Structure-activity relationship and cardiac safety of 2-aryl-2-(pyridin-2-yl)acetamides as a new class of broad-spectrum anticonvulsants derived from Disopyramide.

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.

Disopyramide use in infants and children with hypertrophic cardiomyopathy.

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.

Effects of flecainide on left ventricular pressure gradient and symptoms in obstructive hypertrophic cardiomyopathy: a comparison of flecainide and disopyramide.

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.

Early-Morning Type Ventricular Fibrillation With J Wave.

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.

Negative ionotropic agents for the treatment of left ventricular outflow tract obstruction due to sigmoid septum and concentric left ventricular hypertrophy.

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.

Combined effect of disopyramide and erythromycin on ventricular repolarization in dogs with complete atrioventricular block.

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.

Frequent occurrence of postbreakfast syncope due to carotid sinus syndrome after surgery for hypopharyngeal cancer: A case report.

RATIONALE: Syncope often occurs in patients with advanced head and neck cancers due to the stimulation of the autonomic nervous system by the tumor. Here, we describe a case of frequent syncopal episodes after laryngopharyngectomy for hypopharyngeal cancer. As all syncopal episodes were observed during the forenoon, we also evaluated the heart rate variability using ambulatory electrocardiography to determine why the syncopal episodes occurred during a specified period of the day. PATIENT CONCERNS: A 73-year-old Japanese man who underwent laryngopharyngectomy for recurrent hypopharyngeal cancer started experiencing frequent episodes of loss of consciousness that occurred during the same time period (10:00-12:00). He had never experienced syncopal episodes before the operation. From 23 to 41 days postoperatively, he experienced 9 syncopal episodes that occurred regardless of his posture. DIAGNOSES: Pharyngo-esophagoscopy revealed an anastomotic stricture between the free jejunum graft and the upper esophagus. Swallowing videofluoroscopy confirmed the dilatation of the jejunal autograft and a foreign body stuck on the oral side of the anastomosis. Contrast-enhanced computed tomography revealed that the carotid artery was slightly compressed by the edematous free jejunum. The patient was diagnosed with carotid sinus syndrome (CSS) as the free jejunum was dilated when consuming breakfast, which may have caused carotid sinus hypersensitivity and induced a medullary reflex. INTERVENTIONS: Administration of disopyramide was effective in preventing syncope. Heart rate variability analysis using ambulatory electrocardiography showed that parasympathetic dominancy shifted to sympathetic dominancy during 10:00 to 12:00. The significant time regularity of the syncopal episodes may have been affected by modified diurnal variation in autonomic tone activity. OUTCOMES: After the surgical release and re-anastomosis of the pharyngoesophageal stenosis via an open-neck approach, no recurrent episodes of syncope were reported. LESSONS: We reported a case of frequent syncopal episodes limited to the forenoon due to CSS after surgery for hypopharyngeal carcinoma. The patient was treated with anticholinergics followed by the release and re-anastomosis of the pharyngoesophageal stenosis. When syncope occurs after surgery for head and neck lesions, CSS due to postoperative structural changes should be considered as a differential diagnosis of syncope.

Prospective comparative study of intravenous cibenzoline and disopyramide therapy in the treatment of paroxysmal atrial fibrillation after cardiovascular surgery.

BACKGROUND: It has been reported that approximately one-third of patients undergoing cardiovascular surgery experience paroxysmal atrial fibrillation (AF) during the postoperative period. There is, however, little information on the selection of anti-arrhythmic drugs for terminating postoperative paroxysmal AF. METHODS AND RESULTS: Between April 2007 and March 2009, 118 patients (76 men, 42 women, mean age 68+/-10 years) who had postoperative paroxysmal AF lasting > or =30 min were randomly assigned to receive either iv cibenzoline (70 mg, n=60) or disopyramide (50 mg, n=58) for terminating postoperative paroxysmal AF. The success rate of iv cibenzoline therapy (47%) was significantly greater than that of iv disopyramide therapy (24%; P<0.05). To identify clinical factors to increase the termination efficacy of iv cibenzoline, multivariate logistic regression was used to adjust for several covariates and to generate adjusted odds ratios (OR). The significant variables for the termination of paroxysmal AF after iv cibenzoline therapy were pretreatment with oral beta-adrenergic blockers (OR =8.224, P=0.030) and smaller left atrial dimensions (OR =0.879, P=0.039). CONCLUSIONS: The efficacy of iv cibenzoline for the termination of postoperative paroxysmal AF was significantly better than that of disopyramide, especially in patients with pre-administration of oral beta-adrenergic blockers and those with smaller left atrium.

Oral disopyramide for the acute treatment of severe outflow obstruction in hypertrophic cardiomyopathy in the ICU setting.

When severe COPD and obstructive hypertrophic cardiomyopathy (HCM) coexist, management is challenging and complex. Drug contraindications limit pharmacologic options. Patients may not be candidates for surgical septal myectomy due to severe pulmonary disease. We describe a case of an elderly woman with severe reactive COPD who presented with an infectious exacerbation and dyspnea that progressed to near intubation due to heart failure from coexistent obstructive HCM. Transthoracic echocardiography revealed massive asymmetric septal hypertrophy and a diffusely hyperkinetic left ventricle with a left ventricular outflow tract (LVOT) gradient of 92 mm Hg. Two and a half hours after oral administration of disopyramide, LVOT gradient had decreased to 25 mm Hg with a corresponding immediate improvement in symptoms.

Nifekalant and disopyramide in a patient with short QT syndrome: evaluation of pharmacological effects and electrophysiological properties.

We assessed several pharmacological effects on electrocardiogram parameters and effective refractory period (ERP) in a patient with a short QT syndrome (SQTS). Pharmacological challenge tests revealed that disopyramide and selective I(kr) blocker, nifekalant normalized QT interval, and ERP of the atrial and ventricular myocardium. This study suggested that disopyramide and nifekalant should be feasible for the drug treatment of the SQTS. Moreover, QT interval was paradoxically prolonged at higher heart rates induced with isoproterenol infusion or an exercise test, although the mechanism of this QT prolongation remains to be investigated.

Safety of Outpatient Initiation of Disopyramide for Obstructive Hypertrophic Cardiomyopathy Patients.

BACKGROUND: Disopyramide is effective in ameliorating symptoms in patients with hypertrophic cardiomyopathy; however, its potential for proarrhythmic effect has raised concerns about its use in the ambulatory setting. The risk of initiating disopyramide in this manner has never been evaluated. METHODS AND RESULTS: All charts of patients seen in the outpatient hypertrophic cardiomyopathy clinic between 2010 and 2014 were screened for initiation of disopyramide and data were extracted. Disopyramide in our clinic is usually initiated at a dose of 300 mg daily and titrated during follow-up. A total of 2015 patients were seen in the clinic, including 168 who were started on disopyramide. There were no cardiac events within 3 months of disopyramide initiation. During long-term follow-up (255 patient-years; mean, 447 days; interquartile range, 201-779), only 2 patients developed cardiac events (syncope of unknown cause in both). Thirty-eight patients (23%) developed side effects of disopyramide and 18 (11%) stopped the drug because of these side effects. Of the patients continuing disopyramide long term, 63% remained free of septal reduction interventions at end of follow-up. Disopyramide at a dose of 300 mg prolonged the mean QTc interval by 19±23 ms; however, increasing the dose to 600 mg had no further significant effect. CONCLUSIONS: Initiation of disopyramide in the outpatient setting is safe and the risk of subsequent sudden cardiac death is low. Because of its QT-prolonging effect, precautions may be necessary in patients at higher risk of torsades de pointes.

Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy.

OBJECTIVES: In this study we assessed the long-term efficacy and safety of disopyramide for patients with obstructive hypertrophic cardiomyopathy (HCM). BACKGROUND: It has been reported that disopyramide may reduce left ventricular outflow gradient and improve symptoms in patients with HCM. However, long-term efficacy and safety of disopyramide has not been shown in a large cohort. METHODS: Clinical and echocardiographic data were evaluated in 118 obstructive HCM patients treated with disopyramide at 4 HCM treatment centers. Mortality in the disopyramide-treated patients was compared with 373 obstructive HCM patients not treated with disopyramide. RESULTS: Patients were followed with disopyramide for 3.1 +/- 2.6 years; dose 432 +/- 181 mg/day (97% also received beta-blockers). Seventy-eight patients (66%) were maintained with disopyramide without the necessity for major non-pharmacologic intervention with surgical myectomy, alcohol ablation, or pacing; outflow gradient at rest decreased from 75 +/- 33 to 40 +/- 32 mm Hg (p < 0.0001) and mean New York Heart Association functional class from 2.3 +/- 0.7 to 1.7 +/- 0.6 (p < 0.0001). Forty other patients (34%) could not be satisfactorily managed with disopyramide and required major invasive interventions because of inadequate symptom and gradient control or vagolytic side effects. All-cause annual cardiac death rate between disopyramide and non-disopyramide-treated patients did not differ significantly, 1.4% versus 2.6%/year (p = 0.07). There was also no difference in sudden death rate, 1.0%/year versus 1.8%/year (p = 0.08). CONCLUSIONS: Two-thirds of obstructed HCM patients treated with disopyramide could be managed medically with amelioration of symptoms and about 50% reduction in subaortic gradient over >/=3 years. Disopyramide therapy does not appear to be proarrhythmic in HCM and should be considered before proceeding to surgical myectomy or alternate strategies.

Pathophysiology of hypertrophic cardiomyopathy determines its medical treatment.

Physicians treating hypertrophic cardiomyopathy (HCM) are faced with unique management challenges. Understanding pathophysiology and overall good prognosis forms the basis for medical treatment. Treatment is tailored by the presence or absence of outflow tract gradient and individual symptoms. In all patients, formal stratification for sudden death risk is necessary, with consideration of defibrillator implantation in patients deemed to be at high risk. In patients with no or only mild symptoms the approach of watchful waiting is often appropriate. For symptomatic patients with non-obstructed disease medical treatment with calcium channel blockers and beta-blockers is aimed to improve heart failure symptoms, and ischemia. Verapamil is the most often used, with likely benefit of relieving ischemia. Obstruction, most commonly due to systolic anterior motion of the mitral valve (SAM) and mitral-septal contact, occurs in >/=50% of all HCM patients, worsening symptoms and increasing mortality. Successful medical treatment of obstruction with negative inotropes slows acceleration of left ventricular ejection with delay in SAM, ultimately yielding a lower pressure gradient. Beta -blockers are the first line treatment in obstructive HCM predominantly by mitigating provocable gradients. The magnitude of symptom relief with verapamil is similar to the effect of beta -blockade. Disopyramide combined with beta -blockade is thought by some to be the most effective medical treatment of obstruction, and has been shown to be safe and not pro-arrhythmic. Most symptomatic HCM patients with significant obstruction at rest or provocation can be successfully managed with long-term medication alone.

Combination of disopyramide and mexiletine for better tolerance and additive effects for treatment of ventricular arrhythmias.

The efficacy and tolerance of disopyramide and mexiletine used alone and in combination were studied in 21 patients with frequent (greater than or equal to 30/h) ventricular premature complexes. Ambulatory electrocardiographic monitoring was performed at baseline and during therapy with disopyramide alone, mexiletine alone and a combination of disopyramide and mexiletine. During single drug therapy, the dose of disopyramide was 602 +/- 152 mg/day and that of mexiletine was 738 +/- 144 mg/day. During combination therapy with smaller doses of disopyramide (524 +/- 134 mg/day) and mexiletine (652 +/- 146 mg/day), no patient had side effects. At baseline before therapy, the mean number of ventricular premature complexes per hour, was 608 +/- 757, of couplets per hour was 22.4 +/- 45.8 and of episodes of nonsustained ventricular tachycardia/24 h was 219.7 +/- 758.2. The mean number of ventricular premature complexes per hour was reduced to 156 +/- 217 with disopyramide alone, 188 +/- 298 with mexiletine alone and 76 +/- 144 with combination therapy (p less than 0.05 for combination therapy versus disopyramide or mexiletine alone; p = NS for disopyramide versus mexiletine). Individually, an effective regimen (greater than 83% reduction in ventricular premature complexes and abolition of nonsustained ventricular tachycardia) was found in 5 (24%) of 21 patients during therapy with disopyramide alone, in 3 (14%) receiving mexiletine alone and in 13 (62%) receiving combination therapy (p less than 0.05 for combination therapy versus disopyramide or mexiletine; p = NS for disopyramide versus mexiletine). Thus, the antiarrhythmic effects of disopyramide and mexiletine are additive.(ABSTRACT TRUNCATED AT 250 WORDS)

A placebo-controlled trial of intravenous and oral disopyramide for prevention of neurally mediated syncope induced by head-up tilt.

OBJECTIVES: A double-blind randomized trial was designed to determine the efficacy of intravenous and oral disopyramide phosphate in preventing neurally mediated syncope induced by a head-up tilt test. BACKGROUND: Neurally mediated syncope is a frequent cause of syncope and may be induced by head-up tilt testing. Recent uncontrolled trials have suggested that disopyramide may be an effective therapy in patients with neurally mediated syncope. METHODS: Twenty-two consecutive patients with recurrent neurally mediated syncope and two or more successive positive head-up tilt test responses were randomly allocated to receive either intravenous disopyramide or placebo. Head-up tilt testing at 60 degrees was performed for 15 min. If presyncope or syncope was not provoked, isoproterenol infusion was started at a rate of 1 microgram/min and the rate gradually increased until a 25% increase in heart rate was achieved. Eleven patients were subsequently randomized in crossover fashion to receive oral disopyramide (800 mg/day) or placebo during 1 week. The primary end point was prevention of syncope or presyncope provoked by head-up tilt testing. RESULTS: Head-up tilt test results were positive for syncope in 12 (75%) of 16 patients receiving intravenous placebo and in 12 (60%) of 20 patients receiving disopyramide (p = 0.55 Fisher exact test, 95% confidence interval [CI] -14% to 40%). In the intravenous phase, complete crossover was achieved in 15 patients. Head-up tilt test results during this phase were positive in 13 patients (87%) receiving placebo and in 12 patients (80%) receiving disopyramide (p = 0.50 Fisher exact test, 95% CI -19% to 32%) and were positive in all patients receiving their initially randomized drug or placebo. In the oral phase, head-up tilt results were positive in only two patients (18%) assigned to placebo and in three patients (27%) receiving disopyramide (p = 0.54 Fisher exact test, 95% CI -42% to 24%). A mean follow-up time of 29 +/- 8 months was obtained in 21 of the 22 patients. Syncope recurred in 3 (27%) of the 11 patients receiving disopyramide and 3 (30%) of the 10 patients not treated pharmacologically (p > 0.05). CONCLUSIONS: Intravenous disopyramide was ineffective for the prevention of neurally mediated syncope provoked by head-up tilt testing. No significant effect was observed after oral therapy with disopyramide. There was a striking decrease in the incidence of positive tilt test results over time regardless of intervention, thus discouraging the use of head-up tilt as the single method of assessing therapeutic efficacy. Recurrence of syncope after the investigative protocol was infrequent over long-term follow-up regardless of treatment group.

Concordance and discordance of drug responses in atrioventricular reentrant tachycardia.

Whether the results of some drug studies could be used to predict the results of other drug studies was examined during serial electrophysiologic drug testing in patients with sustained atrioventricular reentrant tachycardia. The drugs studied were intravenous propranolol, 0.1 mg/kg; intravenous ouabain, 0.01 mg/kg; the combination of propranolol plus ouabain; intravenous procainamide, 0.75 to 1.5 g; oral quinidine, 1.2 to 2.4 g/day; and oral disopyramide, 0.8 to 1.6 g/day. Response was inability to induce sustained tachycardia after administration of a drug. Responses due to increased anterograde limb refractoriness. Six of 10 patients with response to propranolol plus ouabain versus 0 of 9 patients without response to this combination had response to propranolol alone (p less than 0.01). Seven of 14 patients with response to the combination versus 0 of 9 patients without response to the combination had response to ouabain alone (p less than 0.05). Responses due to increased retrograde limb refractoriness. Eight of 9 patients with response to procainamide versus 2 of 17 patients without response to this drug had response to quinidine (p less than 0.01). There was not a significant relation between response to procainamide and response to disopyramide, or between response to quinidine and response to disopyramide. Anterograde limb versus retrograde limb. There was not a significant relation between response to propranolol plus ouabain and response to any class I drug. In conclusion, there are relations between drug responses during electrophysiologic studies in patients with atrioventricular reentrant tachycardia. Thus, it should be possible to simplify these studies.

Comparative study of encainide and disopyramide in chronic ventricular arrhythmias: a double-blind placebo-controlled crossover study.

Ten patients suffering from chronic premature ventricular complexes (greater than 60/h) were treated orally in a double-blind crossover study with encainide (50 mg three times a day) and disopyramide (200 mg three times a day), with five 7 day study periods: survey, placebo, encainide or disopyramide, washout placebo and disopyramide or encainide. At the end of each 7 day period, a 12 lead electrocardiogram, a 48 hour ambulatory electrocardiogram and a treadmill exercise test were performed. Blood levels of encainide and its metabolites and of disopyramide were measured at the end of each treatment (steady state). Drug efficacy was assessed by: 1) more than 80% reduction in the number of premature ventricular complexes per 24 hours, and 2) absence of ventricular tachycardia. Encainide was effective in four patients (complete suppression of premature ventricular complexes) and ineffective in five. One patient who showed a 92% reduction in the number of premature ventricular complexes developed sustained ventricular tachycardia after 24 hours of treatment. Disopyramide was effective in three patients (greater than 80% reduction in the number of premature ventricular complexes) and ineffective in seven patients. With encainide, the percent increase in PR, QRS and QT interval duration was, respectively: 32.7 (p less than 0.001), 30.8 (p less than 0.001) and 10.6% (p less than 0.01). With disopyramide this increase was not significant. Despite the variability of drug blood levels, a relation between blood levels and suppression of premature ventricular complexes on the 48 hour ambulatory electrocardiogram was found with encainide, but not with disopyramide.(ABSTRACT TRUNCATED AT 250 WORDS)

Human atrial repolarization: effects of sinus rate, pacing and drugs on the surface electrocardiogram.

OBJECTIVES: We studied the effects of rate and some cardioactive drugs on the atrial surface electrocardiogram (ECG). BACKGROUND: In atrioventricular block, atrial surface ECG is unmasked. The effect of rate alone permits detection of the effect of other exogenous stimulations such as drugs in the presence of rate alterations. METHODS: High fidelity, high gain ECG leads I, II and III were recorded from 51 patients with heart block. Durations of P and Ta waves and the total PTa interval were measured from nonconducted atrial events. RESULTS: No relationship was found between sinus cycle length and PTa, P or Ta in 31 patients. In 20 patients, progressively decreasing the atrial pacing cycle length from 853 ms to 381 ms resulted in a linear reduction of the PTa interval from 444 to 291 ms (rho = 0.76, slope = 0.24). This was largely due to shortening of Ta. A linear rate correction formula was derived: corrected PTa = PTa - 0.24 (PP - 1000). Atropine (0.02 mg/kg) shortened the PP interval (p < 0.001) and the PTa interval (p < 0.01). Propranolol (0.1 mg/kg) prolonged the PP interval (p < 0.001) but did not alter the PTa interval. Neither disopyramide (2.0 mg/kg) nor flecainide acetate (2.0 mg/kg) altered the PP interval, but both prolonged the PTa interval (p < 0.001). This was largely due to P wave lengthening after flecainide (p < 0.001) and to Ta prolongation after disopyramide (p < 0.001). CONCLUSIONS: In heart block, PTa, P and Ta waves can be measured reliably. The effects of pacing and some antiarrhythmic drugs on the atrial myocardium are similar to those known at the ventricular level.

Disopyramide for Hypertrophic Cardiomyopathy: A Pragmatic Reappraisal of an Old Drug.

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by unexplained left ventricular hypertrophy in the absence of other cardiac or systemic etiologies. Approximately two-thirds of patients with HCM develop left ventricular outflow tract (LVOT) obstruction with or without provocation, whereas nearly half develop heart failure with preserved ejection fraction. Medical management of heart failure with preserved ejection fraction is based on the presence of symptoms and LVOT obstruction and frequently includes ß-blockers or verapamil. Disopyramide is a class Ia antiarrhythmic that historically was used for the treatment of arrhythmias; however, its contemporary use is often reserved for patients with HCM who are persistently symptomatic despite ß-blockers or verapamil and have evidence of LVOT obstruction. The pharmacologic rationale for use of disopyramide is largely based on its strong negative inotropic property. Three clinical studies have showed significant improvements in heart failure symptoms and a reduction in the need for invasive therapy in patients treated with disopyramide. Appropriate dosing and monitoring of disopyramide are important to mitigate the potential for anticholinergic adverse events and proarrhythmias. Disopyramide is a safe and effective medication that reduces heart failure symptoms and LVOT gradient and delays the need for invasive therapy in patients with obstructive HCM.

Disopyramide hemodialysis and kinetics in patients requiring long-term hemodialysis.

Disopyramide hemodialysis and kinetics after 200 mg orally in six patients receiving long-term hemodialysis were examined. Mean volume of distribution (area) was 66.5 +/- 13 l. Mean times of the peak serum concentration and mean peak serum concentration were 2.3 +/- 0.9 hr and 3.1 +/- 0.9 microgram/ml. Mean absorption half-life (t 1/2) was 21.6 +/- 12.5 min. Mean disopyramide elimination t 1/2 during dialysis was 16.8 +/- 11.9 hr, not significantly different from mean elimination t 1/2 without dialysis of 16.1 +/- 5.2 hr. End-dialysis bath concentrations of disopyramide showed that not more than 2.4% of the dose was dialyzed during a 2-hr dialysis period. Our data indicate that at therapeutic concentrations disopyramide was not appreciably dialyzed.