Search

Aims: To evaluate the long-term efficacy and safety of an electrophysiologically guided therapy, based on a strategy of treatment using hydroquinidine (HQ) among asymptomatic Brugada patients with inducible ventricular fibrillation (VF)., Methods and Results: In two French reference centres, consecutive asymptomatic type 1 Brugada patients with inducible VF were treated with HQ (600 mg/day, targeting a therapeutic range between 3 and 6 µmol/L) and enroled in a specific follow-up (mean 6.6 ± 3 years), including a second programmed ventricular stimulation (PVS) under HQ. An implantable cardioverter defibrillator (ICD) was eventually implanted in patients inducible under HQ, or during follow-up in case of HQ intolerance, as well as occurrence of arrhythmic events. From a total of 397 Brugada patients, 44 were enroled (47 ± 10 years, 95% male). Of these, 34 (77%) were no more inducible (Group PVS-), and were maintained under HQ alone during a mean follow-up of 6.2 ± 3 years. In this group, an ICD was eventually implanted in four patients (12%), with occurrence of appropriate ICD therapies in one. Among the 10 other patients (22%), who remained inducible and received ICD (Group PVS+), none of them received appropriate therapy during a mean follow-up of 7.7 ± 2 years. The overall annual rate of arrhythmic events was 1.04% (95% confidence interval 0.00-2.21), without any significant difference according to the result of PVS under HQ. One-third of patients experienced device-related complications., Conclusion: Our long-term follow-up results emphasize that the rate of arrhythmic events among asymptomatic Brugada patients with inducible VF remains low over time. Our results also suggest that residual inducibility under HQ is of limited value to predict events during follow-up.

Background: A high prevalence of atrial fibrillation/atrial flutter (AF/AFl) has been reported in small series of Brugada patients, with discordant data., Objective: The purpose of this study was to analyze, in a large population of Brugada patients, the prevalence of AF/AFl, its correlation with prognosis, and the efficacy of hydroquinidine (HQ) treatment., Methods: Among 560 patients with Brugada type 1 ECG (BrECG), 48 (9%) had AF/AFl. Three groups were considered: 23 patients with BrECG pattern recognized before AF/AFl (group 1); 25 patients first diagnosed with AF/AFl in whom Class IC antiarrhythmic drugs administered for cardioversion/prophylaxis unmasked BrECG (group 2); and 512 patients without AF/AFl (group 3). Recurrence of AF/AFl and occurrence of ventricular arrhythmias were evaluated at follow-up., Results: Mean age was 47 ± 15 years, 59 ± 11 years, and 44 ± 14 years in groups 1, 2, and 3, respectively. Seven subjects (32%) in group 1 had syncope/aborted sudden death, 1 (4%) in group 2, and 122 (24%) in group 3. Ventricular arrhythmia occurred in three patients in group 1, none in group 2, and 10 in group 3 at median follow-up of 51, 68, and 41 months, respectively. Nine patients in group 1 and nine in group 2 received HQ for AF/AFl prophylaxis; on therapy, none had AF/AFl recurrence., Conclusion: Prevalence of AF/AFl in Brugada patients is higher than in the general population of the same age. Patients in group 1 are younger than those in group 2 and have a worse prognosis compared to both groups 2 and 3. HQ therapy has proved useful and safe in patients with AF/AFl and BrECG.

A 45-year-old man was hospitalized for syncope due to fascicular ventricular tachycardia degenerating into ventricular fibrillation (VF). The electrocardiogram showed an early repolarization syndrome. The arrhythmia was repetitive and disappeared after oral hydroquinidine. An implantable cardioverter-defibrillator (ICD) was implanted; subsequently, the patient was arrhythmia free at 9 months follow-up., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Mutations in the SCN5A gene can cause Brugada syndrome, a genetically inherited form of idiopathic ventricular fibrillation. We describe the case of a 3-year-old child with a structurally normal heart presenting with monomorphic ventricular tachycardia. Her electrocardiogram suggested a Brugada syndrome and the diagnosis was confirmed by the identification of a Brugada syndrome in her mother and in two other family members. Genetic study led to the identification of a c.2516T-->C SCN5A mutation. The child was treated with quinidine therapy without recurrence of arrhythmic events for a time period of 16 months.

Objectives: We sought to assess hydroquinidine (HQ) efficacy in selected patients with Brugada syndrome (BrS)., Background: Management of asymptomatic patients with BrS and inducible arrhythmias remains a key issue. Effectiveness of class Ia antiarrhythmic drugs, which inhibit the potassium transient outward current of the action potential, has been suggested in BrS., Methods: From a cohort of 106 BrS patients, we studied 35 who received HQ (32 men; mean age 48 +/- 11 years). Patients had asymptomatic BrS and inducible arrhythmia (n = 31) or multiple appropriate shocks from an implantable cardioverter-defibrillator (ICD) (n = 4). Asymptomatic patients with inducible arrhythmia underwent electrophysiologic (EP)-guided therapy. When ventricular tachycardia (VT)/ventricular fibrillation (VF) inducibility was not prevented, or in case of HQ intolerance, an ICD was placed., Results: Hydroquinidine prevented VT/VF inducibility in 76% of asymptomatic patients who underwent EP-guided therapy. Syncope occurred in two of the 21 patients who received long-term (17 +/- 13 months) HQ therapy (1 syncope associated with QT interval prolongation and 1 unexplained syncope associated with probable noncompliance). In asymptomatic patients who received an ICD (n = 10), one appropriate shock occurred during a follow-up period of 13 +/- 8 months. In patients with multiple ICD shocks, HQ prevented VT/VF recurrence in all cases during a mean follow-up of 14 +/- 8 months., Conclusions: Hydroquinidine therapy prevented VT/VF inducibility in 76% of asymptomatic patients with BrS and inducible arrhythmia, as well as VT/VF recurrence in all BrS patients with multiple ICD shocks. These preliminary data suggest that preventive treatment by HQ may be an alternative strategy to ICD placement in asymptomatic patients with BrS and inducible arrhythmia.

Objectives: The purpose of this study was to evaluate the efficacy of various antiarrhythmic drugs at prolonging the QT interval into the normal range and preventing ventricular arrhythmias in patients with short QT syndrome., Background: Short QT syndrome is a recently described genetic disease characterized by short QT interval, high risk of sudden death, atrial fibrillation, and short refractory periods., Methods: Six patients with short QT syndrome, five of whom had received an implantable cardioverter-defibrillator (ICD) and one child, were tested with different antiarrhythmic drugs, including flecainide, sotalol, ibutilide, and hydroquinidine, to determine whether they could prolong the QT interval into the normal range and thus prevent symptoms and arrhythmia recurrences., Results: Class IC and III antiarrhythmic drugs did not produce a significant QT interval prolongation. Only hydroquinidine administration caused a QT prolongation, which increased from 263 +/- 12 ms to 362 +/- 25 ms (calculated QT from 290 +/- 13 ms to 405 +/- 26 ms). Ventricular programmed stimulation showed prolongation of ventricular effective refractory period to > or =200 ms, and ventricular fibrillation was no longer induced., Conclusions: The ability of quinidine to prolong the QT interval has the potential to be an effective therapy for short QT patients. This is particularly important because these patients are at risk of sudden death from birth, and ICD implant is not feasible in very young children.

Two women, aged 77 and 73 years, and one man, aged 71 years, were admitted because of a serious adverse drug reaction (ADR). The first woman had a probable adverse drug reaction caused by digoxin after the addition of a NSAID (diclofenac) to a combination of digoxin and other drugs (furosemide and hydroquinine). The ADR due to digoxin is an example of a pharmacokinetic interaction. The second woman had serious orthostatic hypotension because of a pharmacodynamic interaction between three different antihypertensives. In the man, the ADR was hypoglycaemia while taking glibenclamide, a second generation sulfonylurea derivative. This was probably caused by declining renal function of a transplanted kidney because of bladder cancer. Doctors should be aware of ADRs in older patients, which also can occur when no changes in medication have taken place. In old age, any decline in vitality or function can be due to an ADR.

Background: Previous studies suggest that the antifibrillatory action of class I and III drugs is due to prolongation of the atrial wavelength. The aim of the present study was to directly evaluate the electrophysiological action of antifibrillatory drugs in a goat model of chronic atrial fibrillation (AF)., Methods and Results: Six goats were instrumented with multiple atrial electrodes, and sustained AF was induced by electrical remodeling. During sustained AF, the effects of intravenous infusion of cibenzoline, hydroquinidine, flecainide, and d-sotalol on AF cycle length (AFCL), refractory period (RP(AF)), conduction velocity (CV(AF)), pathlength (PL(AF)), wavelength (WL(AF)), temporal (AFCL-RP(AF)), and spatial (PL(AF)-WL(AF)) excitable gap were studied. The RP(AF) was measured by determining the earliest moment at which single stimuli could capture the fibrillating atria. CV(AF) was measured during regional entrainment of AF. Contrary to our expectation, cardioversion of AF could not be attributed to prolongation of WL(AF). Hydroquinidine and d-sotalol did not affect WL(AF) significantly, whereas cibenzoline and flecainide even shortened WL(AF) by 18% and 36%, respectively. PL(AF) was increased by hydroquinidine and d-sotalol by 30%, whereas cibenzoline and flecainide did not prolong PL(AF). The only parameter that correlated consistently with cardioversion of AF was a widening of the temporal excitable gap (cibenzoline 176%, hydroquinidine 105%, flecainide 86%, d-sotalol 88%)., Conclusions: Pharmacological cardioversion of AF cannot be explained by prolongation of WL(AF). An alternative explanation for the antifibrillatory effect of class I and III drugs may be a widening of the temporal excitable gap.

The abnormal neuronal excitability hypothesized in myotonic dystrophy (MD) might contribute to psychomotor and behavioral disturbances of MD patients. To gain new insights into the pathophysiology of MD, we determined whether the antiarrhythmic drug hydroquinidine would ameliorate slow saccadic eye movements (SEMs), apathy and hypersomnia in MD patients. SEMs were selected as simple modality for psychomotor investigation. The study was conducted in a randomized, placebo-controlled, double-blind, crossover manner. Ten ambulatory patients without contraindications to hydroquinidine administration were enrolled. Hydroquinidine (450 mg/day) or placebo was given orally for 6 weeks with a washout period of 6 weeks between treatments. SEMs were recorded by electrooculography and analyzed by a computer system. Two patients withdrew in the first week of active treatment because of nausea and epigastralgia. Hydroquinidine significantly increased the normalized peak saccadic velocity and shortened the saccadic reaction time compared to placebo. The drug's effects on apathy and hypersomnia are presented in a companion paper.

An abnormal neuronal excitability in myotonic dystrophy (MD) might contribute to psychomotor and behavioral disturbances of MD patients. To gain new insights into the pathophysiology of MD, we determined whether the antiarrhythmic drug hydroquinidine could ameliorate apathy and hypersomnia besides slow saccadic eye movements in these patients. The study was conducted in a randomized, placebo-controlled, double-blind, crossover manner. Ten ambulatory patients without contraindications to hydroquinidine administration were enrolled. Hydroquinidine (450 mg/day) or placebo was given orally for 6 weeks with a washout period of 6 weeks between treatments. Apathy was evaluated by means of the apathy evaluation scale (AES) and hypersomnia by a sleep diary. Two patients withdrew in the first week of active treatment because of nausea and epigastralgia. The drug significantly reduced AES scores and daily sleep time compared to placebo. Thus, hydroquinidine can ameliorate apathy and hypersomnia in MD. However, the possibility of proarrhythmia and the high frequency of cardiac disturbances in MD seriously limit the therapeutic perspective. The effects on eye movements are presented in a companion paper.

Background: Prolongation of the electrocardiographic QT interval by drugs is associated with the occurrence of a potentially lethal form of polymorphic ventricular tachycardia termed torsades de pointes. Women are at greater risk than men for development of this adverse event when taking drugs that prolong the QT interval. To determine whether this may be the result of gender-specific differences in the effect of quinidine on cardiac repolarization, we compared the degree of quinidine-induced QT interval lengthening in healthy young men and women., Methods: Twelve women and 12 men received a single intravenous dose of quinidine (4 mg/kg) or placebo in a single-blind, randomized crossover trial. Total plasma and protein-free concentrations of quinidine and 3-hydroxyquinidine were measured in serum. QT intervals were determined and corrected for differences in heart rate with use of the method of Bazett (QTc = QT/RR1/2)., Results: As expected, the mean QTc interval at baseline was longer for women than for men (mean +/- SD; 407 +/- 7 versus 395 +/- 9 ms, P < .05). The slope of the relationship between change in the QTc interval (delta QTc) from baseline to the serum concentration of quinidine was 44% greater for women than for men (mean +/- SE; 42.2 +/- 3.4 versus 29.3 +/- 2.6 ms/microg per mL, P < .001). These results were not influenced by analysis of 3-hydroxyquinidine, free concentrations of quinidine and 3-hydroxyquinidine, or the JT interval., Conclusions: Quinidine causes greater QT prolongation in women than in men at equivalent serum concentrations. This difference may contribute to the greater incidence of drug-induced torsades de pointes observed in women taking quinidine and has implications for other cardiac and noncardiac drugs that prolong the QTc interval. Adjustment of dosages based on body size alone are unlikely to substantially reduce the increased risk of torsades de pointes in women.

Objective: To investigate the possible involvement of cytochromes CYP1A2 and CYP2C19 in the in vivo oxidative metabolism of quinidine., Methods: This was an open study of six healthy young male volunteers. The pharmacokinetics of a 200-mg single oral dose of quinidine were studied before and during daily treatment with 100 mg fluvoxamine. Biomarkers of other isozyme activities in the form of caffeine, sparteine, mephenytoin, tolbutamide and cortisol metabolism were applied., Results: The results showed a statistically significant median reduction of 2944% in the quinidine total apparent oral clearance, partial clearances by 3-hydroxylation and N-oxidation and residual clearance during fluvoxamine treatment. Renal clearance was unaffected by fluvoxamine., Conclusions: The effect of fluvoxamine on the formation clearances of 3-hydroxyquinidine and quinidine-N-oxide most likely reflects inhibition of cytochrome P4503A4 by fluvoxamine at clinically relevant doses. The results of this study do not rule out a possible involvement of CYP1A2 and CYP2C19 in the in vivo oxidative metabolism of quinidine.

Introduction: Recently, we reported that repetitive induction of atrial fibrillation (AF) in the goat causes electrical remodeling of the atria leading to the development of sustained AF. The aim of the present study was to compare Class IA, IC, and III drugs in their ability to cardiovert chronic AF in remodeled atria., Methods and Results: In 16 goats with sustained AF, hydroquinidine (HQ), cibenzoline (Ci), flecainide (FI), and d-sotalol (dS) were infused. HQ, Ci, Fl, and dS restored sinus rhythm (SR) in 83%, 91%, 67%, and 92% of the cases, while adverse drug effects occurred in 17%, 36%, 56%, and 8%. Prior to restoration of SR, AF cycle length prolonged by 68%, 103%, 53%, and 20%, respectively. The QRS width increased by 14%, 64%, and 58% (HQ, Ci, and Fl), and remained unchanged by administration of dS. RR intervals were slightly prolonged by HQ, Ci, and Fl, and markedly prolonged by dS (48%). The QT interval was moderately prolonged by HQ, Ci, and Fl, and considerably by dS (34%). QTc was only slightly prolonged by each of the drugs. Directly after cardioversion of AF, the atrial refractory period was 87+/-29 (HQ), 119+/-32 (Ci), 66+/-10 (Fl), and 73+/-18 msec (dS) (control: 146+/-18 msec). Atrial conduction velocity was 85+/-6, 71+/-11, 86+/-12, and 110+/-11 cm/sec compared with a control value of 116+/-10 cm/sec. Because directly after cardioversion the atrial wavelength was still very short (5.7 to 8.4 cm), the vulnerability for AF was still very high, and a single premature beat reinduced AF in 71% (Ci) to 100% (HQ, Fl, and dS) of the cases., Conclusion: In a goat model of sustained AF, Class IA, IC, and III drugs restored sinus rhythm in 67% to 92% of the cases. However, after cardioversion, the atrial wavelength was still abnormally short, and AF was readily inducible in 71% to 100% of the cases.

Background: Intravenous procainamide hydrochloride is frequently used in the acute care setting and during electrophysiologic testing, but intravenous quinidine gluconate is rarely used because of concerns about its safety. This study prospectively compares the hemodynamic and electrophysiologic effects of these agents in patients undergoing electrophysiologic testing., Methods and Results: Sixty-five consecutive patients with inducible ventricular tachyarrhythmias were prospectively treated with either intravenous quinidine gluconate or intravenous procainamide hydrochloride in an alternating unblinded fashion. The hemodynamic and electrophysiologic effects of these two drugs were compared. Seven (22%) patients assigned to intravenous quinidine gluconate and eight (24%) patients assigned to intravenous procainamide hydrochloride were rendered noninducible for ventricular tachyarrhythmias. Four (13%) patients assigned to intravenous quinidine gluconate were unable to complete the infusion compared with none (p = 0.05) assigned to intravenous procainamide hydrochloride. Otherwise, the overall hemodynamic and electrophysiologic effects of the two drugs were similar., Conclusions: Intravenous quinidine gluconate is a reasonable alternative to intravenous procainamide hydrochloride in patients requiring a parenteral type IA antiarrhythmic agent.

Quinidine is a potent blocker of the delayed rectifier K+ channels (IK). Although it has been used for understanding the physiology of K+ channels in many organisms and for treating cardiac arrhythmia in humans, mechanisms of its interaction with the channel molecule are not well understood. As a first step in understanding these mechanisms, we used the Shaker mutant of Drosophila in which the delayed rectifier can be resolved in complete isolation from other currents and determined the importance of the major groups of quinidine (methoxy, quinoline, quinuclide and the bridge groups) in the blockade of IK. It appears that the quinoline moiety, while possessing little channel-blocking activity by itself, may provide a template for positioning the groups that may be important for affinity and blockade. These groups, in the order of importance in imparting inhibitory activity to quinoline, seemed to be quinuclide > methylene bridge > 6-methoxy group. In particular, the quinoline ring and the quinuclide group, when linked-together by a hydroxymethylene bridge, might be responsible for a major part of the IK blocking activity of quinidine. Action of quinidine was not affected by either quinuclidine, which did not block IK, or by quinoline.

Class I antiarrhythmic drugs may increase the incidence of cardiac death, and controlled treatment is required in patients with severe ventricular arrhythmias. Electrophysiologically guided antiarrhythmic therapy remains an important method to manage patients with sustained ventricular tachycardia (VT). The purpose of the study was to evaluate the correlations between baseline heart rate variability in ambulatory electrocardiographic recordings of patients with sustained ventricular tachycardia and the response to hydroquinidine on VT inducibility, and to look for the changes in heart rate variability during hydroquinidine treatment. Thirty-five patients with spontaneous and inducible sustained VT were studied. Programmed ventricular stimulation and time and frequency domain analysis of heart rate variability were studied in the control state and 9-12 days after treatment with 300-600 mg of hydroquinidine. In 11 patients (group I), hydroquinidine prevented VT induction. In 24 patients (group II), sustained VT remained inducible during treatment with hydroquinidine. In the control state, heart rate variability was similar in both groups. During treatment with hydroquinidine, heart rate variability tended to decrease in groups I and II, but the changes were significant only in group II: the coefficient of variance (CV) decreased from 13 +/- 4% to 10% +/- 3% (p < 0.01) and low frequency/high frequency amplitude ratio decreased from 4.6 +/- 3.3 to 2.87 +/- 2.42 (p < 0.05). In conclusion, baseline heart rate variability does not differentiate the responders and nonresponders to hydroquinidine. Hydroquinidine decreases heart rate variability in all patients, but principally in those with still inducible VT.

Background: Various skin and mucosal reactions can be observed after administration of quinidine derivatives., Case Report: A patient who was taking Natisédine (quinidine phenylethyl barbiturate) intermittently and at reintroduction developed a papulopurpuric eruption (without thrombopenia) producing extensive centrifugal annular infiltration and central healing which regressed approximately one week after drug withdrawal. This eruption was associated with moderate 24 h proteinuria. The clinical aspect was that of vasculitis purpura as confirmed histology. Direct immunofluorescence only demonstrated C3 deposits in the vessel walls of the superficial dermis. The quinidine moiety of this drug (currently removed from the formulation) appears to be the responsible agent (imputability score: 13 B3)., Discussion: Thrombopenic purpura by synthesis of anti-platelet antibodies induced by quinidine derivatives is well known. Inversely, cases of non-thrombopenic purpura imputable to these same derivatives is uncommon (7 reported cases). The pathophysiological mechanisms involved might be similar (antigenic similarity between the platelet surface and endothelium).

The aim of this study was to assess the effectiveness of propafenone and quinidine to restore sinus rhythm in patients with paroxysmal atrial fibrillation. Eighty consecutive patients with recent onset atrial fibrillation were randomized to one of the following oral treatments: a) propafenone 450 mg as single dose followed by 300 mg t.i.d.; b) hydroquinidine 900 mg/24 hours + digoxin if necessary. Drugs were given for a maximum of three days and withdrawn at the restoration of sinus rhythm. If atrial fibrillation was persistent, the other drug was administered after two days wash out. The two groups did not differ from each other with respect to left atrial size, age and presence of organic heart disease, and kind of cardiopathies between the two groups. Sinus rhythm was restored in 39 patients of group 1 (93%) and 36 of group 2 (95%). In conclusion, oral propafenone is as effective as quinidine in the treatment of paroxysmal atrial fibrillation.

The objective of this study was to compare the efficacy and safety of cibenzoline (130 mg twice a day) and sustained-release hydroquinidine (300 mg twice a day) in the prevention of recurrent atrial fibrillation (AF). This randomized double-blind study was conducted in 87 patients, with a mean age of 62 years, presenting with a history of AF for 72 hours to a maximum of 3 years. After restoration of sinus rhythm, in order for the subjects to be included in the study, echocardiography had to reveal a left ventricular shortening fraction of more than 20%. Patients were followed for one year by clinical examination, ECG and 24-hour Holter monitoring performed 7 days after inclusion, then after 3, 6, 9 and 12 months. The two groups, treated with either cibenzoline (n = 40) or hydroquinidine (n = 44), were comparable. The AF recurrence rates with cibenzoline or hydroquinidine were 34.9% had 36.4% at 6 months, and 41.9% and 43.2% at 12 months, respectively (NS). Most recurrences occurred during the first month. Adverse effects were reported in 10 patients (23.3%) with cibenzoline and 12 patients (27.3%) with hydroquinidine. They led to discontinuation of treatment in 6 patients (14%) treated with cibenzoline and 5 patients (11.4%) treated with hydroquinidine. Serious adverse events included one death from hypoglycaemic coma and one case of persistent ventricular tachycardia with hydroquinidine. In conclusion, oral cibenzoline demonstrated the same antiarrhythmic activity as hydroquinidine in the long-term prevention of recurrent atrial fibrillation, with a similar degree of safety. This drug can therefore constitute an alternative to conventional antiarrhythmics in this context.

The inhibitory effects of dihydroquinidine, quinidine and several quinidine metabolites on cytochrome P450 2D6 (CYP2D6) activity were examined. CYP2D6 heterologously expressed in yeast cells O-demethylated dextromethorphan with a mean Km of 5.4 microM and a Vmax of 0.47 nmol/min/nmol. Quinidine and dihydroquinidine both potently inhibited CYP2D6 metabolic activity (mean Ki = 0.027 and 0.013 microM, respectively) in yeast microsomes and in human liver microsomes. The metabolites, 3-hydroxyquinidine, O-desmethylquinidine and quinidine N-oxide also inhibited CYP2D6, but their Ki values (0.43 to 2.3 microM) were one to two orders of magnitude weaker than the values for quinidine and dihydroquinidine. There was a trend towards an inverse relationship between Ki and lipophilicity (r = -0.90, N = 5, P = 0.07), as determined by the retention-time parameter k' using reverse-phase HPLC. Thus, although the metabolites of quinidine have the capacity to inhibit CYP2D6 activity, quinidine and the impurity dihydroquinidine are the important inhibitors of CYP2D6.

Studies in humans in vivo have demonstrated that substances found in grapefruit juice may increase the bioavailability of dihydropyridine derivatives as a result of the inhibition of liver enzyme activities by flavonoids found in grapefruit. Since the metabolism of dihydropyridine drugs is mediated by cytochrome P-450 (CYP) 3A4, it has been hypothesized that flavonoids may also influence the metabolism of other drugs, such as midazolam and quinidine, which are biotransformed by the same CYP isoform. Three flavonoids, kaempferol, naringenin and quercetin, are found in grapefruit juice but not in orange juice. The effect of these substances on the metabolism of midazolam and quinidine has been investigated in human liver microsomes. In the concentration range 10-160 microM the inhibitory potential of flavonoids was the same for both of the tested drugs; it decreased in the order quercetin >> kaempferol > naringenin. The data suggest that the flavonoids found in grapefruit juice may influence the kinetics of midazolam and quinidine in man.

The effects of two antiarrhythmic agents, hydroquinidine and quinidine on the prevention of pacing induced sustained ventricular tachycardia (VT) were studied in 14 patients. The underlying cardiac disease was old myocardial infarction (12 patients) or dilated cardiomyopathy (2 patients). Sustained monomorphic VT was induced in 14 patients during the initial electrophysiological study performed at least 48 hours after withdrawal of all antiarrhythmic therapy. The same stimulation protocol including 3 extrastimuli (S2 S3 S4) and 2 paced cycles (600 ms and 400 ms) was repeated at least 48 hours after the administration of 600 mg (2 gelules) per 24 hours of hydroquinidine or 1100 mg of quinidine arabogalactane sulphate, 3 to 4 hours after the last dose. This was an open, randomised, crossed over trial. Irrespective of the result observed with the first antiarrhythmic, used in an order attributed by a randomised table, the other antiarrhythmic was tested. Plasma concentrations were measured during the programmed stimulation test for both drugs. Induced VT was prevented by the two antiarrhythmics in 4 patients (28%). In one patient, VT was prevented by hydroquinidine but not by the quinidine compound, resulting in a prevention rate of 35% for the hydroquinidine. On the other hand, the quinidine compound was a total success in one patient in whom only a partial success was observed with hydroquinidine. VT remained inducible with both antiarrhythmics in 9 patients (64%).(ABSTRACT TRUNCATED AT 250 WORDS)

The investigational antiarrhythmic drug LNC-834 ((9S)-10,11-dihydro-6'-methoxy-cinchonan-3,9-diol hydrogen sulfate pentahydrate, CAS 85405-59-0) is structurally related to quinidine. It was investigated, if concurrent administration of LNC-834 affects the single dose pharmacokinetics and pharmacodynamics of warfarin (CAS 81-81-2). The study was performed as an open, randomized two-way cross-over, controlled investigation in 10 healthy volunteers. In treatment A, 2 tablets of LNC-834 (350 mg of hydrated salt corresponding to 226 mg anhydrous free base each) were ingested twice daily for a period of 9 days in total. On the 4th study day, 2 h after the application of LNC-834 in the morning, the volunteers received a mean dose of 0.36 +/- 0.03 mg/kg warfarin orally. In treatment B only warfarin was administered. Pharmacokinetics of warfarin and anticoagulant effect (prothrombin complex activity) were determined from plasma samples withdrawn up to 144 h after administration; LNC-409 (free base of LNC-834) and the metabolite LNC-253 (2'-oxo-analog) were monitored for check of compliance over the same time period. Concurrent administration of LNC-834 decreased significantly the area under the plasma concentration-time curve of warfarin (117,889 +/- 25,010 (A) vs. 125,294 +/- 22,314 ng/ml.h (B); p = 0.0488). Thus, a significant increase in apparent oral clearance (CL/f) of warfarin in the presence of LNC-834 was determined (3.98 +/- 0.63 vs. 3.71 +/- 0.50 ml/min; p = 0.0488). All other pharmacokinetic parameters determined (apparent volume of distribution (V/f), Cmax, tmax, terminal half-life of elimination) were not altered by concurrent treatment with LNC-834.(ABSTRACT TRUNCATED AT 250 WORDS)

The antiarrhythmic activity and acute toxicity of polymeric formulations of quinidine, trimecaine, ethacizine, propranolol, verapamil which had been immobilized on a cellulose carrier (monocarboxylcellulose) and low molecular analogues were studied in various experimental animals (rats, mice, dogs). The polymeric formulations of trimecaine and verapamil were found to have a higher antiarrhythmic activity in different arrhythmia models than trimecaine and verapamil. The toxicity of all new compounds was no more than the values of conventional antiarrhythmic drugs.

To evaluate whether the hydroxylated metabolites of quinidine (Q) and hydroquinidine (HQ): hydroxy-3S-quinidine (OH-Q) and hydroxy-3S-hydroquinidine (OH-HQ), exert electrophysiologic effects and participate in the therapeutic action of the parent drugs, we examined and compared the effects of the metabolites and the parent drugs on the electrical activity of guinea pig ventricular cells recorded by standard microelectrode technique. In addition, we investigated the potential arrhythmogenic properties of these compounds in rabbit Purkinje fibers in low K+ (2.7 mM) Tyrode's solution. The concentration [C]-, frequency-, and voltage-dependent effects of the drugs were investigated. Maximum upstroke velocity of phase 0 (Vmax) was [C]-dependently depressed by both OH-Q and OH-HQ but at a lesser degree than with Q and HQ, respectively: at the [C] of 50 microM, Vmax depression attained 26.7 +/- 2.6% with OH-Q versus 45.9 +/- 1.6% with Q and 32.3 +/- 1.9% with OH-HQ versus 54.6 +/- 1.4% with HQ. This effect was frequency and voltage dependent without significant differences between the four compounds. In the presence of equipotent [C], recovery kinetics of Vmax was significantly slower with metabolites than with respective parent drugs. In contrast, the effects of metabolites on action potential duration at 90% of repolarization (APD90) and effective refractory period (ERP) differed from those observed with parent drugs. With metabolites, APD90 and ERP were increased in a [C]-dependent manner, whereas the Q- and HQ-induced lengthening in APD90 and ERP was observed only at low concentration and low frequency. In addition, the OH-Q- and OH-HQ-induced APD90 lengthening was not altered by increasing pacing rate. In rabbit Purkinje fibers, increase in cycle length and prolonged exposure to either metabolites or parent drug caused early afterdepolarizations (EADs) and triggered activity. With all drugs tested, EADs arose more frequently at the plateau level than at the final repolarization of AP, but the incidence of EADs appeared to be much lower with metabolites than with parent drugs. The present results demonstrate that OH-Q and OH-HQ exert qualitatively similar but quantitatively less potent depressant effects on Vmax than Q and HQ, respectively, but differ in the lengthening effect on APD. We suggest that metabolites may participate in class I antiarrhythmic action of their respective parent drug and contribute to their arrhythmogenicity.

New antiarrhythmic class 1C agents have been proposed in the last few years in an attempt to suppress paroxysmal atrial fibrillation at long-term, as the most commonly used class 1A agents such as quinidine gave highly variable results as regards both side-effects and efficacy. The aim of this randomized prospective study is to evaluate the efficacy and safety of oral propafenone at long term in preventing paroxysmal atrial fibrillation and to compare the results with those obtained using agents such as quinidine. Two hundred patients with recurrent episodes of symptomatic atrial fibrillation were enrolled for this study with entry criteria based upon a history of more than 3 crises in the previous 6 months, with electrocardiographic (standard electrocardiogram or dynamic registration) documentation. According to a randomized selection either propafenone at 300 mg twice daily or hydroquinidine retard 250 mg twice daily were administered to the patients; clinical check-up was carried out every 3 months or if clinical course worsened. The dosages were increased if proved to be inadequate at check-up (i.e. recurrence of atrial fibrillation) up to 300 mg 3 times daily for propafenone and 500 mg twice daily for hydroquinidine. The efficacy at the 3rd month was 71% for propafenone and 60% for hydroquinidine, at the 6th month 60% for propafenone and 56% for hydroquinidine; this trend lowered progressively as the follow-up continued, to 48% for propafenone and 42% for hydroquinidine (NS). More than 70% of the responder patients assumed 600 mg twice for propafenone or 250 twice for hydroquinidine. Propafenone had a percentage of 10% side-effects and hydroquinidine 24% (p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of intravenous LNC-834, a new antiarrhythmic agent, and quinidine sulfate were evaluated and compared in 24-h infarction, programmed electrical stimulation (PES), and ventricular fibrillation threshold (VFT) canine models of cardiac arrhythmias. In the 24-h infarction model (24 h after myocardial infarction), animals averaged 85% arrhythmic beats before treatment. LNC-834 gave greater suppression of these spontaneous arrhythmias (97%) and had a longer duration of action (150 min) than did quinidine (70% and 85 min, respectively) at 10 mg of base/kg, although plasma levels were comparable (1.82 +/- 0.19 and 1.50 +/- 0.27 micrograms/ml of plasma for LNC-834 and quinidine, respectively). At 10 mg of base/kg, LNC-834 and quinidine increased effective refractory periods by 9 and 7%, respectively. In the PES model, LNC-834 (3 mg of base/kg) suppressed ventricular tachycardia (VT) in 33% (2/6) of the dogs tested: none of the six quinidine-treated animals displayed suppression of VT at cumulative doses of 0.3 to 30 mg of base/kg. In PES dogs, inducible and noninducible, mortality was less with LNC-834 treatment than with quinidine [9% (1/11) and 36% (4/11), respectively]. Neither LNC-834 nor quinidine elevated VFT in naive, anesthetized dogs. Although no treatment significantly affected the intrinsic heart rate in VFT dogs, both LNC-834 and quinidine produced significant hypotension; however, LNC-834 caused less hypotension than did quinidine at equal doses. This study demonstrates that LNC-834 may be a useful antiarrhythmic agent with efficacy comparable to and hemodynamic advantages over quinidine.

Maintenance of adequate serum blood levels is crucial to successful antiarrhythmic therapy. Serum levels of four antiarrhythmic agents (long-acting procainamide, quinidine sulfate, quinidine gluconate, and disopyramide) were determined in 98 consecutive ambulatory patients receiving long-term oral therapy. Medication dosages, dosing intervals, and time elapsed from last dosage until blood sampling were determined. Seventy-five patients (76.5 percent) had subtherapeutic blood levels (with mean levels less than 50 percent of the suggested minimum), and only 22 patients (22.5 percent) had therapeutic levels. Even among the 61 patients who claimed to have taken their medications within the six hours prior to blood sampling, 43 (70 percent) had subtherapeutic levels. These ratios held among all subgroups studied. Physicians should be aware of the high proportion of patients receiving long-term oral antiarrhythmic therapy with inadequate serum blood levels when planning therapeutic regimens.

The formation rate constant and elimination rate constant for 3-hydroxyquinidine were determined in eight patients with ventricular tachycardia. These two parameters (mean +/- SD) were found to be 0.784 +/- 0.202 and 0.042 +/- 0.058 h-1, respectively. Coefficients of determination for the computer-generated line of best fit for serum concentration-time data were 0.986 +/- 0.008. Patients received two infusions of quinidine gluconate 5 mg/kg over 30 minutes separated by a 20-30 minute electrophysiologic testing period. Unbound and total 3-hydroxyquinidine concentrations were also determined. Among the eight patients, 3-hydroxyquinidine was 61.9 percent bound. Studies in healthy volunteers had shown 50 percent binding. Linear regression of unbound and total 3-hydroxyquinidine was described by the equation Y = 0.3814X-1.448, r = 0.813. Although half-lives of 3.5-12.4 hours had been reported in healthy volunteers, prolonged half-lives were observed in all but two of our arrhythmia patients.

The efficacy of a new antiarrhythmic agent, lorcainide, was compared with that of quinidine gluconate in a fixed-dose, randomized, crossover trial. Of 26 previously untreated patients with frequent ventricular ectopic beats documented by 24-hour ambulatory monitoring, 17 completed four weeks of therapy with quinidine and 12 with lorcainide. Of 22 patients receiving both drugs, early termination of therapy due to side effects occurred in ten (45 percent) patients receiving lorcainide and five (23 percent) receiving quinidine. Lorcainide (100 mg twice daily or three times daily, dependent on body weight) effectively suppressed ventricular arrhythmias in seven of 12 (58 percent) patients completing four weeks of therapy, and suppression by quinidine gluconate (324 mg three times daily) occurred in five of 12 (59 percent) patients. We conclude that in a dose of 100 mg twice or three times daily, lorcainide is as effective as quinidine gluconate, 324 mg three times daily, for the suppression of chronic ventricular arrhythmias. However, the high incidence of adverse reactions experienced with lorcainide make it an unacceptable agent for first-line antiarrhythmic therapy.

103 patients with atrial fibrillation lasting more than 15 days were treated by cardioversion, with a return to normal sinus rhythm in 92 per cent of cases. If the atrial fibrillation recurred during the first six months, a further electric shock was given and the treated was changed or better adapted to the patient. The sinus rhythm was maintained in 85.7 per cent of patients at one year, 84.4 per cent at 2 years, 80.1 per cent at 3 years and 76.1 per cent at 4 years. The factors which predict a good result are: sex, the presence of mitral valve disease, especially when it has been operated, good tolerance of the arrhythmia and good haemodynamic status prior to the shock. The treatment used were quinidine arabogalactane sulfate (QAGS) and amiodarone. QAGS was better tolerated, while amiodarone proved to be more effective.

Pharmacokinetics and effects of oral hydroxy-3(S)-dihydroquinidine (3-OH-HQ) on heart rate (HR), blood pressure (BP), and ECG intervals were studied in 12 healthy volunteers. Three oral single doses of 3-OH-HQ (225, 450, and 900 mg) and placebo were randomly administered to each subject at one week intervals. Pharmacokinetics of 3-OH-HQ was linear in the range of administered doses, with rapid absorption (tmax 0.5-2.5 h) and distribution (t1/2 alpha 0.8-1.2 h) phases. Elimination half-lives did not significantly change with the three doses (15 +/- 4.3, 13.7 +/- 3.9, and 13 +/- 2.2 h). Unchanged 3-OH-HQ was partially eliminated by urine (mean renal clearance 0.24 +/- 0.02 L h-1 kg-1). 3-OH-HQ significantly increased HR after the three doses as compared to placebo. PR interval was not significantly modified but QRS duration significantly increased from 91 +/- 7 to 108 +/- 11 ms (p less than 0.001) 2 h after the 900 mg dose. QTc interval was significantly prolonged from 0.5 to 8 h after the highest dose (14.4 +/- 8.7% 1 h after dosing). Heart rate QRS, and QTc variations were significantly correlated to 3-OH-HQ plasma levels.

We have compared the ED50 value for antiarrhythmic activity and the acute toxicities in mice of quinidine and 4 recently synthesized analogs. For the ED50 studies, groups of mice were treated intravenously with equally spaced logarithmic doses of 6'-methoxycinchonine (quinidine), 6'-hydroxycinchonine (cupreidine), 6'-isovaleryloxycinchonine, 6'-acetyloxycinchonine and 6'-benzoyloxycinchonine. For the actue toxicity studies, mice were treated intraperitoneally with quinidine and the 4 analogs. Mice were observed over a 24-h period, and thereafter for each additional 24-h period for a total of 120 h. Tests for parallelism of acute toxicity indicated that with the exception of the 6'-isovaleryloxy derivative the drug treatment regression lines were parallel to that of quinidine (P > 0.05). The results indicated decreases of 50% (843 mumol/kg), 52% (857 mumol/kg), and 61% (910 mumol/kg) in the acute toxicities of the 6'-acetyloxy, 6'-hydroxy, and 6'-benzoyloxycinchonine, respectively. The 6'-acetyloxy (18.5 mumol/kg) and 6'-benzoyloxy (14.6 mumol/kg) derivatives had significantly lower ED50 values than quinidine (60.1 mumol/kg). The results suggest that the 6'-acetyloxy and 6'-benzoyloxy derivatives may have much greater antiarrhythmic effectiveness than quinidine.

The aim of our study has been to evaluate the efficacy of Propafenon by a reliable experimental method. We have compared the efficacy of Propafenon (300 mg three times daily) with that of Dihydroquinidine Chloride at an elevated dose (300 mg six times daily). Twelve patients, with chronic arrhythmia (at least 1500 premature ventricular beats - PVBs - during a preliminary 24-hour dynamic electrocardiographic Holter monitoring), have been studied. The study has been performed in a double-blind cross-over fashion, and the drugs were administered according to a randomized sequence by the double dummy technique for 4 days. Placebo administration periods of similar duration were established before, after and between the two periods of drug administration. At the end of each Propafenon Dihydroquinidine Chloride and Placebo administration period a 48-hour Holter monitoring was performed. The number of PVBs/hour measured during the 3 periods of Placebo administration (714 +/- 418, 804 +/- 422, 779 +/- 433 respectively) confirmed the chronic nature of the ventricular arrhythmia and the absence of spontaneous variations during the study. Treatment with Propafenon and Dihydroquinidine Chloride significantly reduced the number of PVBs/hour to 87 +/- 130 and to 216 +/- 453 respectively. The reduction observed during Propafenon administration was more than observed during Dihydroquinidine Chloride administration, but it was not statistically significant because of the different behaviour of the individual patients. All patients but one had an over 65% reduction of PVBs/h; only 8/12 patients showed a reduction greater than 65% during Dihydroquinidine Chloride administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Our previously described HPLC method for the simultaneous analysis of several antiarrhythmic drugs and metabolites in serum [Clin. Biochem. 14. 113-118 (1981)] was correlated with an enzyme immunoassay technique (EMIT) for quinidine, procainamide, N-acetyl procainamide, and disopyramide. Correlation coefficients in each case was greater than 0.95. Our method compared favorably with a fluorescent procedure for the quantitation of propranolol in plasma. Interference studies with 34 drugs indicated that the measurements of quinidine and monodealkyldisopyramide were affected by quinine and lidocaine, respectively. Carbamazepine and glutethimide interfered with propranolol, but additional clean-up extractions removed these interferences.

We investigated the antiarrhythmic activity of two major metabolites of quinidine in human, 3-hydroxyquinidine and quinidine-N-oxide, alone and in combination with the parent drug in an experimental model using reperfusion arrhythmias in an isolated rat heart preparation. No definite pharmacological activity could be shown for quinidine-N-oxide up to concentrations of 16 mg/l. Quinidine and 3-hydroxyquinidine prevented ventricular fibrillation and ventricular tachycardia after coronary reperfusion in a concentration-dependent manner. The relationship between the drug concentration in the perfusate and the fractional suppression of arrhythmia could be described adequately for both compounds by the Hill equation. Whereas no difference was found for the Hill coefficient, the estimates of the concentration associated with 50% arrhythmia suppression was significantly higher for 3-hydroxyquinidine (10.7 +/- 0.3 mg/l vs. 2.2 +/- 0.25 mg/l), indicating that the relative potency of the metabolite was only about 20% compared to the parent compound. To investigate the pharmacodynamic interaction of the two compounds the concentration-response curve was determined for quinidine also in the presence of 3-hydroxyquinidine at a constant concentration of 4 mg/l. A method has been derived that allows quantitative assessment of the pharmacodynamic interaction of two compounds for which the concentration-effect relationship can be described by the Hill equation. The results indicate that the antiarrhythmic effects of 3-hydroxyquinidine and quinidine are additive.

The object of this study was to determine the electrophysiological effects of 3-hydroxy-dihydroquinidine (3-OH-HQ) in man. The electrophysiological parameters were measured in 12 patients before and after intravenous infusion of 5 mg/kg of 3-OH-HQ in 15 minutes. The mean plasma concentrations obtained varied from 2.4 +/- 1.1 mg/l at the 20th minute to 0.9 +/- 0.3 mg/l at the 60th minute. In these concentrations, 3-OH-HQ did not cause hypotension or affect the heart rate and nodal conduction. It did, however, prolong infra-hisian and intraventricular conduction and ventricular repolarisation from the 20th to the 60th minute after starting the infusion. The peak effect was observed at the 20th minute (+19 +/- 3.4 ms; +14.6 +/- 3.5 ms; and +44.5 +/- 6.6 ms, respectively). The 3-OH-HQ increased the effective atrial and ventricular refractory periods at the 30th minute (+21.8 +/- 5.5 ms and +22.3 +/- 7 ms, respectively). However, the ventricular effect only was discernable at the 60th minute. These effects are quantitatively comparable to those of quinidine. Extrapolation of these results to the effects of chronic oral treatment should be reserved as the therapeutic zone of this new molecule has not yet been determined.

The antiarrhythmic and acute toxic actions of quinidine (Q) and dihydroquinidine (DHQ) were investigated in experiments in rats. 1. No significant difference was found between Q and DHQ with regard to the doses necessary to suppress electrically induced ventricular fibrillation in the heart (p greater than 0.05). 2. On oral administration, pure DHQ was slightly less toxic than pure Q. This difference is significant (p less than 0.05). It may be explained by a lower absorption rate of DHQ in the rat. Addition of 15 or 30% DHQ to Q did not produce any significant difference in the acute toxic doses (LD50) in comparison with pure Q (p greater than 0.05). 4. The results of a published clinical study showed that the antiarrhythmic actions of pure Q and "commercial" Q are the same with regard to quality, potency and duration. The frequency of side-effects after adminstration of the two alkaloids also did not differ. 5. Limitation or reduction of the DHQ content of pharmaceutical quality quinidine below a technically practicable level does not seem to be justified from a medical point of view from the results of the animal experiments presented and from the clinical study mentioned.

The aim of this study was to compare the pharmacokinetics and antiarrhythmic activity of dihydroquinidine and quinidine in 14 patients (11 men, 3 women, aged 28 to 67 years) with heart disease and chronic, stable, high-frequency premature ventricular beats (PVB) (greater than 100/hr). A randomized, double-blind, crossover, placebo-controlled protocol was utilized. During Holter monitoring the patients were given either dihydroquinidine or quinidine as the gluconates in an oral solution (600 mg); blood samples were taken 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours later. The patients were then assigned to three successive treatment periods of 7 days each: dihydroquinidine HCl (900 mg/day), quinidine polygalacturonate (1,650 mg/day), or placebo. At the end of each period 24-hour Holter monitoring was carried out and a blood sample was taken for determination of drug concentration. By comparing the area under the curves dihydroquinidine was 59% as available as quinidine; rates of absorption and elimination were similar. Mean peak blood levels of dihydroquinidine and quinidine were 1.06 +/- 0.34 and 2.15 +/- 0.96 micrograms/ml, respectively. After dihydroquinidine, eight patients had a positive response (greater than 50% reduction in PVB frequency), while seven patients responded to quinidine. During maintenance treatment both dihydroquinidine (233 +/- 330) and quinidine (234 +/- 311) reduced the mean PVB frequency per hour compared to placebo (690 +/- 569). Nine patients (64%) on dihydroquinidine and eight (57%) on quinidine had greater than 70% decrease in mean PVB frequency per hour. Steady-state peak plasma concentrations of dihydroquinidine and quinidine were 1.10 +/- 0.41 and 2.24 +/- 1.13 micrograms/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors describe a computer system for the analysis of ventricular arrhythmias and its use in the evaluation of anti-arrhythmic drugs. Provided the arrhythmia is stable, this method allows an estimation of the onset and duration of action of the drug and gives guidelines for the choice of an appropriate drug regimen. Using this system, a comparison can be made between different drugs based on quantification of their efficacy.