piperidines and pirmenol

The Vaughan Williams classification has been used widely by clinicians, cardiologists and researchers engaged in antiarrhythmic drug development and testing in many countries throughout the world since its initial proposal in the early 1970s. However, a major criticism of the Vaughan Williams system arose from the extent to which the categorization of drugs into classes I-IV led to oversimplified views of both shared and divergent actions. The Sicilian Gambit proposed a two-dimensional tabular framework for display of drug actions to solve these problems. From April to December 1996, members of the Guideline Committee met to discuss pharmacologic profiles of 4 antiarrhythmic drugs (aprindine, cibenzoline, pilsicainide, and pirmenol) that were not included in the original spreadsheet but are used widely in clinical practice in Japan. The discussion aimed to fit the drug profiles into the Gambit framework based on all the important literature published to date regarding the actions of the 4 drugs. This report is a summary of that deliberation.

Topics: Animals; Anti-Arrhythmia Agents; Aprindine; Humans; Imidazoles; Lidocaine; Piperidines

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

Pirmenol, a novel pyridinemethanol derivative, is active in a variety of experimental arrhythmic models of diverse etiology. Animal pharmacology studies showed that pirmenol is highly efficacious whether the arrhythmias were atrial or ventricular in origin; chemically, mechanically, or electrically induced; or of the automaticity or reentrant types. The conscious coronary artery-ligated (Harris) dog model best allowed simulation of a variety of clinical situations in which pirmenol could be used either alone or in combination. Pirmenol was highly effective by both the intravenous and oral routes, causing immediate suppression, prevention, or termination of cardiac arrhythmias. Preclinical studies in the dog showed an excellent correlation between the dose of pirmenol, plasma levels, and antiarrhythmic efficacy. Administration of pirmenol in the dog at intentionally accelerated infusion rates suggested a relatively wide margin of safety for pirmenol compared with other class I agents. In vitro electrophysiologic studies in dog Purkinje fibers revealed possibly unique differences of pirmenol from other antiarrhythmic agents. It depresses fast and slow response automaticity and its electrophysiologic effects were less variable than other class I drugs over a spectrum of potassium levels. To test the relevance of the in vitro electrophysiologic results, pirmenol's antiarrhythmic efficacy was assessed in several in vivo dog models in which serum potassium was either increased or decreased. Studies comparing pirmenol and disopyramide clearly showed a relative lack of serum potassium dependence for pirmenol, suggesting a potential clinical advantage over disopyramide and other antiarrhythmics in variable potassium settings. The clinical relevance of these observations will have to be established in patients with variable potassium levels. Overall, pirmenol compared favorably with other reference agents in efficacy and safety in extensive preclinical investigations.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Drug Evaluation, Preclinical; Drug Interactions; Electrophysiology; Heart; Piperidines

Pirmenol hydrochloride is a promising antiarrhythmic agent with quinidine-like (Class Ia) properties presently undergoing evaluation. It's clinical pharmacology and pharmacokinetics are reviewed. The author outlines the effects of pirmenol on the sinus node, atrial tissue, A-V node, and ventricular tissue and describes its antiarrhythmic efficacy in clinical studies to date, including his own study in 21 patients with a history of sustained ventricular tachycardia. The author summarizes the hemodynamic and pharmacokinetic studies of pirmenol noting that its effects are relatively independent of potassium concentration. The drug's side effects profile is presented, and it is concluded that pirmenol is well tolerated. Hypotension has not been a significant problem with intravenous pirmenol. Precipitation or worsening of clinical heart failure appears to occur only rarely. The favorable pharmacokinetics of pirmenol permit dosage at less frequent intervals than with procainamide, quinidine, disopyramide. Pirmenol has shown efficacy for ventricular arrhythmias even in some patients refractory to Class Ia agents. Antiarrhythmic effects appear to be correlated with plasma levels, and a well-defined therapeutic minimum has been determined.

Topics: Administration, Oral; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Drug Evaluation; Half-Life; Humans; Injections, Intravenous; 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

Topics: Administration, Oral; Anti-Arrhythmia Agents; Coronary Disease; Death, Sudden; Dose-Response Relationship, Drug; Humans; Infusions, Parenteral; Kinetics; Lidocaine; Myocardial Infarction; Piperidines; Propranolol

To establish the clinical efficacy of a single oral dose of pirmenol, we evaluated electrophysiologic and hemodynamic effects simultaneously after drug administration, performing electrophysiologic testing in 20 patients with ECG-documented paroxysmal supraventricular tachycardia (PSVT) before and after a single oral 200-mg dose of pirmenol. Hemodynamic measurements were made with a Swan-Ganz catheter in the first 10 consecutive patients. In a different series of patients, we administered a single 200-mg oral dose of pirmenol to evaluate its acute termination effect in 7 patients with PSVT and 9 with paroxysmal atrial fibrillation. Pirmenol prolonged the refractory period of the retrograde conduction system in patients with or without an accessory pathway, and supraventricular tachycardia was no longer inducible at 60 min in 11 patients [8 of 11 with atrioventricular (AV) reentrant tachycardia and 3 of 5 with AV nodal reentrant tachycardia]. Pirmenol increased the heart rate (p < 0.01) and total systemic resistance (p < 0.05), and reduced the stroke volume index (p < 0.01), all significantly. The plasma concentration of pirmenol at 1 h after administration was 0.75 +/- 0.48 microgram/ml. A single oral dose of pirmenol during tachyarrhythmia successfully restored sinus rhythm in 4 of 7 (57%) patients with PSVT and 4 of 9 (44%) patients with paroxysmal atrial fibrillation. A single oral dose of pirmenol was well tolerated as episodic treatment in patients with supraventricular tachyarrhythmias.

Topics: Administration, Oral; Adult; Anti-Arrhythmia Agents; Atrial Fibrillation; Female; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Tachycardia, Atrioventricular Nodal Reentry; Tachycardia, Supraventricular

Previous reports have stated that pirmenol is a Class IA antiarrhythmic drug that prolongs the QT interval, but did not use computerized electrocardiography. We randomized 18 patients with frequent ventricular ectopic depolarizations to pirmenol (8 patients) or quinidine (10 patients). Pirmenol was effective and tolerated for suppression of arrhythmia in all 7 patients treated (1 patient withdrew for personal reasons) but quinidine was effective and tolerated for 4 weeks in only 5 of 10 patients (p less than 0.05). Using computerized 12-lead electrocardiography, the mean change in PR interval from placebo to treatment was 5 +/- 18 ms for quinidine and 5 +/- 11 ms for pirmenol (p = NS). The mean change in QRS interval was 5 +/- 14 ms for quinidine and 10 +/- 5 ms for pirmenol (p = NS). The mean change in QT interval was 46 +/- 30 ms for quinidine and 8 +/- 9 ms for pirmenol (p less than 0.01) and the mean change in JT interval was 41 +/- 36 ms for quinidine and -2 +/- 10 ms for pirmenol (p less than 0.01). After the double-blind phase, 4 quinidine patients had computerized electrocardiographic intervals measured on pirmenol; the above findings were confirmed. These electrocardiographic features of pirmenol clearly distinguish it from quinidine, the prototype Class IA drug. However, pirmenol has minimal effect on the PR and QRS intervals, and thus does not appear to be a Class IC drug either. Although its electrocardiographic features are closest to Class IB, its electrophysiology in isolated cells and its antiarrhythmic and side effect profile are atypical for a IB agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Double-Blind Method; Electrocardiography; Female; Humans; Male; Middle Aged; Piperidines; Quinidine; Stroke Volume

Pirmenol is an investigational type 1A antiarrhythmic drug the long-term efficacy of which has not been fully determined. Therefore the long-term efficacy of oral pirmenol in suppressing ventricular premature depolarizations (VPDs) was assessed in an open-label, dose-titration study. Twelve patients (eight men and four women; mean age 57 +/- 12 years) were treated for 24 to 36 months (mean 33 +/- 4). Seven had structural heart disease (three valvular heart disease, two ischemic heart disease, and two hypertensive heart disease) and five did not. The mean left ventricular ejection fraction was 0.63 +/- 0.13. Exclusion criteria included less than 30 VPDs/hr, greater than 15 beats of ventricular tachycardia (VT), or prior failure of more than two antiarrhythmic drugs. Drug efficacy was assessed by 24-hour ambulatory ECG monitoring performed every 3 months during the first year, every 4 months during the second year, and at 6-month intervals during the third year. The mean hourly frequency of VPDs during the placebo phase was 732 +/- 608. Seven patients (58%) were treated successfully with effective (greater than 75%) long-term suppression of VPDs. Two patients (17%) had a partial response with effective suppression of VPDs for the first 16 months and 5 months of treatment, respectively. Three patients failed to show consistent suppression of VPDs while receiving pirmenol. The daily dose of pirmenol ranged from 200 to 500 mg (mean 317 +/- 94 mg at the beginning of the study and 375 +/- 97 mg at the end). No proarrhythmic effects were identified during long-term treatment, and none of the patients withdrew from the study prematurely.(ABSTRACT TRUNCATED AT 250 WORDS)

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

Pirmenol is a new orally effective antiarrhythmic agent. Reported are the results of oral administration of pirmenol to six patients (age 48.5 +/- 8.6 years, weight 83 +/- 15 kg) with stable ventricular extrasystoles (PVCs)--average ectopy rate 1040 +/- 630/hr (mean +/- SD). Patients received oral doses of placebo or 200 mg of pirmenol in a double-blind cross-over fashion followed by a single-blind rising-dose administration of 250 mg and 300 mg of pirmenol. The time period between doses was 48 hours. Pirmenol was rapidly absorbed (time to peak plasma levels 1 to 1.5 hours) and the mean maximum plasma concentrations were 1.8, 2.7 and 3.4 micrograms/mL with 200-mg, 250-mg and 300-mg doses, respectively. The elimination half-life was 9.3 +/- 3.0 hours and 31 +/- 14% of the dose was recovered in urine. The response criterion (80% suppression of PVCs of control for 8 hours) was met after the 300-mg dose in three patients. In three patients greater than 80% reduction occurred for up to 8 hours after the 200-mg dose. Pirmenol administration was not associated with any significant changes in blood pressure, heart rate, hepatic and renal function, PR interval or QRS duration. LV ejection fraction determined echocardiographically decreased from 63.0 +/- 6.9% predose to 59.7 +/- 5.0% about 2 hours after the 300-mg dose and QT interval increased by less than 10%. Two patients complained of transient bad taste sensation. Our results suggest that 250 mg to 300 mg of pirmenol, administered twice a day will suppress the PVCs effectively.

Topics: Administration, Oral; Anti-Arrhythmia Agents; Blood Pressure; Cardiac Complexes, Premature; Chromatography, High Pressure Liquid; Clinical Trials as Topic; Double-Blind Method; Female; Heart Conduction System; Heart Rate; Humans; Male; Middle Aged; Piperidines; Random Allocation

Topics: Adult; Aged; Anti-Arrhythmia Agents; Cardiac Complexes, Premature; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Female; Humans; Male; Middle Aged; Piperidines; Random Allocation

The efficacy of pirmenol in suppressing ventricular premature complexes (VPCs) was assessed in 196 patients in a placebo-controlled, double-blind, multicenter study. At a daily dosage of 200 to 400 mg, pirmenol was effective in suppressing VPCs. In the double-blind phase of the trial, 60% of patients had at least a 70% reduction in VPC frequency and at least 70% of those patients who entered the open-label phase of the study continued to show at least a 70% reduction in VPC rate. Pirmenol was well tolerated by most patients; 66% of the patients treated with pirmenol in the double-blind phase had no adverse experiences. Of those who did have an adverse experience, the most common complaint was unusual taste. Serious adverse reactions were rare and only 2% of the patients had what may have been a proarrhythmic response. The same pattern of tolerance was seen in the open-label phase of the study when 151 patients were treated for an extended length of time with pirmenol. Pirmenol shows considerable promise for patients in whom the reduction of VPC frequency is desirable. Currently available antiarrhythmic drugs may have limited efficacy, cause serious or intolerable side effects or require frequent administration. Pirmenol has a convenient twice-daily dosing regimen, dependable antiarrhythmic action and a good safety record. This study demonstrated the effectiveness and safety of pirmenol in the control of VPCs.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Cardiac Complexes, Premature; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Female; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Placebos

An 8-center European clinical trial has established that pirmenol in dosages up to 400 mg daily is effective and safe for treating stable, high frequency, ventricular ectopy. At dosages of 300 mg and 400 mg of pirmenol a day, the average frequency of ectopy/hour decreased markedly compared with baseline values. The percentage of responders (premature ventricular contraction suppression of 70% compared with baseline) among the patients receiving 300 mg or 400 mg of pirmenol/day was significantly higher than in the placebo group. Observation of the frequency of reported adverse experiences, clinical laboratory tests and electrocardiographic tracings shows that dosages of pirmenol up to 400 mg daily were well tolerated.

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

The acute effects of pirmenol on atrial fibrillation were investigated in 40 patients with paroxysm of atrial fibrillation. Patients were randomized to receive either pirmenol, 50 or 100 mg intravenously, or placebo. Patients with congestive heart failure or a history of sinus node disorder were excluded. Sinus rhythm was achieved in 12 of 20 patients in 2 to 16 minutes after pirmenol administration and in 3 of 20 patients in the control group within 1 hour. A nodal escape rhythm during sinus slowing was observed in 1 patient. No sinus arrest, atrioventricular conduction disturbance or hypotension appeared. Pirmenol has an antifibrillatory effect on the atria. Sinus rhythm is restored rapidly after intravenous administration. Treatment of atrial fibrillation of recent onset was well tolerated in patients accepted for the study.

Topics: Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Atrial Fibrillation; Humans; Injections, Intravenous; Piperidines; Placebos; Random Allocation

The acute hemodynamic effects of pirmenol and lidocaine were studied in a double-blind, placebo-controlled investigation. Thirty patients undergoing catheterization received one of the following: pirmenol as a 50-mg intravenous bolus injection followed by a 2.5 mg/min infusion, lidocaine as a 75-mg intravenous bolus injection followed by a 3 mg/min infusion or placebo administered in a similar fashion. Mean plasma pirmenol concentrations during steady infusion were 2.3 to 2.4 mg/liter, and mean plasma lidocaine concentrations were 16 to 24 mumol/liter. Pirmenol increased heart rate from baseline by 10 beats/min (p less than 0.001) and mean arterial pressure by 5 mm Hg (p less than 0.001), with similar increases in systemic (p less than 0.05) and pulmonary vascular resistance (p less than 0.01). Lidocaine induced a comparable increase in mean arterial pressure (6 mm Hg, p less than 0.001), but unlike pirmenol, it increased left ventricular and diastolic pressure by 2.8 mm Hg (p less than 0.05). Indexes of left ventricular work were not affected by either drug. Echocardiographic ejection fraction was reduced more by pirmenol (-0.05, p less than 0.0001) than by lidocaine (-0.03, p less than 0.05), a difference that may be related to the changes in heart rate. Side effects were not observed in any patient. The myocardial depressant effect of pirmenol is relatively slight and comparable to that of lidocaine.

Topics: Adult; Anti-Arrhythmia Agents; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Echocardiography; Heart Atria; Heart Rate; Heart Ventricles; Hemodynamics; Humans; Lidocaine; Middle Aged; Piperidines; Placebos; Stroke Volume

The efficacy of pirmenol (a class I antiarrhythmic agent) as a converter of paroxysmal atrial fibrillation was investigated. Forty patients without congestive heart failure or a history of sinus node disorder were randomly allocated to receive either intravenous pirmenol (50-100 mg) or placebo in a double blind trial. In 12 of 20 patients sinus rhythm was restored 2-16 minutes after pirmenol, and in 3 of 20 patients in the control group it returned within one hour. A nodal escape rhythm was seen during sinus slowing in one patient, but in other patients there was no sinus arrest, atrioventricular conduction disturbance, or hypotension. The ventricular rate was slightly increased in patients in whom sinus rhythm was not restored by pirmenol. The results indicate that pirmenol has an antifibrillatory effect on the atria. Sinus rhythm was restored rapidly after intravenous administration. It was well tolerated in patients with atrial fibrillation of recent onset.

Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Electrocardiography; Heart Rate; Humans; Middle Aged; Piperidines

The acute haemodynamic effects of pirmenol, a new Class 1 antiarrhythmic agent, were investigated in a double-blind comparison with lidocaine and placebo. Three groups of 10 patients each received either pirmenol as a 50 mg intravenous injection followed by a 2.5 mg min-1 infusion, or lidocaine as a 75 mg injection followed by a 3 mg min-1 infusion, or placebo. Mean plasma pirmenol concentrations during the 30 min infusion period were 2.3-2.5 mg l-1, and were considered to be therapeutically effective. Compared to measurements taken during a baseline phase of 15 min duration, pirmenol increased heart rate by 10 beats min-1 (P less than 0.001) and mean arterial pressure (MAP) by 5 mmHg (P less than 0.001). It also increased systemic vascular (P less than 0.05) and pulmonary arterial resistances (P less than 0.01). Left ventricular end-diastolic pressure (LVEDP) was not increased significantly. Cardiac index and left ventricular work index remained unchanged. Lidocaine induced a comparable increase in MAP (6 mmHg; P less than 0.001) and elevated LVEDP (2.8 mmHg; P less than 0.05) and did not affect left ventricular work index. Echocardiographic left ventricular ejection fraction was reduced more by pirmenol (-0.05; P less than 0.001) than by lidocaine (-0.03; P less than 0.05), but the greater reduction may partly be explained by the increase in heart rate. Primenol did not induce excessive circulatory responses or side-effects in any patient. Intravenous administration of pirmenol results in increased heart rate and afterload but has little effect on preload. The myocardial depressant effect is relatively slight, and comparable to that of lidocaine.

Topics: Adult; Analysis of Variance; Anti-Arrhythmia Agents; Clinical Trials as Topic; Coronary Disease; Double-Blind Method; Female; Hemodynamics; Humans; Lidocaine; Male; Middle Aged; Myocardial Infarction; Piperidines

Suppression of premature atrial complexes by pirmenol, a new Class I antiarrhythmic agent, was examined following oral and intravenous routes of administration. In 4 patients, single intravenous doses of 50 to 150 mg reduced premature atrial beats greater than or equal to 90% for 2 to 4 h. Oral doses of 75 to 200 mg twice daily induced a mean arrhythmia reduction of greater than or equal to 80% in 5 out of 9 patients during a 24-h electrocardiographic recording compared with a baseline period of 48 h. No significant side-effects occurred. The results indicate that pirmenol effectively suppresses premature atrial complexes, which may be of value in the prevention of supraventricular tachyarrhythmias.

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Heart Atria; Humans; Injections, Intravenous; Middle Aged; Piperidines

We assessed the antiarrhythmic effectiveness, therapeutic plasma concentrations and adverse effects of pirmenol in 16 patients with frequent (mean 933 h-1) premature ventricular complexes (PVC). Progressive increase in dose to a maximum of 200 mg twice daily suppressed PVC in a majority of patients. By preset criteria 11 patients (69%) exhibited an effective suppression of PVCs whereas in 5 patients (31%) the suppression was inadequate despite therapeutic plasma concentrations. The responders exhibited an 87% mean reduction of PVCs and a 97% reduction in repetitive PVC. This therapeutic effectiveness was verified against placebo by repetitive 24-hour ECG monitorings recorded in a double-blind cross-over fashion. The plasma trough concentration during the effective dose averaged 1.31 +/- 0.67 mg-1 (SD). The efficacy was maintained with the twice daily regimen despite an elimination half life of 6.3 +/- 1.7 h (SD) but a slight decrease in PVC suppression was observed towards the end of the administration interval. Pirmenol was well tolerated but aggravation of the arrhythmia occurred in one patient who shared an associated excessive prolongation of the Q-T interval, a feature observed with quinidine-like class I agents.

Topics: Anti-Arrhythmia Agents; Cardiac Complexes, Premature; Coronary Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Evaluation; Electrocardiography; Female; Humans; Kinetics; Male; Myocarditis; Piperidines; Tachycardia

A 3-stage, concentration-maintaining intravenous infusion regimen of pirmenol, a new antiarrhythmic agent, was tested for efficacy and safety in 8 subjects with chronic, stable premature ventricular beats. The regimen, which consisted of (1) a priming bolus of 50 mg over 2 minutes, followed by (2) a rapid loading infusion of 2.5 mg/min for 1 hour, and (3) a maintenance infusion of 0.25 mg/min, rapidly achieved and maintained stable plasma pirmenol levels from 0.94 to 2.75 micrograms/ml, during infusions lasting up to 48 hours. Therapeutic efficacy was evaluated during 4-hour infusions in 5 patients utilizing a randomized, double-blind, placebo-controlled study design. Pirmenol suppressed average premature ventricular beat frequency 93 +/- 6% compared with control values (p = 0.03). Pirmenol infusions were unassociated with toxicity. There were slight but significant increases in diastolic blood pressure, QRS duration, and corrected Q-T interval. No significant changes occurred in systolic blood pressure, heart rate, P-R interval, or laboratory variables. Pirmenol is a promising therapeutic agent that warrants further evaluation. The 3-stage infusion satisfactorily achieves and maintains therapeutic plasma pirmenol levels.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Double-Blind Method; Drug Evaluation; Electrocardiography; Female; Heart Rate; Humans; Infusions, Parenteral; Kinetics; Male; Middle Aged; Monitoring, Physiologic; Piperidines; Random Allocation

The case of a 64-year-old man with Wolff-Parkinson-White syndrome and permanent atrial fibrillation (AF) is reported. The patient was admitted due to electrocardiographic feature of AF with rapid conduction over the left-sided accessory pathway. Administration of pirmenol effectively suppressed the ventricular response via an accessory pathway. A transesophageal echocardiography detected an uncertain thrombus in the left atrial appendage. During the 33-month follow-up period, the ventricular response via an accessory pathway was progressively facilitated. Radiofrequency catheter ablation using a transseptal approach was performed during AF, resulting in complete elimination of the antegrade accessory pathway conduction.

Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Bundle of His; Catheter Ablation; Electrocardiography; Follow-Up Studies; Humans; Male; Middle Aged; Piperidines; Wolff-Parkinson-White Syndrome

A 67-year-old man with neurally mediated syncope (NMS) complicated by prostatic hypertrophy responded well to combined therapy with pirmenol and midodrine. In 2003, syncope occurred while the patient was driving a car. Results of head-up tilt-table testing (HUT) suggested a mixed type of NMS. Oral administration of disopyramide provided severe urinary obstruction. Pirmenol treatment was not associated with syncope during ordinary HUT, but nausea, sweating, and syncope occurred during HUT with provocative administration of isosorbide dinitrate. Combined therapy with pirmenol and midodrine avoided syncope during HUT, and has prevented attacks since discharge from the hospital.

Topics: Aged; Anti-Arrhythmia Agents; Humans; Male; Midodrine; Piperidines; Prostatic Hyperplasia; Syncope, Vasovagal; Tilt-Table Test; Vasoconstrictor Agents

Antiarrhythmic therapy requires monitoring of serum drug concentrations to determine a patient's optimal oral dose of medication. Repeated examination of blood samples, however, is costly and time-consuming, so the present study evaluated whether changes in serum concentrations could be estimated from changes in electrocardiographic (ECG) parameters. Of 36 patients receiving antiarrhythmic drugs for supraventricular or ventricular arrhythmias, 12 were treated with flecainide, 12 with pilsicainide, and 12 with pirmenol. Signal-averaged ECG (SAECG) were recorded before starting drug administration, 1 month later, and twice during ongoing therapy. At the time of the 2nd to the 4th recordings, serum concentrations of the drugs were also measured. As previously reported, all agents, but especially flecainide and pilsicainide, prolonged the filtered QRS (f-QRS) and the duration of low-amplitude signals at the terminal portion of the QRS complex. The SAECG parameters varied between the recordings made during therapy. Differences in the duration of the f-QRS between 2 recordings correlated significantly with differences in serum drug concentrations (r=0.91 for flecainide, r=0.70 for pilsicainide, and r=0.61 for pirmenol). No significant correlation between drug concentration and other SAECG parameters was found. Changes in the serum concentration of flecainide, pilsicainide and pirmenol can be estimated from changes in the duration of the f-QRS on the SAECG and periodic monitoring of such could help reduce the number of repeat measurements of drug concentrations in blood samples.

Topics: Aged; Anti-Arrhythmia Agents; Drug Monitoring; Electrocardiography; Female; Flecainide; Humans; Lidocaine; Male; Middle Aged; Piperidines

Although pharmacological agents are frequently used to control ventricular rate or restore sinus rhythm of patients with atrial fibrillation (AF), there are no reports of the relationship between those agents and left atrial appendage (LAA) function. Two cases of a decrease in LAA blood flow velocity caused by negative inotropic agents are presented as an indication that negative inotropic agents are a risk factor for systemic thromboembolism with AF.

Topics: Atenolol; Atrial Fibrillation; Atrial Function, Left; Blood Flow Velocity; Cardiotonic Agents; Echocardiography, Transesophageal; Humans; Male; Middle Aged; Piperidines; Thromboembolism

In order to complete TDM manual for pirmenol in Sapporo Medical Center NTT East, we developed HPLC method and pretreatment procedure for pirmenol samples obtained from patients. Serum (250 microliters) was alkalinized and pirmenol was extracted into n-hexane, and then the drug was again extracted into an acidic solvent, 0.044 M KH2PO4 (pH 2.6) including 0.5% triethylamine. The aqueous extract was used for quantitative determination of the drug by HPLC. The mobile phase consisted of the above acidic solvent-acetonitrile (5:1, v/v) was delivered at 45 degrees C with a flow rate of 1 ml/min through a 4.6 mm x 25 cm ODS-3, a reversed-phase column. Detection of pirmenol and the internal standard (disopyramide) was achieved at 263 nm. Pirmenol and disopyramide was eluted at 5 and 11 min, respectively. Assay limit (25 ng/ml) and accuracy of the analytical method were satisfactory for TDM of pirmenol. During the HPLC analysis of patient samples, no substances that interfered with pirmenol detection were found. It was shown that 1) hemolysis did not affect pirmenol assay at all, 2) pirmenol was stable in the blood samples for at least 24 h even if they were stood at room temperature, and 3) pirmenol was stable for at least 3 days in frozen serum but there significant decrease was observed in pirmenol concentration after 7 days.

Topics: Anti-Asthmatic Agents; Chromatography, High Pressure Liquid; Drug Monitoring; Humans; Piperidines; Specimen Handling

Topics: Age Factors; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Creatinine; Female; Humans; Male; Piperidines

Electrophysiological effects of pirmenol hydrochloride (pirmenol) were investigated in single atrial myocytes obtained from rabbit and guinea-pig hearts by using a whole-cell clamp technique. Under current clamp conditions, pirmenol (2-30 microM) prolonged action potential duration in a concentration-dependent manner without affecting resting membrane potential in rabbit atrial myocytes. However, in the presence of 4-aminopyridine (4 mM), pirmenol (10 microM) failed to prolong the action potential duration further. Pirmenol also suppressed acetylcholine-induced hyperpolarization and action potential duration shortening, resulting in a significant prolongation of the action potential duration in the presence of acetylcholine. Under voltage clamp conditions, pirmenol (1-1000 microM) inhibited transient outward current (I(to)) in a concentration-dependent manner. The concentration for half-maximal inhibition (IC50) of pirmenol on I(to) was about 18 microM. Pirmenol did not show the use and frequency dependent inhibition of I(to). The voltage dependence of the steady-state inactivation of I(to) and the recovery from inactivation were not significantly affected by pirmenol. Pirmenol accelerated the inactivation of I(to) and blocked I(to) as an exponential function of time, consistent with a time-dependent open channel blockade. Pirmenol (30 microM) did not affect the inwardly rectifying K+ current significantly, but it decreased the voltage-dependent L-type Ca2+ current by about 20%. In guinea-pig atrial myocytes, both acetylcholine and adenosine induced a specific K+ current activated by GTP-binding proteins. Pirmenol suppressed both the acetylcholine- and adenosine-induced K+ current effectively. The IC50 of pirmenol for acetylcholine- and adenosine-induced current was about 1 and 8 microM, respectively. The present results suggest that pirmenol prolongs the action potential duration by primarily inhibiting the transient outward current in atrial myocytes. In addition, since pirmenol inhibits acetylcholine- and adenosine-induced K+ current, pirmenol may effectively prolong the action potential duration in atrial myocytes under various physiological conditions as in the whole heart or ischemia.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Cells, Cultured; Guinea Pigs; Heart; Heart Atria; Patch-Clamp Techniques; Piperidines; Rabbits

Pirmenol hydrochloride is a new orally effective, long-acting antiarrhythmic agent currently used in patients with supraventricular and ventricular tachyarrhythmias. We report on a 56-year-old female who exhibited drug refractory paroxysmal atrial fibrillation, in which marked prolongation of the QT interval and T wave inversion on electrocardiogram was demonstrated reproducibly shortly after the administration of oral pirmenol therapy. The plasma concentration of pirmenol was at a subtherapeutic level and the lymphocyte stimulation test was positive in this patient. Thus, an immunological mechanism might be involved in the mechanism of pirmenol-induced QT prolongation and T wave inversion on the electrocardiogram.

Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Electrocardiography; Female; Humans; Long QT Syndrome; Middle Aged; Piperidines

The pharmacokinetics and pharmacodynamics of pirmenol enantiomers were investigated in coronary artery ligated mongrel dogs. Reduction in frequency of premature ventricular complexes (PVCs) was determined following intravenous administration of 5-mg/kg doses of racemic pirmenol (n = 5), (+)-pirmenol (n = 4), and (-)-pirmenol (n = 4), each given as a 5-min infusion. Electrocardiographic signals and blood samples were obtained serially over a 4-h period. Pirmenol enantiomer concentrations in plasma were determined by a stereospecific assay. Following the racemate dose, (-)-pirmenol had 47% lower clearance and 33% lower steady-state distribution volume than (+)-pirmenol. These differences could be mostly explained by stereoselective plasma protein binding, reflected in a 58% higher unbound fraction for (+)-pirmenol compared with (-)-pirmenol following racemate administration. Unbound pirmenol distribution volumes were nearly identical for both enantiomers, and unbound clearance was only 16% lower for (-)-pirmenol than (+)-pirmenol following administration of the racemate. Similar trends were observed for pirmenol enantiomers administered individually. Both pirmenol enantiomers were equally effective in arrhythmia suppression. The antiarrhythmic response of coronary artery ligated dogs to pirmenol was described by a sigmoid Emax model, and no statistically significant differences were observed in the pharmacodynamic parameters [i.e., EC50 (plasma concentration at 50% of maximum drug effect), S (constant that reflects the sigmoidal shape of the effect-concentration curve), and EC90 (plasma concentration at 90% of maximum drug effect)] for (+)-pirmenol, (-)-pirmenol, or pirmenol racemate.

Topics: Animals; Anti-Arrhythmia Agents; Arteries; Blood Proteins; Coronary Vessels; Dogs; Piperidines; Stereoisomerism

The pharmacokinetics and pharmacodynamics of pirmenol were investigated in 12 patients with premature ventricular contractions (PVCs) after oral administration of racemic pirmenol, 100 mg and 200 mg every 12 hours. Holter monitoring was performed and serial blood samples were collected after the seventh doses. Plasma concentrations of pirmenol enantiomer were determined using a stereospecific liquid chromatographic assay. Clearance of total (-)-pirmenol was 20% higher than that of total (+)-pirmenol, and the difference in unbound clearance was 45% between enantiomers. Total pirmenol showed a smaller difference because of stereoselective protein binding, with 25% (100-mg dose) or 27% (200-mg dose) higher fraction unbound for (+)-pirmenol than for (-)-pirmenol. Distribution volume was similar for both enantiomers. Dose-dependent clearance was observed for unbound pirmenol enantiomers, as both enantiomers showed 20% lower unbound clearance at the higher dose. Antiarrhythmic effect (% reduction in PVCs from baseline) was correlated with plasma concentrations of pirmenol using a sigmoid maximum drug effect model, and patients showed a large variability in their antiarrhythmic response to plasma concentrations of pirmenol. The median value for minimum effective plasma concentration of racemic pirmenol was 1.5 micrograms/mL.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Myocardial Contraction; Piperidines; Protein Binding; Stereoisomerism

We examined the effects of pirmenol and disopyramide on the muscarinic acetylcholine receptor-operated K+ current (I[K.ACh]) in atrial cells and on experimental atrial fibrillation in isolated guinea-pig hearts. In isolated atrial myocytes, both pirmenol and disopyramide concentration-dependently inhibited the I(K.ACh) induced by carbachol or intracellular loading of GTPgammaS. Their inhibitory effects on the carbachol-induced current were more potent than those on GTPgammaS-induced current, suggesting that these drugs inhibit I(K.ACh) mainly by blocking muscarinic receptors. In Langendorff-perfused hearts these drugs reversed the carbachol-induced decreases in effective refractory periods and atrial fibrillation threshold. These drugs may be useful for the prevention of vagally induced atrial fibrillation.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Carbachol; Disopyramide; Electric Stimulation; Guinea Pigs; Heart; Patch-Clamp Techniques; Piperidines; Potassium Channels; Receptors, Muscarinic

The in vitro metabolism of pirmenol (cis-alpha-[3-(2,6-dimethyl-1-piperidinyl)propyl]-alpha-phenyl-2-pyri dinemethanol) and glucuronidation of its metabolites, a 4-hydroxylated derivative of pirmenol (M3) and 3-methylether of M3 (M5), were investigated using a hepatic 9000 x g supernatant and microsomes, respectively, of female and male rats in order to elucidate the higher urinary excretion of M3G and M5G (glucuronides of M3 and M5, respectively) in females previously observed in in vivo metabolism. Pirmenol delta1' iminium ion (M2) and M3 were formed by the oxidation of pirmenol in both sexes; however, M2 was the main metabolite in males, while M2 and M3 were formed at nearly the same level in females. On glucuronidation of M3 and M5, the Vmax values of both compounds were higher in female rats, consistent with the results in vivo. In addition, the sex difference in the urinary excretion ratio of M5G to M3G (1.1 in female, 2.5 in male) might reflect the lower availability of M3 for glucuronidation in male rats in vivo. The chromatographic separation of diastereomers of M5G was also described.

Topics: Animals; Anti-Arrhythmia Agents; Biotransformation; Chromatography, High Pressure Liquid; Female; Glucuronates; Glucuronidase; Hydrolysis; In Vitro Techniques; Male; Microsomes, Liver; Oxidation-Reduction; Piperidines; Rats; Rats, Sprague-Dawley; Sex Characteristics

Column chromatography, thin-layer chromatography, high-performance liquid chromatography, nuclear magnetic resonance spectrometry, and high-resolution mass spectrometry were employed to separate and identify the photodegradation products of pirmenol hydrochloride [(+/-)-cis-alpha-[3-(2,6-dimethyl-1-piperidinyl)propyl]-alpha-phenyl-2- pyridinemethanol monohydrochloride monohydrate], a new antiarrhythmic drug. A methanol solution of pirmenol was irradiated using a low-pressure mercury lamp. The solution afforded four major degradation products, three of which were identified as 3-(cis-2,6-dimethylpiperidinyl)propyl 2-(2-pyridyl)phenyl ketone, 2-(2-pyridyl)benzoic acid, and methyl 2-(2-pyridyl)-benzoate. The degradation followed apparent-first-order reaction kinetics. In addition, the possible photodegradation pathways are discussed with reference to reaction mechanisms.

Topics: Anti-Arrhythmia Agents; Chromatography, Thin Layer; Kinetics; Light; Magnetic Resonance Spectroscopy; Mass Spectrometry; Photochemistry; Piperidines; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet

We used standard microelectrode techniques to study the electrophysiologic effects of pirmenol, its cis-(+) and cis-(-) enantiomers, and its metabolite 2 on canine Purkinje fibers. The parent compound and both enantiomers significantly reduced the amplitude and Vmax of phase 0 of the action potential (AP) and shortened AP duration (APD). No significant differences were detected in the concentration-dependent effects on AP characteristics among these three compounds. Metabolite 2 caused similar changes in the amplitude and Vmax of phase 0, but they were of lesser magnitude. In contrast to the parent compound, metabolite 2 markedly prolonged repolarization. The use-dependent effects of pirmenol and metabolite 2 were studied. At 10(-5) M, the time constant of onset of use-dependent block (tau on) for pirmenol was 10.4 +/- 0.4 (mean +/- SEM) beats; for metabolite 2, it was 7.4 +/- 0.8 beats (p < 0.05). The time constants of recovery from use-dependent block (tau off) were comparable: pirmenol 18 +/- 2 s and metabolite 2 21 +/- 6 s (p > 0.05). Pirmenol and its enantiomers have comparable local anesthetic effects. In contrast to pirmenol, its metabolite 2 prolongs AP duration.

Topics: Action Potentials; Analysis of Variance; Animals; Anti-Arrhythmia Agents; Dogs; Dose-Response Relationship, Drug; Electrophysiology; In Vitro Techniques; Piperidines; Purkinje Fibers; Stereoisomerism

Topics: Administration, Oral; Anti-Arrhythmia Agents; Aprindine; Flecainide; Humans; Imidazoles; Lidocaine; Mexiletine; Piperidines; Propafenone

Voltage-dependent modification of Vmax (the maximum upstroke velocity of the action potential) recovery from use-dependent block (UDB) by pirmenol was examined and compared with those observed with other Class I drugs using standard microelectrode techniques. A partial depolarization of the resting membrane by increasing extracellular potassium concentration ([K+]o) from 4 to 8 mM potentiated UDB at 2 Hz stimulation by any of the following drugs: pirmenol (10 microM), disopyramide (20 microM), pentisomide (50 microM), quinidine (20 microM), mexiletine (30 microM), and flecainide (5 microM). The recovery time constants from UDB of quinidine and mexiletine were prolonged and that of flecainide was unchanged in 8 mM [K+]o. However, the recovery time constant from UDB of pirmenol was shortened in high K+ solution, as observed with disopyramide and pentisomide. Thus, disopyramide and its analogues, including pirmenol, show a voltage dependency of recovery process, which is different from those of other class Ia, Ib, and Ic drugs. The main unblocking pathway of disopyramide and its analogues from sodium channels during diastolic interval may be different from that of other Class I drugs.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Disopyramide; Flecainide; Guinea Pigs; Heart; In Vitro Techniques; Membrane Potentials; Mexiletine; Microelectrodes; Neuromuscular Depolarizing Agents; Papillary Muscles; Piperidines; Propylamines; Pyridines; Quinidine; Sodium Channels

The genotoxicity of pirmenol was tested in the E. coli and S. typhimurium mutagenesis assay, an in vitro mammalian cell chromosome-aberration assay and an in vivo mouse micronucleus assay. The E. coli tester strain WP2s was exposed to concentrations of pirmenol as high as 10,000 micrograms/plate both in the absence (S9-) and presence (S9+) of metabolic activation. Five strains of S. typhimurium (TA98, TA100, TA1535, TA1537, TA1538) were exposed to concentrations of pirmenol as high as 5000 micrograms/plate in the absence and presence of S9. Pirmenol was not mutagenic toward either E. coli or S. typhimurium. Chinese hamster lung V79 cell cultures were exposed to pirmenol at concentrations of 500-2500 micrograms/ml (S9-) and 500-3000 micrograms/ml (S9+). Pirmenol increased the frequency of structural chromosome aberrations (SCAs). The minimum clastogenic concentration was 1500 micrograms/ml (both S9- and S9+) with a peak clastogenic response of 6% (S9-) and 34% (S9+) cells with aberrations. Although there were statistically significant results in the S9- experiment, the percent cells with aberration values for treated groups were within the historical control range (0-6%) of this laboratory. The observed effects in both the absence and presence of S9 appear at high concentrations compared to human circulating plasma levels of 1-3 micrograms/ml and the clastogenicity was confined to chromosome gaps and breaks. Consequently, this in vitro effect would not be expected to be reflected by either in vivo clastogenic or carcinogenic activity. This was supported by findings in the mouse micronucleus study of pirmenol in which single oral doses administered to male CD-1 mice at 5, 55, or 115 mg/kg (80% LD50) produced no statistically significant increases in the frequency of micronucleated polychromatic erythrocytes in bone marrow at 24, 48 or 72 h postdosing. Additionally, no evidence of carcinogenicity was seen in a mouse or rat bioassay.

Topics: Animals; Anti-Arrhythmia Agents; Biotransformation; Bone Marrow; Cell Line; Chromosome Aberrations; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Escherichia coli; Male; Mice; Mice, Inbred ICR; Micronucleus Tests; Mutagenicity Tests; Mutagens; Piperidines; Salmonella typhimurium; Sister Chromatid Exchange

The interactions of the class I antiarrhythmic agents, disopyramide, pirmenol, and pentisomide with peripheral muscarinic receptors were investigated by binding assay with [3H]N-methylscopolamine ([3H]NMS) as a ligand. All the agents inhibited the specific [3H]NMS binding to membrane preparations obtained from guinea pig submandibular gland (SG) and urinary bladder (UB) smooth muscle. The competition curves of these agents for [3H]NMS binding to SG membranes were monophasic, indicating competition with [3H]NMS at a single site. Comparison of results with those of our previous binding experiments using guinea pig left atrial (LA) membranes, showed that pirmenol had sevenfold lower affinity for glandular-type muscarinic receptors (M3) than for cardiac-type muscarinic receptors (M2). On the other hand, the dissociation constants (Ki) for disopyramide and pentisomide in SG were comparable to the high-affinity Ki values for these agents at M2 receptors. The competition curves of the three agents for [3H]NMS binding to UB membranes were biphasic and showed high- and low-affinity states of binding. The high- and low-affinity Ki values for pirmenol in UB were similar to its Ki values at M2 and M3 receptors obtained in LA and SG, respectively. The high-affinity Ki values for disopyramide and pentisomide were consistent with the respective Ki values determined in SG, whereas the low-affinity binding sites for these agents were presumably the result of their allosteric interactions with the receptors. All agents at higher concentrations slowed the dissociation of [3H]NMS elicited by an excess of atropine in both UB and SG, thus indicating allosteric interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Binding, Competitive; Disopyramide; Female; Guinea Pigs; Kinetics; Male; Muscle, Smooth; N-Methylscopolamine; Piperidines; Propylamines; Pyridines; Receptors, Muscarinic; Scopolamine Derivatives; Submandibular Gland; Urinary Bladder

The steady state pharmacokinetics of pirmenol was compared in twelve healthy young (aged 18 to 45 y) and 11 elderly subjects (over 65 y) subjects given pirmenol HCl 100 mg every 12 h for a total of 14 doses. In addition, the single-dose pharmacokinetics of pirmenol was determined following a 100 mg oral dose in the young subject group for comparison with the results of repeated administration. In the young subjects, the mean single-dose and steady-state CLR of pirmenol were similar; however, Ae was 29% higher and CL/f was 22% lower at steady state than after the single dose. Steady-state (fourteenth dose) Cmin, Cmax, tmax, lambda z, Ae, CL/f, CLR and V values were similar in the young and elderly subjects. Based on pharmacokinetic considerations, the dosage of pirmenol is unlikely to differ in young and elderly subjects.

Topics: Adult; Aged; Aging; Anti-Arrhythmia Agents; Drug Administration Schedule; Female; Humans; Male; Piperidines

Since it has been reported that several class I drugs stereoselectively block sodium channels, potassium channels and muscarinic receptors in cardiac tissues, electrophysiologic and anticholinergic effects of enantiomers of pirmenol, a class I antiarrhythmic drug, were examined. Both (+) and (-) pirmenol depressed the maximum upstroke velocity (Vmax) of the action potential in a concentration-dependent manner in guinea-pig papillary muscles driven at 1.0 Hz, and there was no significant difference in the potency of the class I effect between the enantiomers. The onset rates of use-dependent block (UDB) of Vmax at 2.0 Hz for 10 mumol/l (+) and (-) pirmenol were 0.30 +/- 0.03 and 0.29 +/- 0.01 per action potential, and the recovery time constants from UDB for (+) and (-) pirmenol were 27.0 +/- 2.7 and 27.7 +/- 1.9 s, respectively, indicating no difference in the binding and unbinding kinetics to the sodium channel between the enantiomers. Both (+) pirmenol and (-) pirmenol prolonged action potential duration (APD) at low concentrations (1-10 mumol/l) and shortened it at high concentrations (30-100 mumol/l). Again, there was little difference with respect to the effects on APD between the enantiomers. However, in the isolated guinea-pig left atria (-) pirmenol more potently antagonized the negative inotropic effect of carbachol than (+) pirmenol, and the pA2 values for (+) and (-) pirmenol were 6.41 and 6.71, respectively. The functional study was supported by the radioligand binding experiments using [3H]N-methylscopolamine ([3H]NMS) in guinea-pig left atrial membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Action Potentials; Animals; Electrophysiology; Guinea Pigs; Heart; In Vitro Techniques; Kinetics; Membrane Potentials; Membranes; Myocardium; N-Methylscopolamine; Papillary Muscles; Parasympatholytics; Piperidines; Radioligand Assay; Receptors, Muscarinic; Scopolamine Derivatives; Stereoisomerism

The potential for a drug-drug interaction between pirmenol, an extensively metabolized antiarrhythmic agent, and cimetidine, an inhibitor of hepatic drug-metabolizing enzymes, was evaluated in eight healthy adults. A single 150-mg oral dose of pirmenol was administered on study days 1 and 8 and oral cimetidine, 300-mg QID, was administered on study days 4 through 11. Plasma and urine samples were collected after each pirmenol dose for determination of pirmenol concentration. Mean pirmenol concentration-time curves and pharmacokinetic parameters, including elimination rate constant, were not significantly altered by concomitant administration of cimetidine.

Topics: Administration, Oral; Adult; Cimetidine; Drug Administration Schedule; Drug Interactions; Female; Humans; Male; Piperidines

Topics: Adrenergic beta-Antagonists; Amiodarone; Anti-Arrhythmia Agents; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Calcium Channel Blockers; Chlorobenzenes; Flecainide; Humans; Membrane Potentials; Moricizine; Piperidines; Propylamines; Pyridines; Sodium Channels

Effects of pirmenol on electrical induction of sustained ventricular tachycardia (VT) were examined in 14 dogs with 7-day-old myocardial infarctions. Before administration of the drug, sustained VT was induced in 8 of 14 dogs. After administration of 3 mg/kg pirmenol, induction of VT was suppressed in 2 dogs but remained inducible in 6 dogs. After cumulative administration of 5 mg/kg pirmenol, VT was no longer inducible in 3 dogs but in the other 3 dogs VTs were still inducible at increased cycle lengths. After 7 mg/kg pirmenol, VT was not inducible in the remaining three dogs. Arrhythmias could not be provoked in any postinfarction dogs after pirmenol administration. Plasma concentrations after sequential and cumulative administration of 3, 5, and 7 mg/kg pirmenol averaged 0.43, 0.65, and 1.15 micrograms/ml, respectively. Administration of pirmenol increased the effective refractory period (ERP) and paced QRS duration in both the normal and infarcted ventricular myocardium. In the infarcted myocardium, prolongation of the ERP for the second and third extrastimuli was greater than for the first one (p less than 0.05). Results indicate that pirmenol is effective for prevention of sustained VT owing to prolongation of both the ERP and conduction time in recent myocardial infarction.

Topics: Animals; Anti-Arrhythmia Agents; Dogs; Electric Stimulation; Electrocardiography; Electrophysiology; Heart Ventricles; Myocardial Infarction; Piperidines; Tachycardia; Ventricular Function

Effects of pirmenol hydrochloride and lidocaine hydrochloride on intraventricular conduction were examined in the infarcted heart of anesthetized dogs. The effects of the drugs on the excitation induced by ventricular stimulations were determined with coupling intervals between 150 and 1,000 ms. Effects of the drugs on the His bundle electrocardiograms were also examined. Pirmenol in doses of 1-5 mg/kg prolonged the conduction time in the infarcted zones over a wide range of coupling intervals. Pirmenol at 5 mg/kg blocked the delayed conduction at a short coupling interval in the infarcted zones. The effect of pirmenol on the conduction time in the normal zone was slight. Lidocaine in doses of 3 and 10 mg/kg prolonged the conduction time in the infarcted zone at a short coupling interval. Pirmenol did not significantly prolong PQ or AH interval. In conclusion, pirmenol selectively depressed the delayed conduction in the infarcted zone, which could result in a reentrant pathway. The effect of pirmenol on delayed conduction was dependent on the coupling interval and was quite different from that of lidocaine.

Topics: Animals; Anti-Arrhythmia Agents; Bundle of His; Dogs; Electric Conductivity; Electrocardiography; Heart Conduction System; Lidocaine; Myocardial Infarction; Piperidines

Pirmenol enantiomers in dog plasma were quantified using a stereospecific high-performance liquid chromatographic method with ultraviolet detection at 262 nm. Racemic pirmenol and internal standard, (+)-propranolol, were isolated from dog plasma by a three-step extraction procedure using toluene, 0.1 M hydrochloric acid and hexane, respectively. A chiral analytical column (Chiralcel OJ) was used with a mobile phase consisting of hexane-isopropanol-diethylamine (98.9:1.0:0.1). Linear calibration curves were obtained in the concentration range 0.0200-5.00 micrograms/ml for each enantiomer. Precision of the method, expressed as coefficient of variation for nine quality control samples, was 7.1% for (+)-pirmenol and 6.4% for (-)-pirmenol. Bias was +/- 2.2% for (+)-pirmenol and +/- 1.5% for (-)-pirmenol in quality control samples.

Topics: Animals; Anti-Arrhythmia Agents; Chromatography, High Pressure Liquid; Dogs; Hexanes; Hydrochloric Acid; Male; Piperidines; Stereoisomerism; Toluene

A method for the determination of pirmenol in serum is presented in this paper. The method consists of extraction of pirmenol and chlorodisopyramide (internal standard) from serum at an alkaline pH using methylene chloride. The organic extract was analysed using high-performance liquid chromatography. The mobile phase consisted of 0.01 M K2HPO4 (pH 2.4)-acetonitrile (94:6, v/v) delivered at ambient temperature and 2 ml/min through a 25 cm x 0.4 mm C18 reversed-phase column. Detection of the compounds of interest was achieved at 210 nm. The analytical method demonstrated low intra- and inter-assay variation. During the analysis of patient samples and a therapeutic drug mixture test serum, no substances that interfered with pirmenol detection were found. The method is shown to be stable, accurate, selective and sensitive enough to be utilized for the analysis of multiple samples such as may be encountered in clinical or research situations.

Topics: Anti-Arrhythmia Agents; Chromatography, High Pressure Liquid; Humans; Hydrogen-Ion Concentration; Piperidines

The binding profiles of the class I antiarrhythmic agents disopyramide, pirmenol and pentisomide (CM7857) to cardiac muscarinic receptors were characterized by the binding assay using [3H]-N-methyl scopolamine ([3H]NMS) as a ligand and their anti-muscarinic actions were investigated functionally in left atrial preparations. All the agents displaced the specific binding of 200 pM [3H]NMS from guinea pig left atrial membranes. Computer-assisted analysis indicated that pirmenol interacted with a single class of binding sites, but the displacement curves of disopyramide and pentisomide were shallow and best fitted to a two-site model. When the concentration of [3H]NMS was increased to 1 nM, the displacement curve of pirmenol was best fitted to a two-site model. In higher concentrations, these agents inhibited the dissociation of [3H]NMS initiated by 1 microM atropine in a concentration-dependent manner, thus revealing allosteric interactions. Two enantiomers of pirmenol possessed qualitatively the same binding properties as the racemate. In guinea pig left atria, disopyramide, pirmenol and pentisomide shifted the concentration-response curves for the negative inotropic effect of carbachol in a parallel manner. The slopes of Schild plot were not significantly different from unity, indicating that they act as a competitive antagonist of cardiac muscarinic receptors. Excellent correlation between the high affinity pKi values and the pA2 values was established for the antiarrhythmic agents. These findings suggest that disopyramide, pirmenol and pentisomide all interact with cardiac muscarinic receptors in both a competitive fashion and an allosteric one. The dual mode of the interaction with cardiac muscarinic receptors seems to be independent of their chiralities.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Binding, Competitive; Depression, Chemical; Disopyramide; Female; Guinea Pigs; Heart; Heart Atria; Kinetics; Male; Membranes; Myocardial Contraction; Myocardium; Piperidines; Propylamines; Pyridines; Receptors, Muscarinic

The effect of administration of pirmenol, an extensively metabolized and plasma protein-bound antiarrhythmic agent, was evaluated in ten patients on chronic warfarin therapy. After a 3-week baseline period and 7 days of placebo administration, patients received 150 mg of oral pirmenol every 12 hours for 14 days. Prothrombin time was determined during the baseline and placebo periods, during pirmenol administration, and 14 days after the last pirmenol dose (washout). There was no significant difference between mean baseline, placebo, pirmenol, and washout prothrombin times. Coadministration of pirmenol does not appear to affect the anticoagulant activity of warfarin.

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Drug Interactions; Humans; Middle Aged; Piperidines; Prothrombin Time; Thromboembolism; Warfarin

The interactions of the antiarrhythmic agents, disopyramide (D) and its congeners, pirmenol (Pr) and pentisomide (Pt), with peripheral muscarinic receptors (m-AchR) were investigated using binding and functional assays. D, Pr and Pt inhibited the specific binding of [3H]-N-methyl scopolamine ([3H]-NMS) to membrane fractions prepared from guinea pig left atria (LA), submandibular glands (SG) and urinary bladders (UB) in a concentration-dependent manner. Computer-assisted analysis showed that the displacement curves with D obtained from LA and UB were shallow and best fitted by a two-site model, whereas D interacted with a single class of binding sites in SG. Kinetic experiments measuring [3H]-NMS dissociation revealed the existence of allosteric interaction of D with m-AChR, and it might be responsible for the low affinity components of the displacement curves in LA and UB. The pKi values for D in high-affinity receptor sites in LA and UB (pKH) were very close to the pKi for D obtained in SG, and corresponded well to the pA2 values of around 6.0 for antagonism against the carbachol-induced mechanical responses of LA and UB. Pt interacted with m-AChR with qualitatively very similar fashion to that of D, but its potency was very weak (1/10 of D). Pr interacted with a single class of binding sites in LA and SG with pKi of 6.02 and 5.18, respectively, indicating that the affinity of Pr to glandular m-AChR (M3) was 7 fold lower than that to cardiac one (M2). The displacement curve with Pr in UB was best fitted by a two-site model with pKH of 5.93 and pKL of 5.20. The pA2 for Pr in LA and UB were 6.47 and 5.55, respectively, suggesting the existence of a mixed population of M2 and M3 in UB and the contribution of M3 to its contractile response. It is concluded that Pr is able to distinguish M2 from M3, and that D and Pt have almost similar affinity to both subtypes of m-AChR. Pr was less potent than D in interaction with M3.

Topics: Animals; Binding, Competitive; Carbachol; Disopyramide; Drug Interactions; Female; Guinea Pigs; In Vitro Techniques; Male; Muscle Contraction; Myocardial Contraction; N-Methylscopolamine; Piperidines; Propylamines; Pyridines; Receptors, Muscarinic; Scopolamine Derivatives

A series of alpha,alpha-diaryl-1-piperidinebutanols was evaluated for antiarrhythmic activity in the coronary ligated dog model. Structure-activity relationship studies indicated that the 2,6-dimethylpiperidine group yielded compounds with the best antiarrhythmic profiles in this series. The length of the methylene chain separating the diarylcarbinol and the amino group was not crucial. Substitution of a hydrogen or a number of functional groups for the hydroxyl group had little effect on efficacy or duration but yielded compounds that produced severe tachycardias. Replacement of one of the aryl groups by hydrogen or a pyridinyl or cyclohexyl group had little effect on efficacy but decreased the duration of action. Compound 18 (pirmenol) was ultimately chosen for further studies and is now being investigated in man.

Topics: Animals; Anti-Arrhythmia Agents; Benzyl Compounds; Coronary Vessels; Dogs; Heart Rate; Indicators and Reagents; Molecular Structure; Piperidines; Structure-Activity Relationship

The electrophysiological and antiarrhythmic effects of pirmenol HCl were examined using the microelectrode technique applied to multicellular preparations and the suction-pipette whole-cell clamp method applied to ventricular myocytes from rabbit and guinea pig hearts. Pirmenol at 5 microM and higher doses suppressed the sinus node automaticity by depressing the slow diastolic depolarization without changing the maximum diastolic potential. Pirmenol at 1 microM and higher doses depressed the maximum upstroke velocity (Vmax) of action potentials and prolonged the action potential duration at 90% repolarization in atrial muscles and Purkinje fibers without affecting resting membrane potentials. Pirmenol at 5 microM depressed the early part of the plateau and lengthened the final repolarization of the action potentials in ventricular myocytes, of which effects were attributed to the depression of the calcium current and the delayed outward K+ current. Triggered tachyarrhythmias arising from delayed afterdepolarizations in papillary muscles and ventricular myocytes were markedly inhibited by 1-5 microM pirmenol. The drug changed the amplitude and appearance of the transient inward current in ventricular myocytes. These results suggest that pirmenol has electrophysiologic properties that could provide an antiarrhythmic action on various types of arrhythmias.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrophysiology; Guinea Pigs; Heart; In Vitro Techniques; Ion Channels; Microelectrodes; Myocardium; Papillary Muscles; Piperidines; Potassium Chloride; Purkinje Fibers; Rabbits; Sinoatrial Node; Species Specificity

The target of this study was to characterize the effect of pirmenol hydrochloride on the electrophysiological properties of cardiac cells. Action potential studies were carried out using the standard microelectrode technique in isolated rabbit Purkinje fibres. Information about the effect of pirmenol on the fast sodium current was obtained by Vmax-measurement. Furthermore the delayed rectifying current ix was studied by the two microelectrode voltage clamp technique. In concentrations of 0.5-5 mumol/l pirmenol caused a marked prolongation of the action potential duration in isolated rabbit Purkinje fibres. Measurements of the delayed rectifying current ix displayed a strong depression with a KD-value of 1 mumol/l pirmenol. The steady-state current voltage relation showed that pirmenol also caused a reduction of the steady-state sodium window current and/or of the slowly decaying components of the sodium current. In concentrations of greater than or equal to 10 mumol/l pirmenol the action potential duration was diminished again and Vmax was depressed in a use-dependent manner. Furthermore pirmenol caused a depression and a negative shift of the Vmax/Em-relation. Pirmenol blocked sodium channels which recovered from block with a time constant of 6.7 s at a holding potential of -105 mV. Similar to quinidine and sotalol the prolongation of the action potential duration under pirmenol is essentially caused by a diminution of the delayed rectifying current ix. The depression of Vmax is mainly independent from the action potential duration indicating the dominance of an open channel block. Pirmenol is a new drug with class Ia antiarrhythmic action.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Computer Simulation; Dose-Response Relationship, Drug; Female; Male; Membrane Potentials; Models, Biological; Papillary Muscles; Piperidines; Potassium Channels; Purkinje Fibers; Rabbits; Sodium; Sodium Channels; Time Factors

To assess the cardiovascular profiles of pirmenol, a new antiarrhythmic drug, and to compare them with those of disopyramide, isolated canine sinoatrial node, papillary muscle and atrioventricular node preparations cross-circulated with a donor dog were used. Pirmenol injected intraarterially into the isolated preparations showed negative chronotropic and inotropic effects, which were comparable to those of disopyramide; and it also showed coronary vasodilator and negative dromotropic effects on atrio-His as well as His-ventricular conduction, which were significantly more potent than those of disopyramide. Similarly, pirmenol administered intravenously into the donor dog showed more potent negative dromotropic effects on the PQ interval and QRS width than disopyramide, while in the isolated preparations cross-circulated by the donor dog, pirmenol and disopyramide showed equipotent cardiodepressant effects. In the same preparation, pirmenol decreased coronary blood flow following a transient increase, while disopyramide only decreased coronary blood flow. Since the antiarrhythmic action of class I drugs is considered to result from inhibition of the fast inward current, which generates and propagates action potentials and also induces ventricular automaticity, our results suggest that pirmenol possesses an electrophysiologic effect typical to an efficacious class I agent such as disopyramide.

Topics: Action Potentials; Animals; Atrioventricular Node; Coronary Circulation; Cross Circulation; Disopyramide; Dogs; Female; Heart; Heart Rate; Hemodynamics; In Vitro Techniques; Male; Myocardial Contraction; Papillary Muscles; Piperidines; Sinoatrial Node

1. The use-dependent effects of pirmenol, a new antiarrhythmic drug, on the maximal rate of rise (Vmax) of the action potential, conduction velocity, and their corresponding recovery kinetics were studied in isolated papillary muscles of guinea-pig. Standard microelectrode techniques were used to monitor the conduction and action potential characteristics of the muscles. 2. Pirmenol decreased Vmax and the overshoot of action potentials in a dose-dependent fashion. Also, doses of pirmenol greater than 1 mM abolished the generation of action potentials. Low concentrations of pirmenol (3 and 10 microM) prolonged the action potential duration, while concentrations greater than 0.1 mM shortened it markedly. 3. The resting block of Vmax in the presence of 10 and 30 microM pirmenol was 9.48 +/- 3.12 and 20.36 +/- 3.61%, and that of conduction velocity 2.87 +/- 1.52 and 6.58 +/- 2.09%, respectively. 4. The degree of use-dependent block induced by 10 and 30 microM pirmenol during 0.2, 1, 2 and 3 Hz stimulations was dose- and rate-dependent. 5. In the presence of 30 microM pirmenol, mean values of time constants for the onset of the use-dependent inhibition of Vmax and conduction velocity during a 2 Hz stimulation were 1.32 +/- 0.15 and 1.28 +/- 0.09 s, respectively. The recovery time constants averaged 15.83 +/- 2.14 (for Vmax) and 27.80 +/- 8.74 (for conduction velocity) s in the presence of 30 microM pirmenol. 6. These results showed that the characteristics of the use-dependent inhibition of Vmax and conduction velocity induced by pirmenol are similar to those of slow kinetic drugs such as disopyramide rather than of fast ones.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Guinea Pigs; Heart Conduction System; Heart Ventricles; In Vitro Techniques; Kinetics; Membrane Potentials; Microelectrodes; Papillary Muscles; Piperidines

The electrophysiologic and electrocardiographic effects of intravenous pirmenol were compared with intravenous procainamide in 17 patients with symptomatic ventricular tachycardia. Pirmenol was found to prolong the PR interval, the QRS duration, the QTc interval, the HV interval, the atrial effective refractory period, and the ventricular effective refractory period. The sinus cycle length decreased following pirmenol administration. The sinus node recovery time, the PA interval, the AH interval, the Wenckebach cycle length, and the AV nodal ERP were unchanged. In patients whose ventricular tachycardias remained inducible on pirmenol, the cycle length was significantly prolonged compared to baseline. These changes were similar to those seen following the administration of procainamide. All 17 patients had sustained ventricular tachycardia inducible during programmed ventricular stimulation in the baseline state. In four patients the ventricular tachycardia was suppressed with both primenol and procainamide. In the remaining 13 patients ventricular tachycardia remained inducible on procainamide. Of these 13 patients, an additional two patients had their ventricular tachycardias rendered noninducible on pirmenol.. (1) the electrophysiologic and electrocardiographic effects of pirmenol are similar to those of procainamide; (2) although ventricular tachycardia inducibility following procainamide was similar to that of pirmenol, an occasional patient with ventricular tachycardia inducible on procainamide had ventricular tachycardias suppressed on pirmenol.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Electric Stimulation; Electrocardiography; Female; Heart Conduction System; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Piperidines; Procainamide; Recurrence; Tachycardia

Using two-stage coronary ligation-, digitalis- and adrenaline-induced canine ventricular arrhythmias, antiarrhythmic effects of pirmenol were examined, and the minimum effective plasma concentration for each arrhythmia model was determined. Pirmenol suppressed all the arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by 24 hr coronary ligation, 48 hr coronary ligation, digitalis and adrenaline were 1.1 +/- 0.3 (by 3 mg/kg, i.v.), 1.1 +/- 0.3 (by 3 mg/kg, i.v.), 1.1 +/- 0.2 (by 3 mg/kg, i.v.) and 2.5 +/- 1.5 (by 3 mg/kg, i.v.) microgram/ml, respectively (mean +/- S.D.M., n = 6-7). The concentration for adrenaline-induced arrhythmia was significantly higher than those for the other types of arrhythmias. This pharmacological profile is similar to those of mexiletine, tocainide and cibenzoline. Since pirmenol had no deleterious effects on the blood pressure and sinus node activity, its clinical usefulness is expected.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Digitalis; Dogs; Epinephrine; Female; Ligation; Male; Piperidines; Plants, Medicinal; Plants, Toxic

The electrophysiologic effects of pirmenol hydrochloride on rabbit sinoatrial node cells were examined and compared with those of several class I antiarrhythmic agents. At 1 microM, pirmenol decreased the heart rate and the rate of diastolic depolarization and increased the action potential duration at half-amplitude. Above 10 microM, the agent also decreased the maximum rate of rise (Vmax) and the action potential amplitude significantly. The order of the inhibitory potency on Vmax was apridine greater than 711389-S greater than pirmenol greater than mexiletine greater than tocainide. With respect to the current systems, pirmenol decreased the slow inward current (Isi) and the time-dependent potassium outward current (IK). The agent also prolonged the recovery time constant of Isi without any changes in the decay process of the tail current (IK). These findings suggest that pirmenol depresses the spontaneous discharge of the sinoatrial node through a decrease in Isi and Ik.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Electrophysiology; Female; Male; Membrane Potentials; Piperidines; Rabbits; Sinoatrial Node

The potential for drug-drug interaction between pirmenol, an extensively metabolized antiarrhythmic agent, and rifampin, a potent inducer of hepatic drug-metabolizing enzymes, was evaluated in 12 healthy adults. After administration of a single 150-mg oral dose of pirmenol on day 1, pirmenol plasma and urine concentrations were determined for 72 hours postdose. On days 4 through 17, subjects received 600 mg of rifampin once daily. On day 15, subjects were given a second single 150-mg oral dose of pirmenol concomitantly with rifampin, and plasma and urine concentrations were again determined. Coadministration of rifampin with pirmenol resulted in significant (P less than .005) changes in pirmenol pharmacokinetic parameters. A sixfold decrease in pirmenol AUC and sevenfold increase in the apparent plasma clearance of pirmenol were found. Elimination half-life decreased more than twofold. Based on these findings, pirmenol dosage adjustment will be required when pirmenol is given to patients concurrently receiving rifampin. These results suggest that the administration of pirmenol with other agents that induce hepatic enzymes may result in accelerated pirmenol clearance.

Topics: Adult; Anti-Arrhythmia Agents; Chromatography, High Pressure Liquid; Drug Interactions; Female; Humans; Male; Piperidines; Rifampin

The frequency-dependency and voltage-dependency of the suppressing effect of pirmenol, a novel antiarrhythmic agent, on the maximum upstroke velocity (Vmax) of action potentials were examined and compared with those of disopyramide in guinea pig papillary muscles. Pirmenol in concentrations higher than 3 microM decreased Vmax with a slight increase in action potential duration. The reduction of Vmax by pirmenol was enhanced in a frequency-dependent manner over the range of 0.1-2.0 Hz. Pirmenol (30 microM) produced a small resting block (5.5%), whereas disopyramide (100 microM) produced a greater one (25.8%). The onset of frequency-dependent Vmax reduction at 2.0 Hz followed a monoexponential function with a slow rate constant (0.308 +/- 0.055 AP-1). The time constant for the recovery from the frequency-dependent block by pirmenol was also slow (33.5 +/- 5.4 sec), but faster than that of disopyramide (82.5 +/- 12.3 sec). At 1.0 Hz, pirmenol caused a shift (9.5 mV) of the curve relating the resting membrane potential and Vmax along the voltage axis in the hyperpolarizing direction. Thus, pirmenol is a Class Ia drug that has frequency- and voltage-dependent inhibitory actions on Vmax, and its onset and offset kinetics are relatively slow.

Topics: Action Potentials; Animals; Disopyramide; Guinea Pigs; Heart; Heart Ventricles; In Vitro Techniques; Piperidines

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

Pirmenol hydrochloride (CI-845), a new orally effective antiarrhythmic agent, has undergone a comprehensive preclinical safety evaluation program. Repeated dose studies to evaluate chronic toxicity in rodents revealed few drug-related findings. A dose-related body weight gain suppression occurred in mice receiving up to 160 mg/kg for thirteen weeks. Rats also exhibited decreased body weight in a fifty-two-week study. Depressed fasting glucose levels were seen in rats at 50 mg/kg after thirteen weeks, but this effect was less prominent following fifty-two weeks of dosing. No other drug-related signs of toxicity were seen in rodents. Four-week repeated-dose intravenous studies in rats were uneventful. Occasional emesis and salivation, together with dryness of the oral mucosa, occurred in dogs given 10 mg/kg intravenously for four weeks. Drug-related increased heart rates, increased QRS duration, and reduced ST interval were seen thirty minutes postdose in dogs receiving 5 mg/kg or more intravenously. When dogs received pirmenol orally for fifty-two weeks, electrocardiographic and heart rate changes were variable and less pronounced than seen in the intravenous study. Clinical signs consisted of exaggerated pharmacologic responses similar to those found after intravenous dosing. Reproduction studies in rats and rabbits showed that pirmenol is not teratogenic. Reduced food intake and a 50% decrease in body weight gain were seen in rats at the top dose level of 150 mg/kg. Significantly reduced mean fetal weight and increased postimplantation loss indicated that 150 mg/kg was embryotoxic to rats. A top dose of 50 mg/kg in rabbits did not produce any signs of maternal or fetotoxicity, aside from a moderate suppression of maternal weight gain.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Animals; Anti-Arrhythmia Agents; Body Weight; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Heart; Injections, Intravenous; Mice; Piperidines; Rabbits; Rats; Reproduction; Time Factors

The hemodynamic effects of intravenous pirmenol were studied in 21 subjects instrumented with peripheral arterial, pulmonary artery, and left ventricular catheters. Baseline measurements of heart rate, cardiac output, pulmonary artery pressure, systemic arterial pressure, left ventricular end-diastolic pressure, left ventricular stroke work, and ejection fraction were obtained. An infusion of pirmenol hydrochloride was administered and hemodynamic measurements were repeated an average of 16.1 minutes following the start of the infusion after a new stable hemodynamic state was achieved. Significant increases in heart rate and systemic arterial pressure were noted. There were no significant changes in cardiac output, pulmonary arterial pressure, or left ventricular end-diastolic pressure. Significant reductions in left ventricular stroke work and ejection fraction were demonstrated. The amount of decrease in the ejection fraction was not related to the plasma pirmenol level achieved or to the baseline level of ventricular function. These findings suggest a negative inotropic effect of acute infusions of pirmenol and suggest caution should be used in its administration to patients with compromised left ventricular performance.

Topics: Adult; Angina Pectoris; Anti-Arrhythmia Agents; Coronary Disease; Depression, Chemical; Drug Evaluation; Female; Heart Ventricles; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Piperidines; Stroke Volume; Time Factors

In a single-blind study the multiple oral dose kinetics of pirmenol were related to its efficacy in eight patients with frequent (mean, 631; range, 167-1374 beats/hour) premature ventricular contractions (PVC). Oral pirmenol was started at 100 mg bid for 48 hours and increased to 150 mg bid in six patients to obtain more than 70% suppression of PVC counts. Efficacy was achieved without side effects. Pirmenol decreased heart rate but not PR interval, QRS duration, or QTc interval. Peak plasma levels after the first 100-mg dose occurred at 1 to 3 hours and ranged from 0.6 to 1.9 micrograms/mL. Plasma elimination half-life ranged from 9.7 to 31 hours (mean, 18.3). From 67.4 to 171.3 mg pirmenol (mean, 102.3 mg) were recovered in the urine in 48 hours after the last dose. Cumulative excretion in divided urine collections was consistent with a mean elimination half-life of 15 to 20 hours. The pharmacokinetics of pirmenol support oral twice-daily administration. The minimum PVC suppressing plasma level is between 0.5 and 1.5 micrograms/mL.

Topics: Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Half-Life; Humans; Male; Middle Aged; Piperidines

Metabolic disposition and pharmacokinetics of pirmenol were studied in laboratory animals and in patients with premature ventricular beats. After intravenous administration, pirmenol pharmacokinetics were adequately characterized by a 2-compartment body model with elimination half-lives of 3 to 4 hours in animals and 6 to 9 hours in patients. Oral absorption of pirmenol was complete and devoid of significant first-pass metabolism. Systemic oral bioavailability averaged 87% in humans. Pirmenol was 83% to 90% bound to human plasma proteins. Animal studies showed that pirmenol was widely distributed in tissues resulting in higher drug concentrations in tissue than in plasma. Pirmenol was partly eliminated as unchanged drug and partly metabolized. Tracer studies in animals showed that approximately 40% to 50% of the administered radioactive dose was excreted in the urine and the remainder in the feces. The latter route was due to excretion of radioactivity in the bile. Evidence of enterohepatic recycling was established in bile duct-cannulated monkeys. Approximately 23% to 31% of the administered pirmenol dose was recovered unchanged in human urine.

Topics: Administration, Oral; Animals; Anti-Arrhythmia Agents; Cardiac Complexes, Premature; Dogs; Half-Life; Humans; Infusions, Intravenous; Kinetics; Macaca mulatta; Male; Metabolic Clearance Rate; Piperidines; Tissue Distribution

We assessed the electrophysiologic effects and antiarrhythmic efficacy of intravenous pirmenol in 15 patients who had spontaneous and induced sustained ventricular tachyarrhythmias. At a plasma concentration of 2.29 +/- 0.75 micrograms/ml, pirmenol decreased sinus cycle length by 11 +/- 13%, increased QRS, QTc, and HV intervals by 14 +/- 12%, 13 +/- 12%, and 22 +/- 28%, respectively, and increased atrial and ventricular effective refractory periods (ERP) by 20 +/- 14% and 7 +/- 8%, respectively. There was a greater increase in QRS duration during ventricular tachycardia and ventricular pacing than during sinus rhythm (p less than 0.005). By electropharmacologic testing, pirmenol was judged effective in six patients (40%) and was proarrhythmic in one (6%). In the nine patients in whom pirmenol was judged ineffective, the cycle length of induced VT increased by 36 +/- 15% and the associated mean arterial pressure increased by 21 +/- 14 mm Hg. The only side effects were mild hypotension and mild nausea in one patient each. Intravenous pirmenol has type IA electrophysiologic effects. It can be administered safely to patients with sustained ventricular tachyarrhythmias and is as effective as approved antiarrhythmic drugs when assessed by electropharmacologic testing.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Atrioventricular Node; Electrophysiology; Female; Heart Conduction System; Heart Ventricles; Humans; Infusions, Intravenous; Male; Middle Aged; Piperidines; Refractory Period, Electrophysiological; Sinoatrial Node; Tachycardia

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

Pirmenol hydrochloride, a novel pyridinemethanol derivative, is a long-acting class Ia antiarrhythmic agent. Preclinical toxicology data were obtained in rat, mouse, dog and rabbit. In acute toxicity studies by oral and intravenous routes, no pathologic changes were observed in surviving mice, rats and dogs. In repeated dose toxicity studies, no drug-related pathologic changes were evident; dryness of the oral mucosa in dogs and body weight gain reductions in rodents were the only significant clinical signs. In a chronic (52 week) toxicity study in rats, pirmenol given in the diet was tolerated clinically at doses up to 100 mg/kg/day. No drug-related aberrations in clinical laboratory parameters or ophthalmic or pathologic findings were evident. In a similar study in beagle dogs, pirmenol was tolerated clinically at a dosage up to 30 mg/kg/day. No significant changes in biochemical, hematologic, urinary or bone marrow determinations were found in either species. In reproductive toxicology studies in rats, pirmenol had no significant effect on litter size or embryonic viability. In rabbits pirmenol had no effect on average litter size, embryonic viability or fetal wastage. Given to male rats, pirmenol had no overt effects on fertility. Pirmenol failed to elicit deoxyribonucleic acid damage or induce cytogenetic alterations. Pirmenol appears to be without significant limiting toxicologic properties.

Topics: Administration, Oral; Animals; Anti-Arrhythmia Agents; Dogs; Female; Fetus; Injections, Intravenous; Male; Mice; Mice, Inbred Strains; Piperidines; Pregnancy; Pregnancy, Animal; Rabbits; Rats; Rats, Inbred Strains; Reproduction; Species Specificity; Xerostomia

Pirmenol, a novel pyridinemethanol derivative, is active in a variety of experimental arrhythmic models of diverse etiology and has a favorable therapeutic index compared with other class I agents. Animal pharmacology studies showed that pirmenol is highly efficacious whether the arrhythmias were atrial or ventricular in origin, chemically, mechanically or electrically induced or of the automaticity or reentrant types. The conscious coronary artery-ligated (Harris) dog model best allowed simulation of a variety of clinical situations in which pirmenol could be used either alone or in combination. Pirmenol was highly effective by both the intravenous and oral routes, causing immediate suppression, prevention or termination of cardiac arrhythmias. Preclinical studies in the dog showed an excellent correlation between the dose of pirmenol, plasma levels and antiarrhythmic efficacy. Administration of pirmenol in the dog at intentionally accelerated infusion rates suggested a relatively wide margin of safety for pirmenol compared with other class I agents. Analysis of the pharmacokinetic data led to the modeling of a rapid infusion-slow infusion bolus for sustained intravenous administration, thereby optimizing therapeutic utility. In vitro electrophysiologic studies in dog Purkinje fibers revealed possibly unique differences of pirmenol from other antiarrhythmic agents. It depresses fast and slow response automaticity and its electrophysiologic effects were less variable than other class I drugs over a spectrum of potassium levels. To test the relevance of the in vitro electrophysiologic results, pirmenol's antiarrhythmic efficacy was assessed in several in vivo dog models in which serum potassium was either increased or decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Dogs; Guinea Pigs; Infusions, Intravenous; Piperidines; Potassium; Purkinje Fibers; Stroke Volume

Twenty patients with ventricular tachycardia refractory to drug treatment underwent electrophysiologic study with pirmenol. Patients ranged in age from 39 to 84 years (mean 61); the presenting arrhythmia was sustained ventricular tachycardia in 15, nonsustained ventricular tachycardia in 3 and ventricular fibrillation in 2. After discontinuation of all antiarrhythmic drugs (for at least 5 half-lives) and assessment of electrocardiographic and electrophysiologic parameters in the drug-free state, patients underwent comprehensive intracardiac electrophysiologic evaluation with intravenous pirmenol (mean dose 195 +/- 46 mg). Programmed ventricular stimulation began at least 30 minutes after pirmenol infusion was started in each patient. There was significant shortening of sinus cycle length in all patients, from 746 +/- 155 to 683 +/- 107 ms (mean +/- standard deviation). In 7 patients in whom ventricular tachycardia could not be induced after intravenous pirmenol, an oral pirmenol regimen was begun. The dosage was 200 or 250 mg (both 3 times/day) in 2 and 5 patients, respectively. Seven hours after the third dose of oral drug was given, these patients underwent repeat electrophysiologic testing. Intravenous and oral pirmenol significantly prolonged the PR, QT, QTc and JT intervals compared with baseline. Intravenous pirmenol also significantly prolonged the QRS interval compared with baseline. Oral pirmenol significantly prolonged the sinus node recovery time compared with intravenous pirmenol. Intravenous pirmenol significantly increased the HV interval compared with control; oral pirmenol did not demonstrate a significant prolongation of the HV interval, but this is due to the smaller number of patients studied while taking oral drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Electrocardiography; Electrophysiology; Female; Heart Ventricles; Humans; Injections, Intravenous; Male; Middle Aged; Piperidines; Tachycardia; Vasoconstriction

The effects of pirmenol in terminating paroxysmal supraventricular tachycardia were studied in 25 patients. Pirmenol was administered as 1 or 2 injections of 50 mg to 17 patients during a spontaneous attack, or as a 50-mg bolus followed by steady infusion of 2.5 mg/min in 8 patients during a tachycardia that was induced electrophysiologically. Termination was successful in 11 of 17 patients who had a spontaneous attack and in 3 of 8 patients who had induced tachycardia. Pirmenol was effective in 3 of 5 patients with atrioventricular nodal reentrant mechanism, but in none of 3 patients with a reentrant tachycardia with a retrogradely conducting atrioventricular bypass tract. Conversion to sinus rhythm was achieved in 14 of 25 patients (56%). No hemodynamic adverse effects occurred. Pirmenol increased the atrial effective refractory period, but had little effect on conduction in the atrioventricular node and His-Purkinje system. Reentry was abolished through a block in the retrograde part of the dual atrioventricular nodal pathway, which is typical of class I antiarrhythmic agents.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Heart Conduction System; Humans; Middle Aged; Piperidines; Tachycardia, Supraventricular

The effects of pirmenol in the treatment of ventricular arrhythmias were studied in 6 patients with heart disease and in 11 control subjects. In the patients with heart disease, ventricular arrhythmias were associated with myocardial infarction in 3, with mild aortic stenosis in 2 and with hypertrophic cardiomyopathy in 1. Pirmenol was administered in a 100 mg, 150 mg or 200 mg twice daily dosing schedule. Dosages were increased if necessary, until response, defined as greater than 70% suppression in the rate of premature ventricular contractions, occurred. Arrhythmia suppression was maintained in all 6 patients with heart disease at 52 weeks of follow-up.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Double-Blind Method; Female; Heart Diseases; Heart Ventricles; Humans; Male; Middle Aged; Piperidines

The acute antiarrhythmic properties of pirmenol were studied in 12 patients who failed clinical oral drug therapy with a history of a cardiac arrest or sustained ventricular tachycardia (VT). Programmed electrical stimulation studies were performed in ten men and two women with a mean age of 63 +/- 2 years. All patients had inducible ventricular tachycardia by programmed electrical stimulation when they were off all antiarrhythmic therapy. Patients were then tested on procainamide, 1000 mg, administered intravenously, and ventricular tachycardia could be provoked in nine of twelve patients. Pirmenol was given intravenously, 1.1 mg/kg bolus followed by 40 micrograms/kg/min over 40 minutes prior to drug testing. Pirmenol did not significantly change the baseline heart rate, blood pressure, or measured electrocardiographic values from control values. Ten of 12 patients were still inducible to ventricular tachycardia on pirmenol. Procainamide protected one of nine patients against VT induction. In patients still inducible on drug therapy, the VT rate was significantly slowed from 221 beats/min to 166 beats/min on pirmenol and to 200 beats/min on procainamide. The effects of this new antiarrhythmic agent were similar to procainamide in this drug-resistant study population.

Topics: Anti-Arrhythmia Agents; Drug Resistance; Electrocardiography; Electrophysiology; Female; Heart Conduction System; Humans; Male; Middle Aged; Piperidines; Procainamide; Refractory Period, Electrophysiological; Tachycardia

The efficacy, pharmacokinetics, and pharmacodynamics of pirmenol, a class Ia antiarrhythmic agent, were studied in patients with frequent symptomatic premature ventricular complexes (PVCs). Pirmenol was given every 12 hours to eight patients in a dose-ranging protocol, and median PVC suppression of 94% (range 72% to 100%) was achieved. The median effective pirmenol dose was 300 mg/day (range 200 to 500 mg/day), and mean (+/- SD) trough plasma pirmenol concentration at the effective dose was 0.98 +/- 0.29 micrograms/ml. The mean half-life of elimination was 10.5 +/- 2 hours. There was considerable overlap among patients with respect to plasma pirmenol concentration and times at which PVC frequency returned to 25%, 50%, and 75% of baseline during drug washout trials. Altering pirmenol's dose interval (while maintaining a constant daily dose) from 12 to 6 hours did not improve drug efficacy. Pirmenol was given to seven patients for long-term therapy (24 to 44 months). Median PVC suppression at 24 months was 70%. Pirmenol is safe and well tolerated, and it can be administered twice daily for PVC suppression.

Topics: Administration, Oral; Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Monitoring, Physiologic; Piperidines; Time Factors

Salivary concentrations of the anti-arrhythmic, pirmenol, were compared with plasma concentrations in six patients. Group mean salivary values tended to be higher despite high plasma protein binding, suggesting the possibility of an active transport process. The observed salivary concentrations are reasonably close to those detectable in healthy volunteers as tasting unpleasant.

Topics: Adult; Aged; Biological Transport; Cardiac Complexes, Premature; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Random Allocation; Saliva; Taste

The efficacy and electrophysiologic effects of pirmenol were evaluated in 21 patients with a history of sustained ventricular tachycardia (VT) and coronary artery disease. Intravenous pirmenol (0.7- to 1.1-mg/kg bolus, followed by a 35- to 40-micrograms/kg/min infusion) significantly prolonged the PR, QRS, QT and corrected QT intervals, HV interval and right ventricular effective refractory period, and shortened the sinus cycle length and atrioventricular nodal block cycle length. All 21 patients had inducible VT (20 sustained, 1 nonsustained) during programmed stimulation in the control state. After intravenous pirmenol, 5 patients (24%) no longer had inducible VT. In those in whom VT was still inducible, the VT cycle length was prolonged significantly. The 5 patients who responded to intravenous pirmenol were given oral pirmenol (200 to 250 mg every 8 hours) for 1 to 3 days and retested with programmed stimulation. In 4 of these 5, VT could not be induced with oral pirmenol administration; in 1 patient sustained VT was induced and pirmenol therapy was discontinued. Oral pirmenol suppressed recurrent VT during a follow-up of 315 +/- 133 days in 4 patients. However, pirmenol therapy was discontinued in 2 patients because of possible deleterious effects (worsened heart failure in 1 patient and elevated liver function test results in 1). Thus, pirmenol, a type IA antiarrhythmic drug, had an overall efficacy of approximately 19% in patients with sustained VT secondary to coronary artery disease.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Coronary Disease; Heart Conduction System; Humans; Male; Middle Aged; Piperidines; Tachycardia

An assessment was made of the effect of pirmenol in the termination of paroxysmal supraventricular tachycardia (SVT). Sinus rhythm was restored by intravenous administration in 11 of 17 patients during a spontaneous attack. Another 8 patients were studied electrophysiologically. Pirmenol terminated an induced SVT in 3 of 5 patients having an atrioventricular (AV) intranodal re-entry mechanism but in none of 3 patients having an atrioventricular bypass tract as one re-entrant limb. The overall success in restoring sinus rhythm was 14 of 25 patients (56%). The drug was hemodynamically well tolerated even in cases of continued SVT. Pirmenol increased the atrial effective refractory period and had no obvious effect on AH and HV intervals. The functional refractory period of the AV node was decreased, probably by an anticholinergic effect. The effective and functional refractory periods of retrograde atrioventricular conduction via the AV node and bypass tract were increased in some patients. The mechanism terminating the AV intranodal SVT was a block in the retrograde part of the dual AV nodal pathway, a typical antiarrhythmic Class I effect.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Atrioventricular Node; Blood Pressure; Drug Evaluation; Electrocardiography; Humans; Middle Aged; Piperidines; Refractory Period, Electrophysiological; Tachycardia, Paroxysmal

Fertility and perinatal-postnatal studies were performed in CD rats given pirmenol, an antiarrhythmic agent, at dosages of 0, 25, 50, and 100 mg/kg. The drug was administered orally as diet admixtures in all studies. In the male fertility study, mature male rats were treated for 61 days prior to mating with virgin, untreated female rats. In the female fertility study, mature virgin female rats were treated for 15 days prior to mating with untreated partners with treatment continuing throughout mating, pregnancy, parturition, and weaning of the litters. In both studies, one-half of the dams in each group were killed on Day 21 of pregnancy and the remaining dams were allowed to deliver and wean their offspring and postnatal development was monitored. At weaning, two males and two females were arbitrarily selected from each litter, allowed to mature on unmedicated diet, and then mated within treatment groups to produce the F2 generation. In the perinatal-postnatal study, pregnant females were treated continuously from Day 15 of pregnancy until weaning of the litters on Day 21 postbirth. No adverse effects on fertility, general reproductive parameters, or offspring survival and development were evident at doses employed in these studies.

Topics: Animals; Anti-Arrhythmia Agents; Embryonic and Fetal Development; Female; Fertility; Male; Piperidines; Pregnancy; Rats; Reproduction

The electrophysiologic actions of pirmenol, an investigational class I antiarrhythmic agent, were evaluated in eight anesthetized dogs, 5 to 10 days after anterior myocardial infarction. Before administration of the drug, programmed ventricular stimulation failed to initiate nonsustained or sustained ventricular tachyarrhythmias (VT) in any of the postinfarction dogs. After the cumulative administration of 2.5, 5.0, and 10.0 mg/kg pirmenol, programmed stimulation initiated sustained VT in six of the eight postinfarction dogs tested, with one additional dog responding with reproducible nonsustained VT (15 to 20 monomorphic complexes) after pirmenol administration. Only one of eight postinfarction dogs tested remained noninducible throughout the pirmenol dosing schedule. Administration of pirmenol tended to increase ventricular excitation thresholds, relative (p less than 0.05 after 10 mg/kg) and effective refractory periods in ischemically injured ventricular myocardium, and increased the difference or disparity in relative (p less than 0.05 after 5.0 and 10.0 mg/kg) and effective (p less than 0.01 after 2.5, 5, and 10, mg/kg) refractory periods between ischemically injured and normal noninjured ventricular myocardium. These findings suggest a potential for the provocation or aggravation of ventricular arrhythmias by pirmenol in the setting of recent myocardial infarction.

Topics: Animals; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Dogs; Electrophysiology; Heart; Heart Conduction System; Male; Myocardial Infarction; Piperidines; Tachycardia

Pirmenol, a new class IA antiarrhythmic agent, has shown promise in short-term trials, but long-term efficacy has not been documented. We thus evaluated 11 patients with frequent (greater than or equal to 60/h) premature ventricular complexes (PVC) given oral pirmenol for 25-727 days. Ten of 11 patients entering the long-term open trial had shown greater than or equal to 70% (mean 83%) PVC suppression during in-hospital pirmenol dose ranging. Long-term pirmenol was given in divided doses of 100-600 mg/day. Mean PVC frequency during baseline was 13,078/24 h (range, 3,218-32,718); couplets averaged 481/24 h (1-2,829) and runs 45/24 h (0-334). Ambulatory monitoring was performed at 1, 3, 6, and 12 months, then semiannually. Mean absolute PVC suppression at 1 month averaged 75% (p less than or equal to 0.02). Median individual percentage PVC suppression was 94%. During the first 3 months, 8 patients (73%) continued to show a favorable response (greater than or equal to 70% suppression), and 3 had arrhythmia recurrence and were dropped. One responder was withdrawn after the onset of paroxysmal atrial fibrillation, and another early responder was withdrawn after 3 months because of arrhythmia relapse. Six patients have been treated for over 1 year, with 99% mean PVC suppression. Mean couplet and run frequencies at 1 month decreased by means of 76% (p less than or equal to 0.05) and 92% (p = 0.001) respectively. At 1 year, couplets were suppressed 99.8% and runs by 99.7% in the 6 patients remaining on pirmenol.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Heart Ventricles; Hemodynamics; Humans; Male; Middle Aged; Outpatients; Piperidines; Time Factors

The cardiovascular effects of a new antiarrhythmic Class I agent, pirmenol, were assessed noninvasively in 10 patients without heart failure. Infusion of 100 mg pirmenol was given over 30 min following baseline M-mode echocardiography, cuff blood pressure and systolic time interval measurements. The measurements were repeated after the infusion, and 15 and 60 min later. Heart rate increased by 14.7% (P less than 0.01). Significant increases were also noted in afterload parameters, mean arterial pressure (+10.1%; P less than 0.001) and mid-systolic left ventricular wall stress (+8.0%; P less than 0.05). Concomitantly a slight increase was observed in preload, reflected in lengthening of left ventricular end-diastolic diameter (+4.8%; P less than 0.05). A decrease in fractional shortening (-6.5%; P less than 0.05) and an increase in pre-ejection period/left ventricular ejection time ratio (+16.2%; P less than 0.01) suggested a negative inotropic effect. The increased afterload and heart rate may have contributed to changes in these indices, and therefore myocardial depression may appear more pronounced than it actually was. The main effects of intravenous administration of pirmenol are elevations in heart rate and blood pressure. The induced decrease in myocardial contractility is slight.

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

The acute electrophysiologic effects of pirmenol are reported in 8 normal subjects and in 8 patients with Wolff-Parkinson-White (WPW) syndrome. Standard electrophysiologic testing was performed before and after a 50-mg intravenous bolus and a 60-minute infusion of 150 mg of pirmenol. After pirmenol administration, AH interval, atrial refractory period, atrioventricular (AV) nodal functional refractory period and Wenckebach cycle length did not change; however, sinus cycle length decreased from 743 +/- 169 to 650 +/- 133 ms (p less than 0.001), sinoatrial conduction time from 103 +/- 35 to 78 +/- 37 ms (p less than 0.05) and AV nodal effective refractory period from 308 +/- 51 to 272 +/- 23 ms (p less than 0.01). Pirmenol increased the HV interval from 43 +/- 5 to 48 +/- 6 ms (p less than 0.05) and ventricular functional refractory period from 247 +/- 21 to 260 +/- 21 ms (p less than 0.005). Anterograde effective refractory period of the accessory AV pathway increased in 4 of 6 patients with ventricular preexcitation and retrograde effective refractory period increased in all patients. Pirmenol treatment prolonged the shortest preexcited RR interval from 253 +/- 38 to 459 +/- 19 ms (p less than 0.05) and the average RR interval from 354 +/- 26 to 421 +/- 60 ms (p less than 0.01) during atrial fibrillation in all 6 patients with preexcitation. Pirmenol did not influence the inducibility or cycle length of AV reciprocating tachycardia in the patients with WPW syndrome. The pirmenol infusions were well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anti-Arrhythmia Agents; Atrioventricular Node; Female; Humans; Male; Middle Aged; Piperidines; Reference Values; Sinoatrial Node; Tachycardia; Wolff-Parkinson-White Syndrome

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

The antiarrhythmic efficacy and safety of oral pirmenol hydrochloride were assessed during a controlled, dose-ranging and short-term maintenance study in 12 patients with frequent (greater than 480/8 hours) premature ventricular complexes (PVCs). Eleven patients (92%) responded favorably (greater than 70% PVC suppression) to a trial of different doses. Mean interval (8-hour) suppression of PVC frequency was 95% in these 11 and 86% in the entire group. Twenty-four-hour suppression was similar in responders (88%). Repetitive PVCs were essentially eliminated. The mean effective dose was 316 mg/day (105 mg/8 hours). The average predose (trough) plasma concentration at the end of dose ranging was 1.4 micrograms/ml and the drug elimination half-life 7.3 hours (n = 12). Of 11 responding patients, 10 completed a 2-week outpatient trial. Pirmenol continued to be effective and tolerated in 8 patients, maintaining an overall average outpatient PVC suppression of 80%. The electrocardiographic intervals were mildly prolonged after multiple dosing (PR + 7%, QRS + 12%, QTc + 8%; all p less than 0.01). Blood pressure and heart rate did not change during treatment. The echocardiographic ejection fraction was maintained. Thus, oral pirmenol appears to be effective, conveniently administered and well tolerated as an antiarrhythmic agent for control of ventricular extrasystoles.

Topics: Administration, Oral; Adult; Aged; Ambulatory Care; Anti-Arrhythmia Agents; Cardiac Complexes, Premature; Double-Blind Method; Echocardiography; Electrocardiography; Female; Half-Life; Humans; Male; Middle Aged; Piperidines; Stroke Volume; Time Factors

A sensitive, specific, and rapid high-performance liquid chromatographic procedure was developed for the determination of pirmenol in human biological fluids. Plasma or urine samples were alkalinized and extracted with cyclohexane. The organic extract was evaporated to dryness, reconstituted with the mobile phase, and then chromatographed on a microparticulate spherical trimethylsilane stationary phase with UV detection at 254 nm. The procedure for the assay of pirmenol in plasma was linear from 0.125 to 5.0 micrograms/mL. The reproducibility of the peak area ratios of the standard curves had relative standard deviations between 7.7 and 1.8% and a relative error of 0-4.6% over the linear range. The accuracy for the determination of pirmenol in human plasma containing 0.5, 2.5, and 4.0 micrograms/mL had relative errors of 9.0, 3.8, and 3.6%, respectively. Thirty compounds were tested and found not to interfere in the assay of the drug in plasma, and the method was found to be suitable for clinical samples. The urine procedure was linear between 1.0 and 30.0 micrograms/mL. The reproducibility of the peak areas of the standard curves had relative standard deviations that ranged from 1.9 to 6.2% over the linear range. The accuracy for the determination of pirmenol in human urine containing 5.0, 17.5, and 25.0 micrograms/mL had relative errors of 1.4, 0.5, and 2.8%, respectively.

Topics: Anti-Arrhythmia Agents; Chromatography, High Pressure Liquid; Humans; Kinetics; Piperidines; Time Factors

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Heart Rate; Humans; Kinetics; Piperidines

Pirmenol (CI-845), a new antiarrhythmic drug, was studied for the first time in humans to establish a minimum effective i.v. dose in 10 patients with chronic, stable premature ventricular complexes (PVCs) and to evaluate toxicity and pharmacokinetics. Infusions of 70-150 mg were associated with a 90% or greater reduction in PVCs nine of the 12 times they were administered to six patients. Peak plasma concentrations were 1.0-3.8 micrograms/ml at the end of these infusions. At the same time, small but significant increases in diastolic blood pressure (4 mm Hg) and QTc interval (0.01 second) were seen, but both values were within the normal range. Pirmenol was associated with no change in heart rate, systolic blood pressure, PR interval or QRS duration, renal, hepatic or hematologic function, or symptoms. Blood, plasma and free drug concentrations declined biexponentially after cessation of a 150-mg infusion (n = 4), with a terminal half-life of 7-9.4 hours. The therapeutic response, lack of toxicity, and relatively long half-life indicate that pirmenol is a promising antiarrhythmic agent.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Female; Half-Life; Heart; Humans; Kinetics; Male; Middle Aged; Piperidines

We examined the hemodynamic effects of pirmenol, a new antiarrhythmic drug, for the first time in man. Right and left heart pressures, Fick cardiac output, and radionuclide ejection fraction were measured before and during infusion of pirmenol in 10 patients with coronary artery disease who were undergoing routine diagnostic cardiac catheterization. Pirmenol was given as a 50-mg IV injection over 2 min followed by a constant infusion of 2.5 mg/min for up to 36 min. Plasma pirmenol levels were within or near the previously determined therapeutic range in all patients. There were no significant changes in systolic blood pressure or cardiac output. Diastolic blood pressure rose from a mean (+/- SD) 78 +/- 7 during the control period to 82 +/- 6 during the infusion, heart rate rose from 66 +/- 6 during the control period to 75 +/- 7 during infusion and ejection fraction fell from 60 +/- 8 during control to 55 +/- 12 during infusion. Although the left ventricular end-diastolic pressure rose from 6 +/- 2 during control to 8 +/- 3 during the infusion, the left ventricular stroke work index fell and the left ventricular work index per minute did not change. The fall in ejection fraction did not correlate with the control ejection fraction, plasma pirmenol levels, or the change in heart rate. The decline in ejection fraction and the failure of the left ventricular work index per minute to rise despite a small rise in left ventricular end-diastolic pressure may indicate a potential myocardial depressant effect of pirmenol.

Topics: Anti-Arrhythmia Agents; Drug Evaluation; Hemodynamics; Humans; Injections, Intravenous; Male; Middle Aged; Piperidines

The coronary artery-ligated rat was investigated as an experimental model for studying the effects of pirmenol hydrochloride and reference for studying the effects of pirmenol hydrochloride and reference agents on early ventricular arrhythmias. Coronary artery ligation caused 89% lethality (ventricular fibrillation) within 10 min in untreated control rats. Vagal stimulation applied during periods of high-rate ventricular tachycardia reduced sinus, atrioventricular nodal and ventricular ectopic beats, with no uncoupled ectopic beats seen during stimulation. Rats studied with composite epicardial electrodes showed continuous electrical activity throughout diastole. These factors indicate that a reentry mechanism is likely involved. Pretreatment with pirmenol afforded protection in a dose-related fashion. A dose of 1.25 mg/kg increased survival to 58%, and all rats dosed with 2.5 to 10 mg/kg survived. Suppression of ventricular fibrillation was dose related and was complete at 5 mg/kg. The pirmenol plasma levels of 1.2 +/- 0.1 microgram/ml seen after the 5 mg/kg dose are similar to plasma levels seen at clinically effective doses, as well as at doses effective in other experimental arrhythmias. The reference agent quinidine was also highly effective in this model, all rats pretreated with 5 mg/kg survived with reduced premature ventricular beats and without a single episode of ventricular fibrillation or death. Fibrillation and/or death were also reduced by the reference agents, bretylium, lidocaine, propranolol and verapamil. The high efficacy of pirmenol against early ventricular arrhythmias in this study further defines its spectrum of activity, and suggests that pirmenol may be effective in a clinical setting where a reentrant mechanism is operative.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Electric Stimulation; Heart Conduction System; Heart Ventricles; Male; Piperidines; Rats; Rats, Inbred Strains; Vagus Nerve

The oral form of pirmenol has not been administered to man. Pirmenol was given by mouth to eight patients with chronic, stable premature ventricular beats (PVBs) to determine effective dose and kinetics. The patients were evaluated with a dose-ranging protocol following by a double-blind, crossover, placebo-controlled study of doses that were effective during dose ranging. Oral doses of 150 to 250 mg induced at least 90% suppression of PVBs 18 of the 19 times they were administered during both protocols. During the double blind experiment, a single oral dose of pirmenol suppressed 95 +/- 8% PVBs/hr (mean +/- SD) for 3 consecutive hr, while placebo suppressed 4 +/- 42% PVBs/hr (P less than 0.01). a 90% or greater reduction in PVBs persisted for a median of 6 hr (range 1 to 8 hr). The range of plasma pirmenol concentrations associated with an at last 90% reduction in PVBs was 0.7 to 2.0 micrograms/ml. Median half-life (t1/2) was 9.3 hr (range 6.0 to 12.4) with 86.6 +/- 2.4% protein binding and 82.6 +/- 23.6% bioavailability. At peak drug level there was lengthening of the QTc interval (0.036 sec, P less than 0.05), but no change in heart rate, blood pressure, PR interval or QRS duration, or symptoms. In this single-dose study, pirmenol effectively reduced PVBs, has a relatively long t1/2, and was minimally toxic.

Topics: Administration, Oral; Blood Pressure; Cardiovascular Diseases; Dose-Response Relationship, Drug; Double-Blind Method; Heart Rate; Humans; Kinetics; Male; Middle Aged; Piperidines; Time Factors

Stimulation of complex dosage regimens for drugs with multicompartmental kinetics is described using the method of separate exponentials. This approach requires that alpha- and beta-phases are treated separately throughout and summed only at the end of the stimulation. The method was used to devise a loading regimen for pirmenol, comprising a priming injection, and a rapid loading infusion, followed by a maintenance infusion. The regimen was tested in a patient with excellent agreement. The method of separate exponentials is mathematically simple and of informational value in that it demonstrates when the early distribution phase is important. Its use can avoid the potentially dangerous assumption of one-compartmental kinetics in the design of intravenous loading regimens.

Topics: Anti-Arrhythmia Agents; Humans; Infusions, Parenteral; Injections, Intravenous; Kinetics; Mathematics; Models, Biological; Pharmaceutical Preparations; Piperidines

We studied the effects of pirmenol hydrochloride (CI 845), cis-(+/-)-alpha-[3-(2,6-dimethyl-1-piperidinyl)propyl]-alpha-phenyl-2-pyridinemethanol monohydrochloride, on the electrophysiologic properties of canine cardiac Purkinje fibers having normal (fast response) action potentials. CI 845 greater than or equal to 1 X 10(-6) M depressed both maximum upstroke velocity of phase 0 and automaticity. CI 845 greater than or equal to 1 X 10(-5) M significantly decreased action potential amplitude and duration measured at 50% repolarization and prolonged action potential duration measured at full repolarization. In addition, this concentration depressed membrane responsiveness and prolonged the effective refractory period and conduction time. All changes were reversible following superfusion with drug-free Tyrode solution. Increasing extracellular potassium ([K+]0) from 4 mM to 6 mM did not potentiate the CI 845-induced changes. CI 845 1 X 10(-5) M decreased automaticity of slow response action potentials studied in a Na+-free solution but had no effect on the action potential characteristics of these spontaneously discharging fibers. In blood superfusion studies, plasma levels of 0.1--3.0 micrograms/ml CI 845 affected the action potential characteristics in a manner similar to concentrations ranging from 1 X 10(-6) to 1 X 10(-5) M CI 845 in Tyrode solution. At plasma levels greater than or equal to 1.1 micrograms/ml, CI 845 induced a significant prolongation of the electrocardiographic PR interval. These studies indicate that CI 845 has effects on the action potential and ECG similar but not identical to those of 'local anesthetic' antiarrhythmic agents.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Blood Pressure; Dogs; Electrocardiography; Heart Conduction System; Membrane Potentials; Neural Conduction; Piperidines; Purkinje Fibers; Time Factors

Topics: Aconitine; Action Potentials; Administration, Oral; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Disease; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Epinephrine; Female; Heart Conduction System; Hemodynamics; Male; Ouabain; Piperidines; Time Factors; Ventricular Fibrillation

Topics: Administration, Oral; Animals; Anti-Arrhythmia Agents; Dogs; Drug Evaluation, Preclinical; Female; Fetus; Injections, Intravenous; Male; Mice; Piperidines; Pregnancy; Rabbits; Rats; Time Factors