treated patients. CONCLUSIONS: In patients with LVOTO without typical HCM, sequential treatment with negative ionotropes is associated with a significant reduction in the degree of LVOTO and leads to symptomatic improvement.
Asunto(s)
Antagonistas Adrenérgicos beta/administración & dosificación , Antiarrítmicos/administración & dosificación , Cardiomiopatía Hipertrófica Familiar/tratamiento farmacológico , Disopiramida/administración & dosificación , Obstrucción del Flujo Ventricular Externo/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Cardiomiopatía Hipertrófica Familiar/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Ultrasonografía , Obstrucción del Flujo Ventricular Externo/diagnóstico por imagenRESUMEN
The combined effects of disopyramide (DP) and erythromycin (EM) on ventricular repolarization and the inciden-ces of ventricular premature contractions (VPCs) and torsades de pointes (TdP) were investigated in 12 anesthetized dogs with complete atrioventricular block. Monophasic action potentials (MAPs) were measured from the left and right ventricular (LV and RV) endocardium. The right or left ventricle was paced at a cycle length of 750-1000 msec. Dogs were divided into 2 groups and given either intravenous DP at 3 mg/kg and then intravenous EM at 50 mg/kg (group 1, n = 8), or intravenous EM at 50 mg/kg and then intravenous DP at 3 mg/kg (group 2, n = 4). MAP duration at 90% repolarization (MAPD(90)) was measured before drug administration (baseline) and again after administration of each drug. RV MAPD(90) and LV MAPD(90) increased significantly (P < 0.02) after administration of each drug in group 1 (RV MAPD(90): from 247.0 ± 36.3 [baseline] to 283.5 ± 38.3 to 321.8 ± 56.7; LV MAPD(90): from 262.6 ± 49.1 (baseline) to 296.1 ± 58.8 to 351.0 ± 80.6). Early afterdepolarizations developed in 2 group 1 dogs after administration of DP and in 4 additional dogs after administration of EM. Frequent VPCs occurred in 1 dog after administration of DP and in 2 additional dogs after administration of EM, and TdP and ventricular tachycardias developed in 2 of the 3 dogs after administration of EM. Similar trends occurred in group 2. These results indicate a potentially fatal interaction between DP and EM administered in clinically relevant doses.