Sequential treatment with low dose almitrine bismesylate in hypoxaemic chronic obstructive airways disease.

Daily dose schedules of 100-200 mg of almitrine bismesylate improve arterial blood gases in patients with hypoxaemic chronic obstructive airways disease (COPD) but dose related side effects are evident. In the present study, daily doses approximately half of those previously used were employed in a randomised double blind manner in 85 patients (age 35-79 years) with hypoxaemic COPD. After a one month period to check stability of arterial blood gases, patients were allocated to almitrine (A) or placebo (P) using an unequal code (60% A, 40% P). Tablets, 50-100 mg daily were stopped for one month after 3, 6 and 9 months to counteract drug accumulation. 50 patients in group A and 35 in group P were comparable on entry; mean age 65 (SD = 8) yrs., Pao2 7.8 (0.7) kPa (58.3 (5.0) mmHg), PaCO2 5.8 (0.8) kPa (43.2 (6.0) mmHg), forced expiratory volume in one second--FEV1 0.89 (0.25) l and 6 minute walking distance 296 (97) metres. The improvement in baseline PaO2 values was the same 0.8-1.3 kPa (6-9.8 mmHg) as with previous higher dose therapy. Approximately one third of patients did not respond, defined as PaO2 elevation > 0.67 kPa (5 mmHg). The sequential dosing scheme stabilised blood levels of almitrine within the therapeutic range of 280-300 ng.ml-1. After withdrawal of therapy arterial blood gases and spirometry reverted to pre-treatment levels, suggesting no permanent reversal of pathophysiology. Dose related side effects of breathlessness, indigestion and peripheral neuropathy were not observed. Nerve conduction studies revealed no difference in peripheral nerve dysfunction in hypoxaemic COPD between active and placebo therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Noninvasive ventilation during walking in patients with severe COPD: a randomised cross-over trial.

It was hypothesised that noninvasive positive-pressure ventilation (NPPV) applied during walking prevents exercise-induced hypoxaemia and improves exercise performance in severe chronic obstructive pulmonary disease (COPD) patients already receiving long-term NPPV. A total of 20 COPD patients (mean+/-sd age 65.1+/-8.7 yrs, forced expiratory volume in one second 27+/-8% predicted and total lung capacity 116+/-27% pred) reporting dyspnoea, even during mild exertion, underwent two 6-min walking tests with a rollator and supplemental oxygen (2.1+/-0.9 L.min(-1)) in a randomised cross-over design: with and without pressure-limited NPPV as used at home (inspiratory:expiratory pressure 2.9+/-0.44:0.4+/-0.1 kPa (29+/-4:4+/-1 mbar), respiratory frequency 20+/-2 breaths.min(-1)). The arterial oxygen tension significantly increased by 1.39+/-1.43 kPa (95% confidence interval (CI) 0.71-2.07 kPa) after walking with NPPV, but significantly decreased by 1.43+/-1.06 kPa (95% CI -1.92 - -0.94 kPa) without NPPV. Dyspnoea, as assessed by the Borg dyspnoea scale, significantly decreased from 6 (interquartile range (IQR) 4.5-10) to 4 (1.5-4.5) and walking distance significantly increased from 209 (IQR 178-279) to 252 (203-314) m when walking was NPPV-aided. In chronic hypercapnic chronic obstructive pulmonary disease, high-intensity noninvasive positive-pressure ventilation can also be administered during walking with unchanged ventilator settings compared with settings used at rest, thus resulting in improved oxygenation, decreased dyspnoea and increased walking distance. Therefore, noninvasive positive-pressure ventilation during walking could prevent hypoxia-induced complications and could, in future, play a role in palliative care.     

The effect of indomethacin on breathlessness in patients with diffuse parenchymal disease of the lung

We have shown in a previous study that indomethacin reduced breathlessness in normal subjects during exercise. In a double-blind randomized study we have determined the effects of both acute (50 mg) and chronic (25 mg twice daily for 7 days) oral treatment with indomethacin on breathlessness induced by exercise in patients with diffuse parenchymal disease of the lung. The relationship of breathlessness, as measured on a visual analogue scale, to ventilation was not significantly altered by either acute or chronic treatment with indomethacin compared to placebo. There was no significant change in the distance walked in 6 minutes after any of the treatments. Possible explanations for the differing effects on breathlessness observed in normal subjects and in patients are discussed.     

Clinical outcomes of expiratory muscle training in severe COPD patients

The most common symptoms in chronic obstructive pulmonary disease (COPD) patients are breathlessness and exercise limitation. Although both general and inspiratory muscle training have shown clinical benefits, the effects of specific expiratory muscle training remain controversial. OBJECTIVE: To investigate the effects of expiratory training on lung function, exercise tolerance, symptoms and health-related quality of life in severe COPD patients. METHODS: Sixteen patients (FEV(1), 28+/-8% pred.) were randomised to either expiratory muscle or sham training groups, both completing a 5-week programme (30 min sessions breathing through an expiratory threshold valve 3 times per week) (50% of their maximal expiratory pressure (MEP) vs. placebo, respectively). Lung function, exercise capacity (bicycle ergometry and walking test), and clinical outcomes (dyspnoea and quality of life (St. George Respiratory Questionnaire (SGRQ)) were evaluated both at baseline and following the training period. RESULTS: Although lung function remained roughly unchanged after training, exercise capacity, symptoms and quality of life significantly improved. The improvement in both walking distance and the SGRQ score significantly correlated with changes in MEP. CONCLUSION: Our results confirm that a short outpatient programme of expiratory training can improve symptoms and quality of life in severe COPD patients. These effects could be partially explained by changes in expiratory muscle strength.     

Propranolol in angina pectoris: duration of improved exercise tolerance and circulatory effects after acute oral administration.

The duration of the effects of single oral doses of 80 and 160 mg of propranolol was studied in 11 patients with stable, exercise-induced angina pectoris. After administration of both doses, plasma propranolol levels peaked at 2 hours in 8 of the 11 patients and thereafter declined exponentially with an average plasma half-life of 3.98 hours (range 1.4 to 4.3) after the 80 mg dose and 4.28 hours (range 1.9 to 5.4) after the 160 mg dose. There was wide interindividual variation in plasma propranolol concentration at any given time after each dose. Treadmill walking time to the onset of angina, the total duration of exercise and the total external work performed were significantly greater by 1 hour after each dose of propranolol than after placebo. This improvement in exercise tolerance persisted unchanged for 8 hours (P less than 0.001) and was still significant although less marked at 12 hours (P less than 0.05). Improvement in exercise tolerance after propranolol was associated with a significant reduction in S-T segment depression during exercise. Both at rest and during exercise, heart rate, systolic blood pressure and rate-pressure product decreased after propranolol, and these circulatory effects persisted for 12 hours. Changes in walking time, heart rate and systolic blood pressure were similar after 80 and 160 mg of propranolol. Despite the increase in exercise duration and in total work performed after propranolol, the rate-pressure product at the onset of angina was lower after propranolol. In view of the prolonged effects of single oral doses of 80 and 160 mg of propranolol, it is suggested that administration of propranolol twice daily should be adequate in treating patients with stable angina pectoris. These studies also demonstrate that routine measurement of plasma propranolol levels is of little practical value in the management of patients with angina pectoris.     

Dose-response and pharmacokinetic study with almitrine bismesylate after single oral administrations in COPD patients

To better define the dose-effect relationship and the pharmacokinetics of almitrine, sixteen stable hypoxaemic COPD patients received random single oral administrations of almitrine bismesylate 50, 100 and 150 mg or placebo at two-week intervals in a double-blind manner. Resting ventilation, arterial blood gases and plasma almitrine levels were measured. No significant changes were seen after placebo administration. Almitrine 50 and 100 mg caused a significant dose-related improvement in arterial oxygen tension (PaO2) in thirteen of the sixteen patients. Almitrine 150 mg caused little if any additional PaO2 increment. PaO2 returned to near basal values after 24 h. Two patients responded to almitrine 100 and 150 mg only, whereas one patient did not respond at all. Mean PaO2 increases in the sixteen patients were 0.9 kPa (7 mmHg), 1.5 kPa (11 mmHg) and 1.6 kPa (12 mmHg) 3 h after 50, 100 and 150 mg, respectively. A significant mean 0.9 kPa (7 mmHg) decrease in arterial carbon dioxide tension (PaCO2) and a l.min-1 increase in ventilation were observed after almitrine 150 mg. Mean maximum almitrine plasma concentration and area under the curve correlated linearly with dose. The relationship between mean PaO2 improvement and mean almitrine plasma level was curvilinear with a flattening of the curve over plasma levels of 150 ng.ml-1. Almitrine plasma half-life was found to be 116-140 h.     

Tissue depletion and health related quality of life in patients with chronic obstructive pulmonary disease

The relationship between tissue depletion and decreased exercise performance has been well established in patients with COPD. In this study we investigated the influence of the pattern of tissue depletion on health related quality of life (HRQL) and their mutual relationship with exercise capacity and dyspnoea. Patients with low body weight and/or low fat-free mass (FFM; using bioelectrical impedance) were categorized in three groups according to type of tissue depletion: loss of both FFM and fat mass (FM), and loss of FFM or FM only. Handgrip strength (HGS) was used as a functional outcome measure of tissue depletion. Exercise performance was assessed by 12 min walking distance (12MWD) and dyspnoea by visual analogue scale (VAS). HRQL was measured with the St George's Respiratory Questionnaire (SGRQ) and the Medical Psychological Questionnaire for Lung diseases (MPQL). Patients with depletion of FFM irrespective of body weight showed greater impairment in 12MWD, HGS, the 'activity' and 'impact' scores of the SGRQ and the domain 'invalidity' of the MPQL, in comparison with depleted patients with relative preservation of FFM. Exercise performance and dyspnoea were also significantly related to these subscores of HRQL. In addition, dyspnoea related significantly to the domain 'symptoms' of the SGRQ. Tissue depletion pattern remained significantly related to SGRQ-scores and the domain 'invalidity' of the MPQL when dyspnoea and walking distance were added to the model as a covariates. Tissue depletion is an important determinant of HRQL independent of exercise capacity and dyspnoea.     

Physiological and symptom determinants of exercise performance in patients with chronic airway obstruction

To evaluate the physiological and symptom determinants of exercise performance (EP) as measured by a 6-min walking test (6MWD), Watt(max), and peak oxygen consumption (VO2 ml/min/kg), 105 patients with chronic airway obstruction (CAO) [50 chronic obstructive pulmonary disease (COPD): 44 men, aged 63+/-7 years, forced expiratory volume in 1 sec (FEV1) forced vital capacity (FVC)(-1)% 54+/-13; and 55 asthmatic: 23 men, aged 55+/-10 years, FEV1 FVC(-1) % 65+/-10] underwent evaluation of 6MWD, symptom limited cyclo-ergometer exercise test, spirometry, respiratory muscle function, arterial blood gases and sensation of dyspnoea [using the Borg scale, Visual Analogue Scale (VAS) and Baseline Dyspnoea Index (BDI)]. A hierarchical method of analysis identified the residual volume (RV), total lung capacity (TLC)(-1) ratio, BDI and the patient's age as the strongest and most consistent correlates of EP (r2 = 0.14-0.21). The correlation between EP and its various determinants was not influenced by diagnosis. The relationship between breathlessness and EP was different between men and women: at any given level of exercise, women were more breathless than men. In multivariate analyses that contained both RV TLC(-1) and BDI, the RV TLC(-1) ratio was the strongest correlate of EP, although the BDI remained a significant covariate. Overall, age was the major determinant of EP but inclusion of the RV TLC(-1) ratio and the BDI into the model explained a further 9-15% of the variance in EP. These three covariates together explained 26-34% of the variance between patients. We conclude that in stable CAO patients, the prediction of exercise capacity by anthropometric, demographic, clinical and physiological variables is likely to be low. Age, pulmonary hyperinflation and dyspnoea are the strongest and most consistent correlates of impaired exercise performance. Airways obstruction, measured during expiration using FEV1, does not appear to be a predictor of physiological impairment. These results underline the importance of performing exercise evaluation in CAO patients.     

Lack of effect of dextromethorphan on breathlessness and exercise performance in patients with chronic obstructive pulmonary disease (COPD)

We have previously shown that the exercise performance of patients with severe chronic obstructive pulmonary disease (COPD) can be increased with the administration of oral morphine (0.8 mg.kg-1). The purpose of this study was to determine whether the administration of dextromethorphan (DXT), an antitussive structurally similar to codeine, would result in increased exercise performance and decreased dyspnoea in patients with COPD, without the side-effects of opiates. Six eucapnic patients (mean age = 66 +/- 3.8 yrs) with COPD (mean forced expiratory volume in one second (FEV1) = 1.01 +/- 0.07 l) underwent two incremental cycle ergometer tests to exhaustion (Emax) and assessment of their hypercapnic and hypoxic ventilatory responses and mouth occlusion pressure responses following first the oral administration of placebo (P) and then dextromethorphan (60 mg) in a single-blind fashion. There was no statistically significant difference in the maximal exercise performance, perceived dyspnoea (modified Borg scale), breathing pattern or expired gases after the two different treatments. In addition, the ventilatory response to CO2 production during exercise (delta VE/VCO2) and the ventilatory and mouth occlusion pressure responses to hypoxia and hypercapnia did not differ significantly after DXT as compared with after P. Indeed the exercise performance was poorer and the ventilatory responses were brisker after DXT. We conclude from this study that the administration of this opiate analogue does not improve the exercise capacity or decrease the ventilatory response of patients with COPD.     

A comparison of the reproducibility and the sensitivity to change of visual analogue scales, Borg scales, and Likert scales in normal subjects during submaximal exercise

OBJECTIVE: To assess which subjective scale, the visual analogue scale (VAS), the Borg CR10 (Borg) scale, or the Likert scale (LS), if any, is decidedly more reproducible and sensitive to change in the assessment of symptoms. DESIGN: Prospective clinical study. SETTING: Exercise laboratory. PARTICIPANTS: Twenty-three physically active male subjects (mean +/- SD age of 30 +/- 4 years old) were recruited. INTERVENTION: Each subject attended the exercise laboratory on four occasions at intervals of 1 week. Three subjective scales were used: (1) the VAS (continuous scale); (2) the Borg scale (12 fixed points); and (3) the Likert scale (LS; 5 fixed points). Four identical submaximal tests were given (2 min at 60% maximum oxygen uptake [VO(2)max] and 6 min at 70% VO(2)max). Two tests were undertaken to assess the reproducibility of scores that were obtained with each subjective scale. Two other tests were undertaken to assess the sensitivity of each scale to a change in symptom perception: a double-blind treatment with propranolol, 80 mg, (ie, active therapy; to increase the sensation of breathlessness and general fatigue during exercise) or matching placebo. The subjective scale scores were measured at 1 min 30 s, 5 min 30 s, and 7 min 15 s of exercise. Reproducibility was defined as the proportion of total variance (ie, between-subject plus within-subject variance) explained by the between-subject variance given as a percentage. Sensitivity was defined as the effect of the active drug therapy over the variation within subjects. RESULTS: Overall, the VAS performed best in terms of reproducibility for breathlessness and general fatigue, with reproducibility coefficients as high as 78%. For sensitivity, the VAS was best for breathlessness (ratio, 2.7) and the Borg scale was most sensitive for general fatigue (ratio, 3.0). The relationships between the respective psychological and physiologic variables were reasonably stable throughout the testing procedure, with overall typical correlations of 0.73 to 0.82 CONCLUSION: This study suggests that subjective scales can reproducibly measure symptoms during steady-state exercise and can detect the effect of a drug intervention. The VAS and Borg scales appear to be the best subjective scales for this purpose.     

Six-minute walking test in cystic fibrosis adults with mild to moderate lung disease: comparison to healthy subjects

The six-minute walking test (6MWT) has been widely utilized to evaluate global exercise capacity in patients with cystic fibrosis. The aim of this study was to assess the exercise capacity by 6MWT, measuring four outcome measures: walk distance, oxygensaturation and pulse rate during the walk, and breathlessness perception after the walk, in a group of cystic fibrosis adults with mild to moderate lung disease, and in healthy volunteers, as the control group. Moreover, the study examined the relationship between 6MWT outcome measures and pulmonary function in patients. Twenty-five adults (15 females, age range 18-39 years) with cystic fibrosis and 22 healthy volunteers (14 females, age range 20-45 years) performed a 6MWT following a standard protocol. Walk distance, oxygen saturation (SpO2) and pulse rate at rest and during walk, and breathlessness perception after walk assessed by visual analogue scale (VAS) were measured. Cystic fibrosis patients did notdiffer from healthy volunteers in walk distance (626 +/- 49 m vs. 652 +/- 46 m) and pulse rate. Patients significantly differed from healthy volunteers in SPO2 during the walk (mean SpO2) (P < 0.0001) and VAS (P < 0.0001). In patients, SPO2 during the walk significantly correlated with forced expiratory volume in 1 sec (FEV1) (P < 0.0001), residual volume (RV) (P < 0.001), resting SPO2 (base SpO2) (P < 0.001), and inspiratory capacity (IC) (P < 0.01). In addition, VAS significantly correlated with resting SPO2 (P < 0.01) and IC (P < 0.01).On the basis of regression equations by stepwise multiple regression analysis, SpO2 during walk was predicted by FEV1 (r2 = 0.60) and VAS by IC (r2 = 0.31), whereas walk distance was not reliably predicted by any assessed variables. This study showed that cystic fibrosis adults with mild to moderate lung disease covered a normal walk distance with unimpaired cardiac adaptation, but experienced a significant fall in oxygen saturation and an increased breathlessness perception during exercise. Resting pulmonary function was related to oxygen saturation and breathlessness perception during walk, but contributed significantly only tothe prediction of oxygen saturation. We suggest that 6MWT could be valuable for identifying patients who might experience oxygen desaturation and dyspnoea during demanding daily activities.     

The effect of bronchodilators and oxygen alone and in combination on self-paced exercise performance in stable COPD

Both oxygen therapy and bronchodilators reduce exertional breathlessness and improve exercise tolerance in patients with stable chronic obstructive pulmonary disease (COPD). However their relative effectiveness and the value of their combined use on exercise performance has not been assessed. The effects of 5 mg of salbutamol plus 500 microg ipratropium bromide nebulisation followed by a 6-min walking test while breathing O(2) were studied in a randomised, single-blind, placebo controlled, crossover trial in 28 patients with severe or very severe COPD, breathless on exertion and with oxygen saturation < or = 89% at rest or on exercise. Bronchodilator reversibility was minimal. The 6-min walking distance increased from 356 (128)m to 377 (117)m after the bronchodilator (P<0.05), to 406 (109)m after supplementary oxygen but without bronchodilators (P 0.011 versus bronchodilators/air and 0.001 versus placebo/air), and to 430 (109)m after the combination of oxygen and the bronchodilators (P<0.0001 versus placebo/air and bronchodilators/air; P=0.014 versus placebo/oxygen). End-exercise dyspnea only fell significantly when oxygen and bronchodilator were combined. In severe or very severe COPD patients with relatively fixed airway obstruction bronchodilators enhance exercise performance obtained with oxygen. Clinically relevant improvement is possible when therapies with a different mechanism of action are combined.     

An evaluation of the acute impact of pursed lips breathing on walking distance in nonspontaneous pursed lips breathing chronic obstructive pulmonary disease patients

This study was designed to test the effects of pursed lips breathing (PLB) during exercise in patients with chronic obstructive pulmonary disease (COPD) who did not spontaneously perform PLB. Sixty-nine COPD patients, mean FEV1 (SD) 1.09 (0.5), age 68 (51-83) were recruited to the study. They performed three incremental shuttle walk tests (ISWT). The first walk was designed to identify natural PLBs and the next two walks were performed in a random order; ISWT + PLB or ISWT whilst breathing normally. Measures of respiratory rate (RR), breathlessness and oxygen saturation were taken before and after walks. Data was analysed using the t-test. Fifteen patients demonstrated PLB on baseline ISWT and were therefore excluded from further walking tests although baseline data was included in the analysis. There was no significant difference between walks, mean (SD), 298.5 (173.7) PLB and non-PLB; 292.5 (161.9) nor any difference in dyspnoea. There was a significant reduction in end exercise RR and recovery time with PLB, mean difference (95% CI); 6.2 (4.5-7.9) and 24.9 (2.8-47.0) seconds, respectively. Patients who showed a good response with the PLB walk (41%) had significantly higher baseline breathlessness, Borg score, mean (SD), 1.5 (1.0) versus 0.74 (0.96) (P = 0.02). Natural PLB patients demonstrated lower exercise tolerance on the baseline walk (P = 0.01) and a trend towards greater resting breathlessness than those who did not. This study shows PLB during exercise and recovery results in lower post exercise RR and speeds return to pre exercise breathlessness, compared with exercise and non-PLB. Reductions in RR appear to be greatest in those patients with resting breathlessness.     

Failure of propranolol to improve exercise tolerance in patients with mitral stenosis in sinus rhythm.

Propranolol reduces left atrial pressure at rest and during exercise in patients with mitral stenosis by lowering cardiac output and heart rate. Ten patients (aged 19-56) with moderate to severe isolated mitral stenosis were studied to determine whether propranolol increased their exercise tolerance. All were in sinus rhythm and free of left or right ventricular failure. Patients were trained in an individually graded bicycle or treadmill exercise protocol that provoked a reproducible degree of near maximal dyspnoea during the second three minute stage of exercise. Propranolol (80 mg or 120 mg) or matching placebo in two or three divided daily doses was given for one week in random double blind fashion. Exercise testing and questioning about subjective clinical response were carried out at the end of each week by an investigator who was unaware of the patient's heart rate. During propranolol treatment the heart rate was 19 beats/minute slower at rest and 38 beats/minute slower at peak exercise, but there was no change in mean exercise time to dyspnoea (274 s during propranolol vs 283 s during placebo). Four patients felt worse during the propranolol week, one patient felt better during the propranolol week, and five patients felt no difference between the two weeks. Propranolol did not improve objective or subjective exercise tolerance in patients with isolated mitral stenosis in sinus rhythm.     

Failure of propranolol to improve exercise tolerance in patients with mitral stenosis in sinus rhythm

Propranolol reduces left atrial pressure at rest and during exercise in patients with mitral stenosis by lowering cardiac output and heart rate. Ten patients (aged 19-56) with moderate to severe isolated mitral stenosis were studied to determine whether propranolol increased their exercise tolerance. All were in sinus rhythm and free of left or right ventricular failure. Patients were trained in an individually graded bicycle or treadmill exercise protocol that provoked a reproducible degree of near maximal dyspnoea during the second three minute stage of exercise. Propranolol (80 mg or 120 mg) or matching placebo in two or three divided daily doses was given for one week in random double blind fashion. Exercise testing and questioning about subjective clinical response were carried out at the end of each week by an investigator who was unaware of the patient's heart rate. During propranolol treatment the heart rate was 19 beats/minute slower at rest and 38 beats/minute slower at peak exercise, but there was no change in mean exercise time to dyspnoea (274 s during propranolol vs 283 s during placebo). Four patients felt worse during the propranolol week, one patient felt better during the propranolol week, and five patients felt no difference between the two weeks. Propranolol did not improve objective or subjective exercise tolerance in patients with isolated mitral stenosis in sinus rhythm.     

Oral nitroglycerin in angina pectoris—Evaluation of effect by computerized exercise testing using two different doses

Summary The antianginal effects of sustained-released oral nitroglycerin were evaluated in patients with chronic stable angina using a double-blind randomized protocol. Nineteen patients were inducted into the trial and 17 of these completed the study. Two doses of oral nitroglycerin were used; 2.6 mg and 6.5 mg given three times daily for a period of 2 weeks, the patients crossing over to the alternative dose at the end of each period. Evaluation of effect was carried out 2 hours after the morning dose using graded treadmill exercise testing with on-line computer analysis of the electrocardiogram (EKG) (CASE, Marquette Electronics, Inc.). Various exercise parameters were measured and the results compared to placebo values and between the two dosages. The aim was to demonstrate an antianginal effect and to look for a dose-response relationship and for attenuation of effect if any on continued administration. The mean±SEM exercise time on placebo was 6.7±0.6 min, increasing to 8.6±8 min (p<0.02) with 2.6 mg tds dosage and 8.4±0.7 min (p<0.01) with 6.5 mg tds of oral nitroglycerin. None of the other exercise-derived indices were altered significantly by oral nitroglycerin. Two patients were withdrawn because of severe headaches and both were receiving the higher dose. The data did not demonstrate and dose-response relationship but confirmed the anti-anginal efficacy of sustained action oral nitroglycerin. This efficacy did not show any significant attenuation of effect on continued administration, indicating a possible lack of development of tolerance.     

Ambulatory monitoring and exercise testing in the evaluation of a new long-acting calcium ion antagonist KB-944 (Fostedil) for the treatment of exertional angina pectoris

The anti-anginal effects of KB-944 (Fostedil), a new calcium ion antagonist with a half life of approximately 23-28 hr, were evaluated in 20 patients with exertional angina pectoris in a placebo-controlled single-blind dose titration trial. Ambulatory monitoring and multistage treadmill exercise with computer-assisted electrocardiographic analysis was performed after 2 weeks of placebo therapy and after two 2-weekly periods of KB-944 therapy. The mean (+/- SEM) exercise time to the development of angina on treadmill walking increased from 6.9 +/- 0.4 min on placebo to 9.4 +/- 0.5 min on KB-944 100 mg/day (P less than 0.001) and 9.7 +/- 0.8 min on KB-944 200 mg/day (P less than 0.001 vs placebo and not significant vs KB-944 100 mg/day). The time to the development of 1 mm ST-segment depression of 5.3 +/- 0.4 min on placebo increased to 6.5 +/- 0.5 and 6.6 +/- 0.5 min on KB-944 100 and 200 mg/day, respectively (P less than 0.01 vs placebo). The heart rate at rest of 77 +/- 3 beats/min on placebo was reduced to 68 +/- 3 beats/min on KB-944 100 mg/day (P less than 0.001) and 71 +/- 2 beats/min on KB-944 200 mg/day (P less than 0.01). The maximal heart rate and the rate-pressure product were not altered by KB-944 therapy. One patient developed unstable angina during the treatment phase of KB-944 200 mg/day and was withdrawn. Five patients complained of dyspepsia and one of headache and lethargy during KB-944 200 mg/day. One patient developed ventricular tachycardia during treadmill testing while on KB-944 200 mg/day. The 24-hr ambulatory monitoring data confirmed the findings of exercise testing. KB-944 (Fostedil) in a dose of 100 mg once daily was well tolerated as compared to KB-944 200 mg once daily and both the doses were equally effective. The drug merits further evaluation for the treatment of exertional angina pectoris.     

Sustained hemodynamic and antianginal effect of high dose oral isosorbide dinitrate.

Twenty-one patients with documented coronary atherosclerotic heart disease were studied to determine the effect of high dose oral isosorbide dinitrate (ISDN) on heart rate, blood pressure, and exercise time until angina pectoris. Patients were tested in two phases, initially with 0.4 mg of sublingual nitroglycerin and with sublingual placebo, and then with oral ISDN, mean dose 29 mg, and oral placebo. Both phases of the study were conducted in a randomized, double-blind, crossover manner. After ISDN was compared to oral placebo, heart rate increased at 30 to 300 min (P less than 0.01) (peak increase 18 beats/min at 60 min), and systolic blood pressure decreased from 45 to 300 min (P less than 0.005) (peak decrease 18 mm Hg at 60 min). Exercise time at 2 min after sublingual nitroglycerin increased 51% as compared to oral placebo, exercise time increased 54% at 1 hr (P less than 0.005), 37% at 3 hr (P less than 0.01), and 12% at 5 hr (NS). Twelve of 21 patients (57%) improved their exercise time until angina larger than or equal to 25% at 1 hr after oral ISDN. The exercise response to sublingual nitroglycerin was a good predictor of this response to oral ISDN.     

Effects of beta-agonists on breathlessness and exercise tolerance in patients with chronic obstructive pulmonary disease

In a single-blind placebo-controlled trial in 12 patients with advanced chronic obstructive pulmonary disease (COPD) we compared the effects of nebulized salbutamol (1 mg), clenbuterol (30 micrograms) and placebo (4 ml of normal saline) on spirometric indices (FVC, FEV1), maximal expiratory flows (Vmax50 and Vmax25), the distance walked in 6 min (6MD), assessment of breathlessness by visual analogue scale (VAS), and estimates by the patients of perceived exertion (RPE). Both clenbuterol and salbutamol produced significant increases in FEV1, FVC, Vmax50 and Vmax25. With both drugs, 6MD increased significantly (p less than 0.01) and breathlessness decreased significantly without an appreciable increase in RPE after exercise despite the extra distance covered. The absolute improvements in FEV1 and 6MD after clenbuterol were correlated (r = 0.763, p less than 0.01), but these indices were not correlated after salbutamol (r = 0.121, p greater than 0.1). The lack of correlation between the changes in 6MD and FEV1 after salbutamol might indicate that relief of airways obstruction is not the only explanation for the effects on distance walked, at least with salbutamol.