Effect of flosequinan on exercise capacity and symptoms in severe heart failure.

Twenty patients with severe chronic cardiac failure caused by ischaemic heart disease were treated with flosequinan 100 mg daily or placebo in addition to their existing treatment with diuretics and, in some, digoxin in a randomised double blind trial. After eight weeks of treatment, flosequinan significantly improved treadmill exercise time, increased peak achieved oxygen consumption, and improved the New York Heart Association symptom grade when compared with placebo. One patient in the placebo group died and another was withdrawn because heart failure worsened. One patient in the flosequinan group was lost to follow up but there were no other withdrawals. Flosequinan was well tolerated with few adverse effects, and it may prove to be a useful addition to diuretics and digoxin in the treatment of chronic cardiac failure.     

Effect of flosequinan on exercise capacity and symptoms in severe heart failure

Twenty patients with severe chronic cardiac failure caused by ischaemic heart disease were treated with flosequinan 100 mg daily or placebo in addition to their existing treatment with diuretics and, in some, digoxin in a randomised double blind trial. After eight weeks of treatment, flosequinan significantly improved treadmill exercise time, increased peak achieved oxygen consumption, and improved the New York Heart Association symptom grade when compared with placebo. One patient in the placebo group died and another was withdrawn because heart failure worsened. One patient in the flosequinan group was lost to follow up but there were no other withdrawals. Flosequinan was well tolerated with few adverse effects, and it may prove to be a useful addition to diuretics and digoxin in the treatment of chronic cardiac failure.     

Chronic vasodilator therapy with flosequinan in congestive heart failure

This study was conducted to determine the long-term effect of flosequinan, a new orally administered arterial and venous dilator, on the clinical course of patients with moderate to severe congestive heart failure. Seventeen patients on chronic digitalis and diuretic therapy were randomized to receive either flosequinan (n = 9) or placebo (n = 8) in a double-blind fashion. Changes in symptomatology, exercise performance, and left ventricular function were assessed serially during the two-month treatment period. During the course of therapy, a modest improvement in the symptom scores and functional classification of the flosequinan-treated patients was observed. Flosequinan evoked a significant increase in maximal exercise capacity. While long-term flosequinan administration also effected a progressive increase in resting heart rate, it did not consistently improve indices of left ventricular systolic function. The addition of chronic vasodilator therapy with flosequinan to standard digitalis-diuretic regimens is capable of inducing clinical improvement in patients with moderate to severe chronic heart failure. Trials involving larger patient populations will be necessary to confirm the results of this preliminary study and to determine the extent of clinical improvement, subpopulations benefited, role in heart failure therapeutics, and so forth.     

Effects of bisoprolol fumarate on left ventricular size, function, and exercise capacity in patients with heart failure: analysis with magnetic resonance myocardial tagging

Background Recent data suggest that beta-blockers can be beneficial in subgroups of patients with chronic heart failure (CHF). For metoprolol and carvedilol, an increase in ejection fraction has been shown and favorable effects on the myocardial remodeling process have been reported in some studies. We examined the effects of bisoprolol fumarate on exercise capacity and left ventricular volume with magnetic resonance imaging (MRI) and applied a novel high-resolution MRI tagging technique to determine myocardial rotation and relaxation velocity. Methods Twenty-eight patients (mean age, 57 ± 11 years; mean ejection fraction, 26 ± 6%) were randomized to bisoprolol fumarate (n = 13) or to placebo therapy (n = 15). The dosage of the drugs was titrated to match that of the the Cardiac Insufficiency Bisoprolol Study protocol. Hemodynamic and gas exchange responses to exercise, MRI measurements of left ventricular end-systolic and end-diastolic volumes and ejection fraction, and left ventricular rotation and relaxation velocities were measured before the administration of the drug and 6 and 12 months later. Results After 1 year, heart rate was reduced in the bisoprolol fumarate group both at rest (81 ± 12 before therapy versus 61 ± 11 after therapy; P < .01) and peak exercise (144 ± 20 before therapy versus 127 ± 17 after therapy; P < .01), which indicated a reduction in sympathetic drive. No differences were observed in heart rate responses in the placebo group. No differences were observed within or between groups in peak oxygen uptake, although work rate achieved was higher (117.9 ± 36 watts versus 146.1 ± 33 watts; P < .05) and exercise time tended to be higher (9.1 ± 1.7 minutes versus 11.4 ± 2.8 minutes; P = .06) in the bisoprolol fumarate group. A trend for a reduction in left ventricular end-diastolic volume (−54 mL) and left ventricular end-systolic volume (−62 mL) in the bisoprolol fumarate group occurred after 1 year. Ejection fraction was higher in the bisoprolol fumarate group (25.0 ± 7 versus 36.2 ± 9%; P < .05), and the placebo group remained unchanged. Most changes in volume and ejection fraction occurred during the latter 6 months of treatment. With myocardial tagging, insignificant reductions in left ventricular rotation velocity were observed in both groups, whereas relaxation velocity was reduced only after bisoprolol fumarate therapy (by 39%; P < .05). Conclusion One year of bisoprolol fumarate therapy resulted in an improvement in exercise capacity, showed trends for reductions in end-diastolic and end-systolic volumes, increased ejection fraction, and significantly reduced relaxation velocity. Although these results generally confirm the beneficial effects of beta-blockade in patients with chronic heart failure, they show differential effects on systolic and diastolic function. (Am Heart J 2002;143:676-83.)     

Exercise capacity,hemodynamic, and neurohumoral changes following acute and chronic administration of flosequinan in chronic congestive heart failure

Summary We evaluated the responses to 90 minutes and 8 days of therapy with a new long-acting vasodilator flosequinan in ten patients with moderate chronic congestive heart failure in an open, uncontrolled study. Acute administration of 100 mg orally resulted in a decrease of preload, with a reduction of left ventricular end-diastolic volume, left ventricular end-diastolic pressure, pulmonary capillary wedge pressure, and right atrial pressure. Following the acute administration, we found no significant changes of heart rate, cardiac index, stroke volume, peripheral vascular resistance, ejection fraction, and dp/dt. Chronic application for 8 days (100 mg/day) showed persistent effects on preload, with a significant decrease of pulmonary capillary wedge pressure, right atrial pressure, and pulmonary arterial pressure. After 8 days of treatment, cardiac index was significantly increased from 2.2±0.2 l/min/m² to 2.8±0.2 l/min/m² (p=0.013) and stroke volume from 57±10 ml to 74±9 ml (p=0.022). Peripheral vascular resistance decreased by 28%. After 8 days, bicycle exercise capacity increased significantly from 383±44 sec to 422±43 sec (p=0.01) and the patients were able to increase their walking distance over a 6-minute exercise test from 426±46 m to 477±33 m (p=0.007), with a concomitant decrease of dyspnea (p=0.013). Plasma renin concentration showed only a rise 90 minutes after the acute administration on day 8 of the study, and atrial natriuretic peptide and 6-keto-prostaglandin F₁-alpha decreased significantly. Plasma norepinephrine, epinephrine, dopamine, and prostaglandin E₂ did not change. After 8 days body weight was reduced from 76.5±2.1 kg to 75.1±2.4 kg. These data indicate that flosequinan is effective in patients with heart failure during a relatively short duration of treatment, improving cardiac performance and exercise capacity and acting primarily on preload, and it may have cumulative vasodilator effects on arterial vessels during chronic therapy. We observed no substantial stimulation of neurohumoral factors and no fluid retention.     

Efficacy of the calcium antagonist isradipine in angina pectoris

Summary Thirty-six patients with chronic, stable angina pectoris were studied during 2-week treatment periods in which they received, in a randomized double-blind, crossover study, a new calcium entry blocking agent, isradipine, 7.5 mg three times daily or placebo. Antianginal efficacy was determined by treadmill exercise testing carried out 3 and 9 hours after drug administration on the final day of each treatment period. During placebo therapy, treadmill exercise time to the onset of angina (P₁) and to the development of moderate angina (P₂) was similar at 3 and 9 hours and similar to the placebo run-in period. During isradipine therapy, treadmill exercise time 3 hours after dosing was greater than with placebo therapy (P₁ 312±23.0 vs. 267±19.5 seconds,p<0.001; P₂ 410±20.2 vs. 355±18.8 seconds,p<0.002). Nine hours after drug administration, the results of exercise testing were similar to placebo.     

OPC-8212 in the treatment of congestive heart failure: Results of a pilot study

Summary To characterize the effects of OPC-8212, a quinolone inotropic agent, in patients with heart failure, we utilized invesive homodynamics, exercise testing, 24-hour ambulatory electrocardiograms, and two patient self-assessment questionnaires, before and after 1 month of treatment with OPC-8212, in 17 patients with moderate to severe congestive heart failure. There were no significant changes from baseline in heart rate (83±8 beats/min), mean arterial pressure (70±15 mmHg), pulmonary wedge pressure (18±7 mmHg), or cardiac index (2.3±0.4 L/min/m²) following treatment with OPC-8212. Both exercise duration (5.3±1.6 min) and peak oxygen consumption (12.0±2.9 mL/kg/min) were unchanged by OPC-8212. Two independent patient self-assessment scores, the Sickness Impact Profile and the Minnesota Living with Heart Failure Questionnaire, showed improvements from 6.8 to 5.4 and 49 to 38, respectively (both p<.05), suggesting that the patients reported an improvement in daily functioning. The median ventricular premature contraction count and frequency were reduced from 1,118 beats to 243 beats (p<0.05) and 11/1,000 beats to 2,4/1,000 beats (0.05<p<0.10), respectively. Two patients developed agranulocytosis during longer-term treatment following this 1-month study. These data demonstrate that OPC-8212 did not have significant effects on hemodynamics or exercise tolerance. However, the improvement in patient self-assessment scores and the trend for improvement in ventricular arrhythmia profiles suggest that OPC-8212 may have some benefit for patients with congestive heart failure, but additional placebo-controlled, double-blind studies are necessary.     

The new selective IKs–blocking agent HMR 1556 restores sinus rhythm and prevents heart failure in pigs with persistent atrial fibrillation

Background Antiarrhythmic drugs for treatment of atrial fibrillation in patients with heart failure are limited by proarrhythmia and low efficacy. Experimental studies indicate that the pure I_Ks blocking agents chromanol 293b and HMR 1556 prolong repolarization more markedly at fast than at slow heart rates and during –adrenergic stimulation. These properties may overcome some of the above quoted limitations. Methods and results Ten domestic swine underwent pacemaker implantation (PM) and atrial burst pacing to induce persistent AF. Four days after onset of persistent AF, pigs were randomized to HMR 1556 (30 mg/kg, p.o., 10 days) or placebo. All animals receiving HMR 1556 converted to SR (5.2 ± 1.9 days), whereas placebo pigs remained in AF. Pigs treated with placebo developed high ventricular rates (297 ± 5 bpm) and severe heart failure, whereas pigs treated with HMR 1556 remained hemodynamically stable. Left ventricular ejection fraction on the day of euthanization was significantly lower in the placebo compared to the HMR 1556 group (30 ± 4% vs. 69 ± 5%, p < 0.005). Similar results were seen with epinephrine levels (placebo 1563 ± 193 pmol/l vs. HMR 613 ± 196 pmol/l, p < 0.05). Right atrial monophasic action potentials were significantly longer in the HMR 1556 compared to the placebo group (230 ± 7 ms vs. 174 ± 13 ms, p < 0.05). Conclusions The new I_Ks blocker HMR 1556 efficiently and safely restores SR and prevents CHF in a model of persistent AF. Restoration of SR is most likely linked to a marked prolongation of atrial repolarization even at high heart rates.     

Misoprostol is effective treatment for patients with severe chronic constipation

To assess the efficacy of misoprostol in the treatment of patients with severe chronic constipation, nine such patients were enrolled in a double-blind, randomized, crossover study of misoprostol (1200 µg/day) or placebo, that lasted three weeks. During this period each patient received the drug for one week and placebo for another with a week washout period in between. A colonic transit study, using radiopaque markers, was performed during each of the treatment weeks, while the number of stools and their total weight was recorded by each patient for the appropriate periods. Colonic transit time was significantly and consistently decreased by misoprostal compared to placebo [66 hr±10.2 vs 109.4 hr±8.1 (P=0.0005)]. Misoprostrol significantly increased the total stool weight per week [976.5 g±288.8 vs 434.6 g±190.5 (P=0.001)] and also significantly increased the number of stools per week compared to placebo [6.5±1.3 vs 2.5±0.11 (P=0.01)]. The incidence of abdominal pain was similar in both groups. We concluded that misoprostol, during a short trial period, proved effective in increasing the frequency and weight of bowel movements and decreasing colonic transit time in patients with severe chronic constipation. It may be used as a therapeutic measure to treat such patients.This study was supported by a grant from Searle, Chicago, Illinois, and presented at the annual meeting of the American Gastroenterological Association, Boston, Massachusetts, 1993.     

A double-blind, parallel-group comparison of flosequinan and enalapril in the treatment of chronic heart failure.

The effects of flosequinan and enalapril on exercise capacity (bicycle exercise duration), quality-of-life symptomatology (visual analogue scales) and New York Heart Association (NYHA) grading, were compared in 61 patients with chronic heart failure (NYHA, grade III). Bicycle exercise duration improved similarly with flosequinan (+27%) and enalapril (+18%); in patients completing the study, flosequinan produced a significantly greater increase in exercise time at week 12, compared with enalapril (P = 0.02). Improvements in visual analogue scores relating to general health, energy and vitality, ability to perform physical activities and breathing performance, were equivalent for both drugs. Changes in NYHA classification showed that 27 (55%) of 49 patients completing the study had improved by at least one NYHA grade (15 (68%) patients on flosequinan; 12 (44%) on enalapril). The overall safety and tolerability of the two treatments was similar; 18 patients reported adverse effects while on flosequinan, compared with 19 patients on enalapril. Neither treatment was associated with any clinically important changes in haematological or biochemical variables, although some treatment-related effects were observed. This study confirms that flosequinan achieved similar efficacy to enalapril in the symptomatic relief of chronic heart failure. The effect of flosequinan on survival in chronic heart failure has not been tested; pending such studies, our data suggest that it may prove a useful alternative therapy in patients where ACE inhibitors are contraindicated or poorly tolerated.     

Cardiac troponin I: a potential marker of exercise intolerance in patients with moderate heart failure

Background In severe heart failure, increased values of cardiac troponins have been detected during decompensation. In this study, we investigated whether an increase of cardiac troponin I can be observed after symptom-limited exercise and after an exercise training session in patients with moderate heart failure. Methods Twenty-seven patients with moderate heart failure (New York Heart Association II-III, ejection fraction 31% ± 8%) were compared with 9 patients with mild heart failure and 10 subjects without heart failure. They underwent a symptom-limited exercise test and a bicycle exercise training session at >80% of maximal heart rate over 20 to 30 minutes. Plasma cTnI levels were measured at baseline, after symptom-limited exercise (hourly for 5 hours), and after training (4 and 10 hours). Results Patients with moderate heart failure showed an increase of cTnI from 37 ± 49 pg/mL to 73 ± 59 pg/mL (P < .001) after symptom-limited exercise. Four patients with moderate and 1 with mild heart failure and normal cTnI values at rest showed an increase of cTnI above 100 pg/mL after acute exercise but not after training. Subjects without heart failure had lower cTnI levels at rest and significantly lower values after symptom-limited exercise and training (P < .05 for each). Conclusion Patients with symptomatic heart failure reveal an increase of cTnI after symptom-limited exercise at levels that indicate minor myocardial damage. The prognostic impact of this finding should, therefore, be further investigated. (Am Heart J 2002;144:351-8)     

Effects of carvedilol therapy on restrictive diastolic filling pattern in chronic heart failure

Background

Carvedilol therapy during congestive heart failure demonstrated a good efficacy in mortality rate reduction and in improvement of left ventricular (LV) systolic performance. However, currently there is not any finding about the drug's effect on diastolic filling. The aim of this study was to evaluate the effects of β-blocker treatment on LV diastolic function with an eco-pulsed Doppler ultrasound scanning examination at transmitral level in a group of patients who were affected by heart failure with a restrictive filling pattern.

Methods

We studied 27 patients with idiopathic or ischemic dilated cardiomyopathy with LV severe systolic disfunction (ejection fraction <35%). Fourteen patients were randomized to receive carvedilol treatment (carvedilol group), and 13 patients continued to receive standard therapy with angiotensin-converting enzyme inhibitors, diuretics, and vasodilators (placebo group). All patients underwent an echo-Doppler ultrasound scanning examination at the beginning of the study and after 4 and 12 months of treatment.

Results

In the carvedilol group, we found a progressive improvement of Doppler ultrasound scanning parameters after 4 months, with a significant increase of A wave (P <.005), deceleration time (DT; P <.02) and isovolumetric relaxation time (IVRT; P <.02). These improvements were confirmed after 1 year of follow-up, whereas patients in the placebo group did not shown any significant modifications. After 1 year, the differences in these groups were more significant for A wave (39 ± 4 cm/sec carvedilol group vs 30 ± 4 cm/sec placebo group; P <.0001), for E/A ratio (1.8 ± 0.2 carvedilol group vs 2.6 ± 0.5 placebo group; P <.0002), for DT 1(40 ± 16 msec carvedilol group vs 112 ± 13 msec placebo group; P <.001), and for IVRT (74 ± 8 msec carvedilol group vs 57 ± 7 mesc placebo group; P <.0002). These changes seem to happen before systolic and morphological modifications.

Conclusion

Our results show that carvedilol therapy is a means of modifying parameters of diastolic filling favorably in patients with heart failure. These effects seem to be independent of those of systolic function. The improvement of systolic performance occurs after 1 year of treatment. The restrictive filling pattern, related to an unfavorable prognosis, changes toward pseudonormal or altered relaxation pattern during carvedilol therapy. Further investigations with a greater sample size will be necessary to confirm our findings.     

QTc and not QTc dispersion behavior affects the occurrence of ventricular extrasystole during exercise in infarcted patients

Summary Both a long QTc and a large QTc dispersion (QTcd) can predispose infarcted patients to ventricular arrhythmias. The former simply reflects a general prolongation of ventricular recovery time, whereas QTcd is useful for revealing regional inhomogeneities of ventricular repolarization. The aim of our study was to evaluate QTc and QTcd behavior during exercise in 50 patients (all men) with previous myocardial infarction, and its possible correlation with the occurrence of exercise-induced premature ventricular complexes (EIPVC). Our patients underwent ergometric stress test with a load increase of 25W, every 2min, until the maximal age-related heart rate or symptoms were obtained, followed by a 10-min recovery phase. QTc and QTcd measurement was performed at rest (BS) and during exercise at two progressively increasing heart rate steps: 100–115 beats/min (T1) and 116-130 beats/min (T2). The patients were divided into two groups according to the absence (group A;n = 22) or presence (group B;n = 28) of EIPVC. In terms of QTcd, no significant difference was found between the two groups at BS, T1, and T2. As for the mean QTc (QTcm), it was significantly longer in group B at BS (416 ± 22ms versus 395 ± 19ms;P = 0.001) and at T1 (431 ± 24ms versus 410 ± 8ms;P = 0.0001). When group B was further differentiated into two subgroups — Bx and Bz — according to the severity of EIPVC, we noted that patients with the most severe arrhythmic response (group Bz;n = 12) showed a persisting, significantly longer QTcm than group A (BS, 426 ± 28ms versus 395 ± 19ms;P < 0.05; T1, 445 ± 24ms versus 410 ± 8ms;P < 0.05; T2, 427 ± 17ms versus 412 ± 14ms;P < 0.05), and group Bx (n = 16) (BS, 426 ± 28ms versus 409 ± 15ms;P < 0.05; T1, 445 ± 24ms versus 420 ± 19ms;P < 0.05; T2, 427 ± 17ms versus 410 ± 17ms;P < 0.05). Group Bx showed a significantly longer QTcm than group A only at BS (409 ± 15ms versus 395 ± 19ms;P < 0.05). No significant difference in QTcd was found between the three groups at BS, T1, and T2. We also noted that the relationship between QTcm and QTcd was modified by the exercise, changing from a trend of direct relation at BS, towards an inverse one during effort, which reached significance at T2 (r = –0.319;P = 0.037).Based on our data, EIPVC occurrence seems to be more affected by the total duration rather than by regional inhomogeneities of the ventricular recovery time. In those patients with the most severe arrhythmic response, the autonomic modifications generated by the exercise succeed in attenuating only the regional inhomogeneities, but do not eliminate the differences in total duration of the repolarization period.     

A comparison of the effects of captopril and flosequinan in patients with severe heart failure

Summary Angiotensin converting enzyme inhibitors have greatly improved the treatment of patients with chronic heart failure but they are not effective in all patients, and their use may be limited by side effects. There is, therefore, a need to investigate new drugs and to compare their efficacy with angiotensin converting enzyme inhibitors. Flosequinan is a new direct-acting vasodilator that has been shown to be effective in placebo-controlled studies. Patients with chronic heart failure in NYHA classes II or III who remained symptomatic despite at least 80 mg of frusemide daily were recruited from two centers. Following a single-blind placebo run-in period, the patients were randomized double blind to either the addition of captopril or flosequinan for 6 weeks. Following a further 2-week placebo washout period, they were then given the alternative treatment. Symptom-limited treadmill exercise times, scores of perceived exertion, and corridor walk tests were measured at two weekly intervals during the study. Twenty-five patients entered the study, 16 of whom completed without a change in diuretic dose. Five patients were withdrawn while taking captopril and two while taking flosequinan; two were withdrawn during the placebo washout period. For those patients who completed the study, flosequinan increased treadmill exercise tolerance from a mean (SEM) placebo time of 11.5 (1.0) minutes by 2.4 (0.6) (p=0.0002) and captopril from 12.0 (0.8) minutes by 1.2 (0.6) minutes (p=0.08). Comparison of the other measures of efficacy revealed no difference between the groups. In this short-term study flosequinan appeared to be equal in efficacy to captopril.     

A placebo-controlled,randomized, double-blind study of OPC-8212 in patients with mild chronic heart failure

Summary OPC-8212 is a newly synthesized, orally effective inotropic agent. Previous studies have shown short-term hemodynamic and symptomatic improvement in patients with congestive heart failure. However, the long-term efficacy of this agent remains to be established. Eighty-three patients with chronic heart failure were randomly assigned to treatment with either OPC-8212 (n=45) or matching placebo (n-38).Of the placebo-treated patients, two patients died and another six patients were withdrawn from the study because of a deterioration of heart failure, while only 1 out of 45 OPC-8212-treated patients were withdrawn because of increased congestive symptoms.After 12 weeks of treatment, the OPC-8212 group showed a significant improvement in their numerical scores in sense of well-being as judged by the patients' subscale A (p<0.01) and their physician's general impression of the patients' status (p<0.01). The ejection fraction obtained from echocardiography increased from a mean (±SEM) baseline value of 42.8±2.6% to 46.6±2.9% (p<0.05) in the OPC-8212 group and 44.4±3.7% to 45.5±4.1% in the placebo group. These effects were not associated with an increase in the heart rate. The treatment was well tolerated without any limiting side effects.Thus, OPC-8212 is effective in patients with chronic heart failure, providing significant hemodynamic and symptomatic benefit in chronic treatment, together with a possible improvement of the prognosis of patients with heart failure.     

Autonomic and hemodynamic effects of a new selective dopamine agonist, CHF1035, in patients with chronic heart failure

Dopamine agonists have been studied in chronic heart failure, but earlier reports with non-selective compounds demonstrated unfavourable long-term effects. CHF 1035 is an orally active, new selective dopamine agonist, primarily activating DA₂ ^– and ₂ receptors, thereby inhibiting norepinephrine release, which may be beneficial in heart failure. We conducted a double-blind, placebo-controlled comparison of CHF 1035 (10 mg/day, n = 20) and placebo (n = 9) in patients with mild to moderate chronic heart failure (left ventricular ejection fraction <0.45). Patients were clinically stable on diuretics and angiotensin converting enzyme inhibitors. Both acute and chronic assessments were made, including plasma neurohormones and 24-hr Holter monitoring for heart rate variability analysis. CHF1035 was generally well tolerated during the study. After 10 days, there were no significant changes between the groups regarding heart rate and blood pressure. Compared to placebo, plasma norepinephrine levels decreased on CHF1035, both in the first 4 hours and after 10 days (p < 0.05 between groups). Other neurohormones (natriuretic peptides, renin, aldosteron and endothelin) were not significantly affected. Heart rate variability parameters generally increased on CHF1035, but were unaffected by placebo (p < 0.05 between groups). Short-term treatment with the selective dopaminergic agonist CHF1035 is well tolerated, reduces plasma norepinephrine concentrations and increases heart rate variability in mild chronic heart failure.An erratum to this article can be found at     

Long-term evaluation of treatment for chronic heart failure: A 1 year comparative trial of flosequinan and captopril

Summary Two hundred and nine patients with moderate to severe chronic heart failure, all of whom remained symptomatic despite at least 80 mg of frusemide daily, were randomized to 12 months treatment with flosequinan or captopril. The patients were stratified into two groups, a treadmill group and a corridor walk test group, depending upon their exercise capability. Sixty-five out of 102 patients randomized to flosequinan and 43 out of 107 randomized to captopril (p<0.001) did not complete the study. There was no difference between the groups in mortality: 19 patients died while taking flosequinan and 15 while taking captopril. Both drugs had similar effects on treadmill exercise tolerance; the mean increase at week 52 was 117 seconds in the flosequinan group and 156 seconds (p=0.57) for the captopril group. For those patients stratified to the corridor walk test only, there was also very little difference in the improvement at 52 weeks; the mean increase for patients randomized to flosequinan was 61 meters and captopril was 75 meters (p=0.65). However, when the walk tests from all patients are examined, captopril produced a significant improvement compared with flosequinan at week 52 (p=0.015). Flosequinan has similar long-term efficacy to captopril but is associated with a higher incidence of adverse events.     

Effect of cisapride on chronic idiopathic constipation in children

The efficacy of cisapride, a new prokinetic drug, as a treatment for chronic functional constipation of childhood was studied in 20 constipated children. Each subject had a stool frequency less than 4/week and/or total gastrointestinal transit time >33 hr and was randomly assigned to double-blind treatment with either cisapride (N=10) or placebo (N=10) for 12 weeks. Stool habits, total gastrointestinal transit time, and anorectal motility were evaluated in all children before and at the end of the treatment period. Cisapride significantly increased stool frequency from 1.2±0.6 to 5.1±1.9 stools/week (mean±SD;P<0.05), whereas the lesser effect of placebo was not significant (1.2±0.8 to 2.8±0.8 stools/weeks;P=0.4). Both treatments significantly (P<0.05) decreased laxative or suppository use. Total gastrointestinal transit time was decreased by cisapride (90.8±9.2 hr to 57.2±20.2 hr;P<0.05) but was not affected by placebo. Anorectal manometry showed that cisapride, but not placebo, significantly decreaed the rectoanal inhibitory reflex threshold and the conscious rectal sensitivity threshold. It is concluded that cisapride improves gastrointestinal motility and bowel habits in children with cronic idiopathic constipation and may be useful in the management of some children with this disorder.     

Acute and Chronic Effects of Propionyl-L-Carnitine on the Hemodynamics, Exercise Capacity, and Hormones in Patients with Congestive Heart Failure

Carnitine is an important cofactor in the intermediary metabolism of the heart, and carnitine deficiency is associated with congestive heart failure. We therefore studied the effects of acute (IV bolus, 30 mg/kg body weight) and chronic administration (1.5 mg/d for 1 month) of propionyl-L-carnitine on hemodynamics, hormone levels, ventricular function, exercise capacity, and peak oxygen consumption in 30 patients with chronic congestive heart failure (NYHA II–III, mean EF 29.5 ± 7%) in a phase II, parallel, single-blind, randomized, and placebo-controlled study. Acute administration of propionyl-L-carnitine caused a significant reduction in pulmonary artery and pulmonary wedge pressures at both day 1 (P < 0.001) and day 30 (P < 0.05) of the study but no other hemodynamics changes. Hormone levels did not change following acute administration of the drug. Chronic administration of propionyl-L-carnitine increased peak oxygen consumption by 45% (from 16.0 ± 3 to 23.5 ± 2 mL/kg/min, P ± 0.001), exercise time by 21% (from 8.1 ± 0.5 to 9.8 ± 0.4 minutes, P < 0.01), and peak exercise heart rate by 12% (P < 0.01). These changes were concomitant with a reduction of pulmonary artery pressure. In the treated group, there was a slight, but significant (P < 0.01), reduction in left ventricular dimensions. Hemodynamics and hormones measured after 1 month of oral therapy remained unchanged, except for a fall in pulmonary artery pressures, with a nonsignificant trend towards a fall in filling pressures and plasma norepinephrine. The chronic changes in the propionyl-L-carnitine group were seen at 15 days of treatment, and no further changes in these parameters were seen at 1 month. We conclude that propionyl-L-carnitine increases exercise capacity and reduces ventricular size in patients with congestive heart failure. The drug has no significant effects on hemodynamics or neurohormone levels. The use of a single-blind design reduces the impact of the positive finding on exercise capacity.     

Effect of Altering the Left Ventricular Pressure on Epicardial Activation Time in Dogs with and without Pacing-Induced Heart Failure

Background: The influence of an increased left ventricular end-diastolic pressure (LVEDP) on the development of lethal arrhythmias in chronic heart failure is unclear. We investigated the effect of chronic and acute LVEDP increase on the epicardial activation time of sinus (SB) and paced (PB) beats. Methods: Six dogs underwent rapid ventricular pacing at 220–280[emsp4 ]beats/min for 6–14 weeks for induction of heart failure. On the study day, baseline (ba) LVEDP was determined for the surviving heart failure animals (HF-ba), and for seven control animals (C-ba). The epicardial activation time (EAT, time between the earliest and latest epicardial activation) for five consecutive SB and five ventricular PB during the baseline hemodynamic state were recorded using a 504 electrode mapping-sock. In the control animals a 2-litre volume (vl) was infused over 10[emsp4 ]min to acutely increase the LVEDP (C-vl) to a level comparable to the chronic increased LVEDP of the HF-ba. The same volume challenge was performed in two HF animals (HF-vl) and the EAT for SB and PB was redetermined. Results: Three of six HF animals died during induction of heart failure. In the three remaining HF animals, chronic LVEDP increased from 6±1 to 17±10.8[emsp4 ]mmHg (P=0.07), EAT for SB increased by 68±% compared to control animals (HF-ba vs. C-ba, P<0.05). In contrast, in the control animals the acute rise in LVEDP from 6.8±4.5 to 14.7±6.2 mmHg P<0.05), shortened the EAT for SB (C-ba vs. C-vl, P<0.05). A similar decrease in EAT for SB caused by acute volume load was seen in the HF animals, but did not reach significance due to the small sample size (one of the three remaining HF animals died of spontaneous ventricular fibrillation before the volume load). Chronic LVEDP elevation significantly prolonged the EAT for PB from 72±11 to 120±31[emsp4 ]ms (C-ba vs. HF-ba) while acute LVEDP increase had no significant effect on EAT for PB. Conclusion: Chronic HF increases LVEDP and prolongs EAT, while an acute increase in LVEDP shortens the EAT for sinus beats. A prolongation of EAT in heart failure may make the heart more susceptible to ventricular arrhythmias and electromechanical dissociation.