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Biomedical subjects

C R Kerr

Publications and source records attributed to C R Kerr.

At least 19 recordsLinked to original sources
PubMed1992

In vitro protein binding of propafenone and 5-hydroxypropafenone in serum, in solutions of isolated serum proteins, and to red blood cells.

The binding of propafenone (PF) and 5-hydroxypropafenone (5-OH-PF) in serum and in solutions of isolated serum proteins was examined by equilibrium dialysis. Both PF and 5-OH-PF displayed pH-dependent binding in serum and in a solution of alpha-1-acid glycoprotein (AAG). PF displayed extensive binding to AAG (i.e., free fraction of 0.08 +/- 0.02), whereas the binding of 5-OH-PF to AAG was moderate (i.e., free fraction of 0.54 +/- 0.10). The removal of lipoproteins from serum did not alter the free fraction of PF but significantly increased the free fraction of 5-OH-PF compared with that in intact serum. Both PF and 5-OH-PF displayed concentration-dependent binding in a 19.3-mumol AAG solution. Concentration-independent binding was apparent in solutions of human serum albumin, high-density lipoproteins, low-density lipoproteins, and very low density lipoproteins over the PF and 5-OH-PF concentration ranges examined. By use of previously determined binding parameters (affinities and capacities), the binding model of PF provided an estimate of the free fraction in serum that was similar to the observed free fraction, although the free fraction of 5-OH-PF was overestimated. The distribution of PF and 5-OH-PF into red blood cells was extensive when buffer was used as the supernatant; however, when serum was used as supernatant, the amounts of PF and 5-OH-PF that were distributed into red blood cells decreased substantially. PF and 5-OH-PF interacted with all of the proteins examined.

Anti-Arrhythmia Agents↗
PubMed1992

Propafenone-mexiletine combination for the treatment of sustained ventricular tachycardia.

OBJECTIVES: The purpose of this study was to explore the efficacy of combined therapy with propafenone and mexiletine for control of sustained ventricular tachycardia. BACKGROUND: Combination antiarrhythmic drug therapy may enhance efficacy and lead to control of ventricular arrhythmias in some patients. Few reports have studied the combination of class IB and class IC drugs. Thus, this study was designed to investigate a combination of mexiletine and propafenone in patients with refractory ventricular tachycardia. METHODS: Sixteen patients with sustained ventricular tachycardia had their clinical arrhythmia induced by programmed stimulation. Procainamide and propafenone alone failed to prevent reinduction of tachycardia in all. Mexiletine was subsequently added to propafenone and programmed stimulation was repeated. RESULTS: With combination therapy ventricular tachycardia was noninducible in three patients (19%). A fourth who had presented with polymorphic ventricular tachycardia had slow bundle branch reentry (cycle length 500 ms) induced. In the other 12, tachycardia cycle length increased from 262 +/- 60 ms at baseline to 350 +/- 82 ms with propafenone and to 390 +/- 80 ms with propafenone plus mexiletine (p less than 0.0001 compared with baseline). Hemodynamic deterioration requiring defibrillation occurred in six patients at baseline study, in five taking propafenone and in two taking both drugs. CONCLUSIONS: The combination of propafenone and mexiletine is effective in suppressing the induction of ventricular tachycardia in some patients refractory to procainamide and propafenone alone. In those in whom ventricular tachycardia could still be induced, the rate was slower and hemodynamically tolerated.

Adult↗
PubMed1991

High success rate of atrioventricular node ablation with radiofrequency energy.

Radiofrequency current was introduced as an alternative energy source for transcatheter ablation of cardiac arrhythmias to avoid the complications associated with direct current shocks. Initial use of radiofrequency current for complete ablation of the atrioventricular (AV) node yielded only moderate success rates, presumably because of the small size of electrodes and difficulty in localizing the AV node. The use of a larger 4-mm tip electrode for delivery of radiofrequency current and a method to better localize the AV node were prospectively studied in 32 patients undergoing catheter ablation of the AV node. There were 21 men and 11 women with a mean age of 62 +/- 12 years. Complete AV block was achieved immediately in 31 patients (97%) and it persisted in 28 patients (88%) during a mean follow-up period of 12 +/- 6 months. Three patients who had return of AV condition required no drug therapy for control of ventricular rate during atrial fibrillation. The number of radiofrequency pulses used to achieve complete AV block ranged from 1 to 5 (mean 1.9 +/- 1.1). In greater than 50% of the cases, only one radiofrequency pulse was required. The mean power and duration of radiofrequency pulses were 21.2 +/- 4.5 W and 33 +/- 15 s, respectively. All patients developed a stable junctional escape rhythm within 45 min of successful ablation. The QRS configuration was unchanged in 30 patients. One patient had a new right bundle branch block after ablation. There were no complications related to the ablation procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Long term efficacy of propafenone for prevention of atrial fibrillation.

OBJECTIVE: Propafenone, a class IC antiarrhythmic drug, has been successful in the treatment of ventricular and supraventricular arrhythmias. This study retrospectively evaluated the efficacy of propafenone in the prevention of recurrent atrial fibrillation. DESIGN: Propafenone was given to 81 patients (49 males and 32 females, mean age 61 +/- 16 years) with recurrent atrial fibrillation. The mean dose of propafenone was 701 +/- 235 mg. Patients were monitored for recurrent arrhythmias. MAIN RESULTS: Long term follow-up over 30 +/- 1.7 months showed 31 patients (38%) remained on propafenone with complete or partial control of atrial fibrillation. The drug was stopped in 35 due to inefficacy, in 12 due to adverse effects, and in three due to desire for ablation therapy. CONCLUSION: Propafenone may be effective in some patients for long term prevention of atrial fibrillation, although efficacy may decrease over time.

Atrial Fibrillation↗
PubMed1990

Stereoselective pharmacokinetics of tocainide in human uraemic patients and in healthy subjects.

The disposition of tocainide enantiomers were examined in healthy human subjects and uraemic patients following a single i.v. dose (200 mg) of racemic tocainide hydrochloride. In the healthy subjects, the total body clearance of R(-)-tocainide was significantly greater than that of S(+)-tocainide (2.62 vs 1.70 ml.min-1.kg-1). Renal clearance also favoured R(-)-tocainide and appeared to contribute significantly to the stereoselective total body clearance. The volume of distribution of the enantiomers did not differ significantly. Uraemia produced a marked decrease in the total body clearance with no apparent effect on the volume of distribution of both enantiomers. The S/R ratio for total body clearance decreased significantly from 0.66 in healthy subjects to 0.54 in the uraemics, while the ratio for terminal elimination half-life significantly increased from 1.43 to 1.59. These results indicate that uraemia alters the degree of stereoselectivity in the pharmacokinetic parameters of tocainide enantiomers.

Adult↗
PubMed1990

Effects of propafenone on sinus node function in the rabbit heart.

Propafenone is a type 1C antiarrhythmic drug with efficacy for both ventricular and supraventricular arrhythmias. We investigated the effects of propafenone on properties of sinus node function in an in vitro preparation of rabbit sinus node and surrounding atrium. Spontaneous sinus cycle length (SCL), atriosinus conduction time (ASCT), and sinus node effective refractory period (SNERP) at multiple pacing cycle lengths were measured in the control state and during superfusion with propafenone (2.3 microM). SNERP prolonged from 175 +/- 25 ms in the control state to 220 +/- 45 ms (p less than 0.001) with propafenone. ASCT also prolonged significantly (p less than 0.01) from 50 +/- 20 to 65 +/- 20 ms whereas SCL did not change. In four experiments, multiple concentrations of propafenone were utilized and there appeared to a dose-dependent prolongation of SNERP. Thus, propafenone has a significant effect on SNERP and ASCT in an isolated rabbit sinus node preparation.

Animals↗
PubMed1989

Nonsustained ventricular tachycardia arising from the right ventricular outflow tract.

Characteristics of left bundle branch block morphology, inferiorly directed frontal plane QRS axis and repetitive nonsustained salvos were used to define a discrete subgroup of patients with ventricular tachycardia (VT). The origin of this tachycardia was thought to be the right ventricular outflow tract. Twenty-six patients with this definition (group 1) were compared with 29 consecutive patients with all other forms of VT (group 2). When compared with patients in group 2, group 1 patients were younger (average age 37 vs 51 years, p less than 0.005), had less structural heart disease (2 of 26 vs 25 of 29 patients, p less than 0.005) and had a better prognosis (no deaths) after an average follow-up time of 28 months in comparison with 5 deaths after an average follow-up of 35 months (p less than 0.05). Induction of VT was possible using isoproterenol infusion in 14 of 20 group 1 patients, but no VT could be induced in 9 group 2 patients (p less than 0.05). Exercise stress testing induced VT in 11 of 21 group 1 patients and 2 of 9 group 2 patients (p greater than 0.05). Programmed electrical stimulation failed to induce VT in 9 group 1 patients, but did induce it in 15 of 20 group 2 patients (p less than 0.005). Successful therapy in group 1 patients was achieved by beta blockers alone (7 patients), beta blockers plus type 1A antiarrhythmic drugs (9 patients), procainamide alone (2 patients), sotalol (3 patients) and amiodarone (2 patients). Three patients were not treated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1989

In vitro protein binding of propafenone in normal and uraemic human sera.

The protein binding of propafenone, a Class I antiarrhythmic agent, was studied in vitro using a selective and sensitive electron-capture detection gas-liquid capillary chromatographic assay method developed in our laboratory. The concentration-dependency of the serum protein binding of propafenone was confirmed in vitro by equilibrium dialysis, using serum obtained from healthy human subjects and patients with chronic renal failure. In normal serum the unbound fraction of propafenone was 0.027 at a propafenone concentration of 0.25 microgram.ml-1, 0.041 within the therapeutic concentration range (0.5-2 micrograms.ml-1), 0.138 at a propafenone concentration of 25 micrograms.ml-1, and 0.187 when the propafenone concentration was increased to 100 micrograms.ml-1. There was no evidence of significant concentration-dependent changes in unbound fraction within the propafenone concentration range of 0.5-1.5 micrograms.ml-1. However, concentration-dependent binding was demonstrated at concentrations greater than 1.5 micrograms.ml-1. A high-affinity, low-capacity binding site (K1 = 6.53 x 10(5) l.mol-1; n1P1 = 1.73 x 10(-4) mol.l-1) and a low-affinity, high-capacity binding site (K2 = 8.77 x 10(3) l.mol-1; n2P2 = 8.57 x 10(-3) mol. x l-1) were identified. In pooled uraemic serum the unbound fraction of propafenone was approximately 50% of that of normal serum throughout the concentration range studied (1-5 micrograms.ml-1). In sera from patients with chronic renal failure the increase in propafenone binding ratio or the decrease in unbound fraction was associated with the increase in alpha 1-acid glycoprotein concentrations, and there was a correlation (r = 0.8302) between alpha 1-acid glycoprotein concentration and the propafenone binding ratio.

Adult↗
PubMed1989

Atrial pacing: efficacy and safety.

Atrial pacing has the advantages of simplicity, maintenance of AV synchrony, and economy. The major detraction has been the potential for deterioration of atrioventricular conduction. In this study, we followed 43 patients with sick sinus syndrome treated with atrial (AAI) pacing. Excellent initial implant parameters were obtained in all. Three early lead repositionings were required. Minor sensing and pacing problems could all otherwise be handled by reprogramming. Follow-up for a mean of 25 +/- 20 months demonstrated excellent performance of the pacing systems. Pacing and sensing thresholds and lead impedance indicated excellent lead performance. There were no late lead failures. Nine patients have had mild deterioration in atrioventricular conduction and one of these had a change to DDD pacing at the time of elective battery change. All patients are asymptomatic. Thus, chronic atrial pacing in selected patients is safe and reliable with good chronic lead performance and low risk of subsequent conduction system disease.

Adolescent↗
PubMed1989

Impedance to transesophageal atrial pacing: significance regarding power sources.

Transesophageal stimulation is an expeditious method of atrial pacing. Using pulse widths of 10 msec results in reduction of current requirement to values that are usually less than 15 mA. An unknown variable in transesophageal atrial pacing has been impedance. In this study, we investigated the impedance to transesophageal atrial pacing in ten patients using a stimulator with a 63 V power source capable of delivering constant current to 20 mA against an impedance of 2,000 ohms. A bipolar electrode was used to deliver stimuli with a current of 15 mA. Voltage across a known resistance and current were measured on an oscilloscope and the impedance was calculated. Pacing thresholds were also performed and ranged from 6.2 to 16.5 mA (mean 9.4 +/- 2.9 mA, SD). Impedance varied between 720 and 2,670 ohms (mean 1,750 +/- 540 ohms). The stimulator used to measure impedance in man and two other commercially available stimulators were bench tested against known resistances of 500 to 2,000 ohms. The other stimulators with power sources of 12.5 and 15 V had attenuation of the delivered current at resistances of between 1,000 and 2,000 ohms. Thus, this study has demonstrated that transesophageal atrial pacing incurs impedances two to five times greater than incurred with intracardiac pacing leads. Therefore stimulators with high power sources are required to deliver the programmed current against these impedances.

Atrial Function↗
PubMed1989

Effects of acetylcholine, propranolol, and verapamil on sinus node refractoriness of the rabbit.

At a critical premature interval, atrial premature beats encounter sinus node refractoriness and are blocked on entering and fail to reset the sinus node, resulting in interpolation of the premature beat. The transition from reset to interpolated response has been used to define the effective refractory period of the sinus node (SNERP). In an in vitro preparation of rabbit sinus node, we evaluated the effects of acetylcholine, propranolol, and verapamil on SNERP. Results obtained in the control state were compared with those obtained during superfusion with drugs, all of which prolonged refractoriness: acetylcholine from 233 +/- 41 (SD) to 325 +/- 88 ms; propranolol from 215 +/- 60 to 241 +/- 67 ms; and verapamil from 192 +/- 69 to 254 +/- 79 ms (p less than 0.005 with all drugs). The site of block of premature beats was mapped between sinus node and crista terminalis with an intracellular microelectrode. All three drugs resulted in block of premature beats at sites farther from the primary pacemaker site. Thus, acetylcholine, propranolol, and verapamil prolong sinus node refractoriness.

Acetylcholine↗
PubMed1989

The pharmacokinetics of the enantiomers of mexiletine in humans.

1. This study examined the pharmacokinetics of the enantiomers of mexiletine in five healthy subjects who were each given a single, 300 mg, oral dose of racemic mexiletine hydrochloride. 2. The time course of the concentration ratio between the R(-) and the S(+) enantiomers (R/S) in plasma showed a progressive decrease, with a mean +/- S.D. ratio of 1.37 +/- 0.11 at 1 h and 0.64 +/- 0.11 at 48 h. Similarly, the R/S ratios in urine were 1.38 +/- 0.42 and 0.55 +/- 0.12 at 1 h and 72 h, respectively. 3. The terminal elimination half-life of S(+)mexiletine was 11.0 +/- 3.80 h, which was significantly greater (P less than 0.05) than that of the R(-) enantiomer, 9.10 +/- 2.90 h. S(+)Mexiletine also showed a significantly greater apparent volume of distribution (P less than 0.01) and renal clearance (P less than 0.05) than R(-)mexiletine. There was no significant difference in the apparent oral total drug clearance of the enantiomers. 4. The disposition of mexiletine enantiomers in man was stereoselective, and the differences observed between the enantiomers may be due largely to differences in their serum protein binding.

Adult↗
PubMed1988

Effect of pacing cycle length and autonomic blockade on sinus node refractoriness.

Sinus node (SN) refractoriness can be measured indirectly by observing the return responses after the introduction of progressively earlier atrial premature beats. The SN effective refractory period (ERP) is defined as the longest premature interval resulting in an interpolated atrial return response. In the present study, SNERP was analyzed in 71 subjects--51 control persons and 20 patients with evidence of SN dysfunction. SNERP could be measured in 40 of 51 control subjects and was shown to prolong at shorter basic pacing cycle lengths. At a basic cycle length of 600 ms, SNERP was 330 +/- 40 ms, whereas at 500 ms it was 350 +/- 50 ms (p less than 0.05). At a basic cycle length of 600 ms, SNERP was measured in 31 control subjects and 7 patients with SN dysfunction. The values of 330 +/- 40 and 520 +/- 20 ms, respectively, in these 2 groups suggested that this method can be used to differentiate patients with SN dysfunction (p less than 0.001). In 12 control subjects, SNERP was measured before and after partial autonomic blockade with propranolol and atropine. SNERP shortened from 360 +/- 40 to 320 +/- 40 ms (p less than 0.05). It shortened with atropine and prolonged with propranolol. Thus, SNERP prolongs with a shorter basic pacing cycle length and is affected by autonomic manipulation, in a fashion analogous to the atrioventricular node.

Atropine↗