Telemetered common marmosets is useful for the assessment of electrocardiogram parameters changes induced by multiple cardiac ion channel inhibitors.

The objective of this study is to assess the response of telemetered common marmosets to multiple cardiac ion channel inhibitors and to clarify the usefulness of this animal model in evaluating the effects of drug candidates on electrocardiogram (ECG). Six multiple cardiac ion channel inhibitors (sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine) were orally administered to telemetered common marmosets and changes in QTc, PR interval and QRS duration were evaluated. Drugs plasma levels were determined to compare the sensitivity in common marmosets to that in humans. QTc prolongation was observed in the marmosets dosed with sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine. PR prolongation was noted after flecainide and verapamil administration, and QRS widening occurred following treatment with flecainide and quinidine. Drugs plasma levels associated with ECG changes in marmosets were similar to those in humans, except for verapamil-induced QTc prolongation. Verapamil-induced change is suggested due to body temperature decrease. These results indicate that telemetered common marmoset is a useful animal for evaluation of the ECG effects of multiple cardiac ion channel inhibitors and the influence of body temperature change should be considered in the assessment.

Promising approach for the preclinical assessment of cardiac risks using left ventricular pressure-volume loop analyses in anesthetized monkeys.

INTRODUCTION: Load-independent cardiac parameters obtained from the ventricular pressure-volume relationship are recognized as gold standard indexes for evaluating cardiac inotropy. In this study, for better analyses of cardiac risks, load-independent pressure-volume loop parameters were assessed in addition to load-dependent inotropic, hemodynamic and electrocardiographic changes in isoflurane-anesthetized monkeys. METHODS: The animals were given milrinone (a PDE 3 inhibitor), metoprolol (a ß-blocker), or dl-sotalol (a ß+IKr blocker) intravenously over 10min at two dose levels including clinically relevant doses (n=5/drug). RESULTS: Milrinone and metoprolol produced positive and negative inotropy, respectively. These effects were detected as changes in the slope of the preload-recruitable stroke work, which is a load-independent inotropic parameter. However, dl-sotalol did not alter the slope of the preload-recruitable stroke work. That means dl-sotalol produced no inotropy, although it decreased load-dependent inotropic parameters, including maximal upstroke velocity of left ventricular pressure, attributable to decreased heart rate and blood pressure. Other typical pharmacological effects of the compounds tested were also detected. Both ß-blockers produced PR prolongation, decreased left ventricular end-systolic pressure, increased left ventricular end-diastolic pressure, and increased maximal descending velocity of left ventricular pressure and time constant for isovolumic relaxation. dl-Sotalol also prolonged heart-rate-corrected QT interval. Milrinone induced reflex tachycardia, PR shortening, and decreased left ventricular end-diastolic pressure. DISCUSSION: The overall assessment by not only load-dependent inotropic parameters but also load-independent parameters obtained from the ventricular pressure-volume loop analysis using monkeys can provide further appropriate information for the assessment of drug-induced cardiac risks.

Minimal T-wave representation and its use in the assessment of drug arrhythmogenicity.

BACKGROUND: Recently, numerous models and techniques have been developed for analyzing and extracting features from the T wave which could be used as biomarkers for drug-induced abnormalities. The majority of these techniques and algorithms use features that determine readily apparent characteristics of the T wave, such as duration, area, amplitude, and slopes. METHODS: In the present work the T wave was down-sampled to a minimal rate, such that a good reconstruction was still possible. The entire T wave was then used as a feature vector to assess drug-induced repolarization effects. The ability of the samples or combinations of samples obtained from the minimal T-wave representation to correctly classify a group of subjects before and after receiving d,l-sotalol 160 mg and 320 mg was evaluated using a linear discriminant analysis (LDA). RESULTS: The results showed that a combination of eight samples from the minimal T-wave representation can be used to identify normal from abnormal repolarization significantly better compared to the heart rate-corrected QT interval (QTc). It was further indicated that the interval from the peak of the T wave to the end of the T wave (Tpe) becomes relatively shorter after IKr inhibition by d,l-sotalol and that the most pronounced repolarization changes were present in the ascending segment of the minimal T-wave representation. CONCLUSIONS: The minimal T-wave representation can potentially be used as a new tool to identify normal from abnormal repolarization in drug safety studies.

QT interval correction assessment in the anesthetized guinea pig.

INTRODUCTION: The anesthetized guinea pig (ANES GP) has proven to be an effective small animal model to evaluate cardiac electrophysiologic effects of drug-candidate molecules during lead optimization. While heart rate (HR) corrected QT interval (QTc) is a key variable to determine test article-dependent repolarization effects, ideal correction methods are an area of constant debate given the potential influence of anesthesia, autonomic tone, species, strain and gender on the QT/HR relationship. The aim of this study was to characterize the ability of common correction formulas to normalize rate-dependent effects on the QT interval in the ketamine/xylazine ANES GP. METHODS: Atrial pacing (n=10), ivabradine or ephedrine (n=6/group) infusions were used, respectively to evaluate the effects of a wide range of HRs on the QT/HR relationship. Correction formulas (Bazett [QTcb], Fridericia [QTcf] and Van de Water [QTcVdW]) were applied and the best fit formula was determined with the aid of the slope of their QT-HR linear relationship. RESULTS: From 100 to 220bpm, QTcb underestimated the change in QT interval duration (QT/HR slope=0.35 to 0.67). However, QTcVdW was more appropriate in this HR range (QT/HR slope=-0.07 and 0.09). At higher HRs (>220bpm), QTcb performed better (QT/HR slope=-0.02 and 0.07) as compared to QTcf (QT/HR slope=-0.18 to -0.1) and QTcVdW (QT/HR slope=-0.2 to -0.17) (p<0.01). All the correction formulas identified dofetilide- and sotalol-dependent repolarization delay (n=6/group) but QTcb and QTcf demonstrated reduced sensitivity as compared to fixed cardiac pacing (p<0.01). In contrast, QTcVdW resulted in an apparent underestimation of the QT interval duration at HR levels above the basal ketamine/xylazine ANES GP HRs (>220bpm) with ephedrine (n=6). DISCUSSION: The best fit correction formula in the ANES GP was highly dependent on the HR range. In the ketamine/xylazine model, QTcVdW performed best with HR <220bpm and QTcb performed best with HR >220bpm. The QTcVdW correction formula was thus selected in the ketamine/xylazine ANES GP since HRs in this model are generally within the optimal range for this correction formula.

Long-term stability, reproducibility, and statistical sensitivity of a telemetry-instrumented dog model: A 27-month longitudinal assessment.

INTRODUCTION: ICH guidelines, as well as best-practice and ethical considerations, provide strong rationale for use of telemetry-instrumented dog colonies for cardiovascular safety assessment. However, few studies have investigated the long-term stability of cardiovascular function at baseline, reproducibility in response to pharmacologic challenge, and maintenance of statistical sensitivity to define the usable life of the colony. These questions were addressed in 3 identical studies spanning 27months and were performed in the same colony of dogs. METHODS: Telemetry-instrumented dogs (n=4) received a single dose of dl-sotalol (10mg/kg, p.o.), a ß1 adrenergic and IKr blocker, or vehicle, in 3 separate studies spanning 27months. Systemic hemodynamics, cardiovascular function, and ECG parameters were monitored for 18h post-dose; plasma drug concentrations (Cp) were measured at 1, 3, 5, and 24h post-dose. RESULTS: Baseline hemodynamic/ECG values were consistent across the 27-month study with the exception of modest age-dependent decreases in heart rate and the corresponding QT-interval. dl-Sotalol elicited highly reproducible effects in each study. Reductions in heart rate after dl-sotalol treatment ranged between -22 and -32 beats/min, and slight differences in magnitude could be ascribed to variability in dl-sotalol Cp (range=3230-5087ng/mL); dl-sotalol also reduced LV-dP/dtmax 13-22%. dl-Sotalol increased the slope of the PR-RR relationship suggesting inhibition of AV-conduction. Increases in the heart-rate corrected QT-interval were not significantly different across the 3 studies and results of a power analysis demonstrated that the detection limit for QTc values was not diminished throughout the 27month period and across a range of power assumptions despite modest, age-dependent changes in heart rate. DISCUSSION: These results demonstrate the long-term stability of a telemetry dog colony as evidenced by a stability of baseline values, consistently reproducible response to pharmacologic challenge and no diminished statistical sensitivity over time.

Non-invasive telemetric electrocardiogram assessment in conscious beagle dogs.

INTRODUCTION: The primary objective of this investigation was to evaluate the sensitivity of a non-invasive telemetry system for the detection of drug-induced electrocardiogram (ECG) changes in conscious, freely moving dogs. A secondary objective was to compare, in the same set of dogs, ECG data acquired by a non-invasive system with data acquired from a surgically implanted telemetry device (invasive system). METHODS: Continuous beat-to-beat Lead II ECG data were simultaneously acquired from 6 male dogs using a non-invasive and an invasive telemetry system for 1h pre-dose and 6h following a sham control dose or single oral doses of (+/-) sotalol (4, 8 or 16 mg/kg). ECG parameters of heart rate, RR, PQ, QRS, QT and QT corrected for heart rate according to Van de Water (QTcV) and by an individual linear regression formula (QTcR), were determined. RESULTS AND DISCUSSION: Statistically significant dose-dependent reduction of heart rate, and increases in PQ, QT and QTc (V and R) were detected at all dose levels of (+/-) sotalol, with partial recovery during the 6-hour monitoring period. Statistically significant correlations for heart rate, RR, PQ, QT and QTc (V and R) were found between the two systems. QRS duration did not correlate. However, the difference between the two systems was consistent over the range studied. Based on these findings, the non-invasive system is quantitatively comparable to invasive telemetry, and can be used successfully to acquire continuous ECG data on a beat-to-beat basis from conscious freely moving dogs for at least 6h post-dose.

Automated QT analysis that learns from cardiologist annotations.

BACKGROUND: Reliable, automated QT analysis would allow the use of all the ECG data recorded during continuous Holter monitoring, rather than just intermittent 10-second ECGs. METHODS: BioQT is an automated ECG analysis system based on a Hidden Markov Model, which is trained to segment ECG signals using a database of thousands of annotated waveforms. Each sample of the ECG signal is encoded by its wavelet transform coefficients. BioQT also produces a confidence measure which can be used to identify unreliable segmentations. The automatic generation of templates based on shape descriptors allows an entire 24 hours of QT data to be rapidly reviewed by a human expert, after which the template annotations can automatically be applied to all beats in the recording. RESULTS: The BioQT software has been used to show that drug-related perturbation of the T wave is greater in subjects receiving sotalol than in those receiving moxifloxacin. Chronological dissociation of T-wave morphology changes from the QT prolonging effect of the drug was observed with sotalol. In a definitive QT study, the percentage increase of standard deviation of QT(c) for the standard manual method with respect to that obtained with BioQT analysis was shown to be 44% and 30% for the placebo and moxifloxacin treatments, respectively. CONCLUSIONS: BioQT provides fully automated analysis, with confidence values for self-checking, on very large data sets such as Holter recordings. Automatic templating and expert reannotation of a small number of templates lead to a reduction in the sample size requirements for definitive QT studies.

Contrasting time- and rate-based approaches for the assessment of drug-induced QT changes.

The authors aim to highlight the pitfalls of different validated methods used for the assessment of drugs' effect on QT duration. Digital 12-lead Holter electrocardiograms were recorded at baseline and after a single dose of sotalol in 39 healthy subjects (age = 27.4 +/- 8.0 years). Using both time- and rate-based approaches, the authors obtained averaged QRS-T complexes every minute ("time bins") and at different RR intervals ("rate bins"). Time bins were corrected for heart rate using a subject-specific approach. The individual alpha coefficients increased from placebo (0.309 +/- 0.052) to sotalol (0.454 +/- 0.136), P < .0001. When the placebo individual alpha coefficients were applied to correct the QT interval on sotalol, the changes were >5 ms smaller than those obtained using the ON drug alpha coefficients. The "rate"-averaging process leads to a complete loss of the time course of drug effect. In conclusion, the individual correction formula calculated from the placebo condition cannot always be used for QT correction on the drug.

Suitability of commonly used excipients for electrophysiological in-vitro safety pharmacology assessment of effects on hERG potassium current and on rabbit Purkinje fiber action potential.

INTRODUCTION: Regulatory guidelines require investigation of the liability for delayed ventricular repolarization by new chemical entities within a broad concentration range in-vitro. However, investigation can be limited by poor drug aqueous solubility, and by solvent physicochemical attributes that disrupt cell membrane integrity. Although excipients or solubilizing agents may aid to achieve the necessary high concentrations, no comprehensive overview on the suitability of solvents for in-vitro electrophysiological safety studies exists. METHODS: Excipients were tested for potential interference with the hERG (human ether-a-go-go-related gene) K(+) current (whole-cell voltage-clamp, 23+/-2 degrees C), and the shape of rabbit Purkinje fiber action potentials (conventional glass microelectrode technique, 37+/-1 degrees C). RESULTS AND DISCUSSION: Water-soluble complexation builders/carriers had little effect on hERG K(+) current at up to 50 mg/ml (BSA, bovine serum albumin) and 11 mg/ml (HP-beta-CD, hydroxypropyl-beta-cyclodextrin; IC(20), concentration of 20% inhibition). Water-soluble organic (co)solvents inhibited hERG K(+) currents (IC(20), %/mM): 0.7/152, ethanol; 0.9/67, Transcutol; 1.2/154, DMSO (dimethylsulfoxide); 1.6/389, acetonitrile; 1.9/48, polyethylene glycol 400; 2.1/660, methanol. Part of their inhibitory effect is attributed to the osmolality of extracellular solutions, because hERG IC(20) and extrapolated osmolality at the hERG IC(20) strongly correlate. Water-soluble non-ionic solubilizers/surfactants are potent inhibitors of hERG K(+) current with IC(20) concentrations of 0.07% (Cremophor EL) or lower (Tween 20, Tween 80: approximately 0.001%). Part of this inhibitory effect is attributed to their interaction with lipid membranes, because hERG inhibition occurs close to critical micelle concentrations (Cremophor, approximately 0.009%; Tween 20, approximately 0.007%). Purkinje fiber action potentials are little affected by HP-beta-CD at up to 2 mg/ml, while DMSO tends to shorten the action potential duration at 1%. CONCLUSION: When conducting electrophysiological in-vitro assessments of drug effects, solubilizers/surfactants (Cremophor EL, Tween 20, Tween 80) should be avoided. Instead, water-soluble organic (co)solvents (methanol, acetonitrile, DMSO) or complexation builders/carriers (HP-beta-CD, BSA) appear to be more favorable.

Comparison of guinea-pig ventricular myocytes and dog Purkinje fibres for in vitro assessment of drug-induced delayed repolarization.

INTRODUCTION: QT interval prolongation and Torsade de Pointes (TdP) arrhythmias are recognised as a potential risk with many drugs, most of which delay cardiac repolarization by inhibiting the rapidly activating K(+) current (I(Kr)). The objective of this study was to compare the effects of compounds on cardiac action potentials recorded from guinea-pig ventricular myocytes and dog Purkinje fibres. METHODS AND RESULTS: Effects of dofetilide, sotalol, cisapride, terfenadine, haloperidol and sparfloxacin, compounds known to cause QT prolongation (positive controls), and nifedipine and verapamil, not associated with QT prolongation (negative controls) were studied on intracellular action potentials recorded from guinea-pig isolated ventricular myocytes (VM) and dog isolated Purkinje fibres (PF). Prolongation of action potential duration (APD) by sotalol, dofetilide and sparfloxacin was concentration-dependent and of greater magnitude in dog PF compared to guinea-pig VM. The maximum prolongation of APD in guinea-pig VM at 0.5 and 1 Hz was approximately 25% and this was associated with complete inhibition of I(Kr) by dofetilide. Effects on APD of cisapride and haloperidol in both preparations, and terfenadine in guinea-pig VM, were biphasic, consistent with inhibition of multiple ion channels. There was no effect of terfenadine on APD in dog PF. Haloperidol increased APD by more than 25% in guinea-pig VM, consistent with effects on additional repolarizing currents. The negative controls shortened APD to a greater extent in guinea-pig VM compared to dog PF. In general, the positive control drugs increased action potential triangulation (APD(40-90)) to a greater extent than APD(90). CONCLUSION: Guinea-pig isolated VM may be more sensitive for detecting APD prolongation with compounds inhibiting multiple ion channels and action potential triangulation (APD(40-90)). Effects on repolarizing currents other than I(Kr) were also distinguished in guinea-pig VM.

QT PRODACT: inter- and intra-facility variability of the action potential assay using isolated guinea-pig papillary muscles.

Sixteen pharmaceutical companies and 6 contract research organizations in QT PRODACT acquired data on the action potentials in isolated guinea-pig papillary muscles using a standard protocol established by the QT PRODACT. Inter- and intra-facility variability for each of the parameters in the pre-application values and Delta% change after vehicle (0.1% DMSO) or dl-sotalol (30 micromol/L) treatment were examined using a nested model. Inter-facility variability of each of the parameters in the pre-application values were Vmax>APDs=APD30-90>APA=RMP (descending order). The inter-facility variability of all of the parameters was almost the same or was less as compared with the intra-facility variability. Inter-facility variability for the Delta% change for each parameter after dl-sotalol treatment showed a tendency similar to the results for the pre-application values. Comparing the inter- and the intra-facility variability, the inter-facility variation did not exceed the intra-facility variation. All facilities found that dl-sotalol prolonged APD. Therefore, it is suggested that the test system using this standard protocol is useful as a non-clinical evaluation system for QT prolongation. Moreover, the results are considered to be directly comparable between multiple facilities.

QT PRODACT: usability of miniature pigs in safety pharmacology studies: assessment for drug-induced QT interval prolongation.

To investigate whether miniature pigs are useful for evaluating the potential of drugs for drug-induced prolongation of the QT interval, we performed an in vivo QT assay using conscious and unrestricted miniature pigs. Compared with the vehicle average baseline values, haloperidol at 3 and 10 mg/kg, p.o. prolonged the QTcF interval (Fridericia's formula) by 8%-16%. The plasma concentration of haloperidol at which QT interval was prolonged (Cmax=42.9 ng/mL) was almost equal to that in humans. dl-Propranolol at 3, 10, and 30 mg/kg, p.o. caused no alterations in QT interval. dl-Propranolol at 3, 10, and 30 mg/kg, at which plasma concentrations were lower than in humans treated with dl-propranolol at the therapeutic dose level, shortened QTcF interval by 7%-12%. dl-Sotalol at 10 mg/kg, p.o. prolonged QTcF interval by 7%. From the above results, we considered that the miniature pig can be used for prediction of drug-induced prolongation of QT interval in humans, and thus, it is one of the useful animal species for assessing electrocardiograms in safety pharmacology studies.

A benefit-risk assessment of class III antiarrhythmic agents.

The prevalence of arrhythmia in the population is increasing as more people survive for longer with cardiovascular disease. It was once thought that antiarrhythmic therapy could save life, however, it is now evident that antiarrhythmic therapy should be administrated with the purpose of symptomatic relief. Since many patients experience a decrease in physical performance as well as a diminished quality of life during arrhythmia there is still a need for antiarrhythmic drug therapy. The development of new antiarrhythmic agents has changed the focus from class I to class III agents since it became evident that with class I drug therapy the prevalence of mortality is considerably higher. This review focuses on the benefits and risks of known and newer class III antiarrhythmic agents. The benefits discussed include the ability to maintain sinus rhythm in persistent atrial fibrillation patients, and reducing the need for implantable cardioverter defibrillator shock/antitachycardia therapy, since no class III antiarrhythmic agents have proven survival benefit. The risks discussed mainly focus on pro-arrhythmia as torsade de pointes ventricular tachycardia.

Population pharmacokinetics and pharmacodynamics of sotalol in pediatric patients with supraventricular or ventricular tachyarrhythmia.

AIMS: To derive useful pharmacokinetic (PK) and pharmacodynamic (PD) information for guiding the clinical use of sotalol in pediatric patients with supraventricular (SVT) or ventricular tachyarrhythmia (VT). METHODS: Two studies were conducted in-patients with SVT or VT in the age range between birth and 12 years old. Both studies used an extemporaneously compounded formulation prepared from sotalol HCl tablets. In the PK study, following a single dose of 30 mg/m2 sotalol, extensive blood samples (n = 10) were taken. The PK-PD study used a dose escalation design with doses of 10, 30, and 70 mg/m2, each administered three times at 8-hr intervals without a washout. Six ECG recordings for determination of QT and RR were obtained prior to the initial dose of sotalol. Four blood samples were collected six ECG's were determined during the third interval at each dose level. Plasma concentrations of sotalol (C) were assayed by LC/MS/MS. The data analysis used NONMEM to obtain the population PK and PD parameter estimates. The individual PK and PD parameters were estimated with empirical Bayes methodology. RESULTS: A total of 611 C from 58 patients, 477 QTc and 499 RR measurements from 23 and 22 patients, respectively, were available for analysis. The PK of sotalol was best described by a linear two-compartment model. Oral clearance (CL/F) and volume of central compartment (Vc/F) were linearly correlated with body surface area (BSA), body weight or age. CL/F was also linearly correlated with creatinine clearance. The best predictor for both CL/F and Vc/F was BSA. The remaining intersubject coefficients of variation (CV's) in CL/F, and Vc/F were 21.6% and 20.3%, respectively. The relationship of QTc to C was adequately described by a linear model. The intersubject CV's in slope (SL) and intercept (E0) were 56.2 and 4.7%, respectively. The relationship of RR to C was also adequately described by a linear model in which the baseline RR and SL were related to age or BSA. The intersubject CV's for SL and E0 were 86.7 and 14.4%, respectively. CONCLUSIONS: BSA is the best predictor for the PK of sotalol. Both QTc and RR effects are linearly related to C. No covariates are found for the QTc-C relation, while the RR-C relation shows age or BSA dependency.

Comparative assessment of ibutilide, D-sotalol, clofilium, E-4031, and UK-68,798 in a rabbit model of proarrhythmia.

Class III agents have been associated with development of a polymorphic ventricular tachycardia (PVT) known as torsades de pointes. We compared the class III agent ibutilide, which prolongs repolarization through enhancement of an inward sodium current, with the potassium channel blockers E-4031, UK-68,798, clofilium, and D-sotalol for proarrhythmic effects in an anesthetized rabbit model. In these animals, prolongation of repolarization during alpha 1 stimulation with methoxamine produces early after depolarizations (EADs) and a pause-dependent torsades de pointes-like PVT. Agents were compared over dosage ranges that produced maximal increases in QTc interval and monophasic action potential duration (MAPD). PVT typically developed after atrioventricular (A-V) conduction block and slowing of heart rate (HR), and was preceded by development of repolarization arrhythmias characterized by EADs and triggered activity producing extrasystolic beats. Ibutilide administration resulted in significantly lower EAD amplitudes and a lower incidence of repolarization arrhythmias and PVT as compared with administration of other class III agents. The percentage of rabbits developing PVT for each agent was ibutilide 12%, D-sotalol 70%, E-4031 56%, UK-68,798 69%, and clofilium 80%. Rabbits receiving saline vehicle instead of a class III agent never developed conduction or repolarization abnormalities or PVT. Under the conditions of this study at doses that generate maximal class III effects, ibutilide produces lesser increases in QTc interval and MAPD, and EADs of lower amplitude, resulting in a lower incidence of repolarization arrhythmias and PVT as compared with other class III agents.

Efficacy and safety of sotalol in patients with complex ventricular arrhythmias.

Sotalol is a unique beta-blocker that prolongs repolarization. Its use in 626 patients with complex ventricular ectopic activity, as reported in the literature, resulted in suppression of arrhythmia in 50 to 60% of treatment attempts. Detailed analysis of data on arrhythmias in 356 patients that were entered prospectively into a database revealed a median reduction in ventricular premature beats of 76%, compared to a median suppression of repetitive ventricular ectopic activity of 91% and of episodes of nonsustained ventricular tachycardia of 97% (p = 0.002 vs reduction of ventricular premature beats). This marked antiarrhythmic potency of sotalol in repetitive ventricular arrhythmias is thought to be due to its class III activity. Drug efficacy was independent of age, sex, the presence or absence of organic heart disease and the degree of sotalol-induced prolongation of corrected QT interval. Evaluation of left ventricular function in 215 patients treated with the drug demonstrated that depression of left ventricular ejection fraction occurred far less frequently than expected with conventional beta-blockers. Even patients with severely depressed pump function tolerated sotalol surprisingly well. There is a propensity of the drug to aggravate arrhythmia, which resulted in serious proarrhythmic events in 30 (3.5%) of 853 patients. These often consisted of torsades de pointes (9 of 30 patients). Proarrhythmia occurred primarily within the first 3 days of dosing, and exhibited a dose-dependence. In conclusion, sotalol is an effective and well-tolerated antiarrhythmic drug in patients with complex ventricular ectopic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of drug effects on spontaneous and induced ventricular arrhythmias in a 24-h canine infarction model.

The antiarrhythmic efficacy of encainide, sotalol, flecainide and disopyramide was evaluated in anesthetized dogs subjected to 2-stage total occlusion of the left anterior descending coronary artery. Utilization of this canine model, while anesthetized, permitted the assessment of drug effects not only on uni- and/or multi-focal ectopic ventricular arrhythmias, but also on dysrhythmias associated with aberrant conduction or reentrant excitation pathways. The former was assessed by quantification of ectopic-to-total beat ratios while the later was determined by subjecting the animal to provocative stimuli which produced repetitive ventricular responses. At the cumulative i.v. doses studied, encainide (0.5-4 mg/kg), flecainide (1-8 mg/kg) and disopyramide (0.3-10 mg/kg), but not sotalol (2-8 mg/kg), effectively suppressed ventricular ectopic activity in a dose-related manner. In contrast, sotalol was highly effective in preventing the induction of reentrant ventricular tachyarrhythmias. Disopyramide was only modestly active, while flecainide and encainide had the least favorable profiles of effect in suppressing re-entry arrhythmias in this model. Based on these observations, the anesthetized Harris dog appears to represent a useful two-faceted in vivo model for use in the evaluation of potential antiarrhythmic agents.

Enhancement of physiological finger tremor by intravenous isoprenaline infusions in man: evaluation of its role in the assessment of beta-adrenoceptor antagonists.

Graded intravenous isoprenaline infusions produce dose-related increases in finger tremor. The dose-response curves constructed with intra-arterial or intravenous isoprenaline behave similarly in the presence of both atenolol 50 mg and propranolol 40 mg. In Five subjects, practolol 120 mg, atenolol 50 mg, propranolol 40 mg and sotalol 200 mg reduced exercise heart rate by 20.2 +/- 2.3, 21.4 +/- 1.8, 17.4 +/- 2.5, 23.9 +/- 3.6% respectively: the differences were not significant. The corresponding dose-ratios for reduction of an isoprenaline tachycardia were 2.8, 2.3, 19.1 and 16.9 respectively. At doses which had comparable effects on an exercise tachycardia, the non-selective beta-adrenoceptor antagonists, propranolol 40 mg and sotalol 200 mg, attenuated the finger response to isoprenaline (dose ratios 33.3 and greater than 25.0 respectively) more than the beta 1-selective adrenoceptor antagonists, practolol 120 mg and atenolol 50 mg (dose ratios 1.0 and 2.3 respectively). In two out of five subjects, dose-response curves could not be constructed with sotalol, either at a dose of 200 or 100 mg. The enhancement of physiological finger tremor by intravenous infusions of isoprenaline may be useful in the investigation of beta 2-adrenoceptors and their antagonists in man.

Comparative assessment of beta-adrenoceptor blocking agents as simple competitive antagonists in isolated heart muscle: similarity of inotropic and chronotropic blocking potencies against isoproterenol.

The pattern of antagonism between isoproterenol and various beta-adrenoceptor blocking agents was explored in spontaneously beating right atria and in driven left atrial strips from kittens and guinea pigs. The onset of beta-adrenoceptor blockade is usually very slow in such preparations; incubation periods of up to an hour may be required for equilibrium conditions. The speed of onset of the blocking action is directly related to the concentration of the antagonist, and therefore, for a given degree of blockade, inversely related to its potency. beta-Adrenoceptor blocking agents were found to interact with isoproterenol in a manner consistent with a simple competitive antagonism provided that (1) the antagonist had little intrinsic stimulant action on the preparation under study, (2) the concentrations of antagonist used had no direct depressant action on the preparation, (3) precautions were taken to assure that the pattern of antagonism was not distorted by loss of agonist into tissue sinks, and (4) dose-response curves were normalized for changes in the baseline frequency or force in successive curves. Corrections for desensitization were necessary only in inotropic dose-response curves. Estimates of the equilibrium dissociation constants (KB) derived from the antagonism of the chronotropic and inotropic effects of isoproterenol were determined for fifteen beta-adrenoceptor blocking agents of widely differing potency. In no case was there a substantial difference between the inotropic and chronotropic values. Published estimates of binding constants for beta-blockers determined on cardiac membrane particles are more variable than those determined on intact tissues, and tend to be slightly (adenylyl cyclase measurements) or considerably (radioligand binding studies) lower than the values obtained in intact tissues. These differences raise the possibility that the properties of the beta-adrenoceptor may sometimes be altered during the isolation and partial purification of membrane fragments.