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J S Sarma

Publications and source records attributed to J S Sarma.

At least 19 recordsLinked to original sources
PubMed2001

What niche will newer class III antiarrhythmic drugs occupy?

The decline in the use of sodium channel blockers has led to an expanding use of b-blockers and complex class III agents such as sotalol and amiodarone for controlling cardiac arrhythmias. Success with these agents in the context of their side effects has spurred the development of compounds with simpler ion channel-blocking properties with less complex adverse reactions. The resulting so-called pure class III agents were found to have antifibrillatory effects in atrial fibrillation (AF) and flutter, as well as in ventricular tachyarrhythmias. Pure class III compounds are effective in inducing acute chemical conversion of AF, in preventing paroxysmal AF, and in maintaining sinus rhythm in patients with persistent AF restored to sinus rhythm. Examples of such compounds are dofetilide, which selectively blocks IKr, and ibutilide, available only as an intravenous agent, which blocks the IKr and augments the inactivated Na+ current in atrial myocytes. Dofetilide and ibutilide have been introduced into clinical practice. Azimilide is the first of the class III agents that blocks both components (IKr and IKs) of the delayed rectifier current, which may confer certain electrophysiologic advantages. The potential therapeutic niche of ibutilide, dofetilide, and azimilide in the control of cardiac arrhythmias forms the basis of this review.

Anti-Arrhythmia Agents↗
PubMed1999

Electrophysiological effects of dronedarone (SR33589), a noniodinated benzofuran derivative, in the rabbit heart : comparison with amiodarone.

BACKGROUND: To overcome the side effects of amiodarone (AM), its noniodinated analogue, dronedarone (SR), was synthesized. In this study, its electrophysiological effects were compared with those of AM in rabbit hearts. METHODS AND RESULTS: Five animal groups (n=7 each) for 3 weeks received daily oral treatment of 1 of these regimens: (1) control, vehicle only; (2) AM 50 mg/kg (AM50); (3) AM 100 mg/kg (AM100); (4) SR 50 mg/kg (SR50); and (5) SR 100 mg/kg (SR100). ECGs were recorded before drug and at 3 weeks of drug before euthanasia. Action potentials were recorded from isolated papillary muscle and sinoatrial node by microelectrode techniques. The short-term effects were studied in controls (n=5) at various concentrations of SR (0 to 10 micromol/L) in tissue bath. Action potential duration at 50% (APD(50)) and 90% (APD(90)) repolarization and upstroke dV/dt (V(max)) at various cycle lengths were compared by ANOVA with repeated measures. Compared with control, AM and SR increased RR, QT, and QTc intervals (P<0.0001 for all). Ventricular APD(50) and APD(90) were lengthened by 20% to 49% as a function of dose (P<0.005 to <0.0001) and cycle length (P<0.001). SR100 effects were greater than those of AM100 (P<0.002). V(max) was decreased by both AM100 (P<0.0001) and SR100 (P<0.01). Sinoatrial node automaticity was slowed in treated groups compared with that of the control group (P<0.0001 for all). CONCLUSIONS: The electrophysiological effects of dronedarone are similar to those of AM but more potent, despite deletion of iodine from its molecular structure, a finding of importance for the development of future class III antiarrhythmic compounds.

Amiodarone↗
PubMed1999

Antiarrhythmic agents for atrial fibrillation: focus on prolonging atrial repolarization.

Atrial fibrillation (AF) has been the subject of considerable attention and intensive clinical research in recent years. Current opinion among physicians on the management of AF favors the restoration and maintenance of normal sinus rhythm. This has several potential benefits, including the alleviation of arrhythmia-associated symptoms, hemodynamic improvements, and possibly a reduced risk of thromboembolic events. After normal sinus rhythm has been restored, antiarrhythmic therapy is necessary to reduce the frequency of AF recurrence. In the selection of an antiarrhythmic agent, both efficacy and safety should be taken into consideration. Many antiarrhythmic agents have the capacity to provoke proarrhythmia, which may result in an increase in mortality. This is of particular concern with sodium-channel blockers in the context of patients with structural heart disease. Flecainide and propafenone are well tolerated and effective in maintaining sinus rhythm in patients without significant cardiac disease but with AF. Recent interest has focused on the use of class III antiarrhythmic agents, such as amiodarone, sotalol, dofetilide (recently approved), ibutilide (approved for chemical conversion of AF and atrial flutter), and azimilide (still to be approved) in patients with AF and structural heart disease. To date, amiodarone and sotalol still hold the greatest interest, and although controlled clinical trials with these agents have been few, a number are in progress and some have been recently completed. These agents are effective in maintaining normal sinus rhythm in patients with paroxysmal and persistent AF and are associated with a low incidence of proarrhythmia when used appropriately. Because of the relative paucity of placebo-controlled trials of antiarrhythmic agents in patients with AF, experience until recently has tended to dictate treatment decisions. Increasingly, selection of drug therapy is being based on a careful and individualized benefit-risk evaluation by means of controlled clinical trials, an approach that is likely to dominate the overall approach to the control of atrial fibrillation in the largest numbers of cases of the arrhythmia. Pharmacologic therapy is likely to be dominated by compounds that exert their predominant effect by prolonging atrial repolarization.

Amiodarone↗
PubMed1999

Ventricular rate control in chronic atrial fibrillation during daily activity and programmed exercise: a crossover open-label study of five drug regimens.

OBJECTIVES: We compared the effects of five pharmacologic regimens on the circadian rhythm and exercise-induced changes of ventricular rate (VR) in patients with chronic atrial fibrillation (CAF). BACKGROUND: Systematic comparison of standardized drug regimens on 24 h VR control in CAF have not been reported. METHODS: In 12 patients (11 male, 69+/-6 yr) with CAF, the effects on VR by 5 standardized daily regimens: 1) 0.25 mg digoxin, 2) 240 mg diltiazem-CD, 3) 50 mg atenolol, 4) 0.25 mg digoxin + 240 mg diltiazem-CD, and 5) 0.25 mg digoxin + 50 mg atenolol; were studied after 2 week treatment assigned in random order. The VR data were analyzed by ANOVA with repeated measures. The circadian phase differences were evaluated by cosinor analysis. RESULTS: The 24-h mean (+/-SD) values of VR (bpm) were - digoxin: 78.9 +/- 16.3, diltiazem: 80.0+/-15.5, atenolol: 75.9+/-11.7, digoxin + diltiazem: 67.3+/-14.1 and digoxin + atenolol: 65.0+/-9.4. Circadian patterns were significant in each treatment group (p < 0.001). The VR on digoxin + atenolol was significantly lower than that on digoxin (p < 0.0001), diltiazem (p < 0.0002) and atenolol (p < 0.001). The time of peak VR on Holter was significantly delayed with regimens 3 and 5 which included atenolol (p < 0.03). During exercise, digoxin and digoxin + atenolol treatments resulted in the highest and lowest mean VR respectively. The exercise Time-VR plots of all groups were nearly parallel (p = ns). The exercise duration was similar in all treatment groups (p = ns). CONCLUSIONS: This study indicates that digoxin and diltiazem, as single agents at the doses tested, are least effective for controlling ventricular rate in atrial fibrillation during daily activity. Digoxin + atenolol produced the most effective rate control reflecting a synergistic effect on the AV node. The data provides a basis for testing the effects of chronic suppression of diurnal fluctuations of VR on left atrial and ventricular function in CAF.

Aged↗
PubMed1994

Circadian and power spectral changes of RR and QT intervals during treatment of patients with angina pectoris with nadolol providing evidence for differential autonomic modulation of heart rate and ventricular repolarization.

This study evaluates the effects of autonomic manipulation by chronic beta blockade with nadolol on the circadian and power spectral changes of heart rate and QT interval. It was hypothesized that differential innervation of the atria and ventricles by sympathetic and parasympathetic fibers may produce differential effects on heart rate and QT interval variabilities. Holter recordings of 12 male patients (age 63 +/- 7 years) with stable angina were analyzed before and after 3 weeks of nadolol therapy. The QT intervals were individually normalized by an exponential formula to study the circadian variation of QTc. Power spectra of RR and uncorrected QT intervals were obtained by fast-Fourier analysis from 256 consecutive sinus beats during the day at maximal heart rate and during the night at minimal heart rate. Frequency-specific variability was determined from areas under the spectral plots. Both heart rate and QTc exhibited significant circadian patterns (p < 0.01) in opposite phase with each other. Mean heart rate was significantly reduced with nadolol (81 +/- 12 vs 67 +/- 12 beats/min, p < 0.001), with greater reduction during daytime. The mean QTc was unexpectedly reduced after nadolol treatment, with borderline significance (p = 0.06). The RR variability in the frequency range of 0.05 to 0.25 Hz was significantly increased with nadolol at 3:00 A.M. (p < 0.01) but not at 1:00 P.M. The QT variability in the same frequency range of was not significantly increased with nadolol. The power spectra of RR and QT intervals were dissimilar except at the lower frequencies around 0.05 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1994

Amiodarone decreases Na,K-ATPase alpha 2 and beta 2 expression specifically in cardiac ventricle.

Studies have suggested that chronic amiodarone treatment (a class III antiarrhythmic) may have effects on the myocardium that resemble those of hypothyroidism. Since hypothyroidism is associated with decreased expression of Na,K-ATPase alpha 1, alpha 2 and beta 1 subunits in heart and alpha 2 subunit in skeletal muscle, we aimed to test the hypothesis that chronic in vivo administration of amiodarone would result in changes in the expression of Na,K-ATPase isoforms that resembled those seen in hypothyroid rat. Rats were treated with 40 micrograms/g body weight amiodarone for 3 and 6 weeks. Na,K-ATPase alpha 1, alpha 2, beta 1 mRNA and protein levels and beta 2 mRNA were measured in cardiac ventricle and skeletal muscle. After 3 weeks of amiodarone cardiac alpha 1, alpha 2 and beta 1 protein levels were decreased to 0.65, 0.42, and 0.54 of control, respectively. After 6 weeks of treatment, cardiac alpha 1 and beta 1 levels returned to control and alpha 2 remained depressed. At the mRNA level alpha 2 and beta 2 decreased to 0.6-fold of control after 6 weeks treatment. There was no effect of amiodarone on skeletal muscle Na,K-ATPase expression at either time point. We conclude that the effects of amiodarone on myocardial Na,K-ATPase expression are similar to those of hypothyroidism after 3 weeks of amiodarone treatment, but by 6 weeks the similarities are limited to the decrease in alpha 2 and beta 2 expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMed1994

Effects of amiodarone on the circadian rhythm and power spectral changes of heart rate and QT interval: significance for the control of sudden cardiac death.

Effects of chronic amiodarone therapy on the circadian rhythmicity and power spectral changes of heart rate and QT intervals from Holter recordings were evaluated in three groups of patients: group 1 baseline (n = 10); group 2, treated for 3 to 6 months (n = 11); and group 3, treated for > 1 year (n = 13). Amiodarone reduced heart rate, which reached steady state at 3 to 6 months; bradycardia was evident during the entire 24 hours. The corrected QT (QTc) interval increased as a function of treatment duration. It was 457 +/- 39, 530 +/- 28 (p < 0.001), and 581 +/- 36 (p < 0.0002) msec for groups 1, 2, and 3, after 6 months, respectively. The circadian rhythmicity of QTc was abolished in group 3. Power spectral analysis showed a tendency for amiodarone to reduce both R-R and QT interval variabilities, suggesting inhibition of autonomic control on the heart by the drug. The effectiveness of amiodarone against ventricular arrhythmias may result in part from the sustained bradycardia in concert with continuous uniform prolongation of myocardial repolarization.

Aged↗
PubMed1993

Circadian rhythmicity of heart rate and QTc interval in diabetic autonomic neuropathy: implications for the mechanism of sudden death.

Patients with diabetic autonomic neuropathy (DAN) exhibit decreased heart rate variability (HRV) and are prone to sudden death. When HRV was used as an index of DAN, the circadian rhythmicity of heart rate and QT intervals was studied in 17 patients with diabetes who had varying degrees of DAN and 13 healthy control subjects. Heart rate and QT and QTc intervals for all subjects were found to exhibit a significant circadian periodicity. Heart rate was lowest and QT and QTc intervals were longest between midnight and 6:00 AM; heart rate increased and QT and QTc intervals shortened in the hours after waking. The diabetic group with more severe autonomic neuropathy (DAN+, HRV = 76 +/- 20 msec, n = 7) had significantly higher heart rate and shorter QT and QTc intervals compared with the diabetic group without autonomic neuropathy (DAN-, HRV = 120 +/- 13 msec, n = 10) or healthy control subjects (CT, HRV = 119 +/- 26 msec, n = 13). Twenty-four-hour mean heart rate was 90 +/- 7 beats/min (range, 79 to 98 beats/min) for DAN+, 77 +/- 8 beats/min (range, 64 to 86 beats/min) for DAN- (DAN+ vs DAN-; p = 0.005), and 74 +/- 7 beats/min (range, 64 to 80 beats/min) for CT (DAN+ vs CT; p = 0.0004). Mean 24-hour QTc was 391 +/- 13 msec (range, 387 to 399) msec for DAN+, 417 +/- 19 msec (range, 413 to 425 msec) for DAN- (DAN+ vs DAN-; p = 0.01), and 412 +/- 28 msec (range, 408 to 419 msec) for CT (DAN+ vs CT; p = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Autonomic Nervous System Diseases↗
PubMed1992

Electrophysiologic effects of ambasilide (LU 47110), a novel class III antiarrhythmic agent, on the properties of isolated rabbit and canine cardiac muscle.

Electrophysiologic effects of ambasilide in canine isolated cardiac muscle driven at 1 Hz and in rabbit sinoatrial (SA) node preparations were determined by standard microelectrode technique. Ambasilide (10(-7)-10(-5) M) produced concentration-dependent increases in action potential duration measured at -80 mV (APD-80) repolarization time in canine ventricular muscle and in Purkinje fibers. APD measured at -20 mV (APD-20) was also increased in ventricular muscle, but it shortened with 10(-5) M in Purkinje fibers; at this concentration, there was a negligible change in the amplitude and the maximum upstroke velocity (Vmax) of action potentials and in the resting membrane potential. With the stimulation frequency between 30/min and 120/min, ambasilide (10(-5) M) produced a parallel increase in APD-80 as well as in APD-20 of ventricular muscle. In Purkinje fibers, the prolonging effect of ambasilide on APD-80 was more pronounced at lower stimulation frequency, whereas APD-20 shortened at all stimulation frequencies. Ambasilide at 10(-5) M also produced a prolongation of the effective refractory period (ERP) in Purkinje fibers. The drug produced no significant change in the frequency-dependent relationship between ERP and APD-80. A small but significant frequency-dependent inhibition of Vmax was noted in both ventricular muscle and Purkinje fibers. When the stimulus cycle length was reduced from 1,000 to 300 ms, Vmax in ventricular muscle decreased by 8.4 +/- 3.4% in control solution but by 22.6 +/- 5.6% after 10(-5) M ambasilide (n = 8, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Aminobenzoates↗
PubMed1992

Effect of ambasilide, a new class III agent, on plateau currents in isolated guinea pig ventricular myocytes: block of delayed outward potassium current.

The actions of ambasilide (LU-47110) on the action potential and membrane currents of isolated guinea pig ventricular myocytes were studied using voltage clamp techniques. Ambasilide (1 microM) prolonged the action potential (APD) at 20, 50 and 90% repolarization by 11.2 +/- 4.3, 13.8 +/- 3.9 and 13.6 +/- 3.7%, respectively, compared to control (n = 10). APD prolongation was attributed to the block of delayed rectifier outward current (Ik) in a concentration-dependent fashion (0.01-10 microM). The effects on the APD and Ik were both partially reversed after perfusion with drug-free Tyrode's solution. The block of Ik by ambasilide was compared to that by E-4031 (5 microM), a putative selective blocker of that fast, inwardly rectifying component of Ik identified in guinea pig ventricle. E-4031 produced about 65% block of Ik for pulse durations between 80 and 420 msec, but the block decreased as the pulse duration increased further, the block accounting for 34 +/- 5% of Ik at 6.3 sec. In contrast, the percentage of reduction of Ik by 10 microM ambasilide did not produce a consistent magnitude of block over a similar range of short depolarizations, but rather progressively decreased Ik as the pusle duration lengthened. Block at the end of a 2-sec pulse was about 48 +/- 8%, more block than could be attributed to an E-4031-sensitive current block alone. Whereas E-4031 (5 microM) shifted the activation curve of Ik 10 mV toward positive potentials and decreased the slope factor, k, by about 4 mV, ambasilide (5 microM) had no effect on these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1991

Amiodarone toxicity. II. Desethylamiodarone-induced phospholipidosis and ultrastructural changes during repeated administration in rats.

The contribution of desethylamiodarone (DEA), principal metabolite of the antiarrhythmic drug amiodarone, to the major side effects of amiodarone is unclear. The effects of repeated DEA administration to rats on tissue drug accumulation, ultrastructural changes, and phospholipid concentrations were studied. Two groups (n = 8/group) of male Sprague-Dawley rats (250 g body wt) were administered a 5% aqueous solution of DEA (Dose I, 40 mg/kg/day; Dose II, 60 mg/kg/day) intraperitoneally for 21-23 days, while a third group (control, n = 8) received saline. DEA levels were significantly higher with Dose II compared to Dose I in the lung, liver, kidney, spleen, heart, and serum while the tissue to serum ratios were similar with both doses for all tissues except the heart. DEA administration caused a significant elevation in the lipid phosphorus levels of liver, lung, and alveolar macrophages compared to control levels. A strong positive correlation (p less than 0.01) was found between tissue DEA levels and lipid phosphorus for the above tissues. Electron microscopy revealed the presence of lipid inclusion bodies in liver, lung, and alveolar macrophages of DEA-treated rats. A dose-dependent increase in the percentage of vacuolar surface area was found in the lung and alveolar macrophages. The tissue ultrastructural changes after repeated DEA dosing were qualitatively similar to our previous findings with amiodarone. Increased lung and liver phospholipid levels with repeated DEA doses may result from a potent inhibitory action of DEA on tissue phospholipase A as has been observed by others in in vitro studies.

Amiodarone↗
PubMed1990

Circadian rhythmicity of rate-normalized QT interval in hypothyroidism and its significance for development of class III antiarrhythmic agents.

Lengthening of repolarization and refractoriness occurs in hypothyroidism; it is associated with a reduced probability of arrhythmias, with the converse occurring in hyperthyroidism. Because the QT interval and its circadian rhythmicity relative to heart rate is poorly defined in man, we used our new computer-assisted technique to measure QT interval in our analysis of 24-hour Holter tapes before and after (8 to 12 weeks) thyroxine (T4) replacement in 10 patients with hypothyroidism; the findings were compared to those in 6 normal control subjects. QTc interval was prolonged (p less than 0.02) and heart rate decreased (p less than 0.005) during the hypothyroid state. Data were analyzed for circadian rhythmicity by repeated-measures analysis. Circadian variation in QTc and heart rate was statistically significant during hypothyroid and euthyroid states (p less than 0.001) as well as in control subjects, but the circadian rhythmicity of QTc interval and heart rate were out of phase; the maximum prolongation of QTc occurred between midnight and 6 A.M., at a time when heart was at its lowest. QTc interval remained significantly prolonged after 8 to 12 weeks of T4 replacement, when biochemical indexes of hypothyroidism had returned to normal values. The computer-assisted QTc interval determination technique that we used, and our data on the circadian rhythmicity of QTc and heart rate, have significant implications for the development of new class III antiarrhythmic agents.

Adult↗
PubMed1989

Tissue drug accumulation and ultrastructural changes during amiodarone administration in rats.

Pulmonary and hepatotoxicity are the two major side effects of chronic amiodarone therapy. We studied the accumulation of amiodarone and its principal metabolite, desethylamiodarone, in lung and liver of rats treated ip for 21 to 23 days with either 40 or 80 mg/kg/day amiodarone. The ultrastructural changes in liver, lung, and alveolar macrophages in saline controls and in rats on the two amiodarone dosage regimens were investigated. There was a dose-dependent increase in amiodarone and desethylamiodarone levels in serum and in tissues. The desethylamiodarone/amiodarone ratios in liver and lung, but not in serum, increased significantly with increasing dose. Serum also contained another metabolite, monodeiodinated desethylamiodarone. Increase in vacuolization and presence of whorled lamellar inclusion bodies in alveolar macrophages occurred with an increase in dose and higher lung amiodarone and desethylamiodarone levels. Electron microscopy of the liver of amiodarone-treated rats revealed the presence of large inclusion bodies partially filled with amorphous material in the cytoplasm. The quantitative relationship of the above changes to organ toxicity and to phospholipidosis that accompanies amiodarone administration remains to be established.

Amiodarone↗
PubMed1988

Effect of propranolol on the QT intervals of normal individuals during exercise: a new method for studying interventions.

A new method was used to study the effect of a single dose of propranolol on the QT intervals during exercise in 11 normal volunteers. They exercised maximally on a bicycle ergometer and repeated the test after taking propranolol (40 mg) by mouth two hours before. Electrocardiograms were continuously recorded on magnetic tape and the cardiac cycle length (RR interval) and the QT interval were measured every five seconds by a computer aided method. The RR-QT data from each test during the exercise phase were analysed by an exponential formula, QT = A - B x exp (-k x RR) and by Bazett's formula, QT = K x square root of (RR). Three reference QT intervals, QTc1, QTc2, and QTc3, estimated at RR = 400, 700, and 1000 ms respectively from the regression curves of both formulas were compared. The exponential formula, which consistently gave a better fit with the data, showed that propranolol had a biphasic action on the QT intervals during exercise. It significantly prolonged the mean (SD) interval at longer cycle lengths (from 287 (27) to 305 (18) ms at RR = 1000 ms and shortened it at shorter cycle lengths (from 198 (14) to 179 (16) ms at RR = 400 ms). In contrast, Bazett's formula did not show any significant effect when the same raw data were used. The exponential formula can be adapted to study other interventions or conditions that affect QT intervals.

Adult↗