Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of flosequinan and its sulphone metabolite BTS 53,554, on phosphodiesterase isoenzymes isolated from guinea-pig cardiac and vascular smooth muscle using DEAE-cellulose chromatography was investigated. Zaprinast and milrinone showed peak I and peak III selectivity, and IBMX non-selective activity respectively, against both cardiac and vascular smooth muscle isoenzymes, as expected for these reference inhibitors. Flosequinan and BTS 53,554 demonstrated non-selective inhibition with similar potency against both cardiac and vascular smooth muscle isoenzymes and, overall, were the least potent compounds tested. The high inhibitory concentrations observed (IC50 peak III 660 microM for cardiac tissue and 230 microM for vascular smooth muscle with flosequinan) relative to its clinically effective plasma concentration (10 microM) questions the relevance of phosphodiesterase inhibition to the efficacy of flosequinan in heart failure.
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PMID:Effect of flosequinan upon isoenzymes of phosphodiesterase from guinea-pig cardiac and vascular smooth muscle. 131 14

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 Five patients were withdrawn while taking captopril and two while taking flosequinan; two were withdrawn during the placebo washout period.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.
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PMID:A comparison of the effects of captopril and flosequinan in patients with severe heart failure. 145 90

Flosequinan (BTS 49465) is a putative, selective direct-acting balanced vasodilator currently undergoing evaluation for the treatment of congestive heart failure (CHF) and hypertension. We examined the pharmacologic action of flosequinan and compared it to milrinone and nitroprusside (SNP). In ferret papillary muscle, in vitro, flosequinan (1-100 microM) increased the rate of force development up to 116%. The effect was not blocked by nadolol (10 microM). Flosequinan was less effective than milrinone and SNP as a relaxant of canine renal and coronary arteries, in vitro, since 100 microM of flosequinan produced less than 50% relaxation of the arteries, whereas milrinone or SNP (100 microM) produced between 85 and 125% relaxation of the precontracted arteries. Flosequinan, SNP, and milrinone (100 microM) completely relaxed precontracted canine mesenteric veins. Fifteen minutes after intraduodenal administration (i.d.) of flosequinan (0.3, 1.0, and 3.0 mg/kg) to anesthetized dogs (n = 7), mean left ventricular (LV) dP/dT increased by 11, 27, and 54%, respectively, whereas total peripheral resistance (TPR) decreased by 4, 4, and 13%, and mean arterial pressure (MAP) decreased by 7, 14, and 23%, respectively. flosequinan was 4.6 times more potent as a positive inotrope than as a vasodilator. The hemodynamic profile of milrinone was similar to that of flosequinan, except milrinone produced greater increases in LV dP/dT and decreases in MAP and TPR. In contrast, SNP (1, 3, and 10 micrograms/kg/min i.v.) decreased TPR (7, 18, and 34%, respectively) and MAP (14, 32, and 41%, respectively) without any increase in LV dP/dT. In dogs with propranolol-induced heart failure (PIHF), flosequinan (1.0 and 3.0 mg/kg, i.d.) increased mean myocardial dP/dT by 54 and 84% (n = 5) and MAP, but decreased TPR. The data show that (a) the hemodynamic effects of flosequinan in the normal and PIHF dogs were primarily due to positive inotropy rather than to arterial vasodilation and (b) the positive inotropic effect of flosequinan is independent of catecholamines, since it occurred in dogs with PIHF. The beneficial effect of flosequinan in patients with CHF may not be mediated by balanced vasodilation.
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PMID:Positive inotropy contributes to the hemodynamic mechanism of action of flosequinan (BTS 49465) in the intact dog. 169 12

The acute central haemodynamic and neuroendocrine effects of intravenous flosequinan were studied in a group of 10 patients with severe heart failure. Flosequinan improved cardiac output by a maximum of 1.59 l.min-1, it reduced pulmonary capillary wedge pressure by 11.9 mm Hg and it also caused a reduction in right atrial pressure by a maximum of 7.2 mm Hg. It tended to cause a fall in plasma adrenaline levels but not in plasma noradrenaline. There was little fall in blood pressure in response to flosequinan and no patient developed an adverse event. Intravenous flosequinan may be a useful candidate drug for controlled clinical studies in patients with severe heart failure.
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PMID:The central haemodynamic effects of a single intravenous dose of flosequinan in patients with severe heart failure. 188 31

Vasodilator therapy has become a major pharmacologic approach for improving left ventricular function, and consequently, vasodilator drugs are being used increasingly in the treatment of heart failure. Ideally, vasodilator drugs used in the long-term management of heart failure should show clearly defined pharmacodynamic effects. These include reduced impedance to left ventricular ejection, increased venous capacitance, increased left ventricular ejection fraction and reduced heart size, absence of neurohormonal stimulation, and slowed progression of left ventricular dysfunction. The mechanisms of action and sites of activity of the various vasodilator drugs currently available vary considerably, and none as yet has proved ideal for the treatment of heart failure or hypertension. The complexity surrounding the multiple vasoconstrictor mechanisms involved in heart failure has led to a rationale for combined vasodilator therapy and certain combinations are discussed. From a therapeutic standpoint, the development of drugs with multiple mechanisms of action is particularly attractive. Flosequinan is a new vasodilator agent whose cellular mechanism of action remains uncertain. Flosequinan has the advantage of being able to relax both arterial and venous beds and as such may be particularly beneficial in the treatment of heart failure.
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PMID:Future directions in vasodilator therapy for heart failure. 200 Jul 75

Flosequinan is a novel quinolone with cardiovascular activity that is likely to be of value in the treatment of both heart failure and hypertension. Data generated from animal studies indicate that flosequinan produces dilatation in both veins and arteries, with little associated reflex tachycardia. The compound shows some positive inotropic effects, but the potency is very species dependent. The mode of action of flosequinan seems to involve intracellular calcium handling.
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PMID:Pharmacology of flosequinan. 200 Jul 76

The effects of the new arterial and venous vasodilator flosequinan have been evaluated in a variety of ways in different groups of patients with chronic heart failure. Flosequinan improved the central hemodynamic effects of heart failure in one group, with benefits still apparent up to 24 hours after a single oral dose. In another group it also improved calf blood flow and, therefore, blood flow to skeletal muscle. Also, using a number of different tests, it improved the exercise performance of the patients. In a further group the improvement in exercise tolerance produced was similar to that of captopril. Flosequinan has the necessary properties of a drug that is likely to be of benefit in the treatment of patients with chronic heart failure.
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PMID:Clinical efficacy of flosequinan in heart failure. 200 Jul 77

The exercise capability of 12 patients with heart failure was investigated by a variety of different methods before and after treatment with the vasodilator flosequinan. Two treadmill protocols were used, a modified Bruce with incremental workloads and a fixed workload protocol. On placebo, mean exercise time was greater with the Bruce protocol, 526 (64) s, than with the fixed protocol, 359 (59) s, P less than 0.005. Flosequinan increased exercise time more with the fixed protocol, so after 5 weeks' treatment exercise time was the same with both protocols; 680 (64) s with the Bruce and 673 (147) s with the fixed protocol. When the results are expressed as work, the patients achieved less with the Bruce protocol, 7.8 (1.9) kJ, than with the fixed protocol 12.5 (1.5) kJ on placebo, P less than 0.01. After flosequinan, the respective values were 14.5 (2.8) and 25.3 (5.1) kJ. Flosequinan improved corridor walk test times but there was no relationship between this and either treadmill test. Pedometer scores of customary activity were unchanged by flosequinan and were not correlated with any other exercise test. Different methods of assessing exercise capability provide different measures of patients' incapacity.
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PMID:Exercise tolerance in patients with heart failure--how should it be measured? 200 93

The duration and reproducibility of hemodynamic effects of flosequian, a direct-acting, balanced-type vasodilator, were studied in 19 heart failure patients (NYHA class 3.0 +/- 0.7) receiving 100 mg orally (day 1), placebo (day 2), and again 100 mg (day 3). Flosequinan immediately reduced systemic and pulmonary resistance (23% and 35%, respectively, at 60-90 minutes postdrug) and decreased pulmonary wedge, right atrial, mean pulmonary artery, and mean arterial pressure by 38%, 50%, 25%, and 7%, respectively. Concomitantly, cardiac output, and stroke volume and work increased by 26%, 20%, and 22%, respectively. Most hemodynamic effects persisted for 48 hours. In contrast, changes in pulmonary wedge and arterial pressures, stroke volume, and stroke work only lasted for 2-12 hours. Maximum absolute changes on day 3 were generally comparable with first-dose effects with, again, long-lasting effects on systemic resistance and cardiac output. However, changes in pulmonary artery, wedge, and resistance were significantly shorter than after first dose administration. These data indicate sustained and reproducible arterial dilating effects of flosequinan, but less pronounced and shorter lasting pulmonary arterial and venodilator properties.
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PMID:Duration and reproducibility of initial hemodynamic effects of flosequinan in patients with congestive heart failure. 207 81

1. Twenty patients with moderate to severe chronic cardiac failure were entered into a double-blind parallel group study comparing flosequinan 100 mg daily with matching placebo. 2. After at least three prior exercise tests, cardiopulmonary parameters were assessed at rest and during submaximal exercise before and after 2 and 8 weeks of active drug or placebo. 3. Resting minute ventilation and respiratory rate were reduced by flosequinan compared with placebo, but oxygen uptake was unchanged. 4. Comparison of minute ventilation, carbon dioxide production and venous lactate levels at the end of the exercise stage approximating to 50% of peak oxygen uptake demonstrated significant reductions in the flosequinan group compared with placebo at week 2 and week 8 (P less than 0.05). 5. Flosequinan increased the oxygen uptake at anaerobic threshold from 13.2 +/- 2.8 ml min-1 kg-1 to 15.9 +/- 3.4 ml min-1 kg-1 at week 2 and 15.8 +/- 3.7 ml min-1 kg-1 at week 8. These increases were significant when compared with placebo (P less than 0.05). 6. We conclude that flosequinan improves submaximal exercise performance in patients with chronic cardiac failure, probably by enhancing skeletal muscle blood flow.
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PMID:The effects of flosequinan on submaximal exercise in patients with chronic cardiac failure. 211 5


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