piperidines and lorcainide

The last ten years have been a period of extensive research and development of new agents for the treatment of cardiac rhythm abnormalities. Several new subclass Ic agents have been developed, and more recently the class III agents have become the focus of attention. These new agents are all remarkable for their potency and potential for producing side effects. While none of these agents offers the perfect cure for the treatment or prevention of cardiac arrhythmias, they all offer advantages and options that are valuable for clinical management of patients.

Topics: Amiodarone; Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Encainide; Flecainide; Humans; Mexiletine; Piperidines; Propafenone; Propanolamines

Topics: Amiodarone; Anilides; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Dogs; Drug Evaluation; Electric Stimulation; Encainide; Flecainide; Heart Conduction System; Humans; Piperidines

A number of conventional and newer antiarrhythmic agents are available for the treatment and prophylaxis of ventricular tachycardia and sudden death. Using a multifaceted approach of programmed electrical stimulation studies, drug level determinations, exercise tolerance testing, and 24-hour ambulatory electrocardiographic monitoring, the physician can identify those patients who require therapy and then predict the likelihood of efficacy with each antiarrhythmic agent. This approach affords evaluation of both aspects of the sudden death equation-ectopy frequency (triggering mechanism) and vulnerability to development of sustained ventricular tachycardia (substrate). After institution of therapy, careful follow-up is necessary to document sustained drug efficacy and detect side effects. Serious adverse reactions necessitate a change in antiarrhythmic therapy, as opposed to lowering drug dosage to an ineffective level. The unacceptably high incidence of sudden death due to electrical instability can be reversed only by a rigorous and dedicated long-term approach to the management of serious ventricular arrhythmias.

Topics: Adrenergic beta-Antagonists; Ajmaline; Amiodarone; Anilides; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Benzeneacetamides; Bepridil; Bethanidine; Bretylium Tosylate; Disopyramide; Drug Administration Schedule; Encainide; Flecainide; Heart Conduction System; Humans; Imidazoles; Lidocaine; Mexiletine; Moricizine; Myocardial Contraction; Phenothiazines; Phenytoin; Piperidines; Procainamide; Propafenone; Propiophenones; Pyrrolidines; Quinidine; Tocainide; Verapamil

The number of antiarrhythmic drugs available in the United States is increasing, with the discovery of antiarrhythmic properties of drugs previously marketed for other indications (phenytoin, imipramine) and the development of several new drugs, many of which are likely to become commercially available in the next 5 years. The currently available drugs and several promising investigational drugs are reviewed in this report. Their optimal use is dependent on an understanding of their electropharmacologic effects, pharmacokinetics, drug interactions, and clinical pharmacology. Such use may allow better attempts to reduce arrhythmia-related death and morbidity.

Topics: Adrenergic beta-Antagonists; Amiodarone; Anilides; Anti-Arrhythmia Agents; Benzeneacetamides; Biological Availability; Bretylium Compounds; Disopyramide; Encainide; Flecainide; Humans; Imipramine; Lidocaine; Mexiletine; Moricizine; Phenothiazines; Phenytoin; Piperidines; Procainamide; Propafenone; Propiophenones; Quinidine; Tocainide

Topics: Adrenergic beta-Antagonists; Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Calcium Channel Blockers; Electrophysiology; Encainide; Flecainide; Heart Conduction System; Humans; Lidocaine; Moricizine; Phenothiazines; Piperidines; Quaternary Ammonium Compounds; Sotalol; Tocainide

Topics: Amiodarone; Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Encainide; Flecainide; Humans; Lidocaine; Mexiletine; Moricizine; Phenothiazines; Piperidines; Propafenone; Propiophenones; Tocainide

VT may be observed to accompany a wide variety of heart diseases and occasionally no heart disease at all. The efficacy of drug therapy is dependent on antiarrhythmic effects and the mechanism underlying the patient's VT. Conventional antiarrhythmic agents appear to be effective in no more than one third of patients, but a substantial number of other potentially useful antiarrhythmic agents exist. Unfortunately, their effectiveness in treating sustained VT for the most part must still be proved. Other agents such as amiodarone appear effective, but ways to predict which patients will benefit remain unknown. Invasive and noninvasive techniques exist for assessing therapeutic efficacy, but determination of which is more appropriate awaits a wider experience and more direct comparison.

Topics: Adrenergic beta-Antagonists; Amiodarone; Anilides; Anti-Arrhythmia Agents; Aprindine; Benzeneacetamides; Bethanidine; Calcium Channel Blockers; Disopyramide; Drug Therapy, Combination; Electrocardiography; Electrophysiology; Encainide; Heart Ventricles; Humans; Lidocaine; Mexiletine; Phenytoin; Piperidines; Procainamide; Quinidine; Tachycardia; Tocainide

Lorcainide is a type I antiarrhythmic drug of the local anesthetic type. It can be given either intravenously or orally, and its pharmacokinetic properties allow relatively long (12 hours) dosing intervals with oral administration. A slowly eliminated metabolite, norlorcainide, probably contributes to the effects of orally administered lorcainide in chronically treated patients. In mainly short term studies, lorcainide has been shown to suppress ventricular ectopy in about 80% of patients treated either orally or intravenously. Preliminary evidence suggests that its efficacy in suppressing ectopy in the setting of acute myocardial infarction is comparable with that of lignocaine (lidocaine). It is of variable efficacy in preventing recurrent ventricular tachycardia and has been shown to be effective in some patients who have failed to respond to other antiarrhythmic drugs. Experience is limited in treating supraventricular arrhythmia, but initial results in patients with Wolff-Parkinson-White syndrome have been favourable. Adverse cardiac effects are infrequent. Abnormal sinus node function may be exacerbated by lorcainide treatment, however, and bundle branch block may be precipitated in patients with pre-existing conduction system disease. Exacerbation of pre-existing arrhythmias is uncommon, and clinically important myocardial depression has not been observed. The most frequent side effect is disturbed sleep during the initiation of oral treatment, which may occur in the majority of patients but usually responds to treatment with a benzodiazepine and subsides with time. Thus, lorcainide appears useful against a variety of arrhythmias. With its convenient dosage schedule and apparently low incidence of serious side effects it should become a useful addition to the antiarrhythmic agents available, although longer term studies are needed to confirm its continued efficacy and lack of unexpected side effects when used for long periods.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Biological Availability; Clinical Trials as Topic; Drug Interactions; Electrophysiology; Half-Life; Hemodynamics; Humans; Kinetics; Piperidines; Wolff-Parkinson-White Syndrome

The investigational antiarrhythmic agents available for use in this country are predominantly class I drugs with local anesthetic membrane effects. These drugs are often used successfully to control arrhythmias refractory to treatment with the standard antiarrhythmic drugs. Side effects often limit their use, and particular attention needs to be paid to their cardiac side effects, such as exacerbation of arrhythmia or enhanced conduction defects.

Topics: Amiodarone; Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Encainide; Flecainide; Humans; Lidocaine; Mexiletine; Piperidines; Tocainide

The haemodynamic effects of encainide, flecainide, lorcainide and tocainide in man are reviewed. Most of the investigations discussed are acute intervention studies after intravenous administration of the drugs. With all four drugs, haemodynamic changes, when present, were moderate. In most studies a decrease in left ventricular maximal dp/dt is demonstrated, suggesting a negative inotropic action. Left ventricular filling pressures are unchanged or slightly increased. A small decrease in cardiac performance, as determined by measurements of cardiac output and left ventricular ejection fraction, is usually observed, while systemic vascular resistance is increased or remains unchanged. Haemodynamic deterioration and/or hypotensive reactions after intravenous administration of any of the above drugs are uncommon in patients without severe cardiac dysfunction. Conclusions relative to drug safety in frank congestive failure are not warranted, in view of the small number of patients studied. While comparative studies between the drugs discussed have not been performed, the data presented here indicate that, on the basis of haemodynamic action, no one drug can be preferred above the other.

Topics: Anilides; Anti-Arrhythmia Agents; Benzeneacetamides; Encainide; Flecainide; Hemodynamics; Humans; Lidocaine; Piperidines; Tocainide

Topics: Action Potentials; Anilides; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Electrocardiography; Electrophysiology; Encainide; Flecainide; Heart; Heart Conduction System; Humans; Lidocaine; Piperidines; Sinoatrial Node; Tocainide

Topics: Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Coronary Disease; Encainide; Flecainide; Heart Ventricles; Humans; Lidocaine; Mexiletine; Myocardial Infarction; Piperidines; Tachycardia; Tocainide; Ventricular Fibrillation

Most antiarrhythmic drugs are extensively metabolized, and the accumulation of the metabolites of several of these drugs has been documented. In some cases, the steady-state plasma concentrations of metabolites are considerably greater than is the concentration of the parent drug. Several of these metabolites have been evaluated in animal models for antiarrhythmic activity and their potencies have been defined relative to the activity of their parent compound. Evaluations of activity are generally conducted in animal arrhythmia models, and very few metabolites of antiarrhythmic drugs have been evaluated directly in patients. However, from knowledge of antiarrhythmic activity in animals and the degree to which a metabolite accumulates in the plasma of patients, one can make qualitative judgments about its therapeutic role. Such judgments, however, need to be recognized as tenuous. Quantitative judgments require further information regarding the relationship between the parent drug and metabolite when present simultaneously in the myocardium. One must consider whether the effects of the parent drug and metabolite are additive, synergistic, or even antagonistic. The latter case is most possible with drug-metabolite pairs where the metabolite accumulates substantially, but does not have significant antiarrhythmic potency. Other considerations include noncardiac effects of the metabolites. As in the case of the mono-desethyl metabolite of lidocaine, the significance of its accumulation relates more to central nervous system side effects than to direct cardiac actions. The role of active metabolites also much be considered in regard to differences in the disposition kinetics between the parent drug and metabolite. The most obvious situation where this is important is in designing clinical drug evaluation protocols. As illustrated by the metabolites of encainide and lorcainide, the time course of accumulation and disappearance of the metabolites may be much longer than that of the parent drug. Clinical evaluations at steady state must take into account the time required to achieve steady-state concentrations of the metabolites as well. Similarly, after discontinuation of drug administration, the time required before washout is complete may be totally dependent on the kinetics of the metabolite, and not the parent drug. Variability in metabolic activity also needs to be considered. It has been shown with procainamide and encainide that genetic factors can influen

Topics: Amiodarone; Anilides; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Disopyramide; Encainide; Humans; Lidocaine; Piperidines; Procainamide; Quinidine

In order to use antiarrhythmic drugs safely, one must understand their hemodynamic effects. Quinidine and the calcium antagonists have direct cardiac effects and frequently opposing autonomically mediated or indirect cardiac effects. Lidocaine is exceptionally well tolerated, even by patients with severe left ventricular dysfunction. Phenytoin and procainamide have the potential for serious adverse effects, but are generally well tolerated at usual doses. Disopyramide causes serious depression of left ventricular function in many patients because of its direct myocardial depressant and peripheral vasoconstricting actions. Although bretylium causes an immediate increase in contractility, it can ultimately result in important hypotension. In this review the in vitro and in vivo hemodynamic effects of these and other antiarrhythmic drugs are discussed to provide information that will assist the clinician in using these drugs properly.

Topics: Amiodarone; Anilides; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Bretylium Compounds; Calcium Channel Blockers; Disopyramide; Dose-Response Relationship, Drug; Encainide; Flecainide; Hemodynamics; Humans; Lidocaine; Mexiletine; Myocardial Contraction; Phenytoin; Piperidines; Procainamide; Quinidine; Tocainide

New class I antiarrhythmic drugs differ in potency, adverse effects and pharmacokinetics. Encainide and flecainide can totally suppress arrhythmias in some patients, but arrhythmia induction can also occur. At effective dose levels, neurologic and gastrointestinal adverse effects are uncommon. Flecainide pharmacokinetics are suitable for oral use but encainide disposition is complex with variable bioavailability and active metabolites that contribute substantially to activity. Lorcainide is also potent, but neurologic adverse effects are common and dose-dependent bioavailability and an active metabolite may complicate long-term oral therapy. Tocainide and mexiletine can suppress arrhythmias in acute myocardial infarction, during convalescence from myocardial infarction and in patients with arrhythmias resistant to other therapy. Dose-related neurologic and gastrointestinal adverse effects are common, but hemodynamic effects are minor and arrhythmia induction is rare. Tocainide disposition is reasonably predictable and stable in patients, but mexiletine disposition is less so because of variation in distribution and clearance. Although all of the newer agents have some disadvantages, their availability should increase the likelihood of success in the high-risk patient.

Topics: Administration, Oral; Anilides; Anti-Arrhythmia Agents; Benzeneacetamides; Dose-Response Relationship, Drug; Electrophysiology; Encainide; Flecainide; Hemodynamics; Humans; Injections, Intravenous; Kinetics; Lidocaine; Mexiletine; Piperidines; Tocainide

Topics: Anilides; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Electrophysiology; Encainide; Flecainide; Hemodynamics; Humans; Imidazoles; Lidocaine; Mexiletine; Piperidines; Propafenone; Propiophenones; Sotalol; Tocainide

Topics: Action Potentials; Ajmaline; Amiodarone; Anilides; Animals; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Benzeneacetamides; Bretylium Tosylate; Disopyramide; Encainide; Hemodynamics; Humans; Kinetics; Moricizine; Morpholines; Phenothiazines; Piperidines; Verapamil

This is a first review of lorcainide hydrochloride, a new antiarrhythmic agent with local anaesthetic activity. The antiarrhythmic actions of lorcainide are mediated by an impairment of fast sodium conductance. Pharmacologically, this drug appears effective in suppressing reentry phenomena and ectopic pacemaker activity, especially in the ventricles. Lorcainide has only negligible depressant effects on important haemodynamic parameters and its toxicity is minimal. The drug is well absorbed by the oral route and its elimination half-life is long when compared with other substances. Lorcainide-induced QRS widening is directly correlated with the plasma levels of the drug. Preliminary experience in supraventricular arrhythmias is promising but pre-excitation syndromes and the ventricular arrhythmias are the main indications for this drug since a very high response rate has been observed in these conditions. Side effects are harmless and dose-dependent, but may be clinically troublesome.

Topics: Absorption; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Dogs; Electrocardiography; Guinea Pigs; Half-Life; Heart Conduction System; Hemodynamics; Humans; Kinetics; Lethal Dose 50; Mice; Myocardial Contraction; Piperidines; Rats

Newer antiarrhythmic drugs are tentatively classified on the basis of their influence on the transmembrane action potential, the fast sodium inward current and its kinetics, and the slow inward current which is primarily carried by calcium ions. Disopyramide is probably a quinidine-like antiarrhythmic drug, while the effects of aprindine, lorcainide, and tocainide resemble those of lidocaine. Mexiletine and propafenon cannot be classified definitely on the basis of the hitherto available electrophysiological data. Besides their effects on the fast inward current these substances may have additional calcium antagonistic properties.

Topics: Action Potentials; Adrenergic beta-Antagonists; Anilides; Animals; Anti-Arrhythmia Agents; Aprindine; Benzeneacetamides; Calcium; Disopyramide; Electrophysiology; Humans; Lidocaine; Mexiletine; Piperidines; Propafenone; Propiophenones; Quinidine; Sodium; Tocainide

Topics: Anilides; Anti-Arrhythmia Agents; Aprindine; Benzeneacetamides; Disopyramide; Humans; Kinetics; Mexiletine; Piperidines; Tocainide; Verapamil

The aim of antiarrhythmic drug therapy is to terminate or suppress specific arrhythmias and improve cardiovascular function. Short-term studies of the new Class I drugs encainide, mexilitine, and tocainide have demonstrated only minor falls in cardiac index with modest rises in mean aortic pressure. In contrast, disopyramide has been shown to depress myocardial function in both animals and patient studies. Heart failure may be precipitated by therapy with disopyramide and electromechanical dissociation has been reported. Class II agents with beta-adrenergic blocking actions all produce a degree of myocardial depression. Atenolol resembles propranolol in patients with coronary artery disease in its hemodyanmic effects, whereas acebutolol is less of a depressant, resembling practolol. The Class III agent amiodarone has only a mild depressant effect associated with a reduction in afterload and an increase in coronary blood flow. The Class IV agent verapamil, which is a calcium channel blocker, has potent myocardial depressant actions and causes peripheral vasodilatation. Hypotension, heart failure, and shock have been precipitated particularly in patients receiving beta-blocking drugs concurrently. While all the new antiarrhythmic drugs currently studied will cause some degree of hemodyanmic depression in an appropriately high concentration, present investigations suggest that particular caution needs to be taken when disopyramide, aprindine, atenolol, and verampamil are administered either acutely by the intravenous route or chronically by the oral route.

Topics: Acebutolol; Amiodarone; Anilides; Animals; Anti-Arrhythmia Agents; Atenolol; Benzeneacetamides; Disopyramide; Dogs; Hemodynamics; Humans; Mexiletine; Piperidines; Tocainide; Verapamil

Ninety-five patients with suspected acute myocardial infarction were randomly allocated on admission to hospital on a double blind basis to treatment with lorcainide, a Class 1C anti-arrhythmic drug, or matching placebo. Treatment was continued for 6 weeks. Twenty-four-hour ECG tape recordings were made immediately on admission, on the sixth or seventh day after admission, and again just before the end of the treatment period. Lorcainide was shown to be an effective anti-arrhythmic agent. The study was not designed to evaluate the effect of lorcainide on survival, but there were nine deaths among the 49 patients treated with lorcainide compared with only one in the patients given placebo. These findings are consistent with the results of the First and Second Cardiac Arrhythmia Suppression trials (CAST and CAST-II). This study was carried out in 1980 but was not published at the time: it now provides an interesting example of 'publication bias'.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Double-Blind Method; Electrocardiography; Female; Humans; Male; Middle Aged; Myocardial Infarction; Piperidines; Publishing; Survival Analysis; Time Factors

Intravenous lorcainide and lidocaine were administered to 25 patients with symptomatic ventricular tachyarrhythmias in a randomized single-blind crossover study. Prior to drug therapy, each patient underwent 48 hours of ambulatory monitoring and exercise testing on a motorized treadmill. At the completion of baseline studies, patients were randomized to receive either lidocaine or lorcainide intravenously. The dose of lidocaine was 1.0 mg/kg by bolus followed by an infusion of 2 to 3 mg/min. The dose of lorcainide was 2.0 mg/kg followed by a constant infusion of 200 to 300 mg over 24 hours. Two patients developed side effects on lidocaine and the infusion was discontinued prior to evaluation of efficacy. Of the remaining 23 patients, 11 (48%) had their arrhythmia controlled, defined as a greater than 90% reduction in repetitive forms (couplets and ventricular tachycardia) and a 50% reduction in ventricular premature beats. Lorcainide was effective in 8 of the 25 patients (32%). There was no correlation between the effect of lidocaine and the response to lorcainide (p = NS). Oral lorcainide therapy was administered to 17 patients who were free of side effects during the intravenous infusion. The oral drug was effective in nine patients (53%), five of whom had responded to the intravenous drug, and was ineffective in eight, seven of whom were also unresponsive to intravenous lorcainide. The intravenous drug predicted the response to the oral form in 71% of patients, but this was not statistically significant. Side effects occurred in 10 patients (59%) and were primarily neurologic.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Female; Humans; Infusions, Intravenous; Lidocaine; Male; Middle Aged; Piperidines; Random Allocation

Thirty patients with frequent (greater than or equal to 30/hr) and repetitive ventricular premature beats (VPBs) unassociated with acute infarction were randomized to intravenous lorcainide (LOR) or lidocaine (LID). Following at least 2 hours of baseline Holter monitoring, patients received LOR, 2 mg/kg then 200 mg/24hr, or LID, 1 mg/kg then 2 mg/min, with rebolus if needed. Nonresponders detected by bedside telemetry were crossed over. Clinical response was 6 of 25 (24%) including two of nine crossovers with LOR and 8 of 26 (31%) including 3 of 12 crossovers with LID (p = NS). By computer analysis of 24-hour Holter monitors and asymptotic regression of success rates at hourly intervals, it was projected that greater than or equal to 80% reduction in VPBs occurred in 28% of LOR and in 25% of LID (p = NS), and complete suppression of repetitive VPBs occurred in 102% of LOR and in 92% of LID (p = NS). The mean drug levels were 405 ng/ml (range 371 to 463) with LOR and 3.4 micrograms/ml (range 2.1 to 3.6) with LID. Side effects were similar, occurring in 8 of 25 LOR trials and in 11 of 26 LID trials (p = NS). Thus, LOR and LID effectively suppress repetitive VPBs and to a lesser extent VPB frequency. However, neither drug is superior and each may be an effective alternative when resistance to the other is encountered.

Topics: Aged; Arrhythmias, Cardiac; Benzeneacetamides; Chronic Disease; Electrocardiography; Female; Humans; Infusions, Parenteral; Kinetics; Lidocaine; Male; Middle Aged; Monitoring, Physiologic; Myocardial Infarction; Piperidines; Random Allocation

Twenty-eight subjects underwent evaluation of drug toxicity and antiarrhythmic efficacy with oral and intravenous lorcainide. Lorcainide, a new type 1C antiarrhythmic drug, has an active metabolite, norlorcainide, which accumulates after oral but not significantly after intravenous administration. Group 1 consisted of 14 subjects who received intravenous lorcainide with an initial bolus of 2 mg/kg at a rate of 2 mg/min followed by 0.14 mg/min or 200 mg/24 hours. The lorcainide level after bolus was 0.432 micrograms/ml and fell to 0.178 micrograms/ml at 4 to 6 hours despite constant drug infusion. Prior work has demonstrated no detectable norlorcainide levels after intravenous infusion. Group II consisted of 14 subjects who received oral lorcainide, 100 mg orally every 8 hours. Mean lorcainide levels were 0.287 micrograms/ml and mean norlorcainide levels were 0.377 micrograms/ml. Only 2 of 12 subjects in group I experienced headache, dizziness, or sleep disturbance, compared to 12 of 14 subjects in group II (p less than 0.01). Intravenous lorcainide has a lower incidence of central nervous system side effects than oral lorcainide. These effects may be attributable to the accumulation of the norlorcainide metabolite with oral therapy.

Topics: Administration, Oral; Adolescent; Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Central Nervous System; Female; Heart Ventricles; Humans; Infusions, Parenteral; Male; Middle Aged; Monitoring, Physiologic; Piperidines

Nineteen patients with refractory but stable ventricular premature beats (VPB) received 3 medications intravenously at 24-h intervals. Lorcainide (2 mg/kg) and placebo were given double-blind in randomized sequence and the third treatment was 100 mg lidocaine, the standard reference drug. Continuous ECG recordings were made for the first 2 hours after administration to study the antiarrhythmic effect; the stability of the arrhythmia, the absence of residual and of period effects, and the interdrug differences in efficacy were statistically evaluated. Lorcainide significantly reduced the frequency of VPB during the 2-hour period, whereas the effect of lidocaine was more short-lived. The median individual peak reduction in VPB was 96% for lorcainide and 47% for lidocaine. No significant reduction in VPB was observed with placebo. Adverse effects were acceptable with either active treatment.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Cardiac Complexes, Premature; Clinical Trials as Topic; Double-Blind Method; Electrocardiography; Female; Humans; Lidocaine; Male; Middle Aged; Piperidines; Random Allocation; Time Factors

There is a need for effective, well tolerated, intravenous antiarrhythmic agents. The effects of lorcainide, a new class I antiarrhythmic agent, were compared with those of lidocaine in a randomized parallel study with cross-over option in 30 hospitalized patients with frequent (greater than 1/min) complex ventricular arrhythmias. Lorcainide loading dose was 2 mg/kg (at 2 mg/min) supplemented, if needed, with 100 mg in 1 hour; maintenance dose was 8 mg/h. Lidocaine loading dose was 1 mg/kg (at 25 mg/min) supplemented, if needed, with 50 mg in 2 minutes; maintenance dose was 2 or 3 mg/min (as needed). Arrhythmias were compared for 2 hours before and after drug loading. Initially responding patients (minimum of 70% arrhythmia suppression) were continued on maintenance therapy for 24 hours. Patients initially failing or with later arrhythmia escape crossed over to alternating therapy (seven to lidocaine, nine to lorcainide). The median frequency of premature ventricular complexes decreased by 76% after lidocaine (p less than 0.05) and by 93% after lorcainide (p less than 0.001); this difference approached significance (p = 0.06). More than 95% arrhythmia suppression was achieved by lorcainide in 47% of patients and by lidocaine in only 13% (p less than 0.05). Couplets decreased by a median of 100% after lorcainide and by 89% after lidocaine. Couplets were eliminated in 62% of the patients after lorcainide and in 27% after lidocaine (p = 0.06). There was 100% suppression of runs of premature beats in 11 patients after lorcainide and 99% suppression in 10 patients after lidocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Drug Administration Schedule; Electrocardiography; Female; Humans; Infusions, Parenteral; Lidocaine; Male; Middle Aged; Piperidines; Prospective Studies; Random Allocation; Time Factors

Non-sustained ventricular tachycardia (VT) in the late post myocardial infarction (MI) period (7-21 days) has been reported to be a predictor of sudden death. We suspected that patients with 3 beat VT on Holter monitoring in the late infarction period would demonstrate electrical instability at electrophysiologic studies. Forty-seven patients were identified as having at least 3 beat VT on Holter monitoring. Eighteen patients refused electrophysiologic studies or were not referred by their attending physician. The mean ejection fraction of this group was 43 +/- 16%. Eight patients have died, 3 sudden deaths in 13 +/- 5 months, a 17% incidence of sudden death. Twenty-nine patients underwent invasive electrophysiologic studies. Their mean ejection fraction was 37 +/- 7%, and 28 had inducible, 18 sustained ventricular tachycardia and 10 non-sustained VT. No complications were noted with electrophysiological testing in the post infarction patients. Using programmed electrical stimulation studies an effective antiarrhythmic agent preventing VT induction (usually experimental) could be found for each patient. After a mean follow-up of 12.5 +/- 4 months, the patient without inducible VT is alive and 26 of the 28 "inducible" patients are alive and well. Two patients died, one of stroke and one due to pump failure following a second MI. No sudden deaths were observed in this group. Two patients had breakthrough arrhythmias and were treated by alternative antiarrhythmic therapy that was also effective at the initial electrophysiologic studies. Thus, PES studies post MI are safe and may be an effective way to assess therapy for patients in the early post MI period, identified at high risk for sudden death.

Topics: Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Cardiac Pacing, Artificial; Clinical Trials as Topic; Electrocardiography; Female; Heart Rate; Heart Ventricles; Humans; Male; Middle Aged; Myocardial Infarction; Piperidines; Tachycardia

One hundred patients inducible at electrophysiologic studies underwent serial drug testing with procainamide, lidocaine, and lorcainide to determine comparative efficacy. Acute intravenous administration was followed by repeat programmed electrical stimulation (PES) studies on separate days for each antiarrhythmic drug. Lorcainide prevented ventricular tachycardia (VT) induction in 69% of the 100 patients studied, procainamide was effective in 50% of the 75 patients studied, and lidocaine prevented VT induction in 30% of 53 patients. Following PES and serial drug testing, 46 patients were started on lorcainide, nine patients on procainamide, and 45 patients were started on other antiarrhythmic drug regimens. Seventy percent of the patients have remained on lorcainide therapy, while 47% have continued on other drug therapies started over a 20.5 +/- 3.2-month mean follow-up period. Despite sleep-wake disturbances and a need for sedation at night, lorcainide therapy was tolerated well in this population and remained an effective antiarrhythmic with prolonged administration.

Topics: Benzeneacetamides; Cardiac Pacing, Artificial; Drug Evaluation; Electrocardiography; Female; Heart Ventricles; Humans; Injections, Intravenous; Lidocaine; Male; Middle Aged; Piperidines; Procainamide; Tachycardia

In a randomized double-blind cross-over trial, the effectiveness of lorcainide at a dosage of three times 100 mg/d by mouth was compared with that of a placebo for the treatment of subjectively disturbing stable ventricular extrasystoles (VES), using 48-hour continuous ECG monitoring. In 11 of 20 patients there was a regression in the VES rate to under 5%, in other 3 patients to under 50% of the initial values. Continuing the treatment, good therapeutic effect was still demonstrable 14 and 28 days later. However, only three patients had no side-effects. The others had sleep disturbances, hot flushes, sweating, restlessness, anxiety, dizziness, hallucinations and gastrointestinal symptoms. Lorcainide thus has a good anti-arrhythmic effect but, because of its side-effects, it should be used only in special circumstances.

Topics: Adult; Anti-Arrhythmia Agents; Benzeneacetamides; Cardiac Complexes, Premature; Clinical Trials as Topic; Double-Blind Method; Electrocardiography; Female; Humans; Male; Middle Aged; Piperidines; Placebos; Time Factors

Lorcainide is a type I antiarrhythmic drug of the local anesthetic type. It can be given either intravenously or orally, and its pharmacokinetic properties allow relatively long (12 hours) dosing intervals with oral administration. A slowly eliminated metabolite, norlorcainide, probably contributes to the effects of orally administered lorcainide in chronically treated patients. In mainly short term studies, lorcainide has been shown to suppress ventricular ectopy in about 80% of patients treated either orally or intravenously. Preliminary evidence suggests that its efficacy in suppressing ectopy in the setting of acute myocardial infarction is comparable with that of lignocaine (lidocaine). It is of variable efficacy in preventing recurrent ventricular tachycardia and has been shown to be effective in some patients who have failed to respond to other antiarrhythmic drugs. Experience is limited in treating supraventricular arrhythmia, but initial results in patients with Wolff-Parkinson-White syndrome have been favourable. Adverse cardiac effects are infrequent. Abnormal sinus node function may be exacerbated by lorcainide treatment, however, and bundle branch block may be precipitated in patients with pre-existing conduction system disease. Exacerbation of pre-existing arrhythmias is uncommon, and clinically important myocardial depression has not been observed. The most frequent side effect is disturbed sleep during the initiation of oral treatment, which may occur in the majority of patients but usually responds to treatment with a benzodiazepine and subsides with time. Thus, lorcainide appears useful against a variety of arrhythmias. With its convenient dosage schedule and apparently low incidence of serious side effects it should become a useful addition to the antiarrhythmic agents available, although longer term studies are needed to confirm its continued efficacy and lack of unexpected side effects when used for long periods.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Biological Availability; Clinical Trials as Topic; Drug Interactions; Electrophysiology; Half-Life; Hemodynamics; Humans; Kinetics; Piperidines; Wolff-Parkinson-White Syndrome

Lorcainide, a new class I antiarrhythmic agent, was administered intravenously to eight patients with acute myocardial infarction for 24 hours, and thereafter given by mouth, 200 mg daily for ten days. Ten control infarction patients were given lidocaine 3 mg/min during the first 24 hours and the oral betablocking agent, pindolol, for the following ten days. The two groups were comparable with respect to age, sex, onset-admission interval, and site and size of infarction. Ventricular premature beats were monitored with a 24-hour continuous ECG recording on days 1, 6 and 10. Complex ventricular premature beats were common during the first 24 hours of infarction; their occurrence and severity were similar in both groups, as judged by the Lown grading system. The plasma levels of lorcainide after the 24-hour infusion ranged 72-144 ng/ml (mean 95 ng/ml). On the sixth day, 12 hours after previous oral dose, lorcainide plasma levels ranged 11-82 ng/ml (mean 42 ng/ml). No major adverse effects were noticed, mild insomnia being the most disturbing reaction. It is concluded that lorcainide is an acceptable alternative to lidocaine in the treatment of ventricular arrhythmias in the acute stage of myocardial infarction. It has the advantage of being effective by oral route, too.

Topics: Administration, Oral; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Female; Humans; Infusions, Parenteral; Lidocaine; Male; Middle Aged; Myocardial Infarction; Pindolol; Piperidines; Random Allocation

Lorcainide, 100 mg twice daily was compared with placebo in 39 patients with frequent ventricular arrhythmias in a randomized double-blind crossover trial. A mean frequency of ventricular premature beats (VPBs) of at least 30 VPBs/hour was required during a drug-free period of 48 hours. Holter monitoring and a maximal symptom-limited exercise test were performed at the end of each of the 2-week double-blind treatment phase. The group averaged 350 +/- 361 (standard deviation) VPBs/hour. Lorcainide decreased the mean VPB frequency of the group by 46% (p less than 0.01), with VPB reduction beyond the expected variation in 22 of 39 patients. In 13 patients VPBs were unchanged and in 4 they increased. Eight additional patients responded during drug titration, for an overall response rate of 77% (30 of 39). Lorcainide did not significantly reduce the exercise-related VPB frequency. At 6 months 61% of patients had significant VPB suppression. Thus, lorcainide was effective in reducing the frequency and grade of spontaneous ventricular arrhythmias during short- and long-term evaluation.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Exercise Test; Female; Follow-Up Studies; Heart Ventricles; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Random Allocation

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.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Female; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Quinidine; Random Allocation

Lorcainide, a new type I antiarrhythmic agent, was compared to quinidine in respect to antiarrhythmic efficacy and clinical safety. Thirteen subjects completed an open, randomized, crossover study with analysis of 24-hour ambulatory ECG monitoring and drug blood levels. The QRS and Q-T intervals increased with both lorcainide and quinidine. The mean reduction in total ventricular premature beats (VPBs) with quinidine was 16 percent compared to 68 percent with lorcainide (p less than .05). With lorcainide eight of 13 subjects had a significant (greater than 82 percent) reduction in VPBs compared to only three of 13 subjects taking quinidine (p less than .05). This same relationship was observed when mean VPB/1,000 heartbeats was analyzed. Ventricular tachycardia was no longer present in five of nine subjects taking lorcainide and in two of nine taking quinidine. No relationship could be established between drug level and arrhythmia suppression in this small population. Some CNS effects were reported in both groups, but no significant hematologic, chemical, or urinary adverse effects were seen with either drug. Thus, lorcainide compares favorably to quinidine in regard to arrhythmia suppression, but was limited in its clinical utility by CNS side effects.

Topics: Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Female; Humans; Male; Middle Aged; Piperidines; Quinidine; Tachycardia

Topics: Administration, Oral; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Double-Blind Method; Heart Ventricles; Humans; Injections, Intravenous; Piperidines

The feasibility of giving a supplementary starting dose of the antiarrhythmic drug lorcainide, in order to minimalize the impact of the extensive, but saturable first-pass metabolism, was evaluated. Twenty-five adult patients were given 100 mg lorcainide tablets according to one of 3 different dosage schedules: Eight patients took one tablet at 0, 12 and 24 h, 8 took 1 tablet at 0, 1, 12 and 24 h and 9 took 1 tablet at 0, 2, 12 and 24 h. Levels of lorcainide and its metabolite, nor-lorcainide, during treatment were determined by gas-liquid chromatography. The results show that giving a second tablet 1 or 2 h after the first may produce faster saturation of the pre-systemic metabolism of lorcainide in the liver.

Topics: Aged; Benzeneacetamides; Biological Availability; Biotransformation; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Piperidines

Several therapeutic approaches have sought to prevent the occurrence of sudden cardiac death. Many sudden deaths are presumed to be due to an arrhythmia, but the drugs best known for antiarrhythmic activity, the local anesthetic agents, have not been suitable prophylactic agents because of their toxicities and other undesirable pharmacologic characteristics. Several new drugs in this class have been synthesized and are currently being tested for antiarrhythmic activity in clinical trials. One of them may prove to be worthy of a large-scale clinical trial to determine whether chronic arrhythmia suppression reduces the risk of sudden death. The characteristics of the "ideal" antiarrhythmic agent are discussed, and a brief summary of the drugs currently being tested in the United States is presented. The discussion of each drug emphasizes the characteristics that might make it suitable--or unsuitable--for use in a sudden-death trial. Many agents being tested are clearly not satisfactory for such a trial. However, they may be prototypes for an ideal drug or combination of drugs that might yet be developed.

Topics: Acecainide; Amiodarone; Anilides; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Benzeneacetamides; Bretylium Compounds; Clinical Trials as Topic; Death, Sudden; Encainide; Flecainide; Humans; Kinetics; Lidocaine; Mexiletine; Moricizine; Morpholines; Phenothiazines; Piperidines; Tocainide; Verapamil

In a blind cross-over study, 12 patients with ventricular arrhythmias (VPC's; Lown Grades II-IVB) resistant to a daily dose of quinidine 1.2 g, disopyramide 0.8 g, N-propyl-ajmaline 0.1 g were randomly given, each dose for one week, placebo (PL), mexiletine (MEX; 400, 600, 800 mg daily) and lorcainide (LOR; 200, 300, 400 mg daily). On the last day of each treatment period, patients were evaluated by 24-h continuous ambulatory monitoring, 6-channel surface ECG, plasma concentrations and side-effects. During PL I (before) and PL II (after drug treatment), the mean number of VPCs per hour was 670 and 701. VPCs were reduced in 5 of the 12 patients with MEX by 43% (400 mg), 74% (600 mg) and 91% (800 mg). VPCs were reduced in 10 patients with LOR by 60% (200 mg), 78% (300 mg) and 93% (400 mg). Log. lin. plasma conc. effect relationships were constructed for MEX and LOR. Vomiting, nausea, and abdominal pain were seen in 2 patients with MEX; insomnia and feeling heat in 10 patients with LOR. At the end of the LOR-treatment, these side-effects were less in 5 and absent in 5 patients. In this study, LOR seems superior to MEX in refractory ventricular arrhythmias.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Coronary Disease; Dose-Response Relationship, Drug; Electrocardiography; Female; Heart Failure; Heart Ventricles; Humans; Male; Mexiletine; Middle Aged; Mitral Valve Prolapse; Piperidines; Propylamines; Random Allocation

Lorcainide, a new antiarrhythmic drug, was given to 10 patients with frequent (greater than 1/min) premature ventricular contractions (PVCs) on a baseline 24-hour Holter monitor. Each patient received lorcainide, 100 mg twice daily, and an identical placebo, in a randomized double-blind crossover trial, with 1 week in each treatment period. Before the trial and at the end of each period, routine laboratory, clinical evaluation, 12-lead ECG's, and 24-hour ambulatory ECG recordings were performed. Trough drug plasma concentration measurements were done at the end of each treatment period. All patients had reduction in PVCs, comparing drug to placebo, averaging 82.3 +/- 19.7% (mean +/- SD, p less than 0.01 by Wilcoxin ranked sum), and there was also significant decrease in the number of ventricular pairs and runs. Levels of the major metabolite, norlorcainide, ranged from 34 to 254 ng/ml (mean 160 ng/ml) and exceeded those for lorcainide, range 6 to 169 ng/ml (mean 79 ng/ml). Prolongation of PR, QRS, and QTc intervals was evident during drug therapy, as was decrease in heart rate, but these changes were minimal. The major adverse effect noted was sleep disturbance, which was often initially severe, but improved during the week of therapy.

Topics: Administration, Oral; Adult; Aged; Ambulatory Care; Anti-Arrhythmia Agents; Benzeneacetamides; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Female; Humans; Male; Middle Aged; Piperidines; Placebos; Random Allocation; Tachycardia

A new anti-arrhythmic agent, lorcainide, has been compared with lignocaine in patients with acute myocardial infarction. Lorcainide has been shown to be as effective as lignocaine in suppressing ventricular ectopy. Lorcainide is unusually free of side-effects and has the great advantage over lignocaine of being effective when given orally.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Drug Evaluation; Humans; Lidocaine; Piperidines; Time Factors

The disposition and the antiarrhythmic effect of lorcainide (R 15,889) were investigated in 11 patients with ventricular premature beats (VPB) after a single intravenous dose of 100 mg or 2 mg/kg and after multiple intravenous and oral dosing. Pharmacokinetic parameters were computed according to the two-compartment open model. The half-life of the initial phase, t 1/2 (alpha), was calculated as 0.3 +/- 0.1 hr (mean +/- SD) and the terminal half-life, t 1/2 (beta), varied independently of the dose and route of administration between 5.8 and 12.5 hr (7.8 +/- 2.5 hr). After the single intravenous dose total plasma clearance (Cl) ranged from 570 to 1670 ml/min (988 +/- 425 ml/min) while after multiple dosing Cl decreased to 666 +/- 27 ml/min. Comparison of the area under the curves during steady state (ss) indicated a complete bioavailability of multiple oral doses. After the single intravenous dose, VPB were diminished or reduced for about 4 hr if the plasma concentrations exceeded 120 to 150 ng/ml. During ss-therapy plasma levels fluctuated between 200 and 550 ng/ml with an effective prevention of arrhythmias. Thus, the new drug demonstrates a therapeutic range of approximately 150 to 400 ng/ml and oral therapy seems to be effective with 100 mg t. i. d.

Topics: Acetanilides; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Dealkylation; Electrocardiography; Female; Half-Life; Heart Ventricles; Humans; Kinetics; Male; Middle Aged; Piperidines

Lorcainide is a promising antiarrhythmic agent that belongs to the class of local anesthetics. It was tested in 7 patients with malignant ventricular arrhythmias that were resistant to other antiarrhythmic agents. Lorcainide was effective in all cases (complete disappearance of arrhythmias in 6 cases and more than 50% disappearance in the 7th case), and the tolerance was within acceptable limits. The drug was effective at rest, as assessed by 24-h dynamic electrocardiographic monitoring, and during physical exercise. Longer studies with more patients are warranted, since the drug appears to be a promising antiarrhythmic agent.

Topics: Acetanilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Exercise Test; Female; Humans; Male; Middle Aged; Piperidines

Topics: Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Coronary Vessels; Dose-Response Relationship, Drug; Kinetics; Kv1.5 Potassium Channel; Male; Membrane Potentials; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Patch-Clamp Techniques; Piperidines; Potassium Channel Blockers; Potassium Channels, Voltage-Gated; Rabbits; Shab Potassium Channels

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Evidence-Based Medicine; Humans; Myocardial Infarction; Piperidines; Publication Bias

Use of molecular pharmacology to reprofile older drugs discovered before the advent of recombinant technologies is a fruitful method to elucidate mechanisms of drug action, expand understanding of structure-activity relationships between drugs and receptors, and in some cases, repurpose approved drugs. The H3 histamine receptor is a G-protein-coupled receptor (GPCR) primarily expressed in the central nervous system where among many things it modulates cognitive processes, nociception, feeding and drinking behavior, and sleep/wakefulness. In binding assays and functional screens of the H3 histamine receptor, the antiarrhythmic drugs lorcainide and amiodarone were identified as potent, selective antagonists/inverse agonists of human and rat H3 histamine receptors, with relatively little or no activity at over 20 other monoamine GPCRs, including H1, H2, and H4 receptors. Potent antagonism of H3 receptors was unique to amiodarone and lorcainide of 20 antiarrhythmic drugs tested, representing six pharmacological classes. These results expand the pharmacophore of H3 histamine receptor antagonist/inverse agonists and may explain, in part, the effects of lorcainide on sleep in humans.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Cell Proliferation; Drug Inverse Agonism; HEK293 Cells; Histamine Agonists; Humans; Mice; NIH 3T3 Cells; Piperidines; Rats; Receptors, Histamine H3

To compare the prolongation of the effective refractory period (ERP) of a novel complex Class III agent CPU-86017 with compounds blocking INa (lorcainide, Lor), IK (dofetilide, Dof), ICa (verapamil, Ver) and a complex Class III multiple channel blocking agent (amiodarone, Ami) at different frequency levels.. The ERP of the guinea pig right papillary muscle and the anoxic left atrial muscle treated with high K+ at pH 6.6-6.8, in concentrations ranging 0.03-30 micromol/L was compared at frequency levels ranging from 0.5-4.0 Hz.. CPU-86017 showed a positive frequency dependence (PFD) with respect to ERP in the papillary muscles and a mild reverse frequency dependence (RFD) in the diseased atrium. The potency of ERP prolonging effect of various agents at 4.0 Hz was Dof > CPU-86017 > Ver > Ami > Lor, and Dof > CPU-86017 > Ami > Lor > Ver in the normal papillary and diseased atrial muscle, respectively.. The profile and potency of prolonging the ERP by CPU-86017 is similar to Dof which blocks IKr in the diseased atrium, and to Ver which blocks ICa in guinea pig ventricle.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Berberine; Calcium Channel Blockers; Female; Guinea Pigs; Heart Atria; In Vitro Techniques; Male; Papillary Muscles; Phenethylamines; Piperidines; Potassium Channel Blockers; Refractory Period, Electrophysiological; Sulfonamides; Verapamil

A case of lorcainide poisoning with fatal outcome is reported. A young girl of 15 ingested, without high lethality of intent, 2500 mg lorcainide, an antiarrhythmic agent. Bradycardia, shock, coma, and cerebral convulsions rapidly occurred. Despite immediate resuscitative measures with high doses of catecholamines and hypertonic sodium bicarbonate the patient died three hours later. The course of lorcainide poisoning was similar to that of other class Ic antiarrhythmic agents.

Topics: Adolescent; Anti-Arrhythmia Agents; Benzeneacetamides; Fatal Outcome; Female; Humans; Piperidines; Poisoning; Suicide

An analytical method was established for determination of lorcainide hydrochloride concentration in serum using high performance liquid chromatography (HPLC). The stainless steel column was 200 mm x 5.0 mm ID, packed with YWG C18H37, 5 microns. The mobile phase consisted of methanol-water-0.625 mol.L-1 ammonium acetate. (86:13:1 v/v), adjusted to the pH 8.0 with ammonium hydroxide. The flow rate was 1 ml.min-1, using diltiazem as internal standard. Chromatography was performed with ultraviolet detector at 226 nm. The recoveries of lorcainide hydrochloride at 40, 200 and 400 micrograms.L-1 were 95.85%, 100.63% and 100.09%, respectively. The within-day and day-to-day RSD of the determinations at concentrations of 100, 200, 400 and 800 micrograms.L-1 were less than 7%. Linear calibration curve for lorcainide hydrochloride was measured within the range of 20 to 800 micrograms.L-1 with correlation coefficient of 0.9996. The detection limit was 5 micrograms.L-1 in serum. The HPLC method described is suitable for clinical monitoring and pharmacokinetic study of lorcainide hydrochloride.

Topics: Adult; Anti-Arrhythmia Agents; Benzeneacetamides; Chromatography, High Pressure Liquid; Humans; Male; Piperidines

The efficacy of class 1C antiarrhythmic agents was determined in 36 patients with inducible sustained monomorphic ventricular tachycardia during baseline electrophysiology study (EPS), who continued to have inducible monomorphic ventricular tachycardia during EPS on class 1A antiarrhythmic therapy. Of 12 patients who partially responded to class 1A drugs, 11 (91.7%) continued to have a partial response during EPS on class 1C therapy, whereas one patient did not respond. Of 24 nonresponders to class 1A therapy, 2 (8.3%) responded during EPS on class 1C therapy, 7 (29.2%) partially responded, and 15 (62.5%) did not respond. In the 24 nonresponders to class 1A therapy, 9 of 17 patients (53%) with left ventricular ejection fraction (EF) > or = 30% responded or partially responded to class 1C therapy, compared with none of 7 patients with EF < 30% (P < .05). The EPS on class 1C agents in patients who fail to respond to class 1A therapy may be warranted only in those with EF > or = 30%.

Topics: Adult; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Benzeneacetamides; Electric Stimulation; Encainide; Female; Flecainide; Humans; Male; Middle Aged; Piperidines; Quinidine; Retrospective Studies; Stroke Volume; Tachycardia, Ventricular

1. The effects of three class I antiarrhythmic drugs quinidine, lidocaine and lorcainide on undamaged myocardial mitochondrial ATPase [ATP: phosphohydrolase, EC 3.6.1.3] activity were evaluated in guinea pig heart preparations. 2. All three drugs inhibited the enzyme activity in a concentration-dependent fashion. 3. Lorcainide was the most potent, exerting inhibitory effects in the range of less than 1.0 nM-2.0 mM, with IC20 and IC50 values of 9.4 +/- 0.6 nM and 87.2 +/- 5.5 microM. However, in the range of approx. 10 nM-10 microM, the enzyme response decreased only slightly with increasing lorcainide concentrations. 4. Quinidine and lidocaine, on the other hand, inhibited the enzyme activity in the range of 1.0 microM-100 mM. 5. The IC20 and IC50 values for quinidine were 0.92 +/- 0.04 mM and 4.8 +/- 0.6 mM and for lidocaine were 115 +/- 6 microM and 2.3 +/- 0.3 mM. 6. The results show that all three drugs inhibit mitochondrial ATPase activity and that lorcainide is the most potent. 7. These inhibitory effects may be related to the lipophilicity and membrane stabilizing activity of this class of antiarrhythmic drugs.

Topics: Adenosine Triphosphatases; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Chemical Phenomena; Chemistry, Physical; Guinea Pigs; In Vitro Techniques; Lidocaine; Mitochondria, Heart; Piperidines; Quinidine

This work deals with the pharmacodynamic problem of relating a drug effect E(t) to an observable pharmacokinetic (PK) predictor variable r(t), which may be a venous and/or arterial drug level, some other PK variable, or a drug infusion scheme. It is proposed that the relationship between E(t) and r(t) may, in many cases, be appropriately modeled as E(t) = N(F(r(t))) [for practical analysis reasons, F(r(t)) is denoted the biophase level, cb(t), the operator F() is accordingly denoted the biophase level predictor (BLP), and N() is denoted the transduction function (TF)]. This work proposes a method for determining the two fundamental components, BLP and TF, that define the E(t)-r(t) relationship. The BLP is determined by a hysteresis minimization (HM) technique with the following features: (1) the method considers errors in both HM variables; (2) the method is suitable for dealing with the important case in which the predictor variable is a drug infusion scheme; (3) the approach is noncompartmental in contrast to the effect-compartment approaches and it does not require a specific structured modeling of the cb(t)-r(t) relationship when dealing with drugs with linear PKs in a general operational sense; and (4) the method makes use of a dimensionless transformation of the hysteresis variable that eliminates numerical scaling problems so that a complex penalty function optimization approach can be avoided. The TF is determined by a cross validation procedure in conjunction with the BLP determined by HM. The method is demonstrated using pharmacodynamic data for several drugs, considering both concentration-based and drug input-based r(t) values. The significance of the information obtained from the determined BLP and TF is discussed, including the concepts of equilibration dynamics and overloading. The limitations and potential problems of the methodology are discussed.

Topics: Alfentanil; Animals; Benzeneacetamides; Humans; Mathematics; Models, Theoretical; Pharmacokinetics; Pharmacology; Piperidines; Rabbits; Theophylline

1. The effects of three class 1 antiarrhythmic drugs procainamide (class 1A) tocainide (class 1B) and lorcainide (class 1C) on microsomal Na(+)-K(+)-ATPase activity were compared with those of ouabain in guinea pig heart preparations. 2. All three antiarrhythmic drugs exhibited concentration-dependent inhibitory actions on the enzyme activity in a fashion similar to that of ouabain. 3. The rank order of their potencies showed the following tendency: lorcainide much greater than tocainide greater than procainamide. However, while the actions of lorcainide were comparable to those of cardiotonic steroids, those of procainamide became significant only at concentrations above 80 microM. 4. The IC50 values were 1.8 +/- 0.5 microM for ouabain, 14.6 +/- 3.4 microM for lorcainide, 2.8 +/- 0.7 mM for tocainide and 6.7 +/- 1.1 mM for procainamide. 5. The results demonstrate that these antiarrhythmic agents inhibit the ouabain-sensitive myocardial Na(+)-K(+)-ATPase activity in vitro with comparatively varying potencies. 6. These interactions may be pertinent to the proarrhythmic or arrhythmogenic effects of the class 1 type of antiarrhythmic drugs.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Female; Guinea Pigs; Heart; In Vitro Techniques; Lidocaine; Male; Myocardium; Ouabain; Piperidines; Procainamide; Sodium-Potassium-Exchanging ATPase; Tocainide

1. The inhibitory action of lorcainide on the myocardial Na(+)-K(+)-ATPase (EC 3.6.1.3) activity was studied in guinea-pig heart preparations at medium K+ concentrations of 2.5, 5.0 and 10 mM. 2. Lorcainide exhibited characteristically similar concentration-dependent inhibitory effects at all three K+ concentrations tested. However, the inhibitory potencies were significantly increased at decreased K+ concentrations. 3. The IC50 values were 10.4 +/- 3.2 microM at 2.5 mM, 28.3 +/- 7.9 microM at 5.0 mM and 40.7 +/- 9.2 microM at 10.0 mM K+ respectively. Thus, reduction in the K+ concentration from the 'standard' 5.0 to 2.5 mM enhanced the inhibitory potency of lorcainide, the effective concentrations being shifted towards much lower ranges, while increasing it to 10 mM on the other hand produced opposite but less marked effects. 4. These results show that the inhibition of myocardial Na(+)-K(+)-ATPase activity by lorcainide depends on the K+ concentration of the incubation medium. These effects are probably related to the mechanism by which lorcainide interferes with the electrogenic Na+/K+ pump activity of the enzyme, and hence may contribute to some of its cardiac actions.

Topics: Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Female; Guinea Pigs; Heart; In Vitro Techniques; Male; Microsomes; Myocardium; Piperidines; Potassium; Sodium-Potassium-Exchanging ATPase

1. The effects of lorcainide on the myocardial Mg2(+)-dependent, Na+ and K(+)-activated adenosine triphosphatase (Na+, K(+)-ATPase) were compared in guinea-pig heart preparations with those of ouabain, a specific inhibitor of the enzyme activity. 2. Both ouabain and lorcainide inhibited the microsomal Na+, K(+)-ATPase activity in a concentration-dependent fashion. Their inhibitory effective ranges were 0.05-100 microM and 0.15-125 microM, respectively, and the concentrations for half maximal inhibition (IC50 values) were 2.1 +/- 0.3 and 33.5 +/- 7.3 microM, respectively. 3. In a second series of experiments, the combined effects of the two drugs on the enzyme activity were studied. In these experiments, lorcainide produced a concentration-dependent potentiation of the inhibitory effects of ouabain on Na+, K(+)-ATPase activity. 4. The present study demonstrates that lorcainide is a potent inhibitor of myocardial Na+, K(+)-ATPase.

Topics: Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Female; Guinea Pigs; Heart; In Vitro Techniques; Male; Myocardium; Ouabain; Piperidines; Sodium-Potassium-Exchanging ATPase

The paper presents an adverse effect of Lorcainide on the electrocardiographic pattern and left ventricular function in a patient with recurrent ventricular tachycardia in the course of arterial hypertension and ischemic heart disease. Based upon this case report a relatively new and not well known phenomenon of drug arrhythmogenesis is presented.

Topics: Anti-Arrhythmia Agents; Benzeneacetamides; Electrocardiography; Humans; Male; Middle Aged; Piperidines; Recurrence; Tachycardia; Ventricular Function, Left

The electrophysiologic effects of the intravenous administration of a new antiarrhythmic drug, lorcainide, were evaluated by programmed electrical stimulation of the heart in 20 patients with and without Wolff-Parkinson-White (WPW) syndromes. Lorcainide shortened the sinus cycle length from 721.0 +/- 125.9 to 649.5 +/- 100.1 ms (P less than 0.001), but did not influence sinus node function and AV node conduction and refractoriness, slightly increased atrial effective period (ERP) (P less than 0.02) and did not change ventricular ERP (P less than 0.2), obviously lengthened atrial conduction time, H, H-V interval and the width of V wave. Lorcainide caused complete antegrade block of the accessory pathway (AP) in six of 9 WPW patients and resulted in exclusive conduction over the AV nodal. His conduction in two patients with atrial flutter. It also prolonged the retrograde conduction time and refractoriness of AP, and prevented initiation of orthodromic atrioventricular tachycardia (O-AVRT) in six of 12 patients by blocking of the retrograde conduction of the AP, increased the cycle length of tachycardia from 321.7 +/- 43.6 to 361.7 +/- 54.9 ms (P less than 0.005) by marked prolongation of retrograde AP conduction time in 6 patients in whom O-AVRT could still be induced. It is concluded that intravenous lorcainide does not affect sinus node and AV node function, slightly influences atrial and ventricular refractoriness, obviously suppresses atrial, His bundle and intraventricular conduction, and is an effective antiarrhythmic drug for patients with WPW by blocking both the antegrade and retrograde conduction of the AP.

Topics: Adolescent; Adult; Anti-Arrhythmia Agents; Benzeneacetamides; Child; Electrophysiology; Female; Heart Conduction System; Humans; Male; Middle Aged; Piperidines; Tachycardia, Supraventricular; Wolff-Parkinson-White Syndrome

The rate-dependent block (RDB) of changrolin on the maximal rate of depolarization (Vmax) of action potentials was studied in guinea pig right ventricular papillary muscles. The result was compared with that of class IA (quinidine), IB (mexiletine) and IC (lorcainide) drugs to approach the subclassification of changrolin, by using standard microelectrode techniques with computer. Mexiletine exhibited the fastest response in the onset rate of RDB. Vmax reached 61% of its final value by the second beat during a train of stimuli. In response to a similar train of stimuli, quinidine, lorcainide and changrolin produced exponential falls of Vmax with the constants of -0.143, -0.085 and -0.051 AP-1 (AP = action potentials), respectively. Time constants of recovery for mexiletine, quinidine, lorcainide and changrolin were estimated as 1.58, 9.06, 13.37 and 55.16 s. These suggest that the kinetics of RDB of changrolin are similar to those of IC drugs.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Female; Guinea Pigs; In Vitro Techniques; Male; Mexiletine; Papillary Muscles; Piperidines; Quinazolines; Quinidine

The incidence of drug-induced congestive heart failure with several newer antiarrhythmic agents including encainide, ethmozine, lorcainide, mexiletine, propafenone and tocainide was determined in a group of 407 patients who underwent 1,133 drug tests. The incidence rate ranged from 0.7% with lorcainide to 4.7% with propafenone. Congestive heart failure was present in 167 patients (41%) who underwent 491 drug trials. Congestive failure was induced in 15 (9%) of these 167 patients and involved 19 (3.9%) of the 491 tests. Left ventricular ejection fraction was 20 +/- 8% in patients who developed congestive failure, in contrast to 39 +/- 19% in those who did not (p less than 0.001). It is concluded that each of the six antiarrhythmic drugs examined has the potential to aggravate congestive heart failure in patients with reduced left ventricular ejection fraction or a history of congestive heart failure, but the incidence rate is low and its occurrence unpredictable.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anilides; Anti-Arrhythmia Agents; Benzeneacetamides; Encainide; Female; Heart Failure; Humans; Lidocaine; Male; Mexiletine; Middle Aged; Moricizine; Phenothiazines; Piperidines; Propafenone; Risk Factors; Stroke Volume; Tocainide

Effects of SUN 1165, disopyramide, lorcainide, and mexiletine were studied either on the kinetics of onset of and recovery from rate-dependent depression of maximum rate of rise of phase 0 action potential (Vmax) in isolated guinea pig papillary muscles using standard microelectrode techniques or on intraventricular conduction time of extrasystoles evoked at varied coupling intervals in anesthetized dogs. SUN 1165 and lorcainide produced a slow-developing rate-dependent block of Vmax with the rate constant of 0.12 AP-1 and 0.09 AP-1, respectively. Mexiletine also produced a rate-dependent block of Vmax, but with very rapid onset so as not to be fitted by a single exponential curve. Disopyramide produced an intermediate rate-dependent block of Vmax with the rate constant of 0.46 AP-1. The time constants for recovery from the rate-dependent block for SUN 1165, lorcainide and disopyramide were 27.3-28.2, 23.2, and 17.0 s, respectively, while that for mexiletine was 0.118 s. SUN 1165, lorcainide, and disopyramide slowed ventricular conduction time of extrasystoles at all coupling intervals of 800-250 ms. On the other hand, mexiletine slowed conduction time at short coupling intervals of 500-250 ms. These findings suggest that, like lorcainide, SUN 1165 belongs to class Ic antiarrhythmic agents, and that SUN 1165 and lorcainide as well as disopyramide with slow and intermediate kinetics and mexiletine with fast kinetics may inhibit ventricular extrasystoles conducted at long and short range of coupling intervals, respectively.

Topics: Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Cardiac Complexes, Premature; Disopyramide; Guinea Pigs; Heart Conduction System; Heart Ventricles; In Vitro Techniques; Ion Channels; Lidocaine; Male; Mexiletine; Papillary Muscles; Piperidines; Sodium

Lorcainide was used in 17 children and adolescents aged 14 days to 18 years (mean 6.8 years) with the preexcitation syndrome (W-P-W type). Lorcainide was able to control attacks of supraventricular tachycardia in eight of 11 patients with the W-P-W syndrome and tachyarrhythmias. Long-term maintenance therapy prevented new attacks of tachyarrhythmia for an average period of nine (5-15) months in all seven patients who tolerated lorcainide administration. Normalization of the W-P-W pattern was reached in nine of 11 children with the W-P-W syndrome who had tachyarrhythmias and in three of six asymptomatic children with the ECG pattern of W-P-W. Single effective doses ranged from 12.5 mg orally in the neonates to 100 mg in the adolescents. The effect of lorcainide on the ECG usually appeared 2 h after the oral administration of the drug. Dizziness in three with insomnia and vomiting in one patient complicated the treatment. No drug-associated abnormalities in blood cell counts and biochemical values were identified.

Topics: Adolescent; Anti-Arrhythmia Agents; Benzeneacetamides; Cardiac Complexes, Premature; Child; Child, Preschool; Electrocardiography; Female; Heart Conduction System; Humans; Infant; Infant, Newborn; Male; Piperidines; Tachycardia, Supraventricular; Wolff-Parkinson-White Syndrome

Topics: Arrhythmias, Cardiac; Benzeneacetamides; Drug Interactions; Humans; Male; Middle Aged; Piperidines; Rifampin

The effects of lorcainide and its metabolite norlorcainide on the maximal rate of depolarization (Vmax) were compared at different rates of stimulation and at various membrane potentials in ventricular muscle preparations of guinea-pig heart. A standard microelectrode technique was used. The results show that lorcainide and norlorcainide exerted qualitatively similar effects; they both depressed Vmax in a frequency- and potential-dependent way. The following quantitative differences were found: lorcainide was about 50% more potent in depressing Vmax; this difference in potency was observed at 1 and 2 Hz stimulation rates; the block by lorcainide was clearly potential-dependent; in the case of norlorcainide this effect was weak; the onset and removal of block were about twice as fast with lorcainide; the block per action potential was greater with lorcainide. The electrophysiological effects were decreased in the presence of alpha 1-acid glycoprotein, though to a similar extent with both drugs. Taking into account the difference in potency found in the present experiments and the difference in plasma concentration described in the literature, it is concluded that the parent drug and its metabolite both contribute to about the same extent to the in vivo effect of oral treatment with lorcainide.

Topics: Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Blood Proteins; Electric Stimulation; Guinea Pigs; Heart; In Vitro Techniques; Kinetics; Membrane Potentials; Piperidines; Protein Binding

The influence of cardiac function as measured by the left ventricular ejection fraction on the pharmacokinetic variables of a new antiarrhythmic drug, lorcainide, was investigated in 20 cardiac patients. Patients were divided into two groups: those with normal (ejection fraction greater than .40) or depressed (ejection fraction less than .40) left ventricular function. The elimination half-life, plasma clearance rates, or volume of distribution of lorcainide were not significantly different in patients with either normal or depressed cardiac function. A decrease in arrhythmia frequency could be correlated to plasma lorcainide concentration in the majority of patients, and it was noted that at least 0.1 mg/L of lorcainide was required for the presence of an antiarrhythmic effect. Three unusual cases are presented to illustrate the importance of measuring plasma drug concentrations and calculating the drug pharmacokinetics and to correlate these to the antiarrhythmic response in order to minimize the risk of plasma drug accumulation and side effects. A review of published data shows a three- to sixfold interpatient variation in the elimination half-life of lorcainide with practical implications in its use as an antiarrhythmic drug.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Female; Heart Diseases; Hemodynamics; Humans; Male; Middle Aged; Piperidines

The electrophysiologic effects and antiarrhythmic efficacy of lorcainide were evaluated using programmed electrical stimulation (PES) in 14 patients with ventricular tachycardia (VT) refractory to conventional drug therapy. Lorcainide was administered orally (200-400 mg/d, eight patients), intravenously (150 mg/d, one patient), or by both routes (250-380 mg/d, five patients) prior to PES. In 13 patients undergoing both control and lorcainide PES, lorcainide increased the QRS duration (102 +/- 28 to 125 +/- 28 ms, P less than .001) and the QTc interval (430 +/- 39 to 471 +/- 32 ms, P less than .01) but had no effect on the RR interval (786 +/- 156 to 780 +/- 172 ms, P greater than .2). The right ventricular effective refractory period increased from 258 +/- 8 to 285 +/- 22 ms (P less than .001). Lorcainide prevented VT induction or resulted in induction of only well-tolerated, nonsustained VT in six of 14 patients (43%). The cycle length of induced VT increased from 264 +/- 32 to 306 +/- 34 ms (P less than .01). Of six patients started on chronic therapy, four still receive lorcainide after 18 +/- 7 months. Adverse effects have consisted mainly of sleep disturbances. Thus, it can be stated that lorcainide is effective in certain patients with VT refractory to conventional therapy.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Drug Resistance; Electrocardiography; Female; Humans; Male; Middle Aged; Piperidines; Tachycardia

Clinical safety and hemodynamic repercussions were studied after administration of six class I antiarrhythmics (xylocaine, ajmaline, mexiletine, lorcainide, indecainide and tocainide) to patients presenting acute myocardial infarction without complications. The hemodynamic parameters monitored generally followed the same trends. A significant decrease of more than 10 per cent of the initial value was seen in systolic blood flow after injection of lorcainide, indecainide and tocainide. Peripheral vascular resistance increased moderately. Pulmonary capillary pressure increased by more than 40 per cent of the starting value after administration of mexiletine, indecainide and tocainide (significant increase in case of mexiletine). These changes in patients presenting infarction without complications are not of clinical importance. There were, however, two very severe cases of hemodynamic reaction after administration of mexiletine. Other signs of intolerance were seen, but they were of minor importance and administration of the drugs was not interrupted. Xylocaine and ajmaline produced the smallest depression of left ventricular functional activity in these patients.

Topics: Ajmaline; Anti-Arrhythmia Agents; Benzeneacetamides; Fluorenes; Hemodynamics; Lidocaine; Mexiletine; Myocardial Infarction; Piperidines; Tocainide

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Cats; Female; Guinea Pigs; In Vitro Techniques; Male; Piperidines; Rats

Thirty-eight patients with prior history of cardiac arrest underwent programmed electrical stimulation (PES) studies and serial drug testing. Lorcainide was tested acutely in all 38 patients and prevented ventricular tachycardia (VT) or ventricular fibrillation (VF) induction in 14 patients and failed in 24 (efficacy rate 37%). Procainamide had failed clinically (cardiac arrest or breakthrough VT) in 16 patients, seven patients had previously severe adverse side effects, and thus only 15 were tested on procainamide at PES testing with seven protected. Following initial studies, 14 patients were started on lorcainide oral therapy and 24 on other therapy determined effective at PES testing (N-acetylprocainamide-two, flecainide-nine, bethanidine-three, slow-release procainamide hydrochloride-three, quinidine-two, cibenzoline-one, amiodarone-four). After 29 +/- 7 months follow-up, three are alive on lorcainide therapy, five discontinued therapy due to side effects; six died--three sudden deaths (33%) and two cardiac deaths (both myocardial infarctions). Twenty out of 24 patients are alive who were started on PES predicted effective therapy other than lorcainide; four died--three sudden deaths (13%) and one cardiac nonsudden death. Antiarrhythmic therapy guided by PES studies gives overall encouraging results in a cardiac arrest group of patients. Lorcainide, however, is not tolerated well and affords less protection against a sudden death recurrence than is noted in a population on other antiarrhythmic therapy predicted effective at PES testing.

Topics: Arrhythmias, Cardiac; Benzeneacetamides; Blood Pressure; Cardiac Pacing, Artificial; Electrocardiography; Female; Heart Arrest; Humans; Male; Middle Aged; Piperidines; Procainamide; Recurrence

The electrophysiological characteristics and the antiarrhythmic indication areas of lorcainide were studied by using electrophysiological investigations and clinical studies in patients suffering from sustained arrhythmias. According to the data of the arrhythmia analyses (30 patients) the most important electrophysiological effects of lorcainide are: increase of the effective refractory period of the atria and ventricles; prolongation of the conduction time in the His bundle; prolongation of the refractory period and conduction of the accessory pathways. In the course of clinical studies (55 patients) lorcainide proved to be very effective in treating ventricular arrhythmias and preventing or disrupting ventricular tachyarrhythmic attacks. Lorcainide has a very promising antiarrhythmic effect in the suppression of tachyarrhythmias with accessory pathway conduction, too.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Female; Heart Conduction System; Humans; Male; Middle Aged; Piperidines; Refractory Period, Electrophysiological; Tachycardia

Chronic premature ventricular complexes (PVCs) have been effectively suppressed by oral lorcainide as reported in previous short-term studies. The plasma level-effect relation of lorcainide may be affected by the possible cardioactivity of norlorcainide, a metabolite that accumulates after repeated oral doses. This study evaluated the long-term efficacy of lorcainide in suppressing chronic symptomatic PVCs, and examined the relation of arrhythmia suppression to plasma concentrations of lorcainide and norlorcainide. Fourteen patients were treated with lorcainide, 200 to 400 mg/day, 12 of whom achieved nearly complete suppression of arrhythmias after treatment for 1 year. Chronic lorcainide treatment was well tolerated; no patient discontinued treatment because of adverse effects. Lorcainide and norlorcainide plasma concentrations remained stable after the first week of therapy. Antiarrhythmic activity persisted throughout the year. Upon drug withdrawal, the mean lorcainide washout half-life was 14.3 +/- 3.7 hours and the mean norlorcainide washout half-life was 31.9 +/- 8.9 hours. The return of arrhythmias occurred well after the lorcainide plasma concentration had decreased to subtherapeutic levels, suggesting an antiarrhythmic effect of norlorcainide. Thus, long-term lorcainide therapy is effective in treating chronic symptomatic PVCs and is well tolerated by most patients. The metabolite norlorcainide appears to have antiarrhythmic activity independent of lorcainide.

Topics: Benzeneacetamides; Cardiac Complexes, Premature; Electrocardiography; Female; Half-Life; Heart Ventricles; Humans; Kinetics; Male; Middle Aged; Piperidines; Time Factors

Lorcainide, a new antiarrhythmic agent currently undergoing clinical trial, has been pentadeuterated and the usefulness of this labelled compound in pharmacokinetic and metabolism studies has been investigated in dogs. Specific analytical methods based on capillary gas chromatography/mass spectrometry (GC/MS) were developed for quantitative and qualitative analysis of plasma and urine samples. Following oral administration of an equimolar mixture of 5 : 5 mg of (2H0/2H5)lorcainide, eight major metabolites were rapidly identified in urine by the ion cluster technique. Quantitative analysis of (2H0/2H5)lorcainide in plasma and urine indicated an enhanced systematic availability of the deuterated compound, probably due to a secondary isotope effect. According to these findings in the dog, the use of deuterated lorcainide in human bioavailability and metabolism studies is probably of limited value.

Topics: Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Deuterium; Dogs; Gas Chromatography-Mass Spectrometry; Piperidines

One hundred patients inducible at electrophysiologic studies underwent serial drug testing with procainamide, lidocaine and lorcainide to determine comparative efficacy. Acute intravenous administration was followed by repeat programmed electrical stimulation (PES) studies on separate days for each antiarrhythmic drug. Lorcainide prevented VT induction in 69% of the 100 patients studied, procainamide was effective in 50% of the 75 patients studied, and lidocaine prevented VT induction in 30% of 53 patients. Following PES and serial drug testing, 46 patients were started on lorcainide, 9 patients on procainamide, and 45 patients were started on other antiarrhythmic drug regimens. Seventy percent of the patients have remained on lorcainide therapy, while 47% have continued on other drug therapies started over a 20.5 +/- 3.2 month mean follow-up period. Despite sleep-wake disturbances and a need for sedation at night, lorcainide therapy was tolerated well in this population and remained an effective antiarrhythmic with prolonged administration.

Topics: Administration, Oral; Anti-Arrhythmia Agents; Benzeneacetamides; Blood Pressure; Cardiac Pacing, Artificial; Electrocardiography; Female; Heart Rate; Humans; Infusions, Parenteral; Lidocaine; Male; Middle Aged; Piperidines; Procainamide; Tachycardia

The effectiveness and safety of intravenous lorcainide was evaluated in 14 patients with normal (QRS less than 110 ms) and in 9 patients with prolonged QRS duration (QRS greater than or equal to 110 ms) showing chronic high frequency premature ventricular complexes (mean value of PVCs 17 min-1). Lorcainide was infused intravenously by intermittent bolus at 10 mg every minute to a total dose of 160 mg with exception of 5 patients with a prolonged QRS duration who only received 100 mg. The overall reduction of PVCs 1 hour after administration of the drug was 86% (p less than 0.05) in the patients with normal QRS duration and 98.5% (p less than 0.05) in the patients with a prolonged QRS duration. The mean plasma drug level achieved 1 h after treatment was 280 +/- 60 ng/ml in the patients with QRS less than 110 ms and 170 +/- 40 ng/ml in the patients with a QRS greater than or equal to 110 ms. Heart rate and blood pressure did not change but a significant increase (p less than 0.05) in QRS duration (+37%) was observed 30 min after the infusion of 160 mg lorcainide in the patient group with normal QRS duration. Lorcainide was well tolerated. Mild adverse effects were observed in five patients including: warmth sensation, vomiting, paresthesias, transient hypotension and the development of a junctional escape rhythm. Therefore lorcainide appears to be a safe and effective drug, that can even be administered to patients with a prolonged QRS duration.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Blood Pressure; Electrocardiography; Female; Heart Rate; Humans; Infusions, Parenteral; Male; Middle Aged; Piperidines

Fifty patients with drug-refractory (failed 7 +/- 2 other drug trials) sustained ventricular tachycardia or fibrillation were treated with oral lorcainide. Twenty-three patients underwent programmed stimulation both before and after oral lorcainide, and all 23 remained inducible, although ventricular tachycardia cycle length was prolonged and mean arterial pressure was higher. Lorcainide was discontinued in 23 patients prior to hospital discharge because of death in four patients, side effects in five patients, spontaneous clinical arrhythmia recurrence in six patients, and ventricular tachyarrhythmias induced at electrophysiologic study in eight patients. Twenty-seven patients were discharged on an average dose of 169 +/- 56 mg twice a day, including 15 in whom ventricular tachycardia remained inducible. During long-term follow-up the drug was discontinued in 15 patients; three because of side effects, three because of clinical nonfatal arrhythmia recurrence, two who selected other alternative therapy, and seven patients who died suddenly due to ventricular tachyarrhythmias. Twelve patients remain on long-term lorcainide. The actuarial 1-year chance of being arrhythmia free was 38.9%, and 1-year cardiovascular and arrhythmia survival rates were 56.8% and 60.4%, respectively. Based on our data we conclude that: In this extremely drug-resistant patient population the clinical efficacy of lorcainide is low; lorcainide should not be used empirically in such highly drug-resistant patients; persistent ventricular tachyarrhythmia inducibility at electrophysiologic study implies a poor prognosis in patients treated with oral lorcainide; the incidence of becoming noninducible during oral lorcainide therapy in highly drug-resistant patients appears low; and for patients in whom the drug seems partially beneficial it could be used in conjunction with a backup automatic implantable cardioverter/defibrillator.

Topics: Administration, Oral; Benzeneacetamides; Cardiac Pacing, Artificial; Humans; Male; Middle Aged; Piperidines; Tachycardia; Ventricular Fibrillation

The systemic availability of 3H-lorcainide in rats was investigated following oral doses of 1.5 to 100 mg/kg. Systemic availability increased from 14 to about 40% following the lowest and highest dose, respectively. Doses higher than 60 mg/kg produced a less marked increase of the systemic availability. In rats with portacaval shunt following an oral dose of 1.5 or 7.5 mg/kg lorcainide a systemic availability of 47% was found, indicating substantial prehepatic first-pass metabolism of lorcainide. Systemic availability of total radioactivity was 53% in control rats and 90% in rats with portacaval shunt. Since the maximal systemic availability obtained by increasing the dose was found to be identical with that obtained in rats with portacaval shunt, it is suggested that increasing doses will saturate the presystemic metabolism in the liver but will not affect the fraction of the dose which is metabolized in the gut.

Topics: Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Biological Availability; Kinetics; Liver; Male; Piperidines; Rats; Rats, Inbred Strains

There is a need for effective, well-tolerated antiarrhythmic agents, particularly those effective by both intravenous and oral routes. Lorcainide, a new antiarrhythmic drug with such properties, was given long-term orally to 24 patients controlled initially with intravenous therapy--19 with frequent (greater than 1/min) complex premature ventricular complexes (PVCs) on a baseline 24-hour Holter monitor and five with ongoing sustained ventricular tachycardia (VT) or frequent paroxysmal sustained VT, for a mean of 13 months (range 0.03 to 39.4 months). Long-term lorcainide was given in divided doses of 200 to 800 mg/day (median 260, mean 269 +/- 90 mg/day). Response to long-term lorcainide therapy was assessed at a mean of both 26 days and 12.2 months. Frequency of PVCs on baseline averaged 13,490/24 hours (median 10,578, range 2,115 to 61,716); couplets averaged 309/24 hours (median 166, range 0 to 5,686), and runs averaged 33/24 hours (median 30, range 0 to 2,951). Median frequency of PVCs decreased by 94% (p much less than 0.001) and 97% (p less than 0.01) at the first and second lorcainide efficacy assessments, respectively. Couplets decreased by a median of 99% (p much less than 0.001) and 100% (p less than 0.005) at the first and second assessments, respectively. Runs were suppressed by a median of 100% at both evaluations (p much less than 0.001). Only three (16%) of the patients with complex PVCs failed to respond to therapy. No recurrence during lorcainide has been noted in the five patients with ongoing sustained VT or recurrent episodes of VT.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Dose-Response Relationship, Drug; Drug Tolerance; Electrocardiography; Female; Humans; Male; Middle Aged; Piperidines; Time Factors

New antiarrhythmic drugs are chiefly assigned to Class 1C and 1B: "procainamide analogues" (acecainide, lorcainide, flecainide, encainide) and propafenone for the former, and mexiletine, tocainide and aprindine for the latter. Pharmacokinetics vary widely among the different antiarrhythmic agents. These and other problems which regulate therapeutic interventions, such as patient compliance, drug interactions, efficacy/toxicity ratio, drug combinations, and drug monitoring with plasma concentrations of antiarrhythmic agents are briefly considered.

Topics: Acecainide; Amiodarone; Anilides; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Benzeneacetamides; Bretylium Compounds; Drug Interactions; Encainide; Flecainide; Heart Ventricles; Humans; Lidocaine; Mexiletine; Moricizine; Phenothiazines; Piperidines; Propafenone; Propiophenones; Tocainide

Cardiac arrhythmia causing sudden cardiac death is a serious worldwide public health problem. Antiarrhythmic agents have been available for therapy, but the conventional agents cause a high degree of intolerable side effects. The recent development of many new experimental antiarrhythmic agents has increased our capacity to effectively treat cardiac arrhythmias. Using a multifaceted approach of programmed electrical stimulation studies, drug level determinations, exercise testing and 24-hour ambulatory Holter monitoring, it can reasonably be decided which patient needs therapy and if therapy is going to be effective. Both aspects of the sudden death equation, ectopy frequency (triggering mechanism) and the ability to propagate sustained ventricular tachycardia (substrate), may be examined. Careful follow-up is needed to determine continued drug efficacy and the presence of side effects that may compromise patient compliance with therapy. If side effects intervene that may cause continued therapy to be intolerable, changing the antiarrhythmic agent, as opposed to decreasing the dosage to an ineffective range, may be appropriate. A comprehensive approach to arrhythmia management may begin to reduce the high incidence of sudden death due to fatal arrhythmias.

Topics: Adrenergic beta-Antagonists; Ajmaline; Amiodarone; Anilides; Anti-Arrhythmia Agents; Aprindine; Benzeneacetamides; Bepridil; Bethanidine; Bretylium Tosylate; Death, Sudden; Disopyramide; Encainide; Flecainide; Humans; Lidocaine; Mexiletine; Moricizine; Phenothiazines; Piperidines; Procainamide; Propafenone; Propiophenones; Pyrrolidines; Quinidine; Tachycardia; Tocainide; Verapamil

Lorcainide is an antiarrhythmic drug with unusual pharmacokinetics and an active metabolite, norlorcainide, which complicate oral drug loading. In order to characterize the accumulation of lorcainide and norlorcainide and to define the onset of antiarrhythmic action during lorcainide loading, 9 patients with frequent ventricular ectopic beats were studied. During lorcainide loading with 100 mg orally twice daily, frequent ambulatory electrocardiographic recordings were monitored and blood samples for drug concentrations were determined. There was a 10-fold range of intersubject variation in plasma concentrations. Despite a half-life of only 8.9 +/- 2.3 hours, lorcainide did not reach steady state until after 4.5 days of therapy. Norlorcainide had a half-life of 26.5 +/- 7.2 hours and was estimated to come to steady state after 7 to 10 days. There was considerable intersubject variation in time of onset of antiarrhythmic response (2 to more than 4.5 days) and a 4- to 5-fold range of intersubject variation in threshold therapeutic plasma concentration (lorcainide 40 to 200 ng/ml, norlorcainide 80 to 300 ng/ml). These observations suggest that lorcainide should be started at low doses and the dose should not be increased more frequently than once a week.

Topics: Administration, Oral; Adult; Aged; Ambulatory Care; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Cardiac Complexes, Premature; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Kinetics; Male; Middle Aged; Piperidines; Sleep Wake Disorders; Time Factors

This paper is concerned with the effects of Lorcainide (LCN) and Amiodarone (AMD) on stress-induced myocardial lesions in rats. Forty rats were used. The first group (G-1) was used as a control (n = 10) and animals were injected with saline. Animals in group 2 (G-2) (n = 15) received AMD 10 mg per kilogram, and animals in group 3 (G-3) (n = 15) received LCN 3 mg per kilogram. During five minutes before the injections, the rats were submitted to a stress, consisting of intermittent cold water jets (6 degrees C). Animals were sacrificed one hour after injection, and the hearts were histologically studied. The relative areas of necrotic myocardium were assessed by Bertazzoli's modified method. In G-1, myocytolysis in the subendocardium of left ventricle (score: 2.2 +/- 0.79), contraction bands (1.2 +/- 1.03) and subendocardial myocardial damage (0.8) were common findings. In groups G-2 and G-3, the lesions described were found, but to a lesser degree; subendocardial myocytolysis: 1.6 +/- 0.63 and 1.07 +/- 0.4; contraction bands: 0.67 +/- 0.82 and 0.07 +/- 0.26; and subendocardial damage: 0.77 and 0.40. LCN and AMD markedly decreased stress-induced myocytolysis (p less than 0.01) (graph 1), but LCN was more effective than AMD (p less than 0.05). Comparison of severity and extension of contraction bands showed that only LCN had a significant effect (p less than 0.01) (graph 2); the same was observed as regards the decrease of damaged zones (p less than 0.05). From our data, LCN and AMD appears to have the capacity of reversing some of the stress-induced myocardial damage in rats.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Benzofurans; Cardiomyopathies; Female; Male; Myocardium; Necrosis; Piperidines; Rats; Rats, Inbred Strains; Stress, Physiological

Topics: Anilides; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Chemical Phenomena; Chemistry; Dogs; Encainide; Humans; Piperidines

Topics: Aged; Amiodarone; Anti-Arrhythmia Agents; Benzeneacetamides; Electric Countershock; Electric Injuries; Electric Power Supplies; Humans; Male; Mexiletine; Pacemaker, Artificial; Piperidines; Tachycardia; Time Factors

Among the newer antiarrhythmic drugs currently being evaluated are the four so-called lidocaine congeners, encainide, flecainide, lorcainide and tocainide. A knowledge of the pharmacokinetic properties of these agents may help to distinguish between them and may also be important for rational patient prescribing. Encainide and lorcainide both undergo predominantly hepatic elimination: both appear to form metabolites which have antiarrhythmic activity of their own and which have longer elimination half-lives than the parent compounds, resulting in accumulation with chronic administration. Flecainide and tocainide are cleared mainly by the kidneys, do not have active metabolites and have long elimination half-lives. All of the drugs have significant antiarrhythmic activity and this is proportionate to the plasma concentration of either the drug alone or combined with the active metabolites. Comparative effectiveness between the drugs has not been established. In general, all four drugs have only minor adverse effects, principally gastrointestinal or neurological, which may disappear with small dose reductions. However, cardiac effects can also occur and rarely pro-arrhythmic effects have been described, particularly with encainide and flecainide. All four drugs are suitable for long-term administration on a twice-daily basis.

Topics: Anilides; Benzeneacetamides; Encainide; Flecainide; Humans; Kinetics; Lidocaine; Piperidines; Tocainide

Topics: Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Atrioventricular Node; Benzeneacetamides; Encainide; Flecainide; Heart Atria; Humans; Lidocaine; Piperidines; Tachycardia; Tocainide; Wolff-Parkinson-White Syndrome

The widespread use of antiarrhythmic agents to control severe life-threatening arrhythmias evidenced the possibility of a worsening of arrhythmias induced by the same drugs. We performed a retrospective analysis studying the worsening phenomenon in patients who underwent pharmacological invasive and non invasive antiarrhythmic tests to choose the drug to be administered in the chronic treatment. Particularly we reviewed: 101 acute pharmacologic non invasive tests for "stable" ventricular ectopic beats using computerized automatic continuous recording system which allows quantitative and qualitative evaluation of arrhythmias. The drugs tested were: Propafenone (25 patients), Disopiramide (25 patients), Tocainide (11 patients), Lorcainide (8 patients), Lorajmine (13 patients), Nadolol (9 patients). In accordance with Vallebit et al., we considered arrhythmias worsening criteria: the onset of non sustained or sustained ventricular tachycardia; an increase of four fold the number of ventricular ectopic beats and/or ten fold the repetitive forms. A worsening of arrhythmias was observed in 4/101 (3.9% patients); 1/9 treated with Nadolol, 1/25 with Propafenone, 1/35 with Disopiramide, 1/13 with Lorajmine. For one young patient the worsening phenomenon could be considered a toxic picture, because of the very high drug plasmatic levels (Lorajmine) observed for the whole duration of the sustained VT induced from the drug. For the remaining 3 patients the response resambles a paradox effect. 34 pharmacologic invasive tests in 30 patients with common recurrent ventricular tachycardia, during electrophysiologic endocavitary study. The drugs tested were: Propafenone (12 patients), Amiodarone (11 patients), Ajmaline (4 patients), Tocainide (3 patients), Lorcainide (2 patients), Lorajmine (1 patient), Disopiramide (1 patient).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Ajmaline; Amiodarone; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Child; Disopyramide; Female; Follow-Up Studies; Humans; Lidocaine; Male; Middle Aged; Nadolol; Piperidines; Propafenone; Propanolamines; Propiophenones; Tocainide

Topics: Anti-Arrhythmia Agents; Benzeneacetamides; Humans; Piperidines

Lorcainide is a new type 1 antiarrhythmic drug that is well absorbed orally, with bioavailability increasing with both dose and continued administration. It is metabolized through the liver, and patients with significant liver disease will require dosage reduction. The drug has an active metabolite, norlorcainide, whose activity is similar to that of lorcainide but whose half-life is 26 hours instead of 8 for the parent compound. The levels of this metabolite are nearly twice those of lorcainide at steady state. The long half-life of the metabolite and the changing bioavailability of lorcainide require that a given dose be administered for 1 week for the maximum effect to be demonstrated.

Topics: Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Biological Availability; Cats; Dogs; Electrophysiology; Hemodynamics; Humans; Kinetics; Piperidines; Tissue Distribution

Sudden cardiac death continues to be a major health hazard. Control of the problem requires identification of those at risk and effective therapy for prevention. Studies have shown that in patients with coronary disease or cardiomyopathy, salvos of ventricular tachycardia are an independent risk factor for sudden death. Therefore, the objective of therapy is the suppression of these forms. A large number of antiarrhythmic drugs are available, but there are no guidelines for the selection of an effective and well-tolerated agent. We have developed a systematic approach to drug selection which includes 4 phases: phase 0 is a control period to establish the prevalence and density of the arrhythmia; phase 1, acute drug testing, is designed to screen a number of drugs for effectiveness; during phase 2 the drug is administered for a brief period to evaluate efficacy and tolerance; phase 3, once the drug is determined to be well tolerated and effective, it is continued as part of a long-term program. This approach was applied in 76 patients who underwent testing with lorcainide. This drug was continued long term in 15 patients. After 23 months of follow-up, only 1 patient died suddenly. Therefore, patients with life-threatening ventricular arrhythmia can be protected from a recurrence by individualized drug therapy.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Dose-Response Relationship, Drug; Drug Evaluation; Electrophysiology; Follow-Up Studies; Heart Ventricles; Humans; Monitoring, Physiologic; Piperidines

Nonsustained ventricular tachycardia (VT) in the late period (7 to 21 days) after myocardial infarction (MI) is reported to be a predictor of sudden death. Patients with 3-beat VT on Holter monitoring in the late infarction period would be suspected to demonstrate electrical instability on electrophysiologic studies. Forty-seven patients were identified as having at least 3-beat VT on Holter monitoring. Eighteen patients refused electrophysiologic studies or were not referred. Eight patients died; 3 were sudden deaths in 13 +/- 5 months, a 17% incidence. Twenty-nine patients underwent invasive electrophysiologic studies and 28 had inducible VT, 18 sustained and 10 nonsustained. Lorcainide prevented VT induction in 21 of the 28 patients, whereas 12 of the 22 patients studied on procainamide were protected. Lidocaine, tested in 21 patients, prevented VT induction in only 5. Lorcainide and procainamide prolonged refractoriness in those patients protected at programmed electrical stimulation (PES), whereas the QT interval was prolonged in patients in whom VT could still be induced. Twenty-seven of the 28 patients were placed on drugs predicted to be effective by PES studies, 19 on lorcainide. After a mean follow-up of 12.5 +/- 4 months the patient with noninducible arrhythmia is alive and 26 of the 28 patients with inducible arrhythmia are alive and well. Two patients died, 1 of stroke and 1 of pump failure after a second MI. No sudden deaths were observed in this group. Two patients had breakthrough arrhythmias and were treated by alternative antiarrhythmic therapy that was also effective on initial electrophysiologic studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Blood Pressure; Death, Sudden; Drug Evaluation; Electrocardiography; Female; Heart Ventricles; Humans; Lidocaine; Male; Middle Aged; Myocardial Infarction; Piperidines; Procainamide; Risk; Tachycardia

One hundred patients with inducible ventricular tachycardia (VT) on electrophysiologic studies underwent serial drug testing with procainamide, lidocaine and lorcainide to determine comparative efficacy. Acute intravenous administration was followed by repeat programmed electrical stimulation (PES) studies on separate days for each antiarrhythmic agent. Lorcainide prevented VT induction in 69% of the 100 patients studied, procainamide in 50% of the 75 patients studied and lidocaine in 30% of 53 patients. After PES and serial drug testing, 46 patients were started on lorcainide, 9 on procainamide and 45 on other antiarrhythmic drug regimens. Eighty percent of the patients have remained on lorcainide therapy, whereas 47% have continued on other drug therapies started over 17.5-month mean follow-up period. Despite sleep-wake disturbances and a need for sedation at night, lorcainide therapy was well tolerated in this population and remained an effective antiarrhythmic agent with prolonged administration.

Topics: Anti-Arrhythmia Agents; Benzeneacetamides; Drug Evaluation; Electric Stimulation; Electrocardiography; Female; Hemodynamics; Humans; Lidocaine; Male; Middle Aged; Piperidines; Procainamide; Tachycardia

Twenty-six patients (19 men and 7 women) with symptomatic ventricular tachycardia (VT) were studied using invasive and noninvasive techniques to induce VT. Of the study population, 12% had syncope and VT on Holter monitoring, 30% had cardiac arrest and 58% had symptomatic VT. All patients had antiarrhythmic agents stopped 5 half-lives before evaluation and then had autonomic profile (upright tilt, cold pressor test, exercise testing and hand grip) as well as programmed electrical stimulation studies performed. Autonomic profile testing induced VT in 5 of 26 patients (19%) and in only 1 patient was the arrhythmia reproducibly induced. All 26 patients had VT induced on electrophysiologic testing; 9 patients had nonsustained and 17 had sustained VT. Lorcainide administered intravenously prevented VT induction in 20 of 26 patients tested, whereas procainamide was effective in 11 of 24 patients. Ten of the 13 not protected by procainamide were protected by lorcainide. Twenty patients were started on long-term lorcainide therapy and followed up for 29 +/- 3.4 months. Five patients have discontinued therapy, 2 because of breakthrough arrhythmias, 2 because of severe sleep-wake disturbances and 1 because of private physician preference. An additional 3 patients died during therapy because of myocardial infarction in 1, progressive myopathy in 1 and sudden death in 1. Sixty percent of patients started on lorcainide therapy have continued. In this patient population, noninvasive induction of VT is not a sensitive or reproducible technique in assessing antiarrhythmic therapy. Furthermore, when selected on the basis of electrophysiologic testing, lorcainide is a well-tolerated and effective antiarrhythmic agent.

Topics: Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Dose-Response Relationship, Drug; Drug Evaluation; Electric Stimulation; Electrophysiology; Exercise Test; Female; Heart Arrest; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Procainamide; Syncope; Tachycardia

Topics: Aminoglutethimide; Anti-Arrhythmia Agents; Antineoplastic Agents; Benzeneacetamides; Female; Humans; Middle Aged; Piperidines

The effects of lorcainide, a new antiarrhythmic drug, on serum electrolytes and osmolality are described in a series of 33 patients with organic heart disease and complex ventricular arrhythmias treated with lorcainide. In eight patients, a mean decrease in serum Na+ of 8.25 +/- 3.2 mEq/L was observed after a single 200 mg intravenous dose of lorcainide. Sixteen of 33 patients developed significant hyponatremia and hypoosmolality during oral treatment with lorcainide. In all except two patients, serum Na+ returned to normal values within 3 to 12 months of continued lorcainide therapy. Low serum Na+ and hypoosmolality in the absence of volume depletion, clinically manifest edema, and unaltered renal, adrenal, cardiac, or thyroid function suggest that this antiarrhythmic drug produced the syndrome of inappropriate antidiuretic hormone secretion (SIADH). SIADH appeared to be transient and asymptomatic in our patients. One patient developed severe hyponatremia with serum Na+ of 108 mEq/L when hydrochlorothiazide was given to control hypertension. It is concluded that SIADH is an important side effect of lorcainide therapy. We recommend that serum Na+ be carefully monitored in patients started on lorcainide therapy, and extreme caution should be exercised in prescribing diuretics to patients with persistent hyponatremia.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Female; Humans; Hyponatremia; Inappropriate ADH Syndrome; Male; Middle Aged; Piperidines; Potassium; Sodium; Vasopressins

The pharmacokinetics of a single dose of lorcainide (4.5 mg/kg) was studied in rats pretreated with phenobarbital following intravenous and oral administration of lorcainide. In control rats, the total blood clearance of lorcainide was 30 ml/kg/min and the bioavailability was 14%. Pretreatment with phenobarbital increased the apparent oral clearance and reduced the bioavailability about 2fold. However, the pretreatment had a negligible effect on the systemic clearance following intravenous administration. Thus, enzyme induction increases the first-pass metabolism of lorcainide but does not alter the metabolism of drug which is in the systemic circulation.

Topics: Administration, Oral; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Biological Availability; Enzyme Induction; Injections, Intravenous; Kinetics; Male; Piperidines; Rats; Rats, Inbred Strains

The success of pacing stimuli interruption of ventricular tachycardia (VT) was examined in 77 episodes of sustained VT induced in 31 patients undergoing programmed electrical stimulation studies. Once VT was induced, a trial to terminate the arrhythmia by means of the technique of entrainment was attempted. If this failed, rapid burst pacing faster than the VT was begun to try and terminate the tachycardia. In 30 patients off antiarrhythmic agents, entrainment was effective in terminating VT in 27%, while burst pacing was also effective in 27%. In 37% of patients, VT was accelerated or ventricular fibrillation was produced by pacing techniques, and these patients required defibrillation. Following antiarrhythmic therapy that failed to prevent VT induction but did result in slowing of VT rate, entrainment was only successful in 23% of trials, while burst pacing was successful in 34% of trials. The incidence of acceleration of VT on therapy was 32%. There was no appreciable difference in acceleration noted with or without antiarrhythmic therapy. Regardless of therapy, the slower the VT rate, the greater success of pacing termination of VT and the lower the incidence of VT acceleration. Antiarrhythmic agents that significantly slow the VT rate increase the success rate of pacing stimuli interruption of VT and decrease the incidence of VT acceleration and thus the need for defibrillation. The results suggest that antiarrhythmic agents that slow the VT rate may increase the effectiveness of antiarrhythmic pacemakers in terminating VT.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Cardiac Pacing, Artificial; Electrocardiography; Female; Heart Rate; Heart Ventricles; Humans; Lidocaine; Male; Middle Aged; Piperidines; Tachycardia

Lorcainide is a new antiarrhythmic drug undergoing clinical investigation for management of patients with ventricular arrhythmias. In this study we investigated the kinetic profile of lorcainide in nine patients with end-stage renal disease. A single intravenous bolus of 100 mg of the drug was injected while the patients were undergoing hemodialysis or during the off-dialysis period. Renal disease did not alter the kinetic properties of lorcainide; the elimination t1/2 beta during hemodialysis was 8.61 +/- 6.35 h, not significantly different from 7.04 +/- 4.12 h off-dialysis. Serum protein binding of lorcainide was investigated in vitro, and the percent binding of lorcainide to serum proteins of normal volunteers and renal or cardiac patients was not significantly different. These data suggest that renal disease should not alter either the dose or the dosing interval of lorcainide.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Blood Proteins; Half-Life; Humans; Kidney Failure, Chronic; Kinetics; Male; Middle Aged; Piperidines; Protein Binding

Lorcainide, a new antiarrhythmic agent with local anesthetic or membrane-stabilizing properties similar to those of quinidine, was tested in 76 patients with diverse types of heart disease and recurrent ventricular tachycardia or ventricular fibrillation. Lorcainide was administered for 72 to 96 hours in a dose ranging from 200 to 400 mg daily. Evaluation of drug efficacy involved ambulatory monitoring and exercise stress testing in 60 patients who had high grade ventricular arrhythmia. Invasive electrophysiologic testing was carried out in the remaining 16 patients who exhibited infrequent ventricular ectopic activity during control studies. Lorcainide was effective in 21 (38%) of 56 patients evaluated for suppression of ventricular ectopic activity and in 6 (40%) of 15 who had invasive testing. In five patients, the drug was discontinued because of toxic reactions. Thus, 27 (38%) of the 71 patients who completed the drug study responded to lorcainide. Side effects, reported by 42 patients (55.3%), consisted primarily of insomnia and gastrointestinal symptoms; 7 experienced aggravation of arrhythmia. Fifteen patients were discharged while receiving lorcainide therapy, but in four the treatment was discontinued after 2 months because of side effects. Three patients died, one suddenly. It is concluded that lorcainide is of value in a small subset of patients with life-threatening ventricular arrhythmias who have proven refractory to conventional drugs. Its usefulness is limited by the high frequency of insomnia.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Exercise Test; Female; Humans; Male; Middle Aged; Piperidines; Tachycardia; Ventricular Fibrillation

Topics: Adrenergic beta-Antagonists; Amiodarone; Anti-Arrhythmia Agents; Aprindine; Benzeneacetamides; Disopyramide; Flecainide; Humans; Kinetics; Lidocaine; Mexiletine; Piperidines; Procainamide; Quinidine; Tocainide; Verapamil

Topics: Amiodarone; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Benzeneacetamides; Cardiac Complexes, Premature; Coronary Disease; Disopyramide; Electrocardiography; Humans; Lidocaine; Mexiletine; Piperidines; Propafenone; Propiophenones; Tachycardia; Tocainide

Topics: Adolescent; Anti-Arrhythmia Agents; Benzeneacetamides; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Male; Piperidines; Wolff-Parkinson-White Syndrome

Topics: Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Drug Evaluation; Female; Heart Ventricles; Humans; Male; Middle Aged; Myocardial Infarction; Piperidines

Lorcainide disposition kinetics were studied after intravenous and oral administration to patients with ventricular arrhythmias. After intravenous doses ranging from 100 to 200 mg, blood samples were drawn and plasma was analyzed for lorcainide concentration by high-pressure liquid chromatography. A three-compartment model was used to fit the data. The model-independent calculated values for clearance, steady-state volume of distribution, and terminal half-life were 14.4 +/- 3.28 ml/min/kg, 6.33 +/- 2.23 l/kg, and 7.8 +/- 2.2 hr. After nine doses of oral lorcainide (100 mg every 12 hr) blood samples were drawn and analyzed for lorcainide and its active metabolite, norlorcainide. The lorcainide and norlorcainide half-lifes were 9.6 +/- 2.8 and 26.8 +/- 8.2 hr. Mean steady-state level of norlorcainide was 2.2 +/- 0.9 times the level of lorcainide. The data suggest that the clearance of lorcainide decreases with time during long-term dosing.

Topics: Administration, Oral; Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Female; Half-Life; Humans; Injections, Intravenous; Kinetics; Male; Middle Aged; Piperidines; Time Factors

Topics: Adult; Aged; Ajmaline; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Electrocardiography; Female; Humans; Male; Middle Aged; Piperidines; Syncope; Time Factors

Antiarrhythmic actions of lorcainide were compared with those of disopyramide on different types of arrhythmias in animal models. It was shown in dogs that lorcainide and disopyramide were approximately equipotent against the arrhythmias following coronary occlusion. In guinea pigs, lorcainide was less effective than disopyramide against the ouabain-induced arrhythmia. Both drugs showed a weak protective action against the aconitine-induced ventricular arrhythmias, but had no effect on the cardiac arrest. In the arrhythmias induced by the application of acetylcholine on the right auricle of guinea pigs, the disappearance of P-waves and the disturbance of R-R intervals were inhibited by disopyramide, but lorcainide had no influence on these events; both prevented the atrial fibrillation induced by acetylcholine application. Both drugs by themselves induced ventricular arrhythmias in guinea pigs.

Topics: Acetylcholine; Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Coronary Vessels; Disopyramide; Dogs; Female; Guinea Pigs; Ligation; Male; Ouabain; Piperidines

The electrophysiologic effects of lorcainide, a class I antiarrhythmic agent with local anesthetic properties, were studied in 20 patients with the Wolff-Parkinson-White syndrome. After intravenous administration of lorcainide (2 mg/kg), the sinus cycle length decreased in all patients from 705 +/- 117 to 636 +/- 94 ms (p less than 0.001). The atrioventricular conduction time lengthened from 84 +/- 22 to 94 +/- 22 ms (p less than 0.01) and the QRS duration increased from 92 +/- 19 to 120 +/- 29 ms (p less than 0.001). The effective refractory period of the atrium increased from 230 +/- 27 to 243 +/- 35 ms (p less than 0.05), whereas the ventricular refractoriness was unaffected. Retrograde conduction over the accessory pathway was blocked in 5 of 18 patients after lorcainide; in the remaining 13 patients a prolongation from 107 +/- 32 to 162 +/- 57 ms (p less than 0.001) was found. Anterograde conduction over the accessory pathway was blocked in 6 patients, and in all other patients it increased considerably. Circus movement tachycardia could be induced in 14 patients before and in 10 patients after the drug. The shortest R-R interval during tachycardia lengthened from 326 +/- 40 to 364 +/- 67 ms (p less than 0.05). The tachycardia zone was unaffected by lorcainide. In 15 patients atrial fibrillation was induced. After lorcainide anterograde conduction during atrial fibrillation was blocked (n = 5). The shortest R-R interval over the accessory pathway during induced atrial fibrillation increased from 228 +/- 35 to 304 +/- 103 ms (p less than 0.05). Intravenous administration of lorcainide produced a pronounced negative dromotropic effect on the conduction properties of the accessory pathway. Lorcainide appears to be a promising new antiarrhythmic agent in patients with the Wolff-Parkinson-White syndrome.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Benzeneacetamides; Drug Evaluation; Electrocardiography; Female; Heart Conduction System; Humans; Male; Middle Aged; Piperidines; Tachycardia; Wolff-Parkinson-White Syndrome

The electrophysiologic effects of intravenous lorcainide (2.2 mg/kg) in 10 patients were compared with the electrophysiologic effects of oral lorcainide (mean dose 400 mg/day for 8 days) in 11 patients, all with recurrent ventricular tachycardia that could be induced with programmed stimulation. Intravenous and oral lorcainide resulted in similar prolongation of the QRS, QT, and HV intervals, but only oral lorcainide resulted in prolongation of the AH interval and atrial and ventricular effective refractory periods. After both oral and intravenous lorcainide, ventricular tachycardia could still be induced, but the arrhythmia was slower and better tolerated hemodynamically. The mean plasma lorcainide level during a maintenance intravenous infusion was 1254 +/- 662 ng/ml compared with a lorcainide level of 562 +/- 41 ng/ml and a norlorcainide level of 1212 +/- 653 ng/ml after oral dosing. No norlorcainide was detected in plasma after intravenous lorcainide. These data suggest that the short-term electrophysiologic effects of intravenous lorcainide may be different from those of short-term therapy with the oral drug. These differences should be considered during short-term studies of lorcainide.

Topics: Administration, Oral; Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Electrocardiography; Heart Ventricles; Humans; Infusions, Parenteral; Injections, Intravenous; Middle Aged; Piperidines; Recurrence; Tachycardia

Topics: Adult; Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Cardiac Pacing, Artificial; Drug Evaluation; Electrocardiography; Electrophysiology; Female; Humans; Male; Middle Aged; Piperidines; Sleep Wake Disorders; Tachycardia; Time Factors

The voltage- and rate-dependence of the depression of the maximum rate of depolarisation (Vmax) by therapeutic concentrations of flecainide and lorcainide were studied in guinea-pig ventricle by standard microelectrode techniques. At normal resting potentials the drugs produced only minor depression of Vmax in the absence of stimulation ("resting block") but trains of stimuli at inter-stimulus intervals (ISI) less than 4800 ms led to an exponential decline in Vmax to a new plateau over 20 to 50 beats. This "rate-dependent block" (RDB) increased with rate over the range ISI-4800 ms to ISI = 200 ms. The rates of onset of RDB in response to sudden increases in rate were very similar for both drugs and significantly slower than those reported for other anti-arrhythmic drugs. The time constants of recovery from RDB were 15.5 +/- 0.5s for flecainide and 13.2 +/- 1.3s for lorcainide. Both drugs shifted the steady-state relationship between Vmax and membrane potential in the hyperpolarising direction thus producing enhanced depression of Vmax in depolarised cells. It is concluded that these long recovery times may explain the marked depression of conduction of normal sinus beats seen with these drugs. The selective depression of depolarised cells may be of clinical relevance in ischaemic states.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Dose-Response Relationship, Drug; Electric Conductivity; Female; Flecainide; Guinea Pigs; Heart; Heart Ventricles; In Vitro Techniques; Kinetics; Male; Piperidines; Time Factors; Ventricular Function

Topics: Adult; Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Cardiac Pacing, Artificial; Female; Heart Block; Heart Conduction System; Heart Rate; Humans; Male; Middle Aged; Piperidines; Sinoatrial Block; Sinoatrial Node; Time Factors; Wolff-Parkinson-White Syndrome

Topics: Anti-Arrhythmia Agents; Benzeneacetamides; Chromatography, High Pressure Liquid; Humans; Piperidines

The effect of the new antiarrhythmic drug lorcainide was studied on the specialized conducting system of isolated canine ventricle. Transmembrane action potentials were recorded simultaneously from three subendocardial sites within the ventricular basis, free wall and apex. At concentrations of 3 x 10(-6) and 2.4 x 10(-5) M, lorcainide caused a dose-dependent decrease in maximum rates of rise and in amplitude of the action potential; 0.6 x 10(-6) M had no significant effect, resting potential and action potential duration remained unchanged with 0.6 x 10(-6) M and 3 x 10(-6) M. The most prominent effect of 2.4 x 10(-6) M lorcainide was the appearance of an increasing notch resulting in clear separation of the action potential in an initial short spike depolarization (50-120 msec) with or without a subsequent plateau depolarization 280-370 msec). Both components demonstrated an independent and inhomogeneous conduction through functionally different pathways. Changes in stimulation rate or premature stimuli resulted in nonstimulated reexcitations resembling bigemini, ventricular tachycardia or regional ventricular fibrillation. The results indicate that dissociation of the action potential in two components is due to toxic alterations of ionic channels of the fiber membrane and that nonstimulated reexcitations are due to reentry via functionally fast and slow pathways.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Dogs; Heart; Heart Conduction System; Heart Ventricles; Piperidines; Ventricular Function

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Cardiac Pacing, Artificial; Drug Evaluation; Female; Humans; Male; Middle Aged; Piperidines; Time Factors

1 In Langendorff-perfused rabbit hearts, electrical stimulation threshold and ventricular fibrillation threshold (VFT) were measured by applying rectangular impulses of 3 ms duration and increasing current at frequencies of 4 and 20 Hz respectively. 2 Perfusion with lignocaine or one of three new antiarrhythmic drugs, encainide, lorcainide and ORG 6001, produced significant, dose-dependent increases in both thresholds. 3 On a dosage basis, encainide was seven times, lorcainide fourteen times and ORG 6001 twice as potent as lignocaine in raising VFT. 4 In Langendorff-perfused guinea-pig hearts, only lorcainide provided complete protection against ouabain-induced ventricular fibrillation, while 6 of 6, 3 of 6 and 2 of 6 hearts fibrillated in the presence of encainide, lignocaine and ORG 6001 respectively, but with infusion durations significantly higher than control. 5 These results indicate the potential antifibrillatory activity of these new antiarrhythmic agents.

Topics: Androstanols; Anilides; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Encainide; Female; Guinea Pigs; Heart Rate; In Vitro Techniques; Lidocaine; Male; Myocardial Contraction; Ouabain; Piperidines; Rabbits; Species Specificity

The electrophysiological effects of lorcainide (R 15 899) were studied in 15 patients. Atrioventricular conduction was analysed by His bundle recording and cardiac refractory periods were determined by the extra stimulus method. The assessment of sino atrial function was performed by measuring sinus node recovery times and sino atrial conduction times. The electrophysiological data was recorded before and 10 minutes after a slow intravenous injection of 1,5 mg/Kg of lorcainide followed by a continuous infusion at 0,02 mg/Kg/min. The following results were obtained; 1) The HV interval increased in all cases (average : II ms) 2) The QRS and QT intervals were significantly prolonged 3) Lorcainide produced a slowing of conduction and an increase in the refractory periods at atrial level 4) AV nodal conduction was unaffected 5) The sinus rate slightly increased. There were no significant changes in sinus node recovery time or sino atrial conduction. It must be concluded that, in man, lorcainide produces electrophysiological effects of antiarrhythmic agents of the quinidine type.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Electrophysiology; Female; Heart; Heart Conduction System; Humans; Male; Middle Aged; Piperidines

Lorcainide, a new class I antiarrhythmic drug, was administered intravenously to 10 patients with a documented history of ventricular arrhythmias. Three patients had arrhythmias resistant to all conventional antiarrhythmic drugs; in all other patients except one, previous antiarrhythmic drug therapy had to be discontinued because of poor efficacy or unacceptable adverse effects. Lorcainide was injected in incremental doses of 25 mg every 15 minutes and a dose of 182.4 +/- 26.5 mg (mean +/- standard deviation) of the drug was given. Lorcainide reduced the frequency of premature ventricular complexes in a dose-dependent manner. Plasma samples were analyzed for the drug concentrations which ranged from 0.31 to 1.14 mg/liter during the loading phase. Distribution and elimination of lorcainide follow a biexponential pattern and a fourfold intersubject variability in the pharmacokinetics of the drug was observed in these patients. The plasma half-life ranged from 6.2 to 23.1 hours (mean 13.1 +/- 5.0). Three patients are currently being treated orally with lorcainide. These data suggest that lorcainide is an effective antiarrhythmic drug with desirable pharmacokinetic properties, and long-term definitive studies are recommended.

Topics: Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Female; Humans; Kinetics; Male; Middle Aged; Piperidines; Time Factors

Lorcainide hydrochloride given at the doses of 150 mg i.v. proved to be well tolerated at the acute stage of a myocardial infarction; the subjective signs were benign and never prevented us from completing the injection. The haemodynamic changes reflect some depressive effects on the myocardial function. Most of the observed changes are transient, and when significant from the statistical point of view, they remain very mild: the cardiac output decreased from 3.4 to 3.2 l/min per m2, the stroke index from 46 to 41 ml/m2, the pulmonary wedge pressure increases from 6.6 to 8.4 mm Hg (mean values). Lorcainide hydrochloride may thus be used as an antiarrhythmic drug in acute myocardial infarction.

Topics: Anti-Arrhythmia Agents; Benzeneacetamides; Hemodynamics; Humans; Injections, Intravenous; Myocardial Infarction; Piperidines

Topics: Benzeneacetamides; Chromatography, High Pressure Liquid; Humans; Piperidines; Reference Values

11 patients (mean age 52 +/- 16.3 years) with recurrent ventricular tachycardia (VT), in whom VT could be initiated by programmed ventricular stimulation, were studied before and after lorcainide, a new antiarrhythmic agent. Lorcainide was either injected intravenously at a dose of 2 mg/kg within five to ten minutes (n = 3) or infused at a rate of 0.1 mg/kg/min up to the same total dose. After intravenous administration, there was no change in inducibility of VT in three patients, whereas in seven patients VT was either more difficult to induce requiring two instead of one premature beat (n = 2) or a higher rate of basic pacing (n = 2) or VT was no longer inducible (n = 3). In one case, VT was easier to induce. In patients with still inducible VT, the rate of VT decreased from 220 +/- 33 b.p.m. to 186 +/- 49.1 b.p.m. (non-significant). The echo zone for initiation of VT did not show any consistent change. The coupling interval between the last stimulated complex and the first beat of VT increased from 327 +/- 66.8 ms to 390 +/- 98.6 ms (p less than 0.05). The effective refractory period of the right ventricle increased slightly though not significantly. In three cases paradoxical side effects, probably due to lorcainide, were observed. The blood level of lorcainide at the end of injection or infusion immediately before right ventricular stimulation was 0.69 +/- 0.48 micrograms/ml (range 0.11 to 1.74 micrograms/ml). No N-dealkylated metabolite of lorcainide was detected after intravenous injection. Thus far, lorcainide is effective in preventing initiation of VT in some patients making it more difficult to induce in others. However, long-term efficacy and tolerance to the drug cannot be predicted from the data of this study though the data suggest that the drug might be effective on the long-term run against ventricular tachyarrhythmias.

Topics: Benzeneacetamides; Cardiac Pacing, Artificial; Coronary Disease; Heart Failure; Heart Rate; Piperidines; Tachycardia; Ventricular Fibrillation

The electrophysiological effects of the intravenous administration of a new antiarrhythmic drug, lorcainide, were evaluated by programmed electrical stimulation of the heart in 23 patients with atrioventricular conduction disturbances (four patients), ventricular tachycardia (five patients), and accessory atrioventricular pathway (14 patients). Lorcainide did not affect the refractory period of the atrium, ventricle, atrioventricular node, or the AH interval. It lengthened the duration of the HV interval, the refractory period of the accessory pathway, and the width of the QRS complex. The drug terminated ventricular tachycardia in four of five patients. It is concluded that the drug may be of potential benefit in patients with ventricular tachycardia or accessory atrioventricular pathways (especially those with a short refractory period). Lorcainide is contraindicated in patients with bundle-branch block and prolonged HV interval.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Cardiac Pacing, Artificial; Electrocardiography; Female; Heart Block; Heart Conduction System; Humans; Male; Middle Aged; Piperidines; Tachycardia

After a single i.v. dose of 10 mg/kg the time course of 4'-chloro-N-(1-isopropyl-4-piperidyl)-2-phenyl-acetanilide (lorcainide, R 15889) concentrations in plasma, heart, lung, liver, kidney, spleen, brain, muscle and adipose tissue were followed for 10 h in rats. The new antiarrhythmic agent and a dealkylated metabolite were assayed by a specific gas liquid chromatographic procedure. Plasma level data were fitted by a digital computer program (SAAM 25) and analyzed according to the two-compartment open model. A rapid distribution phase with a T1/2(alpha) of 0.48 h was followed by the elimination phase with a T1/2(beta) of 3.3 h. Only minor amounts (less than 1% of the dose) of unchanged lorcainide could be recovered in urine and feces and total plasma clearance averaged 121.5 ml/min/kg. After 15 to 30 min maximal tissue concentrations could be observed, which were highest in spleen and lung (70--75) ng/mg). Only minor amounts could be measured in liver and adipose tissue (0.5--5 ng/mg). In heart, brain, kidney and muscle the maximal levels ranged between 17 and 35 ng/mg. Within 2 h the decline of these concentrations was very rapid and after 8 h lorcainide could be detected only in spleen, lung and adipose tissue.

Topics: Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Biotransformation; Dealkylation; Half-Life; Kinetics; Male; Piperidines; Rats; Time Factors; Tissue Distribution

The effect of oral N-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzene acetamide (lorcainide) was studied in 12 patients with frequent and stable ventricular arrhythmias resistant to a number of other antiarrhythmic agents. Ambulatory electrocardiograms were obtained before and during treatment with lorcainide and in some patients after discontinuation of the drug. Lorcainide suppressed ventricular premature contractions by more than 90% in all but one patient. The daily doses were 200 mg (N = 8), 300 mg (N = 1), 400 mg (N = 1)and 600 mg (N = 2). Plasma concentrations of lorcainide and of the dealkylated metabolite ranged from 0.13 to 0.27 microgram/ml and 0.25 to 0.95 microgram/ml, respectively. Side effects such as insomnia and excessive perspiration were seen in 7 and 3 patients, respectively. Lorcainide is an effective antiarrhythmic agent against ventricular arrhythmias otherwise difficult to treat.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Drug Resistance; Electrocardiography; Female; Heart Ventricles; Humans; Male; Middle Aged; Piperidines

Electrophysiological effects of a new antiarrhythmic agent, lorcainide, were studied in the isolated guinea pig ventricular myocardium and were compared with those of disopyramide; some of the experiments were also made by using the canine ventricular myocardium. Both lorcainide and disopyramide selectively depressed the maximum rate of rise of the action potential with little effect on the resting and overshooting potential. The action potential duration tended to be shortened slightly, and the prolongation of the refractory period produced by these agents was only slight. Both agents did not produce the substantial modification of the slow response produced by isoproterenol in the depolarized muscle at the concentrations enough to depress the maximum rate of rise of the action potential. Both agents also produced the marked depression of the rate of the action potential of the canine ventricular muscle, and the conduction velocity measured in the canine false tendon was markedly decreased by both agents. It was concluded that both lorcainide and disopyramide are typical Class I agents according to the classification proposed by Vaughan Williams and that lorcainide is about 10 times (at least 3 times) more potent than disopyramide in this respect.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Disopyramide; Dose-Response Relationship, Drug; Guinea Pigs; Heart; Heart Conduction System; Heart Rate; In Vitro Techniques; Male; Piperidines; Pyridines; Refractory Period, Electrophysiological

A first series of personal results in the treatment of arrhythmia with lorcainide is presented. Findings were obtained by recording for 24 hr with Holter and compared with those observed in patients treated with quinidine. An ECG study was also made of the atrial and nodal refractory periods. The conclusion is drawn that lorcainaide possesses an undoubted and protracted anti-arrhythmic effect, and does not exert a significant influence on refractory period values.

Topics: Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Drug Evaluation; Female; Humans; Male; Middle Aged; Piperidines

The long-term anti-arrhythmic efficacy of lorcainide (R15 889) was studied in 20 ambulatory postmyocardial infarction patients. Lorcainide reduced the frequency of ventricular ectopic beats by more than 70% and 90% in 17 and 11 of the patients respectively. The anti-arrhythmic response improved with long-term administration of the drug. Fourteen patients complained of insomnia during the early stages of the study, but this side-effect waned later on. On electrocardiographic examination, the P-R interval, QTc interval and QRS duration were prolonged, and T-wave changes were noted while the patients were receiving lorcainide. Lorcainide seems to be a useful addition to the available anti-arrhythmic agents, and should form part of the armamentarium against ventricular ectopic activity.

Topics: Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Electrocardiography; Humans; Male; Middle Aged; Myocardial Infarction; Piperidines; Ventricular Fibrillation

A 68-year-old patient developed increasingly frequent episodes of ventricular and supraventricular arrhythmias over the past five years. During the last 12 months, he was admitted to the hospital on several occasions with complex arrhythmias including multifocal PVCs, bigeminy, trigeminy, ventricular tachycardia, and atrial flutter and fibrillation. Large and frequent doses of quinidine, procainamide, disopyramide, propranolol, and digoxin failed to suppress his arrhythmias. He had no previous history of myocardial infarction or other heart diseases. Coronary arteriography revealed no obstruction of any major arteries or their branches. A new antiarrhythmic drug, lorcainide, was given intravenously and it suppressed all PVCs, including bigeminy and ventricular tachycardia. All his arrhythmias have been completely suppressed by oral regimens of lorcainide, 100 mg four times daily, for the past four months. This is the first case of oral treatment of ventricular arrhythmias with lorcainide in this country.

Topics: Administration, Oral; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Drug Resistance; Humans; Male; Piperidines

The cardiovascular effects of a single i.v. dose (2 mg/kg over 5 min) of lorcainide were studied in 14 patients with heart disease. In the haemodynamic part of the study (6 patients), the aortic and pulmonary systolic, diastolic and mean pressures, left ventricular systolic and end-diastolic pressures, cardiac output and the rate of rise of left ventricular pressure were measured before and for 30 min after administration of the drug. Lorcainide produced a slight and short-lasting decrease in the aortic and pulmonary systolic pressures, and all other pressure values remained unchanged. The cardiac output and systemic vascular resistance were not altered by lorcainide. It consistently depressed the rate of rise of left ventricular pressure (maximum mean decrease 19%). In the angiographic part of the study (8 patients), the ejection fraction and the mean velocity of circumferential fiber shortening were measured before and 5 min after lorcainide. In all but one patient, lorcainide decreased the ejection fraction (mean decrease 11.6%), and the mean velocity of circumferential fiber shortening was uniformly diminished by lorcainide (mean decrease 29.7%). Thus, lorcainide moderately impaired myocardial performance in patients with normal and reduced left ventricular function without producing hypotensive side effects.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Blood Pressure; Cardiac Output; Female; Heart; Heart Diseases; Humans; Male; Middle Aged; Myocardial Contraction; Piperidines; Time Factors; Vascular Resistance

Topics: Anti-Arrhythmia Agents; Benzeneacetamides; Electrocardiography; Heart Conduction System; Humans; Piperidines

The effects of lignocaine and lorcainide on conduction through the AV node and the ventricular conduction system have been investigated in the Langendorff-perfused guinea-pig heart. Basal conduction times were estimated at 80 and 120/min; at each frequency extra-stimuli with variable coupling intervals were applied in order to determine the change in conduction velocity and estimate refractory periods. In most of the preparations paced at 80/min premature impulses were blocked at a site distal to the AV node (distal gate). In therapeutic concentrations (1 to 5 mg . litre-1) and at low frequency of stimulation lignocaine did not change basal conduction times but had a definite slowing effect on the conduction of extra-systoles. Slowing of basal conduction times became prominent at higher frequencies of stimulation or at concentrations above 5 mg . litre-1. In all conditions the effect on the ventricular conduction system was more pronounced than on the AV node. Compared with lignocaine, lorcainide was more effective and more selective. Important changes in basal conduction times and in conduction of premature impulses were observed at 0.31 and 0.63 mg . litre-1. The effect on conduction in the ventricular conduction system was more pronounced than on conduction in the AV node. The dose-effect relationship for different parameters was steeper with lorcainide than with lignocaine. At high concentrations of lorcainide (greater than 1.25 mg . litre-1) intermittent block, especially in the ventricular conduction system, was frequently observed.

Topics: Acetamides; Animals; Anti-Arrhythmia Agents; Atrioventricular Node; Benzeneacetamides; Cardiac Complexes, Premature; Cardiac Pacing, Artificial; Guinea Pigs; Heart Conduction System; In Vitro Techniques; Lidocaine; Perfusion; Piperidines; Time Factors

Topics: Acetanilides; Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Aorta; Aorta, Abdominal; Arrhythmias, Cardiac; Benzeneacetamides; Blood; Blood Proteins; Female; Hepatic Veins; Humans; In Vitro Techniques; Injections, Intravenous; Male; Middle Aged; Piperidines; Protein Binding; Pulmonary Artery

Topics: Acetanilides; Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Electrocardiography; Female; Humans; In Vitro Techniques; Infusions, Parenteral; Injections, Intravenous; Male; Middle Aged; Piperidines

We have compared the disposition of antipyrine orally (15 mg/kg) and the new antiarrhythmic drug lorcainide intravenously (1.5 mg/kg) in 8 patients with alcoholic cirrhosis. Antipyrine (AP) serves as a model drug for drugs which are eliminated independently of liver blood flow and lorcainide (L) elimination as a model for drugs which depend on liver blood flow. Since in healthy subjects elimination half-life (t 1/2) of L increased with age (r = 0.68, p less than 0.01) due to parallel change in the volume of distribution (r = 0.52, p less than 0.05), its disposition had to be compared to age-matched controls. Elimination of both AP and L was impaired in cirrhotic patients, expressed either in terms (mean +/- SD) of t 1/2 (AP = 26.8 +/- 15.0 hr and 12.3 +/- 1.8; L = 12.5 +/- 4.5 hr and 7.7 +/- 2.2 hr, p = 0.002) or of clearance (Cl) (AP = 21.9 +/- 7.9 ml/min and 41.7 +/- 5.5 ml/min; L = 814 +/- 144 and 1002 +/- 304 ml/min, p = 0.06). While the alterations in plasma Cl were great for AP, they were smaller for L. This suggests that elimination of drugs in cirrhotic patients is associated with relatively more impairment of enzyme activity than of hepatic blood flow. The slightly decreased Cl of L in patients with alcoholic cirrhosis would suggest that L should be carefully handled in patients with dysfunction of the liver.

Topics: Acetanilides; Adult; Aged; Anti-Arrhythmia Agents; Antipyrine; Benzeneacetamides; Humans; Liver; Liver Circulation; Liver Cirrhosis, Alcoholic; Middle Aged; Piperidines

The electrophysiological effects of lorcainide 1.25 or 2.5 mg/kg given iv over 2 or 4 min, were studied in 21 patients with normal and diseased impulse formation and conduction, by means of intracardiac recording and stimulation. Sinus rate and the effective atrial refractory period rose following both doses of lorcainide. The corrected sinus node recovery time rose only after lorcainide 2.5 mg/kg and then most markedly in patients with sinus node dysfunction. The P-A interval remained unchanged following the drug. The A-H interval during sinus rhythm, and the pooled A-H intervals during atrial pacing, increased slightly, and the functional and effective A-V nodal refactory period changed variably. Wenckebach periods above the bundle of His occurred at lower atrial pacing rates following both doses of lorcainide in 7 patients, at the same atrial pacing rate in 9 and at higher rates in 3. H-V intervals, pooled H-V intervals and QRS-width lengthened in all patients, most markedly in cases with a conduction delay below the His bundle, who had received lorcainide 2.5 mg/kg. Thus, lorcainide shares some electrophysiological properties with procainamide and aprindine. Higher doses should be used with caution in patients with pre-existing conduction delay below the bundle His.

Topics: Acetanilides; Adult; Aged; Anti-Arrhythmia Agents; Atrioventricular Node; Benzeneacetamides; Bundle of His; Electric Stimulation; Electrocardiography; Electrophysiology; Female; Heart; Heart Conduction System; Humans; Male; Middle Aged; Piperidines; Purkinje Cells; Refractory Period, Electrophysiological

Topics: Acetanilides; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Electrocardiography; Female; Heart Ventricles; Humans; Infusions, Parenteral; Male; Middle Aged; Piperidines; Time Factors

A method is described for the determination of the antiarrhythmic drug lorcainide hydrochloride and its three main metabolites in plasma, urine, faeces and tissues from man and animals. The procedure involves the extract of the parent drug, its metabolites and the internal standard from the biological materials at different alkaline pH values, back-extraction into sulphuric acid and re-extraction into the organic phase (heptane--isoamyl alcohol). After silylation of the different phenolic and the N-dealkylated metabolites, analyses were carried out by automated gas--liquid chromatography with electron-capture detection. The method has a sensitivity limit of 5 ng for lorcainide, and 10--20 ng for the various metabolites, per millilitre of plasma. The method was applied to urine, faeces, plasma and tissue samples from man and animals. It was also suitable for automatic sample analysis.

Topics: Acetanilides; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Dogs; Feces; Gas Chromatography-Mass Spectrometry; Humans; Myocardium; Piperidines; Time Factors

Topics: Acetanilides; Anesthetics, Local; Anti-Arrhythmia Agents; Benzeneacetamides; Blood Pressure; Cardiomegaly; Coronary Disease; Depression, Chemical; Mitral Valve Insufficiency; Piperidines; Stroke Volume

Lorcainide hydrochloride or N-(4-chlorophenyl)-N-[1-(1-methyl-ethyl)-4-piperidinyl]benzeneacetamide mono-hydrochloride (R 15889) is a new anti-arrhythmic drug. Studies in dogs show that lorcainide is effective against post-infarction and ouabain-induced ventricular arrhythmias, and abolishes acetylcholine and aconitine-induced atrial fibrillation; it elevates the threshold of electrically induced ventricular fibrillation. In isolated dog and cow Purkinje fibers, in dog ventricular and in guinea-pig auricular muscle preparations, lorcainide decreases the rate of rise of the transmembrane action potential, the conduction velocity and spontaneous activity. It prolongs the refractory period of isolated Purkpinje and ventricular muscle preparations, and the functional refractory period of the AV node in the guinea-pig heart. It has no effect on Ca mediated electrical activity. Isometric force measurements in isolated cat papillary muscles and hemodynamic studies in anaesthetized and unanaesthetized dogs indicate that lorcainide moderately decreases myocardial contractility. Side effects observed at large doses are of central origin and include salivation, tremor and vomiting. Intravenous injection induces transient peripheral vasodilatation. Lorcainide is an antiarrhythmic of the local anaesthetic type. It is characterized by a good oral absorption, a long duration of action and a large safety factor.

Topics: Acetamides; Acetylcholine; Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Cats; Cattle; Coronary Vessels; Dogs; Electrocardiography; Female; Guinea Pigs; Heart; Hemodynamics; In Vitro Techniques; Ligation; Male; Membrane Potentials; Myocardial Contraction; Ouabain; Piperidines; Refractory Period, Electrophysiological

In rats, the intravenous injection of 1 mg/kg A.D.P. (adenosine-5'-diphosphate) results in transient thrombocytopenia, bradycardia and arrhythmias. Pre-treatment of the animals with the antiarrhythmic compounds lorcainide, aprindine, procaine (1.25, 2.5, 5 mg/kg i.v.) and xylocaine (5, 10, 20 mg/kg i.v.) before A.D.P. injection results in a reduction of bradycardia and a faster normalization of heart rate. All 4 compounds were equipotent in this respect, but the higher dose of xylocaine used should be stressed. The duration of irregular heart rhythm after A.D.P. injection was significantly shortened by all 4 compounds. Peak thrombocytopenia after A.D.P. administration is reduced only by lorcainide and the highest dose of aprindine, with two dose levels of xylocaine, but is not reduced by procaine. Suloctidyl (50 mg/kg orally) had no effect on any of the parameters registered. From this study we conclude that the normalization by the compounds of cardiac rate and rhythm disturbances after A.D.P. is due to their direct antiarrhythmic effect rather than to inhibition of platelet aggregation.

Topics: Acetamides; Adenosine Diphosphate; Animals; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Benzeneacetamides; Drug Interactions; Heart Rate; Lidocaine; Male; Piperidines; Procaine; Propanolamines; Rats; Thrombocytopenia; Time Factors

The anti-arrhythmic properties of a new drug, lorcainide, have been evaluated. Lorcainide is highly efficient for the treatment of ventricular arrhythmias, especially ventricular extrasystoles and recurrent ventricular tachycardia. It is also efficient in the treatment of supraventricular extrasystoles and repetitive auricular tachycardia. It is ineffective in cases of auricular fibrillation and flutter. The drug also has effective anti-arrhythmic properties when administered orally. It has a small negative inotropic effect which was not clinically relevant in the patient group studied. Side effects were within acceptable limits and essentially consist of dizziness, tremor and blurring of vision, occurring only during rapid i.v. injection and depending upon the speed of injection.

Topics: Acetamides; Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Electrocardiography; Humans; Injections, Intravenous; Male; Middle Aged; Piperidines