piperidines and Tachycardia

The review summarizes recent progress in the study of the cardiac actions of second--generation antihistamines. Terfenadine and astemizole, two antihistamines of the second generation, are in vitro potent blockers of potassium channels (K+). It has been considered to be responsible for QT prolongation of the electrocardiogram and life--treating ventricular tachycardias called torsades de pointes. Loratadine and descarboethoxyloratadine, the major metabolite of loratadine were studied on a human cardiac K+ channel (hKv 1.5) cloned from human ventricle. Parent compound and its metabolite in high concentration blocked hKv1.5 channels. However, loratadine (10 mumol/L) failed to inhibit HERG potassium channel and HERG K+. Ebastine also inhibit potassium channels, cloned human Kv 1.5. Cetirizine was completely devoid of any inhibitory action on HERG K+ channels in concentration up to 30 mumd/L. On the other hand terfenadine and astemizole effectively blocked HERG K+ channels with nanomolar affinities (330 and 480 nmol/L, respectively), whereas loratadine was about 300-fold less potent. Fexofenadine--the major metabolite of terfenadine, does not block either HERG or Kv1.5. The quinea pig model (in vitro) revealed that only terfenadine, astemizole and ebastine produced significant QT interval prolongation and arrhythmogenic effects. The other nonsedating antihistamines including cetirizine, loratadine and the major metabolite of ebastine (carabastine), terfenadine (feksofenadine) and astemizole (norastemizole) were devoid of QT interval prolongation and other adverse ECG effects.

Topics: Animals; Area Under Curve; Astemizole; Butyrophenones; Electrocardiography; Heart; Histamine H1 Antagonists; Humans; Loratadine; Piperidines; Tachycardia; Terfenadine; Torsades de Pointes

Topics: Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Disopyramide; Electric Countershock; Electric Stimulation; Electrocardiography; Exercise Test; Flecainide; Heart Ventricles; Humans; Lidocaine; Phenytoin; Piperidines; Procainamide; Quinidine; Risk; Tachycardia; Tocainide; United States; Ventricular Fibrillation; Verapamil

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

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

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

Patients undergoing orthognathic surgery are at high risk of developing emergence agitation. We hypothesised that a single-dose of dexmedetomidine would reduce emergence agitation in adults with nasotracheal intubation after orthognathic surgery.. Seventy adults (20-45 years old) undergoing orthognathic surgery were randomly assigned to two groups. Patients received intravenous dexmedetomidine 1 μg/kg (dex group) or normal saline (control group) for 10 min at the end of surgery. Remifentanil was infused at 0.02 μg/kg/min during emergence in both groups. The severity of emergence agitation was assessed with the Richmond agitation-sedation scale. Cough, haemodynamic and respiratory profiles, pain, and time to eye opening were evaluated.. The incidence of emergence agitation was not different between dex group and control group (38% vs. 47%, P = 0.45). However, severe cough during emergence was reduced in the dex group (P = 0.04). Tachycardia during emergence and recovery phases was attenuated in the dex group. The verbal numeric rating of pain was lower in the dex group. There were no differences in respiratory rate between the two groups. Time to eye opening was prolonged in the dex group.. The addition of a single dose of dexmedetomidine (1 μg/kg) to low-dose remifentanil infusion did not attenuate emergence agitation in intubated patients after orthognathic surgery compared with low-dose remifentanil infusion alone. However, single-dose dexmedetomidine suppressed coughing, haemodynamic changes, and pain during emergence and recovery phases, without respiratory depression. Delayed awakening might be associated with this treatment.

Topics: Adult; Anesthesia Recovery Period; Anesthesia, General; Cough; Delayed Emergence from Anesthesia; Desflurane; Dexmedetomidine; Double-Blind Method; Drug Synergism; Female; Humans; Intubation, Intratracheal; Isoflurane; Male; Middle Aged; Orthognathic Surgical Procedures; Pain Measurement; Piperidines; Psychomotor Agitation; Remifentanil; Tachycardia; Young Adult

We randomly allocated 80 patients to intravenous dexmedetomidine (0.25, 0.5, or 1 μg.kg(-1) ) or placebo 15 min before anaesthetic induction. Dexmedetomidine 0.5 and 1.0 μg.kg(-1) significantly reduced the mean (95% CI) propofol effect-site concentrations by 0.83 (0.63-1.03) μg.ml(-1) , p = 0.001 and 1.29 (1.12-1.46) μg.ml(-1) , p = 0.0003 at intubation, by 1.05 (0.85-1.25 μg.ml(-1) , p = 0.0006 and 1.33 (1.15-1.51) μg.ml(-1) , p = 0.0002 when surgery started, and by 0.59 (0.39-0.79) μg.ml(-1) , p = 0.030 and 0.72 (0.57-0.87) μg.ml(-1) , p = 0.004 on completion of surgery, respectively. Patients' tracheas were extubated sooner after 0.5 and 1.0 μg.kg(-1) dexmedetomidine, by 5.36 (2.39-8.32) min, p = 0.009 and 7.37 (3.24-11.51) min p = 0.003, respectively. Tachycardic responses to intubation were present in five placebo patients and no dexmedetomidine patients. Bradycardia was treated after dexmedetomidine in six patients: five after 1.0 μg.kg(-1) ; and one after 0.25 μg.kg(-1) . Single-dose dexmedetomidine can reduce anaesthetic requirements, with both desirable and undesirable haemodynamic effects.

Topics: Adult; Analgesics, Opioid; Anesthesia; Anesthesia, General; Anesthesia, Intravenous; Bradycardia; Dexmedetomidine; Dose-Response Relationship, Drug; Female; Hemodynamics; Humans; Hypnotics and Sedatives; Infusions, Intravenous; Laryngoscopy; Male; Middle Aged; Monitoring, Intraoperative; Nerve Block; Piperidines; Propofol; Remifentanil; Sample Size; Tachycardia; Young Adult

Automated assessment of circulatory response to surgical stimuli is unsolved. Would detection of cardiac baroreflex inhibition assess adequacy of intra-operative anti-nociception upon incision, as performed on-line on a beat-by-beat basis by a cardiovascular index, CARDEAN™? 18 ASA I-II patients undergoing spinal disc repair were studied, in a prospective randomized single-blinded trial (observational study). During infusion of propofol to maintain bispectral index between 40 and 60, patients were allocated to receive an effect site target-controlled infusion of remifentanil at Ce = 2 or 4 ng ml(-1). Upon incision and during surgery, circulatory response was assessed using beat-by-beat measurements of minor hypertension and tachycardia to give a cardiovascular index, CARDEAN, scaled between 0 and 100. Upon skin incision, CARDEAN increased in the remifentanil Ce = 2 ng ml(-1) group (n = 7, P < 0.05), while it did not increase in the remifentanil Ce = 4 ng ml(-1) group (n = 7, P = 0.18). During surgery, retrospectively, CARDEAN > 60 was associated with tachycardia and hypertension (P (k) = 0.81 ± 0.10). Changes in CARDEAN appeared linked to adequacy of anti-nociception.

Topics: Adult; Analgesics, Opioid; Anesthetics, Intravenous; Baroreflex; Blood Pressure; Female; Heart Rate; Hemodynamics; Humans; Intervertebral Disc; Male; Middle Aged; Monitoring, Intraoperative; Nociception; Piperidines; Propofol; Remifentanil; Single-Blind Method; Tachycardia

The use of remifentanil is often associated with the observation of mesenteric traction syndrome (MTS) soon after manipulation of the intestine during abdominal surgery. MTS symptoms include facial flushing, hypotension, and tachycardia. In the study reported here, we prospectively investigated the effects of remifentanil on the incidence of MTS in abdominal surgery.. One hundred patients scheduled for abdominal surgery were randomly assigned to two groups. In one group (n = 50), fentanyl alone was used as intravenous analgesic (control, group C); in the second group (n = 50), both fentanyl and remifentanil were used (remifentanil group, group R). In all patients, anesthesia was induced with propofol and rocuronium and then maintained with sevoflurane inhalation. Remifentanil was continuously infused for patients in group R as an analgesic. Plasma concentration of 6-keto-PGF(1α) was measured before surgery and 20 min after the skin incision was made in six patients of group R and seven patients of group C.. MTS occurred in 20 cases in group R (40.0%), but in only five cases in group C (10.0%). In both groups, the incidence of MTS was higher in laparotomy than in laparoscopic surgery. The plasma concentration of 6-keto-PGF(1α) was low in both groups before surgery and was elevated 20 min after skin incision in both groups in patients in whom MTS appeared.. The results of this study suggest that the use of remifentanil in laparotomy facilitates MTS.

Topics: 6-Ketoprostaglandin F1 alpha; Abdomen; Aged; Anesthesia Recovery Period; Anesthesia, General; Anesthetics, Intravenous; Flushing; Hemodynamics; Humans; Hypotension; Intraoperative Complications; Laparotomy; Mesentery; Middle Aged; Piperidines; Prospective Studies; Remifentanil; Splanchnic Circulation; Syndrome; Tachycardia

Emergence from general anesthesia can be associated with coughing, agitation, and hemodynamic disturbances. Remifentanil may attenuate these responses.. In a prospective, double-blind, randomized trial, we enrolled 60 adult patients undergoing nasal surgery using remifentanil-based anesthesia. During the emergence phase, the remifentanil group had remifentanil reduced to one tenth of the maintenance rate, whereas the control group had remifentanil discontinued.. Times to awakening and tracheal extubation were similar between the two groups. During emergence, the remifentanil group (infusion rate 0.014 +/- 0.011 microg x kg(-1) x min(-1)) had a significantly lower incidence (40% vs 80%, P = 0.002) and less severe coughing compared with the control group, as well as a lower incidence of nonpurposeful movement (3.3% vs 30%, P = 0.006) and slower heart rates.. Low-dose remifentanil during emergence did not prolong wake-up but reduced the incidence and severity of coughing from the endotracheal tube.

Topics: Adolescent; Adult; Analgesics, Opioid; Anesthesia Recovery Period; Anesthesia, General; Blood Pressure; Cough; Double-Blind Method; Drug Administration Schedule; Female; Heart Rate; Humans; Hypotension; Infusions, Intravenous; Intubation, Intratracheal; Male; Middle Aged; Nose; Piperidines; Prospective Studies; Psychomotor Agitation; Remifentanil; Severity of Illness Index; Tachycardia; Time Factors; Treatment Outcome; Young Adult

A single 90-mg dose of the cannabinoid CB1 receptor antagonist rimonabant attenuates effects of smoked cannabis in humans.. The objective of this study is to evaluate whether repeated daily 40-mg doses of rimonabant can attenuate effects of smoked cannabis to the same extent as a single higher (90 mg) dose.. Forty-two male volunteers received one of three oral drug regimens in a randomized, double blind, parallel group design: (1) 40 mg rimonabant daily for 15 days, (2) placebo for 14 days, then 90 mg rimonabant on day 15, or (3) placebo for 15 days. All participants smoked an active or placebo cannabis cigarette 2 h after medication on days 8 and 15. Subjective effects were measured with visual analog scales and the marijuana-scale of the Addiction Research Center Inventory.. Cannabis-induced tachycardia was significantly lower for the 40-mg group on day 8 and for the 40 and 90 mg rimonabant groups on day 15 as compared to placebo. The 40-mg dose significantly decreased peak subjective effects on day 8. Neither the 90-mg nor 40-mg doses significantly decreased peak subjective effects on day 15. Rimonabant treatment did not significantly affect Delta(9)-tetrahydrocannabinnol pharmacokinetics.. Repeated lower daily rimonabant doses (40 mg) attenuated the acute physiological effects of smoked cannabis to a similar degree as a single 90-mg dose; repeated 40-mg doses attenuated subjective effects after 8 but not 15 days.

Topics: Administration, Oral; Adult; Area Under Curve; Dose-Response Relationship, Drug; Double-Blind Method; Dronabinol; Drug Administration Schedule; Electrocardiography; Heart Rate; Humans; Male; Marijuana Abuse; Marijuana Smoking; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Sex Factors; Tachycardia; Time Factors

Intraoperative combinations of volatile and opioid agents are used to achieve unconsciousness, hypnotic sparing, haemodynamic stability and uneventful recovery. This study describes the influence of different remifentanil concentrations on these variables when combined with desflurane during abdominal surgery.. Sixty-one healthy adult patients were randomly allocated to one of five predefined remifentanil target concentrations (3, 5, 7, 10 or 15 ng ml(-1)). Anaesthesia was titrated to maintain mean blood pressure (MBP), heart rate (HR) and BIS trade mark within predetermined values by adjusting desflurane delivery. Postoperative analgesia using propacetamol and morphine was initiated 30-45 min before skin closure, and continued using morphine PCA.. Desflurane requirements adjusted to both BIS and haemodynamics were not significantly modified by the remifentanil concentration (median Fet(DES) 2.7% before incision, 2.5% intraoperatively, and 2.2% during closure), resulting in a calculated drug consumption of 0.22-0.25 ml min(-1) (with 1.5 l min(-1) fresh gas flow). High remifentanil concentration decreased MBP and HR, and reduced the duration of tachycardia, but increased the duration of hypotension. The optimal balance was obtained with a remifentanil concentration of 5-7 ng ml(-1) for intubation, 3 ng ml(-1) until incision, 10 ng ml(-1) during intra-abdominal surgery and 5-7 ng ml(-1) during closure. Post-operative morphine requirements were not significantly modified by intraoperative remifentanil concentrations (median 30 mg/24 h, range [2-88]).. Remifentanil target concentrations from 3 to 15 ng ml(-1) had little influence on desflurane requirements or postoperative morphine consumption, but markedly modified intraoperative haemodynamic stability, suggesting that the target concentration should closely follow the successive noxious stimulations.

Topics: Abdomen; Acetaminophen; Adult; Analgesia, Patient-Controlled; Analgesics, Opioid; Anesthetics, Inhalation; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Desflurane; Electroencephalography; Female; Heart Rate; Humans; Hypotension; Isoflurane; Male; Middle Aged; Morphine; Nitrous Oxide; Piperidines; Recovery of Function; Remifentanil; Tachycardia

To compare the efficacy of different bolus doses of remifentanil, alfentanil, and saline at controlling the hemodynamic responses to day-case rigid bronchoscopy under general anesthesia.. Prospective, randomized, double-blind, placebo-controlled study.. Tertiary referral cardiothoracic hospital, single center.. Eighty consenting adults scheduled for elective day-case rigid bronchoscopy under general anesthesia.. Patients were randomized to receive a bolus of 10 micro g/kg of alfentanil, 1 micro g/kg of remifentanil, 2 micro g/kg of remifentanil or saline. After this, anesthesia was induced and maintained with a target-controlled propofol infusion (TCI) and succinylcholine was used for muscle relaxation. Heart rate and noninvasive arterial pressure were measured at 1-minute intervals throughout.. Patients' characteristics were similar in all 4 groups. There were no differences in time to return of spontaneous ventilation, wake-up times, or use of rescue vasopressors, and no patients complained of postoperative nausea. Remifentanil provided greater hemodynamic stability than alfentanil and a bolus of remifentanil of 2 micro g/kg significantly attenuated the rise in heart rate and was the most effective in preventing a rise in blood pressure.. A bolus of 2 micro g/kg of remifentanil successfully attenuated the hemodynamic response to rigid bronchoscopy without delaying recovery.

Topics: Aged; Alfentanil; Analgesics, Opioid; Area Under Curve; Blood Pressure; Bronchoscopy; Diastole; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Incidence; Male; Middle Aged; Myocardial Ischemia; Piperidines; Prospective Studies; Remifentanil; Systole; Tachycardia; Time Factors; Treatment Outcome; Vasoconstrictor Agents

SR141716, a recently developed CB1 cannabinoid receptor antagonist, blocks acute effects of Delta-9-tetrahydrocannabinol (THC) and other CB1 cannabinoid agonists in vitro and in animals. These findings suggest that CB1 receptors mediate many of the effects of marijuana, but this has not been evaluated in humans.. Sixty-three healthy men with a history of marijuana use were randomly assigned to receive oral SR141716 or a placebo in an escalating dose (1, 3, 10, 30, and 90 mg) design. Each subject smoked an active (2.64% THC) or placebo marijuana cigarette 2 hours later. Psychological effects associated with marijuana intoxication and heart rate were measured before and after antagonist and marijuana administration.. Single oral doses of SR141716 produced a significant dose-dependent blockade of marijuana-induced subjective intoxication and tachycardia. The 90-mg dose produced 38% to 43% reductions in visual analog scale ratings of "How high do you feel now?" "How stoned on marijuana are you now?" and "How strong is the drug effect you feel now?" and produced a 59% reduction in heart rate. SR141716 alone produced no significant physiological or psychological effects and did not affect peak THC plasma concentration or the area under the time x concentration curve. SR141716 was well tolerated by all subjects.. SR141716 blocked acute psychological and physiological effects of smoked marijuana without altering THC pharmacokinetics. These findings confirm, for the first time in humans, the central role of CB1 receptors in mediating the effects of marijuana.

Topics: Administration, Oral; Adult; Animals; Cannabinoids; Dose-Response Relationship, Drug; Double-Blind Method; Dronabinol; Euphoria; Heart Rate; Humans; Male; Marijuana Abuse; Piperidines; Placebos; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Tachycardia

The efficacy of flecainide acetate in suppressing ventricular premature contractions in 14 patients was evaluated in a double-blind, cross-over, placebo controlled, randomized and balanced study. Each treatment period was 2 weeks followed by a 3-4 d placebo washout period and the study lasted 5 weeks. Flecainide was given in a dose of 200 mg twice daily. A significant reduction in the total number of QRS complexes in a 24 h period was observed during the active compared with placebo treatment (P less than 0.05). In comparison with placebo, flecainide reduced the number of aberrant and premature aberrant QRS complexes (P less than 0.01). The mean suppression rate of aberrant QRS complexes during flecainide treatment was 85.4% and that of premature aberrant complexes was 93.2%. Maximum heart rate measured by 24 h ECG decreased significantly during flecainide therapy (P less than 0.01), although no change occurred with resting heart rate measured clinically or by ECG. Severe dizziness associated with flecainide therapy necessitated withdrawal of 2 patients from the study. A proarrhythmic effect of flecainide, ventricular tachycardia, was observed in one patient.

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

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

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

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

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

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

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

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

The antiarrhythmic efficacy and safety of oral flecainide acetate and quinidine sulfate were compared in a double-blind, 16-center parallel trial involving 280 patients with chronic premature ventricular complexes (PVCs). Eighty-five percent of the flecainide patients had at least 80% suppression of PVCs, vs 57% of the quinidine patients (p less than 0.0001). Sixty-eight percent of the flecainide patients met the above criterion and also had complete suppression of couplets and beats of ventricular tachycardia, vs 33% of the quinidine patients (p less than 0.0001). PR and QRS intervals were prolonged by flecainide without clinical consequence, but they were not substantially affected by quinidine (p less than 0.0001). Quinidine prolonged JT (QT minus QRS) intervals significantly more than flecainide (p less than 0.05). Nineteen of 141 flecainide patients and 21 of 139 quinidine patients discontinued therapy because of side effects (p greater than 0.50). Flecainide side effects included dizziness, blurred vision, headache and nausea. Quinidine side effects included diarrhea, nausea, headache and dizziness. Flecainide was more effective than quinidine in suppressing chronic ventricular arrhythmias (especially complex forms), and thus is an important new antiarrhythmic agent.

Topics: Administration, Oral; Adult; Aged; Arrhythmias, Cardiac; Clinical Trials as Topic; Double-Blind Method; Electrocardiography; Flecainide; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Quinidine; Random Allocation; Tachycardia

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

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

We studied the antiarrhythmic effect of a range of oral doses of encainide in 11 patients with stable high-frequency ventricular arrhythmias. Total suppression of arrhythmia was documented in 10 patients at a wide range of doses and plasma concentrations, and the suppression was subsequently verified in a placebo-controlled crossover study. Drug elimination was rapid (the half-life was 1.9 to 3.8 hours), but the margin between efficacy and side effects was sufficiently wide for therapy every six to 12 hours to be feasible in all 10 patients, with continuing outpatient treatment at six to 12 months. Marked prolongation of PR (mean, 44 per cent) and QRS (mean, 47 per cent) durations coincided with abolition of arrhythmia, but no evidence that these effects were detrimental was observed in radionuclide ventriculograms, exercise testing, or prolonged monitoring. A single patient whose arrhythmia and electrocardiogram were unchanged during therapy eliminated the drug much more slowly than the others and was the only patient in whom no O-demethyl form could be detected in plasma, suggesting that this metabolite may be active. In this study, encainide was a highly effective, well-tolerated antiarrhythmic agent.

Topics: Adult; Aged; Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Dose-Response Relationship, Drug; Electrocardiography; Encainide; Exercise Test; Female; Heart; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Tachycardia; Time Factors

Encainide is a new anti-arrhythmic drug, which is highly effective against ventricular extrasystoles, both single and coupled, in the dose range of 80--140 mg i.v. Ventricular extrasystoles were abolished in 31 out of 33 cases treated. The drug is also relatively effective against supraventricular extrasystoles, but has little effect on atrial fibrillation. Both subjects with clinically normal hearts and those with ischaemic heart disease have been successfully treated. The drug prolongs the QRS and QT duration. Its effectiveness appears to be of the same order of magnitude and the range of indications similar to those of aprindine and lorcainide. Further study of the drug seems to be warranted.

Topics: Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Clinical Trials as Topic; Heart Ventricles; Humans; Middle Aged; Piperidines; Tachycardia; Time Factors

Topics: Adrenergic alpha-Antagonists; Adult; Alcohol Drinking; Analysis of Variance; Blood Pressure; Clinical Trials as Topic; Electrocardiography; Female; Humans; Hypertension; Indoles; Male; Middle Aged; Physical Exertion; Piperidines; Placebos; Smoking; Tachycardia; Time Factors

Topics: Administration, Oral; Adult; Aged; Alanine Transaminase; Angina Pectoris; Blood Pressure; Body Weight; Central Nervous System Diseases; Clinical Trials as Topic; Drug Evaluation; Electrocardiography; Female; Gastrointestinal Diseases; Heart Rate; Humans; Male; Middle Aged; Perhexiline; Physical Exertion; Piperidines; Placebos; Tachycardia; Vasodilator Agents

The endocannabinoid neurotransmission acting via local CB

Topics: Animals; Cannabinoid Receptor Antagonists; Endocannabinoids; GABA Antagonists; GABAergic Neurons; Heart Rate; Hypothalamic Area, Lateral; Male; Models, Neurological; Piperidines; Psychological Distress; Pyrazoles; Pyridazines; Rats; Rats, Wistar; Septal Nuclei; Stress, Psychological; Synaptic Transmission; Tachycardia

Diphenidine is a dissociative drug that shows several psychotropic effects including euphoria, shifts in perception of reality, hallucinations, and transient anterograde amnesia. In this study, a case of acute intoxication occurring after diphenidine intake is reported. A 30-year-old Caucasian male was hospitalized after he was found in a confused and agitated state and unable to communicate. The physical examination displayed tachycardia, miotic pupils, and increased both body temperature and respiratory rate. After a liquid-liquid extraction procedure, GC/MS analysis revealed the presence of diphenidine in plasma and urine at concentrations of 308 and 631 ng/mL, respectively. Methylphenidate and diclazepam were also detected in the plasma. The clinical progress of the patient was favorable, and his symptoms were cured with a symptomatic treatment. The combined circumstantial elements and toxicological results of the case reported revealed the occurrence of an acute intoxication ascribable to the recreational abuse of diphenidine.

Topics: Adult; Akathisia, Drug-Induced; Confusion; Fever; Humans; Male; Piperidines; Psychotropic Drugs; Respiratory Rate; Substance-Related Disorders; Tachycardia

Topics: Adenine; Electrocardiography; Humans; Piperidines; Pyrazoles; Pyrimidines; Tachycardia; Tachycardia, Ventricular

Short acting beta-blockers (SBB) have been utilized effectively to prevent adverse cardiac events perioperatively. After recent introduction of remifentanil in Japan, applications of SBB could have been changed because of its intense analgesic and negative chronotrophic effects. Thus, we evaluated the factors that require SBB during general anesthesia using remifentanil.. Total of 1,631 patients who had general anesthesia with remifentanil were enrolled. Groups were divided by the use of SBB. Using logistic multivariable analysis, the factors significantly increasing the chance of using SBB were evaluated including patients' characteristics, surgical procedures, and anesthetic methods. A P value < 0.05 was considered as statistical significance.. One hundred thirty one patients received SBB perioperatively, 94 of them received only when awake and 34 of them received during remifentanil anesthesia. Emergency operation and preoperative ECG abnormalities were significant factors requiring SBB during anesthesia using remifentanil (OR; 3.0, 4.9 respectively).. Even with use of remifentanil there are the patients, such as those under emergency operation or with ECG abnormalities who require SBB perioperatively.

Topics: Adrenergic beta-Antagonists; Anesthesia, General; Emergencies; Female; Humans; Male; Middle Aged; Perioperative Period; Piperidines; Remifentanil; Tachycardia

Increasing evidence suggests that specific physiological measures may serve as biomarkers for successful treatment to alleviate symptoms of pathological anxiety. Studies of autonomic function investigating parameters such as heart rate (HR), HR variability and blood pressure (BP) indicated that HR variability is consistently reduced in anxious patients, whereas HR and BP data show inconsistent results. Therefore, HR and HR variability were measured under various emotionally challenging conditions in a mouse model of high innate anxiety (high anxiety behaviour; HAB) vs. control normal anxiety-like behaviour (NAB) mice. Baseline HR, HR variability and activity did not differ between mouse lines. However, after cued Pavlovian fear conditioning, both elevated tachycardia and increased fear responses were observed in HAB mice compared to NAB mice upon re-exposure to the conditioning stimulus serving as the emotional stressor. When retention of conditioned fear was tested in the home cage, HAB mice again displayed higher fear responses than NAB mice, while the HR responses were similar. Conversely, in both experimental settings HAB mice consistently exhibited reduced HR variability. Repeated administration of the anxiolytic NK1 receptor antagonist L-822429 lowered the conditioned fear response and shifted HR dynamics in HAB mice to a more regular pattern, similar to that in NAB mice. Additional receiver-operating characteristic (ROC) analysis demonstrated the high specificity and sensitivity of HR variability to distinguish between normal and high anxiety trait. These findings indicate that assessment of autonomic response in addition to freezing might be a useful indicator of the efficacy of novel anxiolytic treatments.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Autonomic Nervous System; Behavior, Animal; Circadian Rhythm; Conditioning, Psychological; Cues; Disease Models, Animal; Electrocardiography, Ambulatory; Electroshock; Fear; Female; Heart; Heart Rate; Mice; Motor Activity; Neurokinin-1 Receptor Antagonists; Noise; Piperidines; ROC Curve; Tachycardia; Telemetry; Time Factors; Video Recording

The most common clinical tachycardia, Atrial Fibrillation (AF), is a progressive disease, caused by cardiomyocyte remodeling, which finally results in contractile dysfunction and AF persistence. Recently, we identified a protective role of heat shock proteins (HSPs), especially the small HSPB1 member, against tachycardia remodeling in experimental AF models. Our understanding of tachycardia remodeling and anti-remodeling drugs is currently hampered by the lack of suitable (genetic) manipulatable in vivo models for rapid screening of key targets in remodeling. We hypothesized that Drosophila melanogaster can be exploited to study tachycardia remodeling and protective effects of HSPs by drug treatments or by utilizing genetically manipulated small HSP-overexpressing strains. Tachypacing of Drosophila pupae resulted in gradual and significant cardiomyocyte remodeling, demonstrated by reduced contraction rate, increase in arrhythmic episodes and reduction in heart wall shortening, compared to normal paced pupae. Heat shock, or pre-treatment with HSP-inducers GGA and BGP-15, resulted in endogenous HSP overexpression and protection against tachycardia remodeling. DmHSP23 overexpressing Drosophilas were protected against tachycardia remodeling, in contrast to overexpression of other small HSPs (DmHSP27, DmHSP67Bc, DmCG4461, DmCG7409, and DmCG14207). (Ultra)structural evaluation of the tachypaced heart wall revealed loss of sarcomeres and mitochondrial damage which were absent in tachypaced DmHSP23 overexpressing Drosophila. In addition, tachypacing induced a significant increase in calpain activity, which was prevented in tachypaced Drosophila overexpressing DmHSP23. Tachypacing of Drosophila resulted in cardiomyocyte remodeling, which was prevented by general HSP-inducing treatments and overexpression of a single small HSP, DmHSP23. Thus, tachypaced D. melanogaster can be used as an in vivo model system for rapid identification of novel targets to combat AF associated cardiomyocyte remodeling.

Topics: Animals; Atrial Fibrillation; Calpain; Disease Models, Animal; Diterpenes; Drosophila melanogaster; Drosophila Proteins; Gene Expression; Gene Expression Regulation; Heart; Heat-Shock Proteins; Heat-Shock Proteins, Small; Myocardial Contraction; Oximes; Piperidines; Tachycardia

To investigate the respiratory, metabolic and hemodynamic effects of clonidine in ventilated patients presenting with withdrawal syndrome after sedation interruption.. Prospective, interventional, single-center study in 30 ventilated ICU patients.. Metabolic [oxygen consumption (VO(2)), CO(2) production (VCO(2)), resting energy expenditure (REE)], respiratory [minute ventilation (V (E)), tidal volume (V (T)), respiratory rate (RR)] and hemodynamic (HR, SAP, MAP) parameters were measured in 30 ventilated ICU patients. Measurements were performed first under sedation with remifentanil-propofol, then after sedation interruption, and finally after clonidine administration (0.9-1.8 mg of clonidine in two doses of 10 min interval).. Sedation interruption produced significant increases in the hemodynamic parameters (SAP and MAP by 33%, HR by 37%), and metabolic rate (increase in VO(2) by 70%, VCO(2) by 88% and REE by 74%), leading to high respiratory demands (increase in V (E) from 9 to 15 l/min). The V (E) was increased due to a twofold increase in the RR; V (T) remained constant. In 25 out of 30 patients, clonidine administration decreased the hemodynamic (SAP, MAP and HR), metabolic (VO(2), VCO(2), REE) and respiratory parameters to values close to those observed with sedation. Clonidine induced mild sedation and patients became more cooperative with the ventilator. All patients responding to clonidine were weaned from the ventilator in 2 days (median, range 1-18 days).. Patients with withdrawal syndrome had significantly elevated hemodynamic, metabolic and respiratory demands. Clonidine significantly decreased these demands, induced mild sedation and facilitated patient cooperation with the ventilator, enabling ventilator weaning.

Topics: Adrenergic alpha-Agonists; Adult; Calorimetry, Indirect; Carbon Dioxide; Clonidine; Electrocardiography; Energy Metabolism; Female; Hemodynamics; Humans; Hypertension; Hypnotics and Sedatives; Male; Oxygen Consumption; Piperidines; Propofol; Prospective Studies; Remifentanil; Respiration, Artificial; Respiratory Insufficiency; Rest; Substance Withdrawal Syndrome; Tachycardia; Ventilator Weaning

Methods to correct the QT interval for heart rate are often in disagreement and may be further confounded by changes in autonomic state. This can be problematic when trying to distinguish the changes in QT interval by either drug-induced delayed repolarization or from autonomic-mediated physiological responses. Assessment of the canine dynamic QT-RR interval relationship was visualized by novel programming of the dynamic beat-to-beat confluence of data or "clouds". To represent the nonuniformity of the clouds, a bootstrap sampling method that computes the mathematical center of the uncorrected beat-to-beat QT value (QTbtb) with upper 95% confidence bounds was adopted and compared with corrected QT (QTc) using standard correction factors. Nitroprusside-induced reflex tachycardia reduced QTbtb by 43 ms, whereas an increase of 55 and 16 ms was obtained using the Bazett (QTcB) and Fridericia (QTcF) formulae, respectively. Phenylephrine-induced reflex bradycardia increased QTbtb by 3 ms but decreased QTcB by 20 ms and QTcF by 12 ms. Delayed repolarization with E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4-methylsulfonylaminobenzoyl)-piperidine), an inhibitor of rectifier potassium current, increased QTbtb by 26 ms but QT prolongation calculations using QTcF and QTcB were between 12 and 52% less, respectively, when small decreases in heart rate (5-8 beats per minute) were apparent. Dynamic assessment of beat-to-beat data, using the bootstrap method, allows quantification of QT interval changes under varying conditions of heart rate, autonomic tone, and direct repolarization that may not be distinguishable with use of standard correction factors.

Topics: Adrenergic beta-Agonists; Animals; Bradycardia; Dogs; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Heart Rate; Humans; Isoproterenol; Long QT Syndrome; Nitroprusside; Phenylephrine; Piperidines; Potassium Channels, Voltage-Gated; Pyridines; Tachycardia

A possible involvement of endocannabinoids in a chronic model of endotoxemia was assessed by measuring the regional (renal, mesenteric, hindquarters) hemodynamic responses to continuous 24-h LPS infusion (150 microg.kg(-1).h(-1)) in conscious, male Sprague-Dawley rats, in the absence or presence of the cannabinoid (CB1) receptor antagonist AM-251 (3 mg/kg). AM-251 inhibited the tachycardic and hindquarters vasodilator effects of LPS, but did not influence the other hemodynamic changes. In subsequent experiments, it was shown that the tachycardic and hindquarters vasodilator effects of LPS were also inhibited by the nonselective beta-adrenoceptor antagonist propranolol. In addition, the late (at 24 h) hindquarters vasodilator effects of LPS were inhibited by the beta2-adrenoceptor antagonist ICI-118551. Against the background of our previous work showing beta-adrenoceptor involvement in the cardiovascular effects of exogenous cannabinoids, we conclude that AM-251 may have been inhibiting endocannabinoid-modulated, sympathoadrenal-mediated activation of vasodilator beta-adrenoceptors in LPS-infused rats rather than suppressing a direct vasodilator action of endocannabinoids.

Topics: Adrenergic beta-Antagonists; Animals; Blood Pressure; Consciousness; Disease Models, Animal; Drug Interactions; Endotoxemia; Lipopolysaccharides; Male; Piperidines; Propanolamines; Propranolol; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptors, Adrenergic, beta; Sympathetic Nervous System; Tachycardia; Vasodilation

We wanted to ascertain whether the lateral parabrachial nucleus was involved in mediating the heart-rate response evoked during stimulation of somatic nociceptors. Reversible inactivation of the lateral parabrachial nucleus, using a GABA(A) agonist, reduced the reflex tachycardia evoked during noxious (mechanical) stimulation of the forelimb by approximately 50%. The same effect was observed after blockade of neurokinin 1 receptors within the lateral parabrachial nucleus, indicating a possible involvement for substance P as a neurotransmitter. Immunocytochemistry revealed a strong expression of substance P-immunoreactive fibers and boutons in all lateral subnuclei, but they were particularly dense in the lateral crescent subnucleus. Histological verification showed that the most effective injection sites for attenuating the noxious-evoked tachycardia were all placed in or near to the lateral crescent nucleus of the lateral parabrachial complex. Many single units recorded from this region were activated by high-intensity brachial nerve stimulation. The brachial nerve evoked firing responses of some of these neurons was reversibly reduced after local delivery of a neurokinin 1 receptor antagonist. However, only a minority of these neurons followed a paired-pulse stimulation protocol applied to the spinal cord, suggesting a predominance of indirect projections from the spinal cord to the parabrachial nucleus. We conclude that the cardiac component of the response to somatic nociception involves indirect spinal pathways that most likely excite neurons located in the lateral crescent nucleus of the parabrachial complex via activation of neurokinin 1 receptors.

Topics: Afferent Pathways; Animals; Brachial Plexus; Decerebrate State; Efferent Pathways; Female; GABA Agonists; GABA-A Receptor Agonists; Heart Rate; Hypertension; Isonicotinic Acids; Male; Neurokinin-1 Receptor Antagonists; Nociceptors; Pain; Piperidines; Pons; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Reflex; Spinal Cord; Substance P; Sympathetic Nervous System; Tachycardia

Previous modeling studies have suggested that the rapid component of the delayed rectifier (I(Kr)) may contribute importantly to action potential dynamics during tachycardia. To test this idea experimentally, I(Kr) was measured as the E-4031-sensitive current in isolated canine endocardial myocytes at 37 degrees C using the perforated patch-clamp technique. Command potentials were trains of action potential waveforms recorded at cycle lengths (CLs) of 1000, 500, 320, 170, and 120 ms. Action potential duration (APD) alternans occurred at CLs of 170 and 120 ms. During an action potential, I(Kr) increased gradually to a maximum at -55 to -60 mV. Peak I(Kr) increased initially as CL was shortened from 1000 to 500 ms (from 0.55+/-0.03 to 0.57+/-0.03 pA/pF), but decreased progressively as CL was shortened further (to 0.45+/-0.03 pA/pF at CL=120 ms). Baseline I(Kr) was negligible at CLs of 1000 to 320 ms, but increased to 0.12+/-0.01 pA/pF at a CL of 120 ms. During APD alternans, peak I(Kr) was larger for the short than for the long action potential (0.48+/-0.03 versus 0.46+/-0.03 pA/pF). A computer model of I(Kr) based on these data indicated that increasing I(Kr) suppressed alternans and decreasing I(Kr) increased alternans. In support of the latter result, inhibition of I(Kr) by E-4031 increased the maximal amplitude of alternans. These results indicate that I(Kr) contributes importantly to rate-related alterations of repolarization, including APD alternans. Modifying I(Kr) may be a promising approach to suppressing alternans and thereby preventing ventricular tachyarrhythmias.

Topics: Action Potentials; Animals; Computer Simulation; Delayed Rectifier Potassium Channels; Dogs; Endocardium; Female; Ion Transport; Male; Models, Cardiovascular; Myocytes, Cardiac; Patch-Clamp Techniques; Piperidines; Potassium; Potassium Channels; Potassium Channels, Voltage-Gated; Pyridines; Tachycardia; Ventricular Function, Left

We have compared the effect of two distinct Ih inhibitors on the temporal properties of the ERG response that, as previously shown, correlates well with the HCN activation in rods. The present results confirm the notion that cilobradine is more effective than zatebradine in inducing bradycardia. Importantly, the doses of cilobradine that reduce the heart rate to values comparable to, or lower than, those obtained with higher doses of zatebradine have little effect on the frequency response of the ERG. While more potent than zatebradine in its bradycardic action, cilobradine appears comparatively less effective on the visual response. A possible explanation is that the affinity of cilobradine for the HCN channels in the heart is higher than that for the HCN channels of retinal neurons.

Topics: Animals; Benzazepines; Bradycardia; Cardiotonic Agents; Dose-Response Relationship, Drug; Electroretinography; Heart; Heart Rate; Ion Channels; Membrane Potentials; Piperidines; Rats; Rats, Long-Evans; Retina; Retinal Ganglion Cells; Retinal Rod Photoreceptor Cells; Tachycardia

Somatic noxious stimulation can evoke profound cardiovascular responses by altering activity in the autonomic nervous system. This noxious stimulation attenuates the cardiac vagal baroreflex, a key cardiovascular homeostatic reflex. This attenuation is mediated via NK1 receptors expressed on GABAergic interneurones within the nucleus of the solitary tract (NTS). We have investigated the effect of noxious stimulation and exogenous substance P (SP) on the sympathetic component of the baroreflex. We recorded from the sympathetic chain in a decerebrate, artificially perfused rat preparation. Noxious hindlimb pinch was without effect on the sympathetic baroreflex although the cardiac vagal baroreflex gain was decreased (56 %, P < 0.01). Bilateral NTS microinjection of SP (500 fmol) produced a similar selective attenuation of the cardiac vagal baroreflex gain (62 %, P < 0.005) without effect on the sympathetic baroreflex. Recordings from the cardiac sympathetic and vagal nerves confirmed the selectivity of the SP inhibition. Control experiments using a GABAA receptor agonist, isoguvacine, indicated that both components of the baroreflex (parasympathetic and sympathetic) could be blocked from the NTS injection site. The NTS microinjection of a NK1 antagonist (CP-99,994) in vivo attenuated the tachycardic response to hindlimb pinch. Our data suggest that noxious pinch releases SP within the NTS to selectively attenuate the cardiac vagal, but not the sympathetic, component of the baroreflex. This selective withdrawal of the cardiac vagal baroreflex seems to underlie the pinch-evoked tachycardia seen in vivo. Further, these findings confirm that baroreflex sympathetic and parasympathetic pathways diverge, and can be independently controlled, within the NTS.

Topics: Animals; Baroreflex; GABA Agonists; Heart; Hindlimb; Isonicotinic Acids; Male; Microinjections; Nociceptors; Pain; Parasympathetic Nervous System; Physical Stimulation; Piperidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Solitary Nucleus; Substance P; Sympathetic Nervous System; Tachycardia; Vagus Nerve

1. The effects of tachykinin NK(1), NK(2) and NK(3) receptor agonists and antagonists were measured on blood pressure (MAP) and heart rate (HR) after bilateral microinjection into the substantia nigra (SN) of awake, unrestrained rats. 2. Increasing doses (25 pmol - 1 nmol) of selective agonists at NK(1) ([Sar(9),Met(O(2))(11)]SP), NK(2) ([beta-Ala(8)]NKA(4 - 10)) and NK(3) (senktide) receptors into the SN produced tachycardia which was selectively and reversibly blocked by the prior injection of tachykinin antagonists at NK(1) (RP67580, 250 pmol), NK(2) (SR48968, 250 pmol) and NK(3) (R-820, 500 pmol) receptor. A rapid fall in MAP followed by a pressor response was seen with 1 nmol of [Sar(9),Met(O(2))(11)]SP. Behavioural activity was elicited by 1 nmol of [Sar(9),Met(O(2)(11)]SP (sniffing > face washing = grooming) and senktide (sniffing > wet dog shake > rearing = locomotion). Tachykinin antagonists had no direct cardiovascular or behavioural effects. 3. The tachycardia produced by 100 pmol of [beta-Ala(8)]NKA(4 - 10) or senktide was abolished by an i.v. treatment with atenolol (beta(1)-adrenoceptor antagonist, 5 mg kg(-1)) while that evoked by [Sar(9),Met(O(2))(11)]SP was reduced. A combination of atenolol (5 mg kg(-1)) and atropine (muscarinic antagonist, 1 mg kg(-1)) blocked the response evoked by [Sar(9),Met(O(2))(11)]SP. 4. These data suggest that the SN is a potential site of modulation of cardiac activity by tachykinins. In addition to the withdrawal of the cardiovagal activity by NK(1) receptor, the three tachykinin receptors appear to increase the sympatho/adrenal drive to the heart. This occurs independently of changes in MAP and behaviour. Hence, this study highlights a new central regulatory mechanism of cardiac autonomic activity.

Topics: Adrenergic beta-Antagonists; Animals; Atenolol; Atropine; Benzamides; Blood Pressure; Hemodynamics; Indoles; Isoindoles; Male; Microinjections; Muscarinic Antagonists; Neurokinin-1 Receptor Antagonists; Oligopeptides; Peptide Fragments; Piperidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Receptors, Tachykinin; Substance P; Substantia Nigra; Tachycardia; Tachykinins

Cannabinoids, including the endogenous ligand anandamide, elicit pronounced hypotension and bradycardia through the activation of CB1 cannabinoid receptors. A second endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), has been proposed to be the natural ligand of CB1 receptors. In the present study, we examined the effects of 2-AG on mean arterial pressure and heart rate in anesthetized mice and assessed the role of CB1 receptors through the use of selective cannabinoid receptor antagonists and CB1 receptor knockout (CB1(-/-)) mice. In control ICR mice, intravenous injections of 2-AG or its isomer 1-AG elicit dose-dependent hypotension and moderate tachycardia that are unaffected by the CB1 receptor antagonist SR141716A. The same dose of SR141716A (6 nmol/g IV) completely blocks the hypotensive effect and attenuates the bradycardic effect of anandamide. 2-AG elicits a similar hypotensive effect, resistant to blockade by either SR141716A or the CB2 antagonist SR144528, in both CB1(-/-) mice and their homozygous (CB1(+/+)) control littermates. In ICR mice, arachidonic acid (AA, 15 nmol/g IV) elicits hypotension and tachycardia, and indomethacin (14 nmol/g IV) inhibits the hypotensive effect of both AA and 2-AG. Synthetic 2-AG incubated with mouse blood is rapidly (<2 minutes) and completely degraded with the parallel appearance of AA, whereas anandamide is stable under the same conditions. A metabolically stable ether analogue of 2-AG causes prolonged hypotension and bradycardia in ICR mice, and both effects are completely blocked by SR141716A, whereas the same dose of 2-AG-ether does not influence blood pressure and heart rate in CB1(-/-) mice. These findings are interpreted to indicate that exogenous 2-AG is rapidly degraded in mouse blood, probably by a lipase, which masks its ability to interact with CB1 receptors. Although the observed cardiovascular effects of 2-AG probably are produced by an arachidonate metabolite through a noncannabinoid mechanism, the CB1 receptor-mediated cardiovascular effects of a stable analogue of 2-AG leaves open the possibility that endogenous 2-AG may elicit cardiovascular effects through CB1 receptors.

Topics: Anesthesia; Animals; Arachidonic Acids; Blood Pressure; Camphanes; Cardiovascular Agents; Cardiovascular Diseases; Dose-Response Relationship, Drug; Endocannabinoids; Female; Glycerides; Heart Rate; Hypotension; Indomethacin; Ligands; Male; Mice; Mice, Inbred ICR; Mice, Knockout; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Tachycardia

1. It has been suggested that the tachycardic response to 5-hydroxytryptamine (5-HT) in the spinal-transected cat is mediated by '5-HT1-like' receptors since this effect, being mimicked by 5-carboxamidotryptamine (5-CT), is not modified by ketanserin or MDL 72222, but it is blocked by methiothepin, methysergide or mesulergine. The present study was set out to reanalyse this suggestion in terms of the IUPHAR 5-HT receptor classification schemes proposed in 1994 and 1996. 2. Intravenous (i.v.) bolus injections of the tryptamine derivatives, 5-CT (0.01, 0.03, 0.1, 0.3, 1, 3, 10 and 30 microg kg(-1)), 5-HT (3, 10 and 30 microg kg(-1)) and 5-methoxytryptamine (3, 10 and 30 microg kg(-1)) as well as the atypical antipsychotic drug, clozapine (1000 and 3000 microg kg(-1)) resulted in dose-dependent increases in heart rate, with a rank order of agonist potency of 5-CT >> 5-HT > 5-methoxytryptamine >> clozapine. 3. The tachycardic effects of 5-HT and 5-methoxytryptamine were dose-dependently antagonized by i.v. administration of lisuride (30 and 100 microg kg(-1)), ergotamine (100 and 300 microg kg(-1)) or mesulergine (100, 300 and 1000 microg kg(-1)); the highest doses of these antagonists used also blocked the tachycardic effects of 5-CT. Clozapine (1000 and 3000 microg kg(-1)) did not affect the 5-HT-induced tachycardia, but attenuated, with its highest dose, the responses to 5-methoxytryptamine and 5-CT. However, these doses of clozapine as well as the high doses of ergotamine (300 microg kg(-1)) and mesulergine (300 and 1000 microg kg(-1)) also attenuated the tachycardic effects of isoprenaline. In contrast, 5-HT-, 5-methoxytryptamine- and 5-CT-induced tachycardia were not significantly modified after i.v. administration of physiological saline (0.1 and 0.3 ml kg(-1)), the 5-HT(1B/1D) receptor antagonist, GR127935 (500 microg kg(-1)) or the 5-HT(3/4) receptor antagonist, tropisetron (3000 microg kg(-1)). 4. Intravenous injections of the 5-HT1 receptor agonists, sumatriptan (30, 100 and 300 microg kg(-1)) and indorenate (300 and 1000 microg kg(-1)) or the 5-HT4 receptor (partial) agonist cisapride (300 and 1000 microg kg(-1)) were devoid of effects on feline heart rate per se and failed to modify significantly 5-HT-induced tachycardic responses. 5. Based upon the above rank order of agonist potency, the failure of sumatriptan, indorenate or cisapride to produce cardioacceleration and the blockade by a series of drugs showing high affinity for the cloned 5-ht7

Topics: 5-Methoxytryptamine; Animals; Blood Pressure; Cats; Cisapride; Decerebrate State; Heart Rate; Piperidines; Receptors, Serotonin; Recombinant Proteins; Serotonin Antagonists; Serotonin Receptor Agonists; Sumatriptan; Tachycardia

1. We investigated the affinity of SB 207710 for sinoatrial 5-HT4 receptors and the density of right atrial 5-HT4 receptors with [125I]-SB 207710 in right atria of new-born piglets. 2. SB 207710 (1-100 nM) antagonized the 5-HT-evoked tachycardia surmountably with a pKB of 9.8. 3. [125I]-SB 207710 (5-1500 pM) labelled a small population of saturable binding sites with a pKD of 10.1 and with 5-HT4 receptor characteristics. The density of atrial binding sites with 5-HT4 receptor characteristics was 174 and 22 times lower respectively than those of atrial beta 1- and beta 2-adrenoceptors, labelled with (-)-[125I]-cyanopindolol. 4. We suggest that the small 5-HT4 receptor population may in part explain why the maximal tachycardia caused by 5-HT is smaller than that caused by catecholamines.

Topics: Animals; Animals, Newborn; Atrial Function, Right; Binding, Competitive; Dioxanes; Dose-Response Relationship, Drug; Female; Male; Piperidines; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Swine; Tachycardia

R56865 has been described as a substance that protects cells from intracellular Na+ and Ca2+ overload. The aim of this study was to investigate its mechanism of action, which is at present unknown.. The haemodynamic and (rate dependent) electrophysiological effects of R56865 (0.48 mg.kg-1) were examined and compared with its antiarrhythmic effect on ouabain-induced ventricular tachycardia (n = 10), and ventricular tachycardia occurring within 24 h of occlusion of the left anterior descending artery (n = 8). The experiments were all performed in dogs.. In anaesthetised dogs R56865 increased (p < 0.05) the cycle length of the sinus rhythm, the corrected QT duration (+8%) and the effective refractory period (+16%) of the right ventricle. No rate dependency was found. R56865 had no effect on blood pressure, conduction, or refractoriness of the AV node, nor on conduction in the ventricle. In conscious dogs, R56865 did not change the cycle length of the sinus rhythm, but it did increase the QT duration (+5%, p < 0.05). The cycle length of the slower ouabain induced ventricular tachycardias which were terminated by R56865 increased to a greater extent (+55%) than that of the non-suppressible, faster ventricular tachycardias (+16%): 335(SD 30) ms, n = 5 v 285(10) ms, n = 5. The effect of R56865 on ventricular tachycardias 24 h after infarction was considered to be of minor antiarrhythmic importance.. R56865 has (1) class III effects, (2) a partial effect in terminating ouabain induced ventricular tachycardias which is inverse rate dependent, and (3) a weak effect on ventricular tachycardias 24 h after infarction.

Topics: Animals; Anti-Arrhythmia Agents; Benzothiazoles; Dogs; Dose-Response Relationship, Drug; Female; Heart Rate; Hemodynamics; Male; Ouabain; Piperidines; Tachycardia; Thiazoles

Topics: Adult; Aged; Cardiac Complexes, Premature; Cisapride; Female; Humans; Male; Middle Aged; Piperidines; Serotonin Antagonists; Tachycardia

Topics: Cisapride; Humans; Piperidines; Serotonin Antagonists; Tachycardia

Topics: Cisapride; Humans; Piperidines; Serotonin Antagonists; Tachycardia

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 a new antiarrhythmic agent, E-4031, on reentrant types of tachycardias in rabbit right atrial preparations were studied using the microelectrode technique. E-4031 at concentrations of 0.1 and 1.0 microM prolonged the refractory period (RP) of the atrium and atrioventricular node (AVN) without affecting the intraatrial conduction time. In 13 of 17 preparations, premature stimulation repeatedly induced tachycardias lasting more than 10 beats. Twelve of 13 preparations exhibited a smooth AV conduction curve and showed activation patterns compatible with intraatrial reentry (IAR) during tachycardias, whereas the remaining preparation started tachycardia with a jump on the AV conduction curve, indicating dual AVN reentrant tachycardia (AVNRT). Application of 0.1 and 1.0 microM E-4031 completely prevented the initiation of both types of tachycardias by producing intraatrial conduction block due to prolonged effective refractory period (ERP) of the atrium. The results indicated that E-4031 exhibiting pure class III antiarrhythmic properties is effective for prevention of reentrant type of supraventricular tachycardias (SVTs).

Topics: Animals; Anti-Arrhythmia Agents; Atrioventricular Node; Electric Stimulation; Heart; Heart Atria; In Vitro Techniques; Myocardial Reperfusion; Piperidines; Pyridines; Rabbits; Refractory Period, Electrophysiological; Tachycardia

MDL 11,939 (alpha-phenyl-1-[2-phenylethyl]-4-piperidine-methanol) is a new class III antiarrhythmic agent that was evaluated for antiarrhythmic activity in anesthetized dogs. Intravenous (i.v.) administration of MDL 11,939 (1, 3, and 10 mg/kg) increased left ventricular effective refractory periods. Q-T interval, and Q-Tc in a dose-related way. The effects of MDL 11,939 on ventricular refractoriness were similar to those observed with administration of identical doses of d-sotalol, with the exception that those produced by MDL 11,939 lasted longer. Intraduodenal administration of 10 mg/kg MDL 11,939 also increased left ventricular effective refractory period (LV ERP). The increase in left ventricular refractoriness produced by MDL 11,939 occurred without a significant increase in QRS duration. MDL 11,939 (10 mg/kg i.v.) also protected against induction of ventricular tachycardia (VT) and ventricular fibrillation (VF) induced with programmed electrical stimulation (PES) in anesthetized dogs with chronic 4- to 7-day myocardial infarctions. In comparison, antiarrhythmic effects of bretylium (10 mg/kg i.v.) against PES-induced ventricular arrhythmias were dependent on additional administration of propranolol (0.1 mg/kg i.v.), whereas propranolol alone (0.1 mg/kg i.v.) was ineffective. The results observed with MDL 11,939 are consistent with its in vitro class III antiarrhythmic action and suggest utility for this agent in treatment of VT and VF.

Topics: Animals; Anti-Arrhythmia Agents; Bretylium Compounds; Dogs; Drug Therapy, Combination; Electrocardiography; Electrophysiology; Female; Heart; Heart Ventricles; Male; Piperidines; Propranolol; Tachycardia; Ventricular Fibrillation

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

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

By using a Langendorff-perfused ring of anisotropic rabbit epicardium, sustained reentrant ventricular tachycardia with a cycle length of 168 +/- 13 msec (n = 26) was induced by programmed electrical stimulation. Continuous left ventricular epicardial mapping with 256 simultaneously recorded unipolar electrograms demonstrated that the tachycardia was based on circuital movement of the impulse around a fixed obstacle. Because of the anisotropic properties of the myocardium, the circuit consisted of a ring with segments in which the circulating wave propagated slowly (20 +/- 2 cm/sec) or faster (62 +/- 4 cm/sec). This was related to transverse or longitudinal propagation in relation to fiber direction. In six of 26 experiments, sudden acceleration in rate of the tachycardia was observed during programmed electrical stimulation. This acceleration was caused by the occurrence of double-wave reentry (two successive waves traveling in the same direction and using the same circuit). In one of the experiments, induction of double-wave reentry was only possible at basal conditions but not after the administration of a class III antiarrhythmic drug. In a seventh experiment, induction of double-wave reentry became possible after the administration of a class IC antiarrhythmic drug. Because conduction velocity around the ring was depressed during acceleration, the total revolution time of the circuit during double-wave reentry was about 120% of that during single-wave reentry. Ventricular tachycardias in which double-wave reentry could be elicited had longer cycle lengths (197 +/- 11 vs. 156 +/- 8 msec, p less than 0.001) and larger excitable gaps (71 +/- 16 vs. 28 +/- 5 msec, p less than 0.001) than those not showing this phenomenon. Double-wave reentry might have important clinical implications in understanding ventricular tachycardia acceleration during programmed electrical stimulation, proarrhythmic effects of drugs, and pathophysiology of rapid ventricular tachycardias.

Topics: Animals; Anti-Arrhythmia Agents; Chromans; Electric Stimulation; Electrocardiography; Electrophysiology; Female; Heart Ventricles; Male; Myocardium; Piperidines; Rabbits; Tachycardia

Effects of E-4031, a class III antiarrhythmic agent, on re-entrant ventricular arrhythmias were studied in eight dogs with a 7-day-old myocardial infarction. Epicardial mapping and local refractory periods were obtained using 47-channel bipolar electrodes attached to the epicardium. The induction of sustained ventricular tachycardia by programmed electrical stimulation was not suppressed by i.v. infusion of E-4031 at 1 microgram/kg/min, but was suppressed markedly by infusion at 10 micrograms/kg/min in six of seven dogs. During the infusion of E-4031 at 10 micrograms/kg/min, epicardial conduction velocity in the normal ventricle did not change (0.7 +/- 0.12 to 0.71 +/- 0.13 m/sec, n = 6), whereas slowed conduction in the infarct zone improved (0.58 +/- 0.10 to 0.77 +/- 0.13 m/sec, n = 6). E-4031 at 10 micrograms/kg/min prolonged effective refractory periods (ERP) in the normal zone (139 +/- 8 to 164 +/- 18 msec, P less than .01, n = 8), nontransmural infarct zone (145 +/- 7 to 177 +/- 15 msec, P less than .01, n = 8) and transmural infarct zone (156 +/- 14 to 191 +/- 22 msec, P less than .01, n = 8). The degrees of ERP prolongation were almost equal in all zones. On epicardial mapping, the areas of longer ERP and delayed conduction were observed to become inexcitable after the administration of E-4031. These results demonstrated that E-4031 effectively prevented the induction of re-entrant ventricular tachycardia in canine myocardial infarction model, and suggested that E-4031 rendered re-entrant circuits inexcitable by marked ERP prolongation in both normal and infarct zones.

Topics: Animals; Anti-Arrhythmia Agents; Dogs; Electric Stimulation; Electrodes; Electrophysiology; Heart Conduction System; Infusions, Intravenous; Myocardial Infarction; Piperidines; Pyridines; Tachycardia

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

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

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

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

The effects of intravenous infusions of paroxetine, a novel inhibitor of 5-hydroxytryptamine (5HT) uptake, and of the tricyclic antidepressant, amitriptyline, on the cardiovascular system have been compared in the conscious rabbit and in the anaesthetised cat. As judged by the dose required to produce changes in ECG waveform (including PR and QTc intervals) and disorders of heart rhythm, paroxetine was less cardiotoxic than amitriptyline in both species. Thus, paroxetine has the advantage over amitriptyline of being less toxic to the cardiovascular system which could constitute a considerable advantage in clinical use particularly as other work has shown it to be more potent than amitriptyline in tests for antidepressant activity.

Topics: Amitriptyline; Animals; Antidepressive Agents; Cats; Drug Evaluation, Preclinical; Electrocardiography; Female; Heart Conduction System; Hypotension; Infusions, Parenteral; Male; Myocardial Contraction; Paroxetine; Piperidines; Rabbits; Seizures; Serotonin Antagonists; Tachycardia

In the treatment of chronic ectopic atrial tachycardia, standard antiarrhythmic therapy has been shown to be ineffective in the majority of patients. The intravenous and oral effects of two class IC antiarrhythmic drugs, encainide and flecainide, in five patients with chronic ectopic atrial tachycardia were studied using exercise testing, 24 hour long-term electrocardiography and programmed electrical stimulation. All patients had been treated unsuccessfully with at least four antiarrhythmic drugs. In two patients tachycardia was persistent, and in three patients tachycardia occurred intermittently for more than 12 hours/day. Intravenous encainide and flecainide at doses ranging from 0.3 to 2.0 mg/kg and from 0.5 to 1.5 mg/kg body weight, respectively, terminated atrial ectopic tachycardia in all patients. Oral encainide, 150 to 225 mg/day, completely suppressed ectopic atrial activity in four patients during a mean follow-up period of 8 +/- 3 months. In the remaining patient encainide markedly reduced the number of episodes of tachycardia. In three patients encainide had to be withdrawn because of intolerable side effects. These patients were well controlled with oral flecainide, 200 to 300 mg/day, without side effects. On the basis of these results, the efficacy of encainide and flecainide in the treatment of chronic ectopic atrial tachycardia appears to be not drug-specific but rather a general class IC property.

Topics: Adult; Anilides; Chronic Disease; Electrophysiology; Encainide; Female; Flecainide; Heart Atria; Humans; Male; Middle Aged; Piperidines; Tachycardia

Ninety-four patients with ventricular tachycardia (VT), 49 with sustained and 45 with nonsustained VT, who had been refractory to or intolerant of other antiarrhythmic agents were treated in a multicenter, open-label study with flecainide acetate. Most had serious cardiac disorders associated with their arrhythmia: 49 patients (52%) had 1 or more conduction disorders on electrocardiography; 43 (46%) had congestive heart failure; 30 (33%) had left ventricular ejection fractions of 30% or less. Patients were initially treated orally in the hospital with 100 mg twice daily; dosage was titrated upward as needed at 4-day intervals to a maximal dose of 200 mg twice daily. Flecainide plasma level monitoring was performed to ensure plasma levels remained in the therapeutic range of 0.2 to 1.0 micrograms/ml. Patients were discharged with flecainide therapy if investigators judged it to be safe and effective. Minimum efficacy requirements included elimination of sustained VT and reduction of other ventricular arrhythmias as determined by 1 or more of the following: 24-hour electrocardiographic monitoring, programmed electrical stimulation, exercise testing and in-hospital monitoring. Sixty-eight patients (72%) were discharged with flecainide therapy. After a mean follow-up of 8 months, 45 patients (48%) were still taking flecainide, including 22 of 49 (45%) with sustained and 23 of 45 (51%) with nonsustained VT. Nine patients with sustained VT and 1 patient with nonsustained VT had aggravation of arrhythmia. Two patients had third-degree heart block. Nine patients died after discharge from the hospital: 6 from out-of-hospital sudden death and 3 from acute myocardial infarctions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Arrhythmias, Cardiac; Electrocardiography; Female; Flecainide; Humans; Male; Middle Aged; Piperidines; Tachycardia

A 32-year-old woman with prolapsed mitral valve was treated with flecainide because of an episode of primary ventricular fibrillation. The drug was chosen because several hundred short runs of ventricular tachycardia unrelated to exercise were observed during 24-hour monitoring. Oral medication at a dose of 200 mg twice daily suppressed all repetitive ventricular ectopy. Eighteen months later, however, a further 24-hour recording showed a ventricular arrhythmia which was provoked early in the morning by exercise. Because the tablets were taken late in the evening and early in the morning it was suspected that toxic levels of flecainide may have produced the arrhythmia. Measurement confirmed this suspicion. Reducing the dosage abolished the arrhythmia.

Topics: Adult; Anti-Arrhythmia Agents; Electrocardiography; Female; Flecainide; Heart Ventricles; Humans; Mitral Valve Prolapse; Physical Exertion; Piperidines; Tachycardia; Ventricular Fibrillation

Topics: Aged; Anti-Arrhythmia Agents; Flecainide; Heart Ventricles; Humans; Lidocaine; Male; Middle Aged; Piperidines; Tachycardia

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

Thirty-two patients received flecainide acetate for nonsustained ventricular tachycardia after having had unsuccessful treatment with a mean of four antiarrhythmic drugs. The mean left ventricular ejection fraction was 41% in 27. Thirty-one patients had organic heart disease, and 22 patients had arrhythmia-related symptoms. Total suppression of ventricular tachycardia occurred in 22 patients. Thirty patients were discharged from the hospital receiving flecainide at a mean (+/- SD) dosage of 315 +/- 76 mg/d and 26 of these patients attained a mean trough plasma drug level of 567 +/- 254 ng/mL. One patient had proarrhythmia and 3 had worsening of heart failure. Twenty-two patients remained in the trial for a mean follow-up of 13 +/- 7 months. Five patients died (1 suddenly) during the follow-up period. Our data indicate that flecainide suppresses refractory nonsustained ventricular tachycardia in 69% of patients who have organic heart disease. Serious adverse effects were minimized by initiation of treatment in the hospital and careful surveillance of electrocardiograms and plasma drug levels.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Coronary Disease; Electrocardiography; Female; Flecainide; Follow-Up Studies; Heart Ventricles; Humans; Male; Middle Aged; Monitoring, Physiologic; Piperidines; Tachycardia

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

The antiarrhythmic agent flecainide acetate was resolved by fractional crystallization of its diastereomeric alpha-bromocamphor-pi-sulfonate salts. Optical purity of the two enantiomers was shown to be greater than 99% by an NMR technique using the chiral shift reagent Eu(hfbc)3. Antiarrhythmic effects of flecainide and its enantiomers were assessed in two different animal models, chloroform-induced ventricular fibrillation in mice and ouabain-induced ventricular tachycardia in dogs. The two enantiomers were highly effective in suppressing both of these experimental arrhythmias and appeared to be essentially equipotent. No significant differences were found either between the two enantiomers or between the enantiomers and racemic flecainide.

Topics: Animals; Anti-Arrhythmia Agents; Chloroform; Dogs; Female; Flecainide; Magnetic Resonance Spectroscopy; Mice; Ouabain; Piperidines; Stereoisomerism; Tachycardia; Ventricular Fibrillation

The effect of flecainide acetate, a class 1c antiarrhythmic agent, was examined in 15 patients with recurrent ventricular tachycardia. Intravenous flecainide was administered in a dose of 2 mg/kg at the time of intracardiac stimulation and recording studies. Oral flecainide was given to 10/15 patients and retesting was undertaken using an indwelling electrode. Intravenous flecainide terminated sustained stable tachycardia in 8/11 patients and prevented reinitiation of tachycardia in 5/10 patients. Oral therapy prevented induction of tachycardias in only 2/10 patients. Five patients had non-sustained tachycardia and three had slower sustained tachycardia. "New" non-clinical tachycardias could be induced in six patients after flecainide but five of these had had more than one type of induced tachycardia. Four of 10 patients remained free of tachycardias during follow-up. Withdrawal of oral treatment was necessary in three patients, one of whom had severe proarrhythmic effects. Two patients required additional antiarrhythmic therapy. Long-term suppression could not be predicted from the results of oral therapy, but testing after intravenous drug seemed to be a more useful prognostic indicator. In summary, intravenous flecainide is effective for slowing and termination of stable ventricular tachycardia. Oral therapy is also effective but caution should be exerted in patients with multimorphic tachycardias.

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Coronary Disease; Electrocardiography; Female; Flecainide; Heart Aneurysm; Heart Ventricles; Humans; Infusions, Parenteral; Male; Middle Aged; Piperidines; Recurrence; Tachycardia

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

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

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

The response of sustained supraventricular tachycardia to intravenous and oral flecainide acetate was investigated in 5 children, aged 5.5 to 11.5 years, who had tachycardias associated with Wolff-Parkinson-White syndrome. All children had failed to respond to at least 2 conventional agents. The effect of flecainide was studied using intracardiac techniques. Intravenous flecainide terminated tachycardia in all 5 patients. After drug infusion, slow, sustained tachycardia could be initiated in 1 patient. With oral treatment, slow, sustained tachycardia was started in 2 children and nonsustained in 2. One child had no inducible tachycardias. In 4 of 5 patients, long-term treatment has reduced the frequency of episodes and the drug is well tolerated. Thus, flecainide may be used to terminate and suppress junctional tachycardias in children who have failed to respond to conventional therapy.

Topics: Administration, Oral; Anti-Arrhythmia Agents; Child; Child, Preschool; Electrocardiography; Female; Flecainide; Humans; Injections, Intravenous; Male; Piperidines; Tachycardia; Wolff-Parkinson-White Syndrome

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

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

Flecainide, a new Vaughan-Williams Class Ic anti-arrhythmic agent, was used in 21 patients with an accessory AV conduction pathway which was apparent in 16 cases (WPW syndrome), latent in 1 case and concealed in 4 cases (block in the anterograde direction). Seventeen patients had spontaneous and inducible arrhythmias; 13 supraventricular tachycardias (SVT) due to orthodromic reentry including the accessory AV pathway and 4 atrial arrhythmias. Intravenous flecainide (2 mg/kg over 5 minute period) terminated the 13 cases of SVT in an average of 3 minutes by depressing then blocking retrograde conduction in the accessory pathway and 3 out of 4 cases of atrial arrhythmias. Conduction in the accessory pathway was blocked in the anterograde direction in 75% of cases and depressed in the rest; it was blocked in the retrograde direction in about half the cases and depressed in the rest. Intravenous flecainide completely prevented the induction or arrhythmias in 13 out of 17 patients (76%). Oral flecainide blocked the accessory pathway in the anterograde direction in 68.7%, and in the retrograde direction in 62% of patients, and prevented arrhythmias during provocative testing in 82% of patients (14 out of 17). With an average follow-up of 20.7 +/- 2.6 months with oral doses adapted to body weight and to the response to IV flecainide only one recurrence of atrial fibrillation was observed, a 100% prevention of spontaneous SVT and 94% prevention of all arrhythmias (16 out of 17 cases). The predictive value for the response to oral therapy of the tests of regularisation of SVT by IV flecainide and of the tests of non-provocation of SVT with oral or IV flecainide was excellent (100%). The cardiac tolerance was very good in these 21 patients (17 of whom had no valvular or myocardial lesion). There were 6 minor cases of general intolerance to oral therapy which were not dose related, only 1 of which required interruption of therapy. Flecainide appears one of the best choices for the treatment of preexcitation syndromes and their related arrhythmias at the present time.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Electrocardiography; Electrophysiology; Female; Flecainide; Heart Conduction System; Humans; Infusions, Parenteral; Male; Middle Aged; Neural Pathways; Piperidines; Tachycardia; Wolff-Parkinson-White Syndrome

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

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

Flecainide was initially prescribed at a dose of 200 mg twice daily, but after early toxicity in patients with ventricular tachycardia (VT), the dosage was reduced to 100 mg twice daily. The effects of flecainide were studied in 40 patients (29 men and 11 women, mean age 62 +/- 2 years, ejection fraction 45 +/- 3%) who underwent programmed electrical stimulation to determine the efficacy of flecainide in preventing VT chronically at the reduced dose. Sustained VT was induced in 21 patients and nonsustained VT in 19. Flecainide prevented VT induction in 26 patients (65%). At a mean dose of 1.5 +/- 0.1 mg/kg, prolongation occurred in the effective refractory period of the first (280 +/- 5 vs 249 +/- 5 ms) and second (254 +/- 6 vs 209 +/- 9 ms) extrastimuli (p less than 0.01). In the patients protected by flecainide, the effective refractory periods increased by a 17 +/- 2% and 21 +/- 3%, in contrast to only a 7 +/- 3% and 6 +/- 4% increase in the nonprotected group (p less than 0.05), despite a higher mean dose (1.9 +/- 0.1 vs 1.35 +/- 0.1 mg/kg). Twenty-one patients were discharged on flecainide therapy, 100 mg twice daily, and were followed for a mean of 11 months. Sixteen patients are alive and well, 1 died suddenly, 1 died from a noncardiac cause and 1 had a "breakthrough" arrhythmia. Two were switched to quinidine therapy by their referring physicians, but were without problems while receiving flecainide.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anti-Arrhythmia Agents; Drug Administration Schedule; Electrocardiography; Female; Flecainide; Follow-Up Studies; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Procainamide; Tachycardia; Time Factors

Intravenous flecainide successfully terminated atrial tachycardia in three patients. Maintenance treatment with oral flecainide prevented the recurrence of tachycardia for up to three years. These results suggest an additional use for flecainide which should be further explored.

Topics: Adult; Anti-Arrhythmia Agents; Flecainide; Humans; Male; Middle Aged; Piperidines; Tachycardia

Twenty-two patients with coronary artery disease and spontaneous ventricular tachycardia (VT) or ventricular fibrillation (VF) underwent intracardiac electrophysiologic evaluation and, when possible, ambulatory monitoring before and after therapy with flecainide (mean dose 418 +/- 87 mg [mean +/- standard deviation]). An average of 4 antiarrhythmic agents were used and were unsuccessful before therapy with flecainide was begun. During 64 +/- 16 hours of control Holter monitoring in 16 patients, all had 1 or more salvos of VT, as well as ventricular premature complexes (VPCs). Programmed stimulation during the control period induced VT in 17 of 22 patients. After flecainide therapy, Holter monitoring showed elimination of all forms of VT in all but 1 patient, as well as significant reduction of paired VPCs by 95% (p less than 0.03) and single VPCs by 70% (p less than 0.005). Electrophysiologic study during flecainide therapy showed significant increases in AH, HV, PR, QRS and QTc intervals, and the ventricular effective refractory period. Programmed stimulation in 17 patients taking flecainide, with a mean plasma level of 1,075 +/- 521 ng/ml, showed ablation of inducible VT in only 2 patients, a worsening in 5 and continued VT inducibility in 10. Adverse effects that required drug withdrawal were infrequent and encountered in patients who received higher drug levels: 1 patient with congestive heart failure and 1 with severe sinus bradycardia. Thus, although flecainide suppresses complex ventricular arrhythmias on Holter recordings, it rarely alters the response to programmed stimulation. Caution is recommended in its use for recurrent sustained VT or VF and in the interpretation of electrophysiologic studies until the predictive value of programmed stimulation with flecainide therapy is established.

Topics: Adult; Aged; Ambulatory Care; Anti-Arrhythmia Agents; Coronary Disease; Electrocardiography; Female; Flecainide; Follow-Up Studies; Heart Ventricles; Humans; Male; Middle Aged; Monitoring, Physiologic; Piperidines; Tachycardia; Ventricular Fibrillation

Topics: Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Flecainide; Humans; Middle Aged; Piperidines; Syncope; Tachycardia

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

New pharmacologic agents have been developed which are highly effective in suppressing ventricular premature beats, but their chronic efficacy in patients with sustained ventricular arrhythmias remains uncertain. We observed the appearance of ventricular tachycardia with an unusual sinusoidal QRS complex in three of five such patients treated with flecainide acetate, 200 mg twice daily. Our experience suggests that the early reports of successful suppression of ventricular premature beats in stable patients may not be directly applicable to sicker patients with recurrent sustained ventricular arrhythmias. In these patients, life-threatening arrhythmias may appear as the first manifestation of drug toxicity.

Topics: Aged; Anti-Arrhythmia Agents; Cardiac Complexes, Premature; Electrocardiography; Female; Flecainide; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Procainamide; Tachycardia

Topics: Child, Preschool; Humans; Parasympatholytics; Piperidines; Tachycardia

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

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

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

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

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

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

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

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

Flecainide acetate, a new potent class I antiarrhythmic agent, was given to 152 patients (46 orally and 106 intravenously) over a period of 22 months. Seven patients developed proarrhythmic effects. The only conduction abnormalities induced were PR interval prolongation and QRS complex widening, and no patient developed significant sinus bradyarrhythmias; patients with known serious abnormalities of impulse generation or conduction were excluded from this study. Five patients developed ventricular tachycardia or ventricular fibrillation of whom only three had preexisting ventricular arrhythmias. QT and QTc interval prolongation was observed but was due to QRS complex widening rather than to an increase in the JT interval. A patient with the Wolff-Parkinson-White syndrome had an inducible orthodromic atrioventricular (AV) tachycardia prior to flecainide, but only an antidromic tachycardia was induced after the drug. In one patient flecainide administration resulted in an increase of atrial flutter cycle length which resulted in development of 1:1 AV conduction and overall faster ventricular rate. Two patients who developed ventricular arrhythmias were taking other antiarrhythmic agents, and in this series proarrhythmic effects occurred with both normal and high flecainide concentrations.

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrioventricular Node; Dose-Response Relationship, Drug; Electrocardiography; Female; Flecainide; Humans; Infusions, Parenteral; Male; Middle Aged; Piperidines; Tachycardia

Topics: Aged; Arrhythmias, Cardiac; Dose-Response Relationship, Drug; Flecainide; Heart Ventricles; Humans; Male; Piperidines; Tachycardia

The clinical effectiveness of flecainide acetate was evaluated in 36 patients (29 male and 7 female, average age 56 years) in whom therapy with previous antiarrhythmic agents had failed. All patients had documented ventricular tachycardia on Holter electrocardiographic recording and 31 of 36 (86%) had had syncope or required cardiopulmonary resuscitation, or both. Angiographic findings demonstrated significant coronary artery disease in 22 (61%) and primary left ventricular dysfunction in 14 (39%), with a left ventricular ejection of 0.39 +/- 0.4. Patients were treated with an average flecainide dose of 302 +/- 76 mg/day. The follow-up time was 101 +/- 156 days. Thirty-two of 36 patients (89%) had complete elimination of ventricular tachycardia from Holter monitoring and only 2 patients had flecainide discontinued because of noncardiac side effects (numbness, blurred vision and ataxia). However, the drug was subsequently discontinued in 5 patients because of cardiac side effects (proarrhythmic effect in 2, sinus bradycardia in 1, complete atrioventricular block in 1 and new left bundle branch block in 1) and 10 patients died during flecainide therapy (1 with cerebral stroke, 3 with congestive heart failure and 6 with incessant ventricular tachycardia). A comparison of the general cardiac features of those who died with those who did not revealed a significantly lower ejection fraction (0.24 +/- 0.1 vs 0.45 +/- 0.1, p less than 0.05) and a significantly higher flecainide dose (350 +/- 85 versus 276 +/- 59 mg/day, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Anti-Arrhythmia Agents; Death, Sudden; Electrocardiography; Female; Flecainide; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Risk; Tachycardia

In a heterogeneous group of 15 patients with clinical syncope or documented sustained ventricular tachycardia (VT), with induced sustained or nonsustained VT at programmed electrical stimulation, flecainide prevented tachycardia induction in 9 of 15 patients (60%) and improved responses in 2, for a 73% initial favorable response rate. Cycle length of induced rhythms increased an average of 141 ms after the drug. Antiarrhythmic response rate was higher in the absence of coronary artery disease. Ten of these patients were selected for a long-term drug trial. After a median follow-up of 13.5 months, 8 patients (53%) continue to receive flecainide, 6 (40%) successfully treated with flecainide alone and 1 each treated with concomitant therapy with amiodarone and a programmable antitachycardia pacemaker. Minor dosage adjustments were made during early outpatient therapy in 5 patients. Those continuing on therapy show a remarkable absence of side effects and stable drug concentrations. Therapy failed in 2 patients at 0.5 and 4 months, in 1 in association with progression of cardiomyopathy and in another with recurrence of sustained (slow) VT. Although our results have been favorable, preliminary reports from other laboratories have been mixed. Therefore, further experience is needed. In summary, flecainide appears promising in selected patients with VT using a carefully monitored approach including electrophysiologic induction studies.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Electrocardiography; Female; Flecainide; Follow-Up Studies; Humans; Male; Middle Aged; Piperidines; Tachycardia

Flecainide has unusual electrophysiologic properties and a high potency for the suppression of ventricular tachyarrhythmias. Little is known about its inotropic and hemodynamic actions. In isolated rabbit papillary muscle, it produced a concentration-dependent depression of contractile force, the threshold concentration being 1.0 micrograms/ml. In patients undergoing coronary angiography for ischemic heart disease and given 1 (n = 11) and 2 mg/kg (n = 11) of flecainide acetate i.v., there was no change in heart rate or mean arterial pressure. The vehicle in which i.v. flecainide was suspended had no significant effects in 6 patients in whom it was tested. Both doses produced comparable hemodynamic effects irrespective of the level of the left ventricular ejection fraction. The mean right atrial pressure increased by 12% (p less than 0.05) after 1 mg/kg and by 15% (p less than 0.01) after 2 mg/kg of the drug. The corresponding increases in mean wedge pressure were 44% (p less than 0.05) and 33% (p less than 0.05), in mean pulmonary artery pressure 27% (p less than 0.01) and 28% (p less than 0.05), in systemic vascular resistance 10% (p less than 0.05) and 9% (not significant [NS]) and in pulmonary vascular resistance 6% (NS) and 49% (p less than 0.05). Significant decreases in cardiac index (8 and 12%, p less than 0.05), stroke volume index (11 and 15%, p less than 0.01) and stroke work index (12%, p less than 0.05, and 21%, p less than 0.01) as well as in left ventricular ejection fraction (15 and 16%, p less than 0.01) were also induced by the 2 doses of flecainide.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Animals; Anti-Arrhythmia Agents; Cardiac Catheterization; Coronary Disease; Female; Flecainide; Heart; Heart Failure; Hemodynamics; Humans; In Vitro Techniques; Male; Middle Aged; Piperidines; Rabbits; Retrospective Studies; Tachycardia

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

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

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

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

The efficacy and safety of oral flecainide for treatment of ventricular arrhythmias were assessed during a 3-day period in patients with various cardiac diseases. Of 11 patients who received a low dose of flecainide (median daily dose 240 mg), only 4 responded with 90% or greater reduction in premature ventricular complex frequency. Ventricular tachycardia could not be suppressed. During treatment no electrocardiographic changes occurred. 14 of the 19 patients who received a high dose of flecainide (median daily dose 480 mg), demonstrated a 90% or greater reduction in premature ventricular complexes, and ventricular tachycardia did not recur during treatment in 7 out of 9 patients. However, PQ, QRS, and QTc intervals were significantly increased. In general, flecainide was well tolerated and drug administration did not have to be discontinued because of side effects. Flecainide acetate treatment, with a median dose of 480 mg daily, appears to be highly effective for suppressing complex ventricular arrhythmias.

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chronic Disease; Drug Evaluation; Electrocardiography; Female; Flecainide; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Tachycardia

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

The effect of flécaïnide (new class I antiarrhythmic) on ventricular rhythm troubles was studied in 24 patients using Holter's method. The following results were obtained. For ventricular tachycardia, two cases of suppression, three cases of distinct reduction in the number and duration of attack and one failure were recorded. For single ventricular extrasystoles, doublets and triplets, nine very good results (80 to 100 per cent reduction of arrhythmia) and four 50 to 80 per cent reductions in ventricular prematurity were obtained. Results were uncertain in two patients as the disappearance of extra-systoles was not followed by relapse after termination of treatment. There were three failures. A twenty-fifth patient was treated with flécaïnide IV followed by oral administration with uncertain results. Undesirable effects are infrequent and are often characterized by sinusal bradycardia. Blurred vision and paraesthesia were encountered. The principal biological parameters remained unchanged.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Female; Flecainide; Humans; Male; Middle Aged; Piperidines; Tachycardia; Ventricular Fibrillation

To determine the effect of flecainide acetate, a Class IC antiarrhythmic drug, The medication was given to 28 patients with ventricular pacing electrodes. Eleven patients with temporary pacing electrodes (Group I) received intravenous flecainide (2 mg/kg over 10 minutes). Ten patients with chronic permanent electrodes (Group II) were given the same dose at the time of elective pulse generator change. Seven, with implanted multiprogrammable pacemakers capable of threshold analysis (Group III), were given intravenous flecainide and 5 of these were then given the drug orally for up to 3 weeks (100 mg/day increasing to 400 mg/day). In Group I the threshold measured at a pulse width of 0.5 ms rose from a control value of 0.66 to 1.44 volts after 10 minutes (p less than 0.01). In Group II the threshold rose from 1.73 to 2.13 volts (p less than 0.01) and 2 patients had total suppression of their ventricular escape rhythm for approximately one hour. In Group III patients, intravenous flecainide resulted in a rise escape rhythm for approximately one hour. In Group III patients, intravenous flecainide resulted in a rise of the pulse width threshold measured at 2.7 volts from 0.14 to 0.22 ms (p less than 0.02) and at 4.9 volts from 0.06 to 0.11 ms (p less than 0.05) after 10 minutes. After 3 weeks of oral therapy the threshold at 2.7 volts had risen to 0.11 ms /ms (p less than 0.05 after 10 minutes. After 3 weeks of oral therapy the threshold at 2.7 volts had risen from 0.09 to 0.28 ms (p less than 0.02) and at 4.9 volts from 0.06 to 0.16 ms (p less than 0.05) Flecainide significantly increased both acute and chronic thresholds and the most marked rise (greater than 200%) occurred during chronic oral therapy. Both intravenous and oral flecainide should be used with care in patients with either temporary or permanent pacing systems.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Dose-Response Relationship, Drug; Electrocardiography; Female; Flecainide; Heart Block; Humans; Male; Middle Aged; Pacemaker, Artificial; Piperidines; Tachycardia

A case is reported of a patient with functional duality of AV nodal conduction in whom, during ventricular extrastimulus testing, there was a gap in retrograde fast pathway conduction which allowed the temporary expression of retrograde slow pathway conduction. The administration of the antiarrhythmic agent flecainide, which has disparate effects on retrograde fast and slow pathway conduction characteristics, accentuated this phenomenon. The electrophysiological basis of gap phenomena is discussed.

Topics: Adult; Anti-Arrhythmia Agents; Atrioventricular Node; Bundle of His; Cardiac Pacing, Artificial; Electrophysiology; Flecainide; Heart Conduction System; Humans; Male; Piperidines; Purkinje Fibers; Tachycardia

Four patients with recurrent, symptomatic ventricular tachycardia (VT) refractory to conventional antiarrhythmic agents were given flecainide acetate to control arrhythmias. Ventricular stimulation studies were performed in all patients before and 1 to 2 weeks after initiation of oral flecainide therapy. Before flecainide, all patients had easily inducible VT that was morphologically identical to their spontaneously occurring arrhythmia. Flecainide increased the mean PR interval (from 0.17 to 0.23 second), mean QRS duration (from 0.08 to 0.12 second) and mean ventricular effective refractory period (from 235 to 270 ms). Mean corrected QT interval did not change (0.51 second). In 2 patients, VT could not be induced during follow-up stimulation studies. One patient has been treated successfully for 10 months, with no clinically apparent episodes of VT. One patient had recurrent nonsustained VT and was withdrawn from the study as a treatment failure after 6 months of therapy. Two patients had inducible, polymorphous VT that degenerated into ventricular fibrillation that required 2 countershocks before the successful restoration of sinus rhythm. One of these patients had VT stimulation by atrial pacing at a cycle length of 320 ms in the postflecainide electrophysiologic study. VT was not inducible by atrial pacing during this patient's preflecainide study. Thus, sustained oral flecainide administration may precipitate serious electrical instability in susceptible patients, and ventricular stimulation studies and other clinical variables may be useful in selecting patients with recurrent VT who may benefit or may be endangered by oral flecainide therapy.

Topics: Administration, Oral; Adult; Anti-Arrhythmia Agents; Electrocardiography; Flecainide; Heart Ventricles; Humans; Middle Aged; Piperidines; Recurrence; Stroke Volume; Tachycardia

Flecainide acetate is a new class I antiarrhythmic agent which slows atrial, A-V nodal and ventricular conduction velocity, and prolongs refractoriness of these structures (Borchard et al., 1982; Hodess et al., 1979). Recent studies with oral flecainide therapy suggested its high potential for suppression of ventricular tachycardia in humans (Anderson et al., 1981; Duff et al., 1981; Hodges et al., 1982). Its favorable pharmacokinetics with an average plasma half-time of about 20 hours allows in most patients twice daily dosing (Duff et al., 1981). Usually, the drug seemed to be well tolerated and side-effects, such as blurred vision, could be resolved with smaller but still effective doses (Duff et al., 1981). Actually, the ideal antiarrhythmic agent which represents a high degree of effectiveness, a low level of toxicity, a wide therapeutic range, and a prolonged antiarrhythmic action does not exist (Dreifus and Ogawa, 1977). In this report we describe a patient with flecainide-induced aggravation of ventricular tachycardia necessitating resuscitation because of severe hemodynamic deterioration.

Topics: Anti-Arrhythmia Agents; Female; Flecainide; Heart Rate; Humans; Middle Aged; Piperidines; Tachycardia

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Blood Pressure; Bundle of His; Cardiac Pacing, Artificial; Coronary Disease; Electrophysiology; Female; Flecainide; Heart Rate; Humans; Male; Middle Aged; Piperidines; Sinoatrial Node; Tachycardia; Time Factors

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

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

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

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

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

Topics: Anti-Arrhythmia Agents; Female; Flecainide; Heart Ventricles; Humans; Middle Aged; Piperidines; Tachycardia

Topics: Coronary Disease; Electrocardiography; Flecainide; Humans; Male; Middle Aged; Piperidines; Tachycardia; Time Factors

13 patients (54 +/- 11.8 years) with either spontaneously occurring ventricular tachycardia (N = 12) or recurrent syncope (n = 1) probably due to ventricular tachycardia were studied electrophysiologically. In all patients, ventricular tachycardia could be initiated by programmed right ventricular stimulation during the control study. Ventricular tachycardia was sustained in eleven patients and non-sustained in the remaining two. After several days of oral administration of flecainide (400 to 500 mg per day) sustained ventricular tachycardia could still be initiated in seven cases that had to be interrupted by overdrive stimulation in five cases, and by cardioversion in the remaining two. In six cases, short, self-terminating episodes of ventricular tachycardia were induced. In four patients, induction of ventricular tachycardia was unchanged or made easier, whereas in seven cases ventricular tachycardia was more difficult to induce (i.e. later during the step-like stimulation program). The mean rate of induced ventricular tachycardia decreased from 215 +/- 59.4/min (+/- S.D.) to 169 +/- 44.1/min during flecainide (p less than 0.025). The interval between the tachycardia-initiating beat and the first beat of tachycardia increased from 323 +/- 61.1 ms to 438 +/-148.3 ms (P less than 0.02). The effective refractory period of the right ventricle was prolonged from 240 +/- 20.5 ms t 279 +/- 37.3 ms (P less than 0.005). The plasma concentration of flecainide at the time of stimulation was 995 +/- 238 ng/ml. Thus, flecainide exerts a marked effect on the rate of induced ventricular tachycardia, whereas the mode of induction did not change considerably. The prophylactic effect of long-term therapy with flecainide in patients with recurrent ventricular tachycardia needs further studies.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Coronary Disease; Electrocardiography; Female; Flecainide; Heart Failure; Heart Rate; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Tachycardia

Topics: Animals; Dogs; Female; Nitriles; Phencyclidine; Piperidines; Tachycardia

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

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

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

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

A novel benzanilide derivative, MJ 9067, has been shown to abolish experimental atrial and ventricular arrhythmiase effectively and promote the return of normal sinus rhythm in a variety of animal models. At intravenous dose levels ranging from 0.5 to 3.2 mg/kg, MJ 9067 successfully converted atrial fibrillation induced by either local application of aconitine or electrical stimulation, and ventricular tachycardia elicited by intravenous injection of ouabain or digoxin. The compound was equally effective in vagotomized or nonvagotomized dogs, and in intact cats and monkeys. The ventricular ectopic rate in conscious dogs 18 to 20 hours after two-stage ligation of a coronary artery was also markedly reduced by the drug at 2 mg/kg i.v. At antiarrhythmic dose levels, there were no undesirable effects noted on peripheral blood pressure, heart rate or the configuration of the electrocardiogram.

Topics: Aconitine; Anilides; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Blood Pressure; Cats; Digoxin; Dogs; Electric Stimulation; Electrocardiography; Female; Haplorhini; Heart Rate; Male; Ouabain; Piperidines; Saimiri; Tachycardia

Topics: Adult; Angina Pectoris; Blood Flow Velocity; Blood Pressure; Cardiac Output; Coronary Circulation; Coronary Vessels; Heart Rate; Humans; Lactates; Middle Aged; Myocardium; Oxygen Consumption; Pacemaker, Artificial; Perhexiline; Piperidines; Tachycardia; Vascular Resistance; Vasodilator Agents

Topics: Adult; Aged; Androstanes; Anesthetics; Blood Pressure; Body Temperature; Drug Interactions; Electrocardiography; Female; Halothane; Humans; Ketones; Male; Methoxyflurane; Middle Aged; Neuromuscular Nondepolarizing Agents; Piperidines; Pregnanes; Pulse; Respiration; Tachycardia; Trichloroethylene; Tubocurarine

Topics: Amides; Anesthetics, Local; Animals; Arrhythmia, Sinus; Arrhythmias, Cardiac; Blood Pressure; Cats; Epinephrine; Female; Guinea Pigs; Halothane; Ileum; In Vitro Techniques; Indoles; Lidocaine; Male; Muscle Contraction; Nicotine; Ouabain; Piperidines; Procaine; Propranolol; Quinidine; Tachycardia; Ventricular Fibrillation

Topics: Anesthesia, Intravenous; Blood Glucose; Blood Pressure; Female; Humans; Male; Phencyclidine; Piperidines; Postoperative Complications; Preanesthetic Medication; Tachycardia