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Biomedical subjects

C R Kerr

Publications and source records attributed to C R Kerr.

At least 37 records · Page 2Linked to original sources
PubMed1995

Pharmacokinetics of mexiletine enantiomers in healthy human subjects. A study of the in vivo serum protein binding, salivary excretion and red blood cell distribution of the enantiomers.

1. The disposition kinetics of serum free (unbound) and total mexiletine enantiomers were studied in 12 healthy subjects following oral administration of 200 mg racemic mexiletine hydrochloride. The disposition of the enantiomers of mexiletine in urine, saliva, and red blood cells was also examined. 2. The mean peak serum total mexiletine concentration of 217 +/- 69 ng/ml for R(-)-mexiletine was found to be significantly greater than a mean of 197 +/- 56 ng/ml for S(+)-mexiletine. The mean serum total R(-)-mexiletine concentrations were also found to be significantly greater than those for S(+)-mexiletine during the first 6 h following drug administration. The oral absorption, as well as the rapid and the terminal disposition kinetic parameters between the mexiletine enantiomers, were not significantly different. 3. Comparative in vitro serum protein binding of mexiletine enantiomers examined by ultrafiltration and equilibrium dialysis indicated a pH-dependent stereoselective binding of the enantiomers to serum proteins. A serum pH ranging from 6.3 to 9.4 was found to correlate with serum protein binding of the enantiomers from approximately 30-80% respectively. Within the same serum pH range, the serum free drug R(-)/S(+) ratios were found to decrease from 1.0 to 0.7 respectively. At serum pH7.4, a mean serum free fraction of 0.57 +/- 0.7 and 0.56 +/- 0.6 were observed for R(-) and S(+)-mexiletine respectively. 4. The overall mean saliva/serum-free mexiletine enantiomer area under the concentration-time curve ratios of 6.10 +/- 2.82 and 7.49 +/- 3.48 for R(-)- and S(+)-mexiletine respectively were found to be significantly different. The overall mean saliva R(-)/S(+) enantiomer ratio of 0.89 +/- 0.02 (mean +/- SE) over 48 h suggested a stereoselective disposition of the mexiletine enantiomers in saliva. 5. The mean mexiletine red blood cells to serum-free drug concentration ratios among 11 subjects studied were found to range from 0.6 to 1.4 for R(-)-mexiletine and from 0.6 to 1.8 for S(+)-mexiletine. The overall mean ratios of 0.85 +/- 0.06 and 0.84 +/- 0.08 (mean +/- SE) over 48 h for R(-)- and S(+)-mexiletine respectively were both slightly but significantly different from unity. This data together with an overall red blood cell mean R(-)/S(+)-mexiletine concentration ratio of 0.91 +/- 0.13 suggested a non-stereoselective and passive diffusion of the enantiomers into red blood cells. 6. The cumulative amounts of unchanged R(-)- and S(+)-mexiletine in the urine were found to be variable among the 12 subjects with a mean percent urinary recovery of 3.49 +/- 3.35% for R(-)-mexiletine and 3.68 +/- 3.94% for S(+)-mexiletine.

Adult↗
PubMed1994

High-performance liquid chromatographic analysis using a highly sensitive fluorogenic reagent, 2-anthroyl chloride, and stereoselective determination of the enantiomers of mexiletine in human serum.

A stereoselective and highly sensitive HPLC assay was developed for mexiletine enantiomers using a new fluorogenic derivatization reagent, 2-anthroyl chloride. The reagent was synthesized and utilized for the fluorescent detection (excitation at 270 nm, emission at 400 nm) of mexiletine enantiomers as their N-anthroyl derivatives on a Pirkle phenylglycine ionic HPLC column. The assay had a lower limit of quantitation at 2.5 ng/ml with a limit of detection measured at 0.5 ng/ml for each enantiomer in serum with a signal-to-noise ratio of 5:1. In a preliminary pharmacokinetic study, 200 mg of racemic mexiletine hydrochloride were administered orally to two healthy volunteers. Serum samples were collected at timed intervals over 48 h. The terminal elimination half-lives determined for total R(-)- and S(+)-mexiletine were 10.9 and 11.5 h, respectively. The serum free fractions for R(-)- and S(+)-mexiletine were found to be 0.56 and 0.53, respectively.

Anthracenes↗
PubMed1994

Efficacy of sotalol guided by programmed electrical stimulation for sustained ventricular arrhythmias secondary to coronary artery disease.

Sotalol is a class III antiarrhythmic drug with additional beta-blocker activity that has been shown to be effective in supraventricular and ventricular arrhythmias. Its long-term efficacy for ventricular arrhythmias is not as well described. Patients with documented sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) who had their clinical arrhythmia inducible at baseline electrophysiologic study received sotalol 320 to 640 mg/day. Repeat programmed stimulation was performed after a minimum of 72 hours while receiving the final dose. Of 28 patients (25 men and 3 women) whose arrhythmias were inducible at baseline, 15 had their arrhythmias suppressed with sotalol. Sotalol had greater success in suppressing arrhythmias in those with VF (8 of 9, 89%) than in those with VT (7 of 19, 37%, p < 0.01). In patients with a history of coronary artery disease but no history of myocardial infarction the arrhythmia was suppressed in 7 of 8 (88%) compared with 8 of 20 (40%, p < 0.05) patients with a history of myocardial infarction. All 15 patients in whom ventricular arrhythmias were suppressed continued to take long-term sotalol, and at a follow-up of 10.3 +/- 6.4 months none has had arrhythmia recurrence. Thus, sotalol is an effective drug for the suppression of ventricular arrhythmias as judged by programmed electrical stimulation. It appears to be more effective in patients in whom the clinical arrhythmia is VF rather than VT.

Aged↗
PubMed1994

Electrophysiologic properties of a narrow isthmus in rabbit atrial tissue: cycle length dependent effect of quinidine.

The modulation of quinidine's effect by pacing cycle lengths was assessed over an isthmus of atrial myocardium, simulating the Wolff-Parkinson-White syndrome. Isolated rabbit atria were dissected so that two tissue blocks, A and B, were linked by an isthmus, 1 mm in width. Effective refractory period in the tissue blocks and over the isthmus was measured at cycle lengths of 1,000, 600, and 400 ms, and the minimum cycle length to sustain 1:1 conduction over the isthmus was measured before treatment, during quinidine superfusion (4 mg/L), and after washout. Longitudinal velocity over the isthmus was also measured. The increment in the effective refractory period in the tissue blocks by quinidine appeared to be similar, about 10% at three pacing cycle lengths (p > 0.05). However, the increment of the effective refractory period over the isthmus was modulated by pacing cycle lengths: greater increase at shorter cycle lengths (p < 0.001). Quinidine prolonged the minimum cycle length over the isthmus by 44 +/- 17%. Regression analysis showed that after quinidine there was a correlationship between conduction velocity and refractoriness over the isthmus (R = 0.85, p < 0.001). Intracellular implements showed stable action potentials, confirming the integrity of the preparation. We conclude that (i) quinidine preferentially prolongs refractoriness over the isthmus and (ii) quinidine's effect on refractoriness over the isthmus is cycle length dependent.

Action Potentials↗
PubMed1994

Regional differences in rabbit atrial repolarization: importance of transient outward current.

Regional differences in rabbit atrial repolarization were investigated using a conventional microelectrode technique. A more rapid phase 1 repolarization (lower phase 1 amplitude) was seen in the left atrial (LA) roof area compared with the right atrial (RA) roof area: 54 +/- 10 vs. 82 +/- 6 mV at 1,000 ms (P < 0.001). In addition, action potential duration at 40 mV above the resting potential (APD40) was shorter in LA and was associated with a slower phase 3 repolarization rate. Furthermore, the recovery time constant of phase 1 amplitude at 500 ms was 0.9 +/- 0.2 s in LA and 3.5 +/- 1.5 s in RA (P < 0.001). Pacing cycle lengths (2,000, 1,500, 1,000, 800, and 500 ms) modulated phase 1 amplitude, APD40, and phase 3 rate in both regions. 4-Aminopyridine (4-AP; 1 mM), a selective transient outward current (I(to)) blocker, abolished cycle length dependence of the above action potential parameters and diminished the differences in electrophysiological properties between the two regions. 4-AP also flattened the restitution curve of phase 1 amplitude in both regions. In conclusion, the findings suggest that the different kinetics of I(to) play an important role in regional differences of atrial repolarization.

4-Aminopyridine↗
PubMed1994

Atrioventricular nodal reentrant tachycardia in patients with ventriculo-atrial conduction block.

OBJECTIVE: To demonstrate the reversibility of retrograde ventriculo-atrial block by isoproterenol in patients with atrioventricular nodal reentrant tachycardia (AVNRT). DESIGN: Three case reports and their electrophysiological features. PATIENTS: Three patients with documented or suspected paroxysmal supraventricular tachycardia. INTERVENTIONS: At routine electrophysiology study, no supraventricular tachycardia was inducible in the baseline state. Infusion of isoproterenol (1 to 5 micrograms/min) was given and stimulation procedures were repeated. RESULTS: At baseline, all three patients had discontinuous antegrade atrioventricular (AV) nodal conduction, but very poor (two patients) or absent (one patient) ventriculo atrial conduction prevented induction of AVNRT. During infusion of isoproterenol, retrograde conduction was enhanced so that 1:1 retrograde occurred to cycle lengths of 300, 340 and 260 ms. AVNRT was then inducible in all patients, reproducing their clinical symptoms. CONCLUSION: Absent or poor ventriculo-atrial conduction in patients with suspected AV node reentry does not preclude the development of tachycardia with sympathomimetic enhancement. Isoproterenol should be given to attempt reversal of retrograde block in these patients.

Adult↗
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↗