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Biomedical subjects

N Edvardsson

Publications and source records attributed to N Edvardsson.

At least 37 records · Page 2Linked to original sources
PubMed1997

Effects of almokalant, a class III antiarrhythmic agent, on supraventricular, reentrant tachycardias. Almokalant Paroxysmal Supraventricular Tachycardia Study Group.

The aim of the present study was to investigate the effects of almokalant on sustained reentrant supraventricular tachycardias. Reentrant tachycardias were induced, using transesophageal atrial stimulation, in 82 patients with atrioventricular reentrant tachycardia (n = 54) or AV nodal reentrant tachycardia (n = 28). After a baseline procedure during which the tachycardia was induced and overdrive terminated, the tachycardia was reinduced and studied during 12 minutes of infusion of either placebo or almokalant, aiming at plasma concentrations of 20, 50, 100, and 150 nmol/l. Each patient was studied at two dose levels during the same procedure. There was an increase in the RR interval during tachycardia of 6% at 100 nmol/l (p = 0.001 vs. baseline tachycardia). The QT interval during tachycardia increased by 5% (p = 0.001) at 50 nmol/l and by 10% (p = 0.001) at 100 nmol/l. Bundle branch block during tachycardia developed in 13% during almokalant infusion, aiming at 20 nmol/l, in 25% at 50 nmol/l, in 50% at 100 nmol/l, and in 33% at 150 nmol/l. Rapid baseline tachycardia, increasing almokalant dose, and an increasing number of induced tachycardias correlated with the appearance of bundle branch block. In six patients with AV nodal reentrant tachycardia, 2:1 AV block occurred, in all cases preceded by bundle branch block. The QT prolongation during sustained tachycardia was larger in patients who were noninducible at the same plasma concentration level than in the inducible patients. Almokalant caused bundle branch block and 2:1 AV block during sustained supraventricular tachycardia. These findings emphasize the importance of studying drug effects at rates in the range of clinical tachycardias that expose the conduction system to the limits of its refractoriness.

Adult↗
PubMed1997

Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers.

We have compared the incidence of CNS symptoms and changes in echocardiography and electrophysiology during i.v. infusions of ropivacaine, bupivacaine and placebo. Acute tolerance of i.v. infusion of 10 mg min-1 was studied in a crossover, randomized, double-blind study in 12 volunteers previously acquainted with the CNS effects of lignocaine. The maximum tolerated dose for CNS symptoms was higher after ropivacaine in nine of 12 subjects and higher after bupivacaine in three subjects. The 95% confidence limits for the difference in mean dose between ropivacaine and bupivacaine were -30 and 7 mg. The maximum tolerated unbound arterial plasma concentration was twice as high after ropivacaine (P < 0.001). Muscular twitching occurred more frequently after bupivacaine (P < 0.05). The time to disappearance of all symptoms was shorter after ropivacaine (P < 0.05). A threshold for CNS toxicity was apparent at a mean free plasma concentration of approximately 0.6 mg litre-1 for ropivacaine and 0.3 mg litre-1 for bupivacaine. Bupivacaine increased QRS width during sinus rhythm compared with placebo (P < 0.001) and ropivacaine (P < 0.01). Bupivacaine reduced both left ventricular systolic and diastolic function compared with placebo (P < 0.05 and P < 0.01, respectively), while ropivacaine reduced only systolic function (P < 0.01).

Adult↗
PubMed1996

Assessment of frequency dependency of the class III effects of almokalant: a study using programmed stimulation and recording of monophasic action potentials and ventricular paced QT intervals.

The aim of the present study was to assess the frequency dependency of the effects of almokalant, a selective class III antiarrhythmic drug, on ventricular repolarization using recordings of monophasic action potentials and measurements of ventricular paced QT intervals. Twenty male volunteers were studied during almokalant infusion aiming at plasma concentrations (Cpl) of 20, 50, 100, and 150 nmol/l. The duration of monophasic action potential at 90% repolarization (MAPD) was measured during incremental and premature ventricular extrastimulation. The ventricular paced QT interval was measured during incremental stimulation from the apical region (RV APEX) and the outflow tract (RVOT) of the right ventricle, and the frequency dependence was analyzed using a linear regression model. At an almokalant dose of Cpl > or = 50, there was a significant prolongation of the MAPD of 10-15%. The prolongation was of equal magnitude at all paced cycle lengths (CL). The MAPD of ventricular extrasystole increased in parallel over the range of coupling intervals studied and was significantly prolonged at Cpl 100 and 150. The ratio between the MAPD of the extrasystoles and preceding beats was unaltered after almokalant infusion. The ventricular paced QT intervals increased during almokalant infusion in a similar manner as that of the MAPD. During RV APEX stimulation, the prolongation was more pronounced at low heart rates, an effect that was not seen during RV OT stimulation. Almokalant significantly prolonged the MAPD at dose levels Cpl > or = 50. There was no evidence of a frequency dependence of this effect. The ventricular paced QT intervals were prolonged in a similar manner as that of the MAPD, and this effect exhibited a small reverse frequency dependence during RV APEX stimulation.

Action Potentials↗
PubMed1996

Torsades de pointes induced by transesophageal atrial stimulation after administration of almokalant.

This case-report describes a patient who developed a torsades de pointes tachycardia after infusion of almokalant, a selective class III antiarrhythmic agent. The patient was studied with transesophageal atrial stimulation because of Wolff-Parkinson-White syndrome. After a base-line procedure during which an orthodromic tachycardia was induced and pace-terminated, almokalant was given intravenously. The corrected QT interval was markedly prolonged despite similar plasma concentration compared to the rest of the studied patients. During the continued pacing protocol several episodes of non-sustained ventricular tachycardia was observed after pacing induced pauses. A sustained orthodromic tachycardia with left bundle branch morphology was induced, and another almokalant infusion was given. At a plasma concentration of approximately 252 nmol/l the corrected QT interval was further prolonged to 680 ms and the patient developed a torsades de pointes tachycardia after a pacing induced pause. The tachycardia degenerated into ventricular fibrillation that required immediate defibrillation. One week later the patient underwent ablation of the accessory pathway. The QT interval was in the absence of preexcitation normal, and programmed electrical stimulation did not reveal any ventricular arrhythmias. Further studies will have to be performed to clarify whether an early and marked QT interval prolongation, such as observed in this patient, will be useful in identifying patients prone for proarrhythmias in relation to therapy with selective class III drugs.

Anti-Arrhythmia Agents↗
PubMed1995

Tolerance and effects of almokalant, a new selective Ik blocking agent, on ventricular repolarization and on sino-atrial and atrioventricular nodal function in the heart: a study in healthy, male volunteers utilizing transesophageal atrial stimulation.

Almokalant, (4-(3-ethyl(3-propylsulfinyl)propyl)amino)-2-hydroxy-propoxy)- benzonitrile), is a newly developed Ik channel blocker that exhibits pure class III effects. Using a noninvasive approach with transesophageal atrial stimulation (TAS), we wished to identify the dose of almokalant, given as an intravenous bolus infusion, that prolonged ventricular repolarization in the healthy human heart to an extent of potential clinical interest. Furthermore, we defined the electrophysiological effects of this dose on the heart, as well as the pharmacokinetics, safety, and tolerance throughout a wide dosing range. In the titration part, increasing doses were given to identify the dose that produced a reproducible QTend prolongation of approximately 20%. This dose (12.8 mumol) was then given in a placebo-controlled, double-blind, cross-over fashion. In the double-blind part, almokalant significantly prolonged the QTend intervals during sinus rhythm and during TAS at 100 beats/min and increased the effective refractory period of the atria (AERP). There was no alteration in either the cardiac conduction (PQ and QRS), or blood pressure (BP) sinus node function, or the ERP of the atrioventricular (AV) node. Therefore, almokalant exhibited pure class III effects with no signs of beta-blockade or unwanted hemodynamic effects. The plasma concentration-time curve showed a biexponential decrease with a terminal half-life (t1/2) of approximately 3 h. There was a large interindividual variation in the plasma concentration at the end of infusion, Cmax. This variability diminished considerably 60 min after infusion, and the pharmacokinetic characteristics studied appeared to be proportional to the dose. The drug was well tolerated, and the only side effect noted was a brief metallic taste after a dose of 25.6 mumol. Corresponding to high plasma peak values, T-wave morphology changes of short duration were observed, sometimes with the development of pronounced, biphasic T waves.

Adult↗
PubMed1995

Effect of almokalant, a selective potassium channel blocker, on the termination and inducibility of paroxysmal supraventricular tachycardias: a study in patients with Wolff-Parkinson-White syndrome and atrioventricular nodal reentrant tachycardia. Almokalant PSVT Study Group.

Almokalant is a newly developed selective blocker of the delayed outward K+ current and exhibits the electrophysiological properties of a class III antiarrhythmic agent. In a Scandinavian multicenter, placebo-controlled trial, the antiarrhythmic efficacy of almokalant was investigated in patients with paroxysmal supraventricular tachycardia: 87 patients with mean age of 50 +/- 14 years (range 21-71 years), with reciprocating tachycardia due to either Wolff-Parkinson-White (WPW) syndrome (n = 58) or atrioventricular nodal reentry tachycardia (AVNRT) (n = 29) were studied with transesophageal atrial stimulation. After a baseline procedure, during which sustained tachycardia was induced and overdrive terminated, tachycardia was reinduced and an intravenous (i.v.) infusion of either placebo or almokalant (aiming at a pseudoequilibrium plasma level of 20, 50, 100, or 150 nM) (Cpl 20-Cpl 150), was administered. Each patient was studied at two Cpl. Thirty-nine patients were randomly assigned in a double-blind fashion to either placebo+almokalant at Cpl 20 or Cpl 20 + Cpl 50; 26 patients were studied openly at Cpl 50 + Cpl 100, and 22 were studied openly at Cpl 100 + Cpl 150 almokalant. The antiarrhythmic efficacy was assessed as the ability to terminate induced tachycardia and to suppress inducibility: The proportion of patients in which the tachycardia was terminated was placebo 3 of 20 (15%); Cpl 20, 7 of 36 (19%): Cpl 50, 10 of 36 (28%); Cpl 100, 14 of 35 (40%); and Cpl 150, 5 of 9 (56%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Selective Ik blocker almokalant exhibits class III--specific effects on the repolarization and refractoriness of the human heart: a study of healthy volunteers using right ventricular monophasic action potential recordings.

Almokalant, a recently developed potassium-channel blocker, has exhibited properties of a selective class III agent in vitro and in animal experiments. We report the first invasive study in humans in which the electrophysiological characteristics of almokalant were assessed. Thirty-four healthy males received bolus and maintenance infusions of almokalant to two of our target plasma concentrations of 20, 50, 100, and 150 nM. Electrophysiological variables were assessed during stimulation at 100 and 120 beats/min at baseline and at two consecutive targeted levels. Almokalant dose-dependently increased the duration of the monophasic action potential (MAP) above a mean plasma concentration of 60 nM. The duration at 90% repolarization significantly increased by 20% from baseline at 100 beats/min (p < 0.00005), and by 19% at 120 beats/min (p < 0.00005), at a mean plasma concentration of 116 nM. During atrial stimulation, there was a significant increase in the QT interval, amounting to 24% at 100 beats/min (p < 0.00005) and to 30% at 120 beats/min (p = 0.0006), at 124 nM. During right ventricular stimulation in the apical region, the QT interval significantly increased by 17% at 100 beats/min (p < 0.00005), and 13% at 120 beats/min (p < 0.00005). During stimulation from the right ventricular outflow tract, the QT interval increased to a lesser extent and significantly only at 120 beats/min: 9% at 100 beats/min (p = NS) and 6% at 120 beats/min (p = 0.001) at 118 nM. The effective refractory period (ERP) of the atria increased by 18% at 100 beats/min at 119 nM (p = 0.005). The right ventricular ERP increased by 16% at both heart rates (HR) (p < 0.00005) during stimulation from the apical region, and by 11% during stimulation from the outflow tract (p = 0.0001 at 100 beats/min and p = 0.0006 at 120 beats/min). There was no effect on the ERP of the atrioventricular node, (AVN) on the sinus node function or cardiac conduction. Two individuals experienced a transient metallic taste during bolus infusion aiming at 50 and 100 nM, but this side effect did not occur in the group receiving the highest doses. Pronounced T-wave/U-wave (TU) morphology changes were observed in 4 individuals. Almokalant exhibited characteristics of a pure class III agent with no effects on cardiac conduction or sinus node function when given intravenously. Although no proarrhythmias were observed, the development of TU morphology changes and increased spatial dispersion of repolarization after the highest doses warrants further studies regarding the safety profile of the drug.

Action Potentials↗
PubMed1995

Prospective study of left ventricular function after radiofrequency ablation of atrioventricular junction in patients with atrial fibrillation.

BACKGROUND: In patients with drug resistant incessant supraventricular tachycardia, radiofrequency induced ablation of the atrioventricular junction and pacemaker implantation have hitherto been considered a treatment of last resort. OBJECTIVE: To assess the short and long term effects of ablation of the atrioventricular junction on systolic and diastolic left ventricular function in patients with atrial fibrillation with and without impaired left ventricular function. PATIENTS: 29 patients (19 men; mean age 65 (SD 7) years (range 50-76)) undergoing ablation of the atrioventricular junction for drug refractory atrial fibrillation were examined a mean of 2, 65, and 216 days after ablation of the bundle of His. MAIN OUTCOME MEASURES: Left ventricular ejection fraction and early filling deceleration times (Edec) were assessed by Doppler echocardiography after 1 to 2 hours of ventricular pacing at a rate of 80 beats/minute. RESULTS: In 14 patients with a left ventricular ejection fraction < 50% left ventricular ejection fraction increased significantly from 32% (11%) to 39% (11%) (65 days) and 45% (11%) (216 days) (P < 0.001); Edec increased from 142 (46) ms to 169 (57) ms (65 days) and 167 (56) ms (216 days) (P < 0.05). In 15 patients with an ejection fraction > or = 50% at the initial examination no significant change in systolic function was observed. CONCLUSIONS: In patients with left ventricular dysfunction long term improvement of systolic and diastolic left ventricular function was seen after ablation of the atrioventricular junction for rate control of atrial fibrillation. This procedure had no adverse effects on normal left ventricular function.

Aged↗
PubMed1994

Atrioventricular block progression in patients with bifascicular block assessed by repeated electrocardiography and a bradycardia-detecting pacemaker.

Syncope may be due to intermittent high-degree atrioventricular (AV) block, but a cause-relation is sometimes difficult to prove. Diagnostic methods with high predictive value proven by instruments for safe and sensitive follow-up are needed. A bradycardia-detecting pacemaker was used in patients with bifascicular block, who had been the subjects of pharmacologic stress testing of the His-Purkinje system. Thirty-seven patients were included, of whom 26 had experienced at least 1 syncopal episode of suspected bradycardia origin, and 11 had previously documented transient high-degree AV block. The electrophysiologic study included injection of disopyramide 2 mg/kg (up to 150 mg) over 5 minutes. A positive test result was defined as spontaneous or pacing-induced His-Purkinje high-degree AV block after drug or a drug-induced HV prolongation of > or = 50%. Patients were followed an average 63 months with repeated electrocardiography and a diagnostic pacemaker (n = 23). Altogether, 24 patients had a significant bradycardia diagnosed by either or both methods. The sensitivity and positive predictive values were: HV interval > or = 70 ms at baseline, 47% and 88%; a positive disopyramide test result, 75% and 80%; and HV interval > or = 70 ms or a positive disopyramide test result, 93% and 74%, respectively. Thus, the diagnostic pacemaker is a safe and sensitive tool for evaluating the information obtained at electrophysiologic study, and pharmacologic stress testing with disopyramide has an informative value in patients with bifascicular block and syncope when results at baseline are inconclusive.

Aged↗