Is it safe to use intravenous verapamil to treat a patient who is taking oral verapamil?
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Administration, Oral↗
Biomedical subjects
M J Reiter
Publications and source records attributed to M J Reiter.
Efficacy, safety, and pharmacokinetics of a concentration-maintaining regimen of intravenous pirmenol.
A 3-stage, concentration-maintaining intravenous infusion regimen of pirmenol, a new antiarrhythmic agent, was tested for efficacy and safety in 8 subjects with chronic, stable premature ventricular beats. The regimen, which consisted of (1) a priming bolus of 50 mg over 2 minutes, followed by (2) a rapid loading infusion of 2.5 mg/min for 1 hour, and (3) a maintenance infusion of 0.25 mg/min, rapidly achieved and maintained stable plasma pirmenol levels from 0.94 to 2.75 micrograms/ml, during infusions lasting up to 48 hours. Therapeutic efficacy was evaluated during 4-hour infusions in 5 patients utilizing a randomized, double-blind, placebo-controlled study design. Pirmenol suppressed average premature ventricular beat frequency 93 +/- 6% compared with control values (p = 0.03). Pirmenol infusions were unassociated with toxicity. There were slight but significant increases in diastolic blood pressure, QRS duration, and corrected Q-T interval. No significant changes occurred in systolic blood pressure, heart rate, P-R interval, or laboratory variables. Pirmenol is a promising therapeutic agent that warrants further evaluation. The 3-stage infusion satisfactorily achieves and maintains therapeutic plasma pirmenol levels.
Adult↗
A system for the analysis of long-term electrocardiographic studies in clinical research and training.
A computer system has been developed for the analysis of data from long-term electrocardiographic studies in the context of an institution committed to clinical research and training. The major characteristics required of such a system are intelligence, flexibility, friendliness, and maintainability. These attributes are achieved by a user interface which consists of menus and interactive graphics, and by the use of highly modular software developed in a high-level programming language. The system has been used in studies of the effects of drugs on cardiac arrhythmias and has been easy to learn and convenient to use.
Academies and Institutes↗
Verapamil plasma binding: relationship to alpha 1-acid glycoprotein and drug efficacy.
The relationship between alpha 1-acid glycoprotein (AAG) plasma concentration and plasma verapamil binding was examined in samples obtained 15 minutes after 10 mg IV verapamil to 15 subjects. There was a good correlation (r = 0.83) between the binding ratio and AAG concentration, suggesting that AAG could bind verapamil. This was confirmed in vitro by the addition of AAG to an albumin solution, which resulted in a strong correlation between binding ratio (r = 0.99) and AAG concentration. The relationship between both free and total plasma concentrations and the effects of verapamil on the PR interval was also examined several times after 10 mg IV verapamil in seven of the subjects. While there was a correlation between log of both concentrations and the percent prolongation in PR interval (P less than 0.001), the correlation was stronger with free drug concentration (r2 = 0.58) than with total plasma concentration (r2 = 0.36). The range of free concentrations associated with a given effect (220%) was also narrower than that for total concentration (300%). While these data indicate that AAG is responsible for most of the variability in plasma verapamil binding, which in turn contributes somewhat to variation in effectiveness of a given total plasma concentration, neither of these causes of individual variations is likely to have a major clinical impact in patients who, apart from arrhythmia, are otherwise healthy.
Chromatography, High Pressure Liquid↗
Bystander accessory pathway during AV node re-entrant tachycardia.
Between 1970 and July 1980, wide QRS tachycardia due to re-entry confined to the AV node with bystander involvement of an accessory atrioventricular pathway (AAV) was documented in three of 290 patients with the Wolff-Parkinson-White syndrome studied at Duke Medical Center. In each of the patients, at least one transition between wide and narrow QRS morphology was recorded without change in either the cycle length of tachycardia or the atrial activation sequence. Two of the three patients had a single left-sided AAV (lateral, postero-lateral) showing antegrade conduction only. The third patient had two right-sided AAVs (free wall, septal), each capable of bidirectional conduction. Initiation and termination of repetitive concealed conduction into the ventricular insert of an AAV appeared to be one mechanism determining bystander AAV participation. Documentation of the retrograde sequence of atrial activation during tachycardia, and examination of the effects of interpolated premature depolarizations from both the ventricle and mid-line atrium are the most helpful features in resolving the differential diagnosis of wide QRS tachycardia in patients with W-P-W syndrome.
Adolescent↗
The electrophysiologic basis and management of symptomatic recurrent tachycardia in patients with Ebstein's anomaly of the tricuspid valve.
Twenty-two patients with Ebstein's anomaly were evaluated because of recurrent tachycardia. A total of 30 accessory pathways were present in 21 of the 22 patients. Twenty-six accessory pathways were of the atrioventricular (A-V) type while four were Mahaim fibers. Multiple accessory pathways were present in eight patients. Twenty-five of the 26 accessory A-V pathways were right-sided, either in the posterior septum (12 pathways) or the posterolateral free wall (13 pathways); one patient with corrected transposition of the great arteries had a left-sided accessory A-V pathway in a lateral free wall location. Patients with accessory A-V pathways had a long minimal ventriculoatrial (V-A) conduction time during reciprocating tachycardia (192 +/- 47 ms) and usually showed a persistent complete or incomplete right bundle branch block morphology. At surgery, preexcitation was invariably localized to the atrialized ventricle. The long V-A conduction time during reciprocating tachycardia appeared to consist of late activation of the local ventricle in the region of the accessory pathway with a further delay occurring before excitation of adjacent atrium presumably due to conduction over the accessory pathway. Accessory A-V pathways were successfully sectioned with no deaths in 13 of 15 patients. On the basis of these data, certain electrocardiographic findings encountered in the study of patients with recurrent tachycardia should point to the possibility of associated Ebstein's anomaly: morphology of the surface electrocardiogram suggesting preexcitation of the right posterior septum or right posterolateral free wall as well as the combination during reciprocating tachycardia of a long V-A interval and right bundle branch block.
Adolescent↗
Pharmacokinetics of verapamil: experience with a sustained intravenous infusion regimen.
Disappearance kinetic characteristics of verapamil were determined in 9 patients after a single intravenous dose. From the pharmacokinetic variables determined, we designed an intravenous regimen to maintain a plasma verapamil concentration of 150 ng/ml consisting of (1) a loading bolus (10 mg over 2 minutes), followed by (2) a rapid loading infusion (0.375 mg/min) for 30 minutes, and finally (3) a maintenance infusion (0.125 mg/min). We tested this regimen in 7 patients for 2 to 12 hours, and found it to be safe and to produce stable prolongation of the P-R interval. Verapamil concentration was highest immediately after the bolus administration and was prevented from falling below 67 ng/ml by the rapid infusion. Maintenance concentration remained between 77 and 156 ng/ml for all patients, and averaged 122 ng/ml. Transient and slight decreases in brachial blood pressure and sinus cycle length occurred coincident with the maximum verapamil concentration. Maximum P-R prolongation lagged behind peak plasma concentration but was sustained for the duration of the infusion. Prolongation of the P-R interval was not significantly different at the end of the infusion from that 90 minutes after the start of the regimen. No patient demonstrated significant side effects, arrhythmia, or clinically important hypotension. Although the specified regimen produced a final concentration averaging 125 ng/ml, it is predicted that infusion regimens producing other plasma concentrations can be similarly devised by changing the bolus, rapid loading infusion, and maintenance infusion doses in proportion to the desired final plasma concentration.
Adult↗
Hemodynamic effects of acute atrioventricular sequential pacing in patients with left ventricular dysfunction.
Acute atrioventricular (A-V) sequential pacing was compared with ventricular pacing in seven men with symptomatic left ventricular failure (New York Heart Association functional class III and IV) and depressed left ventricular ejection fraction (mean 29 percent, range 18 to 40). Cardiac index was higher during A-V sequential pacing than during ventricular pacing for every patient at paced rates of 75 to 100 beats/min. The mean increment was 17 percent (range 10 to 37) at a paced rate of 75 beats/min, 23 percent (range 8 to 45) at a paced rate of 85 beats/min and 29 percent (range 19 to 55) at a paced rate of 100 beats/min. The increase in cardiac index in an individual patient did not correlate with baseline characteristics including functional class, cardiothoracic ratio, resting ejection fraction, cardiac index or balloon-occluded pulmonary wedge pressure. Arterial pressure varied from beat to beat during ventricular pacing because of the changing relation of atrial to ventricular systole. When an atrial contraction preceded a ventricular paced beat by a physiologic interval intraarterial pulse pressure uniformly increased. That increase correlated strongly (r = 0.993) with the increase in cardiac index that occurred during A-V sequential pacing. Measurement of the pulse pressure during A-V dissociation is a simple technique that may be useful for predicting the degree of improvement in cardiac output expected with methods of pacing that restore A-V synchrony.
Aged↗
Pirmenol kinetics and effective oral dose.
The oral form of pirmenol has not been administered to man. Pirmenol was given by mouth to eight patients with chronic, stable premature ventricular beats (PVBs) to determine effective dose and kinetics. The patients were evaluated with a dose-ranging protocol following by a double-blind, crossover, placebo-controlled study of doses that were effective during dose ranging. Oral doses of 150 to 250 mg induced at least 90% suppression of PVBs 18 of the 19 times they were administered during both protocols. During the double blind experiment, a single oral dose of pirmenol suppressed 95 +/- 8% PVBs/hr (mean +/- SD) for 3 consecutive hr, while placebo suppressed 4 +/- 42% PVBs/hr (P less than 0.01). a 90% or greater reduction in PVBs persisted for a median of 6 hr (range 1 to 8 hr). The range of plasma pirmenol concentrations associated with an at last 90% reduction in PVBs was 0.7 to 2.0 micrograms/ml. Median half-life (t1/2) was 9.3 hr (range 6.0 to 12.4) with 86.6 +/- 2.4% protein binding and 82.6 +/- 23.6% bioavailability. At peak drug level there was lengthening of the QTc interval (0.036 sec, P less than 0.05), but no change in heart rate, blood pressure, PR interval or QRS duration, or symptoms. In this single-dose study, pirmenol effectively reduced PVBs, has a relatively long t1/2, and was minimally toxic.
Administration, Oral↗
Comparison of intravenous and oral verapamil dosing.
To compare the effects of intravenous and oral verapamil we examined the prolongation of the PR interval in 11 patients after (1) a single 10 mg IV bolus given over 2 min, (2) a single oral dose of 120 mg, and (3) a sustained concentration-maintaining infusion. Maximal PR interval prolongation was delayed relative to peak plasma verapamil concentration in all patients after the bolus and in seven of 11 patients after oral dosing. In all 11 patients oral verapamil was less potent than a single intravenous bolus of verapamil; the plasma verapamil concentration corresponding to a 10% prolongation of the PR was 39.5 +/- 21.7 ng/ml after the bolus and 146.3 +/- 75.1 ng/ml after the oral dose (P = 0.001). However, there was no such difference between oral verapamil and an infusion in six patients. The plasma verapamil concentration corresponding to a 10% PR prolongation was 35.7 +/- 24 ng/ml after the bolus, 132.5 +/- 80.8 ng/ml after the oral dose, and 85.2 +/- 29.9 ng/ml after the infusion. Maximum PR prolongation (drug efficacy) was comparable for the three methods of administration. There was no evidence of tachyphalaxis during prolonged infusions. We conclude that both oral doses and infusions of verapamil are less potent then bolus doses, but that drug efficacy at the concentrations reached is equivalent for the three. Plasma verapamil concentrations determined after bolus doses appear to underestimate effective plasma concentration when the drug is given by the oral or infusion methods.
Administration, Oral↗
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↗
Comparison of croton oil and cantharidin induced inflammations of the mouse ear and their modification by topically applied drugs.
The inflammatory response to topical application of cantharidin or croton oil to the mouse ear was studied. Croton oil dermatitis developed more rapidly and reached its apparent peak earlier than cantharidin dermatitis. Either dermatitis detected topical rather than systemic antiinflammatory activity of glucocorticosteroids and distinguished between steroid esters and their alcohols. A number of drugs were tested for their ability, after topical application, to inhibit these dermatitides. Nonsteroidal antiinflammatory drugs weakly inhibited croton oil dermatitis but were without effect on cantharidin dermatitis. Beta-adrenergic agonists and antagonists inhibited both dermatitides. It is suggested that the use of these simple models of dermatitis is appropriate for identifying new, topically effective antiinflammatory drugs.
Administration, Topical↗
Affinity labeling of the acetylcholine receptor in the electroplax: electrophoretic separtion in sodium dodecyl sulfate.
Electroplax, single cells dissected from electric tissue of Electrophorus, are labeled in a two-step procedure: reduction by dithiothreitol followed by alkylation by the affinity label 4-(N-maleimido)-alpha-benzyltri-[methyl-(3)H]methylammonium iodide, either alone or in combination with [2,3-(14)C]N-ethylmaleimide. Electrophoresis in sodium dodecyl sulfate on polyacrylamide gel of an extract, prepared with this detergent, of single-labeled or of double-labeled cells results in a major peak of (3)H activity, with a mobility corresponding to a polypeptide of molecular weight 42,000. In addition, in the double-labeled samples, there is a unique peak in the ratio of (3)H to (14)C that is coincident with the (3)H peak. The electrophoretic patterns of extracts of cells in which affinity alkylation of the reduced receptor has been suppressed by dithiobischoline, an affinity oxidizing agent, by cobratoxin, an irreversible ligand, or by hexamethonium, a reversible ligand, show a considerably diminished peak of (3)H activity in the region of molecular weight 42,000. This is the predominant difference between the electrophoretic patterns of extracts of unprotected and of protected cells. Furthermore, extracts of cells protected with dithiobischoline before labeling with both tritiated affinity label and [(14)C]N-ethylmaleimide do not show the peak in the (3)H to (14)C ratio seen in the absence of protection. Thus, by several diverse criteria, the peak of (3)H activity corresponding to a molecular weight of 42,000 contains affinity-labeled acetylcholine receptor or receptor subunit.
Acrylamides↗
Interactions of a cobra neurotoxin and affinity labels of the acetylcholine receptor in the electroplax.
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Acetylcholine↗
Paroxysmal supraventricular tachycardias.
Paroxysmal supraventricular tachycardia (PSVT) is a distinct clinical syndrome. Most patients present with the abrupt onset of palpitations, dizziness, dyspnea, or chest pain. The electrocardiogram (ECG) demonstrates a fast heart rate (150-250 beats per min), a regular rhythm, and most often, a narrow QRS complex. The P wave is usually hidden within the QRS complex. PSVT is caused by reentry, and the tachycardias are classified, electrophysiologically, according to the anatomic location of the reentry circuit. Atrioventricular nodal reentry is the most common form of PSVT. In A-V nodal reentry, there are two conducting pathways (alpha and beta) that have different conduction times and refractory periods; both pathways are confined to the A-V nodal and perinodal atrial tissue. The other common form of PSVT, termed atrioventricular reciprocating tachycardia, depends on an anatomically distinct, or "accessory," pathway that may conduct impulses between the atria and the ventricles, while bypassing the AV node. The two forms of PSVT may be distinguished in many cases by examining the 12-lead electrocardiogram. In the majority of cases of A-V nodal reentry, the atria and ventricles are depolarized simultaneously, and the P waves are hidden in the QRS complex. If the reentry circuit includes an accessory pathway, the P wave always follows the QRS, and usually the R-P interval exceeds 70 msec. Several principles should guide the management of PSVT: (a) Unstable patients require emergent electrical cardioversion; (b) A 12-lead ECG should be obtained immediately to confirm that the tachycardia has a narrow complex (ventricular tachycardia may masquerade as PSVT if only a single lead is examined); (c) Vagal maneuvers may be attempted (the Valsalva maneuver is safer and more efficacious, especially in the elderly); and (4) In most patients, adenosine is the first-line agent to treat PSVT. Contraindications to adenosine and drug interactions are noted in this article. In addition, the use of adenosine in wide complex tachycardias and the indications for admission and referral for electrophysiologic evaluation are discussed.
Adenosine↗
A summary and assessment of the findings and conclusions of the ESVEM trial.
The Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial was completed in 1992 and the primary results were reported in 1993. Since then, considerable discussion about this trial has taken place and new trial results have been reported. Trial analysis has yielded seven principal findings to date concerning treatment of patients with ventricular tachyarrhythmias, ie: (1) similar accuracy of electrophysiologic study (EPS), Holter monitoring (HM), and EPS combined with HM for predicting antiarrhythmic drug efficacy; (2) greater efficiency and lower cost of HM; (3) improved survival associated with predicted drug efficacy; (4) predictors of response to EPS and HM; (5) greater efficacy and lower cost of therapy with sotalol compared with drugs with class-l effects; (6) lack of a relationship between presenting and recurring arrhythmia; and (7) preponderance of nonarrhythmic deaths in trial participants. A number of additional specific findings of the trial are reviewed in this symposium. Several criticisms of the trial's enrollment, methods, and efficacy criteria are reviewed and discussed. Some criticisms are valid. Many are related to misunderstandings of ESVEM trial methodology and to bias of the individual critics. Some are simply incorrect. The importance of the ESVEM trial in the present day may be limited by the growing use of implanted devices rather than drugs for treatment of ventricular tachyarrhythmias. If clinical trials ultimately prove devices to be no more effective than drugs, the findings of the ESVEM investigators will grow in importance.
Adrenergic beta-Antagonists↗
Influence of Holter monitor and electrophysiologic study methods and efficacy criteria on the outcome of patients with ventricular tachycardia and ventricular fibrillation in the ESVEM trial.
Because not all laboratories use the monitoring and stimulation protocols used in the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial, we reanalyzed the ESVEM patients' data using alternative, commonly used Holter monitor (HM) and programmed stimulation efficacy criteria to determine if different criteria would have changed the trial's conclusions. Also, because beta-blocker use and coronary artery disease frequency were not equally distributed between the two limbs in ESVEM, we reanalyzed the ESVEM data adjusting for the possible effect of these variables. In the HM limb, drug efficacy in the original ESVEM analysis was declared by reduction of total premature ventricular complexes (PVCs) by 70%, pairs by 80%, runs of 3 to 15 beats by 90%, and all ventricular tachycardia (VT) more than 15 beats by 100%. In this analysis, we examine outcome in subjects meeting two more stringent sets of criteria, (1) reduction of total PVCs by 70%, of pairs by 80%, and of all VT by 100% (new criteria set 1) and (2) reduction of total PVCs by 80%, of pairs by 90%, and of all VT by 100% (new criteria set 2). In electrophysiology (EPS) limb patients, we compared arrhythmia recurrence when efficacy was declared with triple extrastimuli as compared with maximally testing with double extrastimuli, and arrhythmia recurrence was compared in patients tested with identical versus any more aggressive protocol on drug than was used before drug. We also compared the predictive accuracy of zero versus 3 to 15, and 0 to 5, 6 to 10, and more than 10 induced beats on drug. Additionally, we compared predictive accuracy of the HM- and EP-guided limbs excluding patients on beta blockers and those with noncoronary disease. Lastly, to determine whether concordant results on HM and EPS testing would provide more accurate efficacy predictions than EP testing alone, HM recordings obtained in EPS-limb patients but not processed or used during the course of the EVSEM study were analyzed. The original ESVEM HM criteria, new set 1, and new set 2 yielded predicted drug efficacy rates of 77%, 68%, and 58%, respectively; however, arrhythmia recurrence rates were unchanged. Similarly, arrhythmia recurrence rates for patients tested with triple versus less than triple extrastimuli (p=.238), more aggressive versus identical protocols (p=.955), and 0 to 5 v 6 to 10 v more than 10 induced beats (p=.263) or 0 v 3 to 15 induced beats (p=.106) were unchanged. in the 215 (of 286) patients with coronary disease and not receiving beta blockers, there was still no difference in arrhythmia recurrence or mortality between the noninvasive and invasive limbs in ESVEM. Lastly, in patients with drug efficacy predictions by EPS testing, there was no difference in outcome in patients who had concordant versus discordant efficacy prediction by simultaneously obtained HMs. The use of more stringent testing methods and efficacy criteria would not have significantly improved the predictive accuracy of drug assessment by HM or EPS in the ESVEM trial. Additionally, excess noncoronary disease in EP-guided patients and excess beta-blocker used in HM-guided patients did not influence the results in the ESVEM trial.
Actuarial Analysis↗