Pharmacokinetic studies: their role in determining therapeutic efficacy of agents designed to prevent sudden death.
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Administration, Oral↗
Biomedical subjects
E L Pritchett
Publications and source records attributed to E L Pritchett.
Pirmenol, a new antiarrhythmic agent: initial study of efficacy, safety and pharmacokinetics.
Pirmenol (CI-845), a new antiarrhythmic drug, was studied for the first time in humans to establish a minimum effective i.v. dose in 10 patients with chronic, stable premature ventricular complexes (PVCs) and to evaluate toxicity and pharmacokinetics. Infusions of 70-150 mg were associated with a 90% or greater reduction in PVCs nine of the 12 times they were administered to six patients. Peak plasma concentrations were 1.0-3.8 micrograms/ml at the end of these infusions. At the same time, small but significant increases in diastolic blood pressure (4 mm Hg) and QTc interval (0.01 second) were seen, but both values were within the normal range. Pirmenol was associated with no change in heart rate, systolic blood pressure, PR interval or QRS duration, renal, hepatic or hematologic function, or symptoms. Blood, plasma and free drug concentrations declined biexponentially after cessation of a 150-mg infusion (n = 4), with a terminal half-life of 7-9.4 hours. The therapeutic response, lack of toxicity, and relatively long half-life indicate that pirmenol is a promising antiarrhythmic agent.
Anti-Arrhythmia Agents↗
Electrocardiogram recording by telephone in antiarrhythmic drug trials.
The purpose of this study was to evaluate ECG recording by telephone as a research tool for documenting the cardiac rhythm during symptoms of paroxysmal atrial tachycardia. Eleven patients were enrolled in the study during the first year. They transmitted 34 rhythm strips during symptoms, 17 of which showed paroxysmal atrial tachycardia; only one of the 34 was uninterpretable. Three patients thought they were having paroxysmal atrial tachycardia when their rhythm strips showed that they were having sinus tachycardia. Patient compliance and satisfaction with our follow-up system were high. Our study supports the use of ECG recording by telephone as an excellent tool to document arrhythmias in patients enrolled in clinical trials.
Anti-Arrhythmia Agents↗
A comparison of clinical electrophysiologic studies in different institutions.
Although electrophysiologic studies have been used to evaluate tachycardia and AV conduction for over 10 years, there are no data comparing measurements obtained on the same patient studied in two institutions. We compared the records of 27 patients who underwent electrophysiologic studies at two different institutions and one patient studied twice in the same institution by two different investigators. We sought to determine if basic intervals, observed tachycardia, and diagnoses were comparable. We found no significant difference between the reported sinus cycle length, atrial-His interval, and His-ventricular interval when the patients were evaluated as a group. However, there were important measurement differences between the two studies in individual patients. The cycle length of induced tachycardias having similar QRS morphology and AV relation was also similar for the group, but individual patients again demonstrated important differences between the two studies. The diagnosis of the tachycardia varied in four patients. This report suggests that intracardiac recordings and the diagnosis of observed tachycardias are comparable among institutions studying the same patient when the group results are compared. However, individual patients demonstrate important measurement differences between the two institutions.
Adolescent↗
Persistent left superior vena cava in patients with congenital atrioventricular preexcitation conduction abnormalities.
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Adolescent↗
Reduced verapamil clearance during long-term oral administration.
Plasma concentrations of verapamil and its metabolite, norverapamil, were measured in six patients with supraventricular tachycardia after the first and seventh dose of a regimen consisting of 120 mg every 8 hr by month. Steady state was reached by the seventh dose and the area under the concentration-time curve (AUC) at steady state (1999 +/- 435[SD] ng/ml . hr) was greater than that after the first dose (788 +/- 224, P less than 0.001). This unexpected cumulation was associated with prolongation of verapamil half-life (t1/2) from 2.75 +/- 1.14 to 4.52 +/- 1.10 hr. Norverapamil AUC also rose from 1225 +/- 405 to 2312 +/- 963 ng/ml/hr during the attainment of steady state. We conclude that verapamil cumulates to a greater extent than predicted from its t1/2, due to reduction in hepatic clearance.
Administration, Oral↗
The method of separate exponentials: a simple aid to devising intravenous drug-loading regimens.
Stimulation of complex dosage regimens for drugs with multicompartmental kinetics is described using the method of separate exponentials. This approach requires that alpha- and beta-phases are treated separately throughout and summed only at the end of the stimulation. The method was used to devise a loading regimen for pirmenol, comprising a priming injection, and a rapid loading infusion, followed by a maintenance infusion. The regimen was tested in a patient with excellent agreement. The method of separate exponentials is mathematically simple and of informational value in that it demonstrates when the early distribution phase is important. Its use can avoid the potentially dangerous assumption of one-compartmental kinetics in the design of intravenous loading regimens.
Anti-Arrhythmia Agents↗
Simplified esophageal electrocardiography using bipolar recording leads.
Diagnosing cardiac arrhythmias is easier if the P wave can be identified clearly. Esophageal electrocardiography with a unipolar recording lead attached to the V1 terminal of an ECG machine has been used in the past to show P waves. We used both bipolar and unipolar recording leads and standard ECG equipment to record the esophageal ECG and then compared the results obtained with both leads. Twenty-two cardiac rhythms were evaluated in 15 patients. The unipolar lead recorded a P wave that was smaller than the QRS complex (0.83 +/- 0.47 mV and 1.28 +/- 0.79 mV, respectively, p less than 0.01) and was obscured when the two depolarizations were nearly simultaneous. The bipolar lead recorded a P wave that was larger than the QRS complex (0.93 +/- 0.62 mV and 0.33 +/- 0.3 mV, respectively, p less than 0.001) and was never obscured. The unipolar lead recorded a P-to-QRS ratio that was smaller than that recorded by the bipolar lead (0.8 +/- 0.5 and 3.3 +/- 1.8, respectively, p less than 0.001). A bipolar esophageal lead can be recorded simply at the bedside using a standard ECG machine and is superior to the conventional unipolar lead.
Electrocardiography↗
The surgical approach to supraventricular arrhythmias.
The relatively small amount of experience with the surgical treatment of supraventricular tachycardias due to abnormalities other than a Kent bundle has been reviewed. The surgical procedure is direct but may not be definitive. With increasing knowledge concerning the nature of the arrhythmias as well as the identification of the site of the heart from which they originate, it is hoped that definitive operation will be possible. The experience at Duke with the surgical interruption of Kent pathways has now evolved to the point that the patient can be successfully treated at a low risk and with the promise of a satisfactory result.
Arrhythmias, Cardiac↗
Arrhythmogenic epilepsy: an hypothesis.
This report describes a clinical syndrome of arrhythmias that may have neural origin. Two patients presented with episodes of loss of consciousness, disorientation, and paroxysmal supraventricular tachycardia (PSVT). One patient reported experiencing neurologic symptoms without tachycardia. When electrophysiologic testing with intracardiac recordings and programmed stimulation yielded no abnormalities that could account for the arrhythmias, a primary neurologic abnormality was sought. The electroencephalograms of both patients showed epileptiform discharges that supported this hypothesis. Arrhythmias and neurologic symptoms were controlled by treatment with the antiepileptic drug carbamazepine in one patient. Findings in these two patients suggest that in some patients arrhythmias may be a manifestation of seizures.
Adolescent↗
'Dual atrioventricular nodal pathways" in patients with Wolff-Parkinson-White syndrome.
'Dual atrioventricular nodal pathways" were found in five patients who also had the Wolff-Parkinson-White syndrome. All five patients had a re-entrant tachycardia that used the atrioventricular node for conduction in the anterograde direction and an accessory atrioventricular pathway for conduction in the retrograde direction. One of the patients also had a re-entrant tachycardia that originated within the atrium or the atrioventricular node. Dual atrioventricular nodal pathways were identified in three of the five patients during their first electrophysiological study because the effective refractory period of the accessory atrioventricular pathway in the anterograde direction was longer than the effective refractory period of the fast atrioventricular nodal pathway. In the other two patients the dual atrioventricular nodal pathways were found only after operative division of an accessory atrioventricular pathway. Re-entrant tachycardia that uses an accessory pathway may be cured by operative division of the accessory pathway. Tachycardia resulting from re-entry within the atrioventricular node cannot be cured by an operation unless the normal conduction system is divided and a permanent pacemaker implanted. These five patients indicate the importance of determining the aetiology of tachycardia by studying the tachycardia itself and not only the type of atrioventricular conduction present.
Atrioventricular Node↗
Cryosurgical ablation of the atrioventricular node-His bundle: long-term follow-up and properties of the junctional pacemaker.
We used a cryosurgical technique to ablate the atrioventricular (AV) node-His bundle in twenty-two selected patients with disabling supraventricular tachyarrhythmias unresponsive to medical management. Successful AV block was achieved in seventeen. There was no intraoperative mortality and significant surgical complications were not encountered. Electrophysiologic studies performed 7-10 days after surgery revealed that the subsidiary pacemaker had a narrow QRS complex morphology and a mean cycle length of 1244 msec. Isoproterenol (1-4 microgram/min i.v.) significantly increased (p less than 0.01) the rate of the subsidiary pacemaker (mean maximum response 1008.3 msec); atropine (2 mg i.v.) had no effect on its rate. The cycle length of the subsidiary pacemaker during long-term follow-up (mean 14.8 months) showed a small but significant (p = 0.024) increase (mean cycle length 1430 msec). Treadmill exercise in seven patients did not result in the subsidiary pacemaker exceeding the rate of the implanted demand pacemaker set at 70 beats/min. The properties of the subsidiary pacemaker suggest an intra-Hisian site of impulse formation.
Adult↗
Origin of the atrial electrogram recorded from the esophagus.
The purpose of this study was to ascertain the origin of the atrial electrogram recorded on the esophageal lead. The atria and esophagus were mapped during reciprocating tachycardia in 11 patients with the Wolff-Parkinson-White syndrome and one patient with atrioventricular nodal reentry, and during right ventricular pacing in four additional patients. The esophagus was mapped by recording atrial electrograms at 1-cm intervals throughout the esophagus beginning at the most distal area where atrial depolarization was seen. The retrograde atrial activation time recorded on the esophageal lead in its distal position occurred at the same time as atrial septal depolarization in all patients. In 14 of 16 patients, the distal esophageal ventriculoatrial (VA) conduction time was also the shortest esophageal VA conduction time recorded. In two of five patients with left lateral accessory pathways, the shortest esophageal VA conduction time was noted during pullback of the lead from the esophagus instead of at the most distal area. The most likely explanation for this was an unusual anatomic relationship between the esophagus and left atrium in these two patients. We conclude that 1) the most distal esophageal atrial electrogram probably records posterior paraseptal atrial depolarization; 2) it is unusual to record clearly identifiable left atrial activation in the esophagus; and 3) the esophageal lead is not useful in locating left-sided accessory pathways.
Atrioventricular Node↗
The "compensatory pause" of atrial fibrillation.
A long pause after an abnormal heat during atrial fibrillation has been called a "compensatory pause" and has been used to identify premature ventricular complexes (PVCs) and to differentiate them from supraventricular beats with aberration. The diagnostic value of the compensatory pause is controversial and has not been tested systematically with programmed stimulation and intracardiac recordings. In this study we used these methods to determine if PVCs induced during atrial fibrillation were followed by compensatory pauses. Five patients were studied who had ECGs with a normal PR interval and a normal QRS duration and morphology during sinus rhythm. Atrial fibrillation was induced by rapid atrial pacing. PVCs were induced by coupling a ventricular extrastimulus to every eighth or tenth QRS complex during atrial fibrillation. The coupling interval of the PVC was changed in 10- or 20-msec increments until the entire cardiac cycle was scanned. The mean duration of recorded atrial fibrillation was 15.7 minutes. Fifty-seven to 163 PVCs were induced in each patient. The mean cycle after the induced PVC was calculated and compared with the mean control cycle. The mean cycle after the PVC was 107-136 msec longer than the mean control cycle (p < 0.001 in every patient). This study confirms the presence of a compensatory pause after stimulated PVCs in atrial fibrillation.
Adult↗
Accessory atrioventricular pathways that conduct only in the antegrade direction.
Patients with accessory atrioventricular pathways that conduct only in the antegrade direction represent an unusual variant of the Wolff-Parkinson-White syndrome. This report describes such patients and compares them with patients with accessory pathways that demonstrate bidirectional conduction. Of 143 patients with single accessory pathways, seven demonstrated exclusive antegrade conduction (study group), 111 demonstrated bidirectional conduction (control group), and 25 demonstrated exclusive retrograde conduction. Study group patients were significantly older than patients in the control group (42 +/- 9.8 years and 31.4 +/- 13.9 years, respectively, p < 0.0001). Refractoriness and conduction characteristics of the accessory pathways in the antegrade direction in the study group were not different from those in the control group. Control group patients presented with atrioventricular reentrant tachycardia (58 of 111), atrial fibrillation (23 of 111), both of these arrhythmias (19 of 111), or no documented arrhythmia (11 of 111). Study group patients presented with only atrial fibrillation (six of seven). An accessory pathway with only antegrade conduction is a rare cause of symptoms in the Wolff-Parkinson-White syndrome. These patients are asymptomatic until atrial fibrillation develops as the patient ages. Despite the absence of retrograde conduction over the accessory pathway, its antegrade functional properties are similar to pathways that demonstrate bidirectional conduction.
Adolescent↗
Ventricular fibrillation in the Wolff-Parkinson-White syndrome.
To examine the risk of ventricular fibrillation in patients with the Wolff-Parkinson-White syndrome, we compared patients who had this syndrome and a history of ventricular fibrillation related to preexcitation with patients who had the syndrome without this history. Ventricular fibrillation occurred during atrial fibrillation, with rapid conduction over the accessory pathway, and these patients had a higher prevalence of both reciprocating tachycardia and atrial fibrillation (14 of 25 vs. 18 of 73, P = 0.004) and multiple accessory pathways (five of 25 vs. four of 73, P = 0.012). The shortest preexcitation R-R interval during atrial fibrillation was less in the group with ventricular fibrillation (mean shortest R-R, 180 vs. 240 milliseconds, P less than 0.0001) as was the average R-R interval (mean average R-R, 269 vs 340 milliseconds, P less than 0.0001). Patients with Wolff-Parkinson-White syndrome who are most susceptible to ventricular fibrillation have a history of atrial fibrillation and reciprocating tachycardia, demonstrate rapid conduction over an accessory pathway during atrial fibrillation and have multiple accessory pathways.
Adolescent↗
Reentry within the atrioventricular node: surgical cure with preservation of atrioventricular conduction.
Paroxysmal supraventricular tachycardia (PSVT) is commonly caused by reentry within the atrioventricular (AV) node. This arrhythmia was abolished by operative dissection of the AV junction in a patient with disabling tachycardia that was not controlled by drugs. The operation was intended to create complete AV block, but AV conduction persisted after surgery. An electrophysiologic study 1 year after the operation revealed that the operation changed AV conduction in both the antegrade and retrograde directions, which may explain the absence of tachycardia. The patient has been free of arrhythmias for 18 months.
Atrioventricular Node↗
The natural history of conduction system disease in myotonic muscular dystrophy as determined by serial electrophysiologic studies.
To evaluate the progression of conduction system disease in myotonic muscular dystrophy, nine patients underwent serial electrophysiologic studies at a mean of 35 months apart. At the initial study, seven patients had first-degree atrioventricular block and three of these seven had disease in the His-Purkinje system (HV greater than 55 msec). At the second study, seven patients had prolonged HV intervals, and during the almost 3-year period, HV intervals increased by at least 5 msec in all seven patients. No electrophysiologic or electrocardiographic measures could be found that correlated with progression of conduction disease in these patients. Because of the failure of electrophysiologic measures to predict progression of conduction disease in these patients, electrophysiologic studies are recommended only for symptomatic patients. If significant disease is found in either impulse formation or conduction, permanent pacemaker therapy is warranted.
Adult↗