Exercise-induced Heart Rate Research Articles

Controlled-Release Carvedilol in Heart Failure and Post-MI LVD: Pharmacokinetics, Pharmacodynamics and Safety

Objective: We compared pharmacokinetic (PK) and predicted pharmacodynamic (PD) profiles of immediate-release carvedilol (IR) and a novel, once-daily controlled-release (CR) carvedilol formulation in patients (pts) with heart failure (HF) or post-myocardial infarction (MI) left ventricular dysfunction (LVD). Research Design and Methods: In this open, nonrandomized, multicenter, crossover study we included pts with stable mild to severe HF and asymptomatic survivors of a recent MI with LV ejection fraction ≤ 40%. Pts received their standard carvedilol IR dose for 2 weeks followed by 24-hr PK assessment; they were switched to an equivalent dose of carvedilol CR (10, 20, 40 or 80 mg once a day). Carvedilol CR and IR were compared for observed steady-state PK (area under the concentration-time curve [AUC], trough plasma concentration [Cmin], and maximum plasma concentration [Cmax]). Predicted steady-state PD (area under the effect curve [AUEC], maximum effect [PDmax], and PD at trough [PDmin]) was assessed for the two formulations based on a PK/PD model developed in healthy volunteers for changes in exercise induced heart rate. Results: Of 187 pts entered (28% mild, 29% moderate, 27% severe HF; 16% asymptomatic post-MI LVD), 93% completed the study. Mean exposure was 28.3 days (range 1 to 51). Doses used were 20% carvedilol CR 10 mg, 29% 20 mg, 27% 40 mg, and 24% 80 mg. Consistent with its extended-release properties, median tmax was 3 h longer with carvedilol CR vs. IR and the Fluctuation index (CR:IR ratio for [Cmax-Cmin]/concentration at steady state [Css]) was approximately 1. Based on analysis of data pooled across all pt and dose groups, carvedilol CR and IR had equivalent observed PK and predicted PD effects. Both formulations were well tolerated; when pts switched to carvedilol CR there were 20 (11%) events during the first week of therapy with 2 reports of dizziness. Conclusions: Pharmacokinetic parameters for the CR and IR carvedilol formulations were equivalent in pts with mild to severe HF or asymptomatic post-MI LVD. Predicted PD effects (AUEC, PDmin, and PDmax) were also equivalent. When administered as either formulation, carvedilol was generally safe and well-tolerated in this study. These data support the use of carvedilol CR in HF and post MI-LVD patients.

Impact of a Beta-Blocking Agent on Exercise Tolerance in Type 2 Diabetic Patients

Patients with type 2 diabetes without cardiovascular complications present exercise intolerance compared to non diabetic subjects. It has been shown that beta-blocking agents reduce exercise tolerance in the latter. However, it is not known if this medication lowers the already reduced exercise tolerance in type 2 diabetic patients. PURPOSE: To evaluate the impact of a beta-blocking agent on the maximal systemic oxygen transport and exercise tolerance in type 2 diabetic patients. METHODS: A total of 6 sedentary men with type 2 diabetes have been recruited to participate in this study. All patients were treated with oral hypoglycaemic agents and/or diet. The maximal exercise tolerance was evaluated for each subject using an incremental protocol performed on an ergocycle. The subjects were evaluated without (WBB group) and following the intake of a beta-blocking agent for 5 consecutive days (BB group). RESULTS: Per study design, each subject were their own control. The BB group had a lower resting heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP) [(54±3 vs 74±13 bpm; 128±8 vs 135±9 mmHg and 79±5 vs 86±9 mmHg respectively (all p < 0.05)]. At maximal exercise, we observed a 13% reduction in absolute peak oxygen uptake (peak VO2) (2.59±0.49 vs 2.99±0.60 L · min-1;p < 0.05) concomitantly to a 3 5 % and 21 % reduction in maximal HR and SBP respectively [111 ± 10 vs 170±15 bpm; 174±21 vs 220±17mmHg (all p < 0.01)]. Of note, the exercise-induced HR and SBP increase were reduced in the BB group [(58±10 vs 96±19 bpm; 53±15 vs 85±15 mmHg (all p < 0.05)]. Interestingly, the beta-blocking agent lowers maximal ventilation in the BB group compared to the WBB group (100±15 vs 130±18 L · min−1; p < 0.001). CONCLUSIONS: These results suggest that the beta-blocking agent alters the exercise tolerance in patients with type 2 diabetes without cardiovascular complications. With beta-blockers, the systemic oxygen transport might limit maximal exercise tolerance in this population. Finally, this beta-blocking agent appears to have a significant impact on the pulmonary ventilation in these patients.

Use of atropine in patients with recent myocardial infarction during exercise myocardial perfusion study

Patients with recent myocardial infarction frequently require a myocardial perfusion study for risk stratification. However a conclusive study cannot be accomplished in many due to non-attainment of target heart rate. To evaluate the effect of pre-stress administration of atropine in exercise performance of patients with recent myocardial infarction. Study included 43 test and 43 control patients and were matched for their age, sex, status of pretest exercise tolerance, area of infarction and for interval between infarction and stress thallium test. Atropine (0.01 mg/kg) was administered intravenously 3 min prior to treadmill stress in all the 43 test patients and no atropine was administered to control patients. Target heart rate was attained in 95.3% patients receiving atropine compared to in 67.4% of control patients. There was no significant difference between mean ages (p>0.33), basal BP (p>0.47), peak BP (p>0.18) of both groups. There was significant difference between the increment in exercise-induced heart rate (p<0.004), peak heart rate (p<0.001) and double product (p<0.001) attained between both groups. No significant adverse effect was noted in patients who received atropine. Pre-stress administration of atropine in patients with recent myocardial infarction is safe and results in a significantly better exercise performance, which might be useful in decreasing the number of equivocal myocardial perfusion studies.

Improving exercise capacity, 6 wk training tends to reduce circulating endothelin after heart transplantation

Short-term survival is no longer the pivotal issue after heart transplantation but, most heart-transplant (Htx) patients still present with increased circulating endothelin-1 (ET) and reduced exercise capacity. ET-1 limits both exercise-induced vasodilation and blood flow redistribution toward acting muscles and might be accessible to training. This study was performed to investigate the effect of training on ET-1 and whether an eventual training-induced improvement in exercise capacity may be related to reduced baseline or exercise circulating ET-1 in Htx patients. Five Htx patients performed a maximal bicycle exercise test and an endurance exercise test before and after a training program of 18 exercises sessions during 6 wk. ET-1 was determined by radioimmunoassay at rest, end endurance exercise and 30 min recovery, before and after training. Training improved significantly Htx's maximal oxygen uptake (+13.1 +/- 4.8%; p < 0.05) and also reduced significantly the endurance exercise-induced heart rate increase. Resting ET-1 was increased in Htx (5.98 +/- 1.88 vs. 1.61 +/- 0.25 pmol/L in controls; p < 0.01) but although ET-1 modulation might participate in training-induced beneficial effects, training failed to modulate either resting or exercise ET-1 plasma level. Training-induced improvement in exercise capacity might not mainly due to decreased ET-1 after heart transplantation. Further supporting the usefulness of training, these preliminary data suggest that improved exercise capacity may not be mainly due to decreased ET-1 in Htx patients. Further, larger scale studies will be needed to investigate whether an impaired nitric oxide pathway stimulation might explain such results and whether a longer training program can reduce local ET-1, arising from working muscles after heart transplantation.

This Issue of Acta

This Issue of Acta

Safety of unoprostone isopropyl as mono- or adjunctive therapy in patients with primary open-angle glaucoma or ocular hypertension.

This review summarises the safety of unoprostone isopropyl (both at the 0.12 and 0.15% concentrations) instilled twice daily in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OH). For unoprostone 0.15%, combined data from two 12-month comparative monotherapy studies are reported, as well as data from three adjunctive therapy studies and two special population studies. With unoprostone monotherapy, most adverse events were mild or moderate and transient in nature. Less than 7% of unoprostone-treated patients discontinued therapy due to an adverse event. The most common adverse events associated with unoprostone were burning/stinging, burning/stinging directly upon drug instillation, ocular itching, and conjunctival hyperaemia. Unoprostone had no clinically notable effects on vital signs, laboratory profiles, or comprehensive ophthalmic examinations. One of 659 unoprostone 0.15%-treated patients had a change in iris colour after 12 months of monotherapy. Except for a higher incidence of burning/stinging and burning/stinging upon instillation, unoprostone was comparable to timolol 0.5% twice daily and betaxolol 0.5% twice daily. No safety concerns were raised with use of unoprostone as adjunctive therapy. Unoprostone had no significant effect on exercise-induced heart rate in healthy subjects or on pulmonary function in patients with mild-to-moderate asthma. The safety profile of unoprostone 0.15% was consistent with published information on the 0.12% formulation. In conclusion, unoprostone has an excellent safety profile in patients with POAG or OH.

Development of a sequential linked pharmacokinetic and pharmacodynamic simulation model for ivabradine in healthy volunteers

Ivabradine is a novel bradycardic agent that has been developed for the prevention of angina. Ivabradine has an active metabolite S-18982. The aim of the study was to develop a linked pharmacokinetic–pharmacodynamic simulation model for the description of exercise-induced heart rate. The pharmacodynamic data (heart rate) were pooled from two studies and included a total of 78 healthy subjects. The data consisted of multiple dose oral administration of ivabradine. The multiple dose regimens were administered every 12 h. There were eight active dosing levels and placebo, and a no-dose run in the period before each study. The modelling was performed using the NONMEM software. Both ivabradine and S-18982 possess bradycardic activity, although the extent of the activity of both could not be determined from the data available. A multiple ligand pharmacodynamic model provided the best fit to the data. The model was assessed in terms of its posterior predictive performance and was able to describe the original data adequately when used for simulation purposes.

Evaluation of partial beta-adrenoceptor agonist activity.

A partial beta-adrenoceptor (beta-AR) agonist will exhibit opposite agonist and antagonist activity depending on the prevailing degree of adrenergic tone or the presence of a beta-AR agonist with higher intrinsic activity. In vivo partial beta-AR agonist activity will be evident at rest with low endogenous adrenergic tone, as for example with chronotropicity (beta 1/beta 2), inotropicity (beta 1) or peripheral vasodilatation and finger tremor (beta 2). beta-AR blocking drugs which have partial agonist activity may exhibit a better therapeutic profile when used for hypertension because of maintained cardiac output without increased systemic vascular resistance, along with an improved lipid profile. In the presence of raised endogenous adrenergic tone such as exercise or an exogenous full agonist, beta-AR subtype antagonist activity will become evident in terms of effects on exercise induced heart rate (beta 1) and potassium (beta 2) responses. Reduction of exercise heart rate will occur to a lesser degree in the case of a beta-adrenoceptor blocker with partial beta 1-AR agonist activity compared with a beta-adrenoceptor blocker devoid of partial agonist activity. This may result in reduced therapeutic efficacy in the treatment of angina on effort when using beta-AR blocking drugs with partial beta 1-AR agonist activity. Effects on exercise hyperkalaemia are determined by the balance between beta 2-AR partial agonist activity and endogenous adrenergic activity. For predominantly beta 2-AR agonist such as salmeterol and salbutamol, potentiation of exercise hyperkalaemia occurs. For predominantly beta 2-AR antagonists such as carteolol, either potentiation or attenuation of exercise hyperkalaemia occurs at low and high doses respectively. beta 2-AR partial agonist activity may also be expressed as antagonism in the presence of an exogenous full agonist, as for example attenuation of fenoterol induced responses by salmeterol. Studies are required to investigate whether this phenomenon is relevant in the setting of acute severe asthma.

Evaluation of partial β‐adrenoceptor agonist activity

A partial β‐adrenoceptor (β‐AR) agonist will exhibit opposite agonist and antagonist activity depending on the prevailing degree of adrenergic tone or the presence of a β‐AR agonist with higher intrinsic activity. In vivo partial β‐AR agonist activity will be evident at rest with low endogenous adrenergic tone, as for example with chronotropicity (β1/β2), inotropicity (β1) or peripheral vasodilatation and finger tremor (β2). β‐AR blocking drugs which have partial agonist activity may exhibit a better therapeutic profile when used for hypertension because of maintained cardiac output without increased systemic vascular resistance, along with an improved lipid profile. In the presence of raised endogenous adrenergic tone such as exercise or an exogenous full agonist, β‐AR subtype antagonist activity will become evident in terms of effects on exercise induced heart rate (β1) and potassium (β2) responses. Reduction of exercise heart rate will occur to a lesser degree in the case of a β‐adrenoceptor blocker with partial β1‐AR agonist activity compared with a β‐adrenoceptor blocker devoid of partial agonist activity. This may result in reduced therapeutic efficacy in the treatment of angina on effort when using β‐AR blocking drugs with partial β1‐AR agonist activity. Effects on exercise hyperkalaemia are determined by the balance between β2‐AR partial agonist activity and endogenous adrenergic activity. For predominantly β2‐AR agonists such as salmeterol and salbutamol, potentiation of exercise hyperkalaemia occurs. For predominantly β2‐AR antagonists such as carteolol, either potentiation or attenuation of exercise hyperkalaemia occurs at low and high doses respectively. β2‐AR partial agonist activity may also be expressed as antagonism in the presence of an exogenous full agonist, as for example attenuation of fenoterol induced responses by salmeterol. Studies are required to investigate whether this phenomenon is relevant in the setting of acute severe asthma.

Heart rate increase and maximal heart rate during exercise as predictors of cardiovascular mortality: a 16-year follow-up study of 1960 healthy men.

Resting heart rate is directly associated and maximal exercise-induced heart rate inversely associated with cardiovascular mortality, and therefore their difference might contain prognostic information from both variables. The comparative long-term prognostic values of maximal exercise-induced heart rate and of the difference between it and resting heart rate were studied in apparently healthy middle-aged men. Resting heart rate and maximal exercise-induced heart rate were measured, and their difference calculated, in 1960 apparently healthy men aged 40-59 years, and mortality was recorded over a period of 16 years. Conventional coronary risk factors were assessed at baseline. Both the difference between the two heart rates and the maximal exercise-induced heart rate were strongly, independently and inversely associated with cardiovascular mortality after adjustment for age, smoking, systolic blood pressure, lung function, glucose tolerance, serum cholesterol level, serum triglycerides level, physical fitness and exercise ECG findings. The adjusted relative risk of cardiovascular death in heart-rate difference quartiles 3 and 4 compared with that in quartile 1 (the lowest heart-rate difference quartile) was 0.54 (95% confidence interval 0.33-0.86; P = 0.009). The corresponding value for maximal exercise-induced heart rate was 0.56 (95% confidence interval 0.34-0.89; P = 0.018). Within the lowest heart-rate difference quartile, but not within the lowest maximal exercise-induced heart rate quartile, a further, strong, negative gradient in cardiovascular mortality was observed. In the high working capacity range, low heart-rate difference but not low maximal exercise-induced heart rate predicted very high cardiovascular disease mortality. Heart-rate difference and maximal exercise-induced heart rate were also inversely associated with non-cardiovascular disease mortality. Both heart-rate difference and maximal exercise-induced heart rate were strong, graded, long-term predictors of cardiovascular mortality among apparently healthy middle-aged men, independent of age, physical fitness and conventional coronary risk factors. However, low heart-rate difference was a better predictor than low maximal exercise-induced heart rate for recognizing individuals who were at particularly high risk of dying prematurely from cardiovascular diseases.

801–1 QT Interval Dispersion at Rest and During Exercise in Normal Subjects

QT dispersion (QTd, the maximal interlead QT difference) is increased in post· MI patients and in patients who have torsades de pointes while taking. Class la antiarrhythmic drugs. Studies to date have been in resting patients, however, and the effects of heart rate increases on QT dispersion have not been studied. To evaluate the latter, we measured QT dispersion on a beat-to-beat basis in 13 normal subjects (8 male. 5 female. mean age = 30 yrs) before, during and after graded supine bicycle exercise. The 12-lead ECG was digitized at 500 samples/sec/lead and recorded directly to a PC hard disk for later analysis. The ECG was recorded at rest for 15 min, during exercise to exhaustion. then during recovery for 15 min. The times from Q onset to T wave peak (QTp) and end (QTe) were automatically measured on every beat in each lead using custom software. Median values for QTp and QTe were obtained during specified 10 msec R-R interval windows (e.g., between 695 and 705 msec for the 700 msec values). QTd (longest QT minus shortest QT) was calculated for all 12 leads (12L) and for the 6 precordial leads only (VL). Average QTd values for the 13 subjects (all intervals in msec; X = average [n = 7], SD = standard deviation. CV = coefficient of variation):QTd using:R–R IntervalsXSDCV4505006007008009001000QTp in 12L39.636.437.941.637.338234.938.02.25.7%QTp in VL28.828.524.327.927.029.227.127.51.76.0%QTe in 12L37.035.434.128.827.427.829.531.44.012.6%QTe in VL24.824.122.317.420.719.121.721.42.612.3% Regression analysis revealed no significant changes in QTd with changes in R-R intervals, except for QTe in 12L; examination of those data revealed problems with identifying the end of the T wave in standard leads at short R-R intervals. QT intervals shortened normally with exercise in all leads. QT dispersion does not change with exercise-induced heart rate increases in normal subjects. QT dispersion is smaller in the precordial leads than in all 12 leads. QT dispersion is greater, and is measured with less variance, using QTp. These data provide a base for comparison with disease states such as myocardial infarction.

The Cardiovascular, Pulmonary, and Ocular Hypotensive Effects of 0.2% Brimonidine

To compare the cardiovascular, pulmonary, and ocular hypotensive effects of 0.2% brimonidine tartrate with those of 0.5% timolol maleate, 0.25% betaxolol suspension, and brimonidine vehicle. A single-center, double-masked, randomized, crossover study of 24 young, healthy men. Baseline heart rate, blood pressure, respiratory rate, and intraocular pressure were recorded at hour 0. At hour 2, heart rate, blood pressure, respiratory rate, and forced expiratory volume in 1 second were measured and a 15-minute treadmill test performed. Hour 0 measurements were repeated at hour 4. On four subsequent visits, we instilled one drop of a study medication into each eye after the baseline measurements at hour 0. Timolol reduced resting (-5.3 to -6.5 beats/min, P < or = .004) and exercise-induced heart rate (-4.3 to -13.6 beats/min; P < or = .022) compared with brimonidine, betaxolol suspension, and brimonidine vehicle. At hour 4, brimonidine reduced resting systolic blood pressure compared with all other study medications (-5.2 to -7.3 mm Hg; P < or = .024). Timolol reduced systolic blood pressure during exercise and brimonidine reduced systolic blood pressure during recovery more than betaxolol suspension and brimonidine vehicle (-5.1 to -7.7 mm Hg; P < or = .033; and -5.4 to -6.0 mm Hg; P < or = .002, respectively). Mean respiratory rate and forced expiratory volume in 1 second were not significantly altered by any study medication. At hour 4, brimonidine lowered intraocular pressure as well as timolol and better than betaxolol suspension (-1.9 mm Hg; P < .001) or brimonidine vehicle (-1.8 mm Hg; P < .001). The cardiopulmonary effects of 0.2% brimonidine were limited to a slight reduction in systolic blood pressure during recovery from exercise and at 4 hours after instillation. The ocular hypotensive effect of brimonidine was comparable to that of timolol and greater than that of betaxolol suspension in this patient population.

Prognostic significance of exercise blood pressure and heart rate in middle-aged men.

Systolic blood pressure and heart rate measured at rest and during a standardized exercise test were analyzed in the cohort of middle-aged male employees followed-up an average of 17 years in the Paris Prospective Study I. The population sample selected for the analysis included 4,907 men who completed at least 5 minutes of bicycle ergometry, who had no heart disease at entry, and whose resting blood pressure was less than or equal to 180/105 mm Hg. Exercise-induced increase in systolic blood pressure was positively correlated with resting systolic blood pressure (r = 0.104, p less than 0.0001), whereas the correlation of exercise-induced heart rate increase with resting heart rate was negative (r = -0.169, p less than 0.001). Using Cox regression analysis with the inclusion of resting systolic blood pressure and heart rate; exercise-induced elevations of systolic blood pressure and heart rate; and controlling for age, smoking, total cholesterol, body mass index, electrical left ventricular hypertrophy, and sports activities, cardiovascular mortality was found to be associated with the systolic blood pressure increase (p less than 0.05), whereas no association with resting systolic blood pressure was found. Total mortality was predicted by resting systolic blood pressure and its elevation (p less than 0.01 for both) and by resting heart rate (p less than 0.0001). The heart rate increase did not contribute to death prediction. In conclusion, the magnitude of the exercise-induced increase of systolic blood pressure, but not of heart rate, may represent a risk factor for death from cardiovascular as well as noncardiovascular causes, independently of resting blood pressure and heart rate.

The Effect of Verapamil in Patients with Asymptomatic Stress-Induced Ischemia

• In 25 patients with asymptomatic exercise-induced positive stress tests heart rate, blood pressure, double product, exercise duration, and ST-segment changes were studied prior to and 4 weeks after administration of 120 mg of verapamil therapy three times a day. Significant improvement was observed at rest and at peak exercise in heart rate, pressure values, double product, and maximal ST depression with a prolongation of exercise duration. Measurements at the same work load in the post-verapamil test as at the pretreatment peak exercise showed a slower heart rate, lower blood pressure, less double product, and less ST depression as a more pronounced expression of drug efficacy. There was no deterioration in any parameter. In conclusion, improved myocardial performance can be demonstrated in asymptomatic ischemic patients when treated with verapamil, and this effect is particularly evident when data are compared with equal exercise duration in the posttreatment test as with peak exercise prior to therapy. ( Arch Intern Med . 1989;149:1062-1064)

Concentration/response relations for the multiple antiarrhythmic actions of sotalol

Sotalol, one of the first β-receptor antagonists synthesized, is a promising investigational agent with remarkable efficacy for treatment of patients with ventricular and supraventricular arrhythmias. Unlike other β blockers, sotalol also possesses class III antiarrhythmic action, evidenced by prolongation of the myocardial action potential duration. This additional action probably accounts for the greater antiarrhythmic efficacy of sotalol compared with other β blockers. Sotalol's class III antiarrhythmic action becomes apparent at concentrations higher than those necessary for significant β-receptor antagonism, both in vitro and in human subjects. In a study correlating dosage and antiarrhythmic response with prolongation of rate-corrected QT (QTc) (a measure of class III action) and the degree of β-receptor blockade (assessed by the reduction of the maximal exercise-induced heart rate), 11 of 17 patients had an antiarrhythmic response. Eight of these 11 responders had been unresponsive to conventional β-receptor antagonists. The plasma concentration associated with significant QTc prolongation (2.55 μg/ml) was found to be much greater than that associated with 50% reduction in maximal slowing of heart rate (0.8 μg/ml). As with other μ-receptor antagonists, the activities of sotalol's 2 stereoisomers differ, with the l-isomer having far more β-blocking activity. However, both isomers have equal class III antiarrhythmic activity. When increasing doses of the d-isomer of sotalol (50 to 400 mg every 12 hours) were evaluated in patients with chronic ventricular arrhythmias, arrhythmia frequency was suppressed >80% in 3 patients and 50% in 1 patient. With 800 mg/day, QTc was prolonged by 12.3 ± 7% (p < 0.01) and the decrease in heart rate at rest by 19.3 ± 8.4% (p < 0.05) and during peak exercise by 12.3 ± 7% (p < 0.001) compared with placebo. One interpretation of the observed slowing of the heart rate could be that d-sotalol has clinically significant β-receptor antagonist properties. However, a comparison of the effects of d-sotalol with those of atenolol (a β-blocker without class III activity) on indicators of β-receptor antagonism showed that d-sotalol slows heart rate predominantly by prolonging repolarization. d-Sotalol reduces heart rate predominantly at short cycle lengths, when action potential duration has its maximal contribution to heart rate. Furthermore, the degree of reduction in exercise heart rate with d-sotalol correlated with the increase in QT interval, and d-sotalol did not alter blood pressure. Therefore, the conclusion of these studies is that d-sotalol is an effective antiarrhythmic agent due predominantly to its class III action. Racemic sotalol has predominantly β-blocking activity at low dosages and has increasing degrees of class III antiarrhythmic action at higher dosages.

The Effect of Verapamil in Patients With Asymptomatic Stress–Induced Ischemia

In 25 patients with asymptomatic exercise-induced positive stress tests heart rate, blood pressure, double product, exercise duration, and ST-segment changes were studied prior to and 4 weeks after administration of 120 mg of verapamil therapy three times a day. Significant improvement was observed at rest and at peak exercise in heart rate, pressure values, double product, and maximal ST depression with a prolongation of exercise duration. Measurements at the same work load in the post-verapamil test as at the pretreatment peak exercise showed a slower heart rate, lower blood pressure, less double product, and less ST depression as a more pronounced expression of drug efficacy. There was no deterioration in any parameter. In conclusion, improved myocardial performance can be demonstrated in asymptomatic ischemic patients when treated with verapamil, and this effect is particularly evident when data are compared with equal exercise duration in the posttreatment test as with peak exercise prior to therapy.

The effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of metoprolol

The impact of cimetidine, ranitidine and placebo on the pharmacokinetics of metoprolol, given either as a single dose (100 mg) or for 7 days (100 mg b.d.), has been evaluated in two separate studies. The doses used were 800 mg cimetidine daily and 300 mg ranitidine daily. The subjects were all young, healthy volunteers. In the single dose study, cimetidine produced a marked increase in the peak plasma concentration of metoprolol and in the area under the plasma concentration-time curve; ranitidine had less effect, though the area under the curve was significantly greater than placebo. In the chronic dosing study, the area under the curve for metoprolol was also significantly higher on cimetidine (1796 ng h/ml; P less than 0.001) whereas the area under the curve on ranitidine (1258 ng h/ml) was comparable to that on placebo (1183 ng h/ml). Despite these drug-induced changes in plasma metoprolol concentration, neither cimetidine nor ranitidine altered the change in exercise-induced heart rate during dosing with metoprolol.

Exercise testing: Uses and limitations considering recent studies

Accurate use and interpretation of exercise test results depend on an understanding of physiologic principles, meticulous attention to proper methodlogy, and realization of the appropriate applications and limitations of testing. Understanding the relationship between myocardial and ventilatory oxygen consumption and exercise test variables will aid in the diagnosis and prognostic evaluation. Use of proper methodology in preparing the patient, performing the examination, and interpreting the results is critical to obtaining the maximum information with maximum safety for each individual patient. Improvements in methodology including the use of the Borg scale to estimate individual effort, abandonment of the predicted maximum heart rate, and the increased use of ventilatory oxygen uptake measurements should be applied. Exercise capacity should not be reported in total time but rather as the VO 2 or MET equivalent of the workload achieved. This permits the comparison of the results of many different exercise testing protocols. The most useful exercise ECG variable for the diagnosis of coronary artery disease remains the ST segment shift. Unfortunately, it is not as helpful in localizing myocardial ischemia. Diagnostic accuracy can be improved by adjusting ST depressions for exercise-induced heart rate increase. Accuracy can be further increased by combining ECG, clinical, and radionuclide variables in probabilistic formulas that retain the independent diagnostic information from each variable and accurately predict disease probability. To avoid errors in clinical decision making, care must be used to insure that the mathematical formula used was derived from a population of patients that is similar to those being tested. The clinical applications for exercise testing include diagnosis of patients with chest pain syndromes, determination of disease severity, and prognosis in patients with known coronary artery disease, evaluation of arrhythmias, screening of asymptomatic patients, and evaluation of medical, surgical, and angioplastic therapy for coronary disease. In spite of studies involving thousands of patients, controversy exists regarding the diagnostic power of exercise testing. The large differences in reported accuracies are largely due to methodologic problems that have been encountered by various investigators. Clinicians should be made aware of these problems when reading the literature on ECG and radionuclide exercise testing. Such awareness will help them understand the limitations of these noninvasive procedures. Exercise testing can be used to predict coronary disease severity and prognosis. heart rate adjustment of ST depressions, exercise-induced hypotension, and reduced exercise capacity have been helpful in predicting critical coronary disease. Though exercise testing is helpful in evaluating the presence and severity of cardiac dysrhythmias, it is of little assistance in determining their prognostic significance. Careful evaluation of exercise testing as a screening device for asymptomatic patients reveals that it is somewhat disappointing in this application. Its use for evaluating the effects of therapy is also controversial, since studies evaluating antianginal agents have been greatly hampered by the increased in treadmill time that occurs merely by performing serial tests, and studies of bypass surgery and angioplasty are confounded by differences in medication states before and after intervention.

Concentration-dependent pharmacologic properties of sotalol

Sotalol is a nonselective β-receptor antagonist that prolongs action potential duration and refractoriness in vitro at higher concentrations than those associated with heart rate slowing. To determine if this additional action can be expressed in humans, 17 patients with chronic stable ventricular premature complexes were studied. Each patient was hospitalized and arrhythmia frequency was quantified during a 48-hour drug-free baseline and during every third day of therapy with increasing incremental sotalol dosages. The dosages were 160, 320, 640 and 960 mg/day, administered in 1 or 2 doses. An index of action potential duration, the rate-corrected QT (QTc), was measured using serial 12-lead electrocardiograms on the third day of each dosage at presumed steady state and the degree of β-receptor blockade was assessed by the reduction of the maximal exercise-induced heart rate. Of the 17 patients, 11 had an antiarrhythmic response (70 to 100% reduction in VPCs), at a wide range of plasma concentrations (340 to 3,440 ng/ml). the responders to sotalol included 8 patients in whom therapy with conventional β-receptor antagonists had failed. In the group as a whole, the concentration associated with significant QTc prolongation (2,550 ng/ml) was greater than that associated with 50% reduction of the maximal slowing in heart rate (804 ng/ml). Sotalol was generally well tolerated, but in 1 nonresponder torsades de pointes developed 3 hours after the first 640-mg dose at a plasma sotalol concentration well within the concentration range measured in other patients. Sotalol's repolarization-prolonging actions are seen at higher concentrations than those associated with heart rate slowing and may contribute to its clinical effects.

Cardiovascular response to exercise and regional haemodynamics during treatment with prizidilol hydrochloride (SK&amp;F 92 657) in moderately severe essential hypertension

Fourteen men with moderately severe essential hypertension were treated with prizidilol hydrochloride 400-700 mg once daily (mean +/- S.D. 612 +/- 56 mg/day). The study was open and ambulatory, with an initial placebo period followed by dose titration of prizidilol. Prior to treatment and during optimal control of blood pressure cardiovascular adaptation was examined in a submaximal exercise test. Plethysomographic assessment of vascular flow, resistance and tone in the calf musculature during supine rest and during maximal vasodilatation was also performed. A highly significant reduction in systolic (from 164 +/- 4.5 to 141 +/- 2.7 mmHg; p less than 0.001) and diastolic blood pressure (from 105 +/- 1.6 to 87 +/- 1.3 mmHg; p less than 0.001) at supine rest was noted during therapy with prizidilol. There was no significant change in heart rate. Systolic pressure in the standing position was reduced (from 159 +/- 4.2 to 139 +/- 2.9 mmHg; p less than 0.001) and so was the diastolic pressure (from 111 +/- 2.5 to 95 +/- 1.9 mmHg; p less than 0.001). The heart rate in the standing position was significantly increased compared to supine rest in the placebo period and during optimal treatment with prizidilol. The beta-adrenoceptor blocking properties of prizidilol were apparent as a reduction in the exercise-induced heart rate response at even the lowest work load. During prizidilol therapy an increase in resting calf muscle blood flow was found from 3.1 +/- 1.5 ml/min X 100 ml to 4.3 +/- 2.1 ml/min X 100 ml (p less than 0.025). Vascular resistance and vascular tone were significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)