flosequinan and flosequinoxan

The pharmacokinetics of flosequinan and its active metabolite, flosequinoxan, were investigated following a single 100-mg oral dose in 10 patients with compromised hepatic function. Plasma and urine samples were collected for up to 144 h postdose and analyzed by HPLC. All 10 patients provided analyzable data even though one patient withdrew before the 144-h sample because of an adverse event unrelated to the study medication. Interpatient variability was appreciable for the plasma and urine concentrations was well as for the calculated pharmacokinetic parameters. Relative to a comparative cohort of normal subjects, flosequinan concentrations in the study patients were elevated, showing increases in mean AUC0-t (62.8 +/- 49.4 vs 3.4 +/- 1.5 micrograms.h/mL), AUC0-infinity (70.2 +/- 58.3 vs 3.8 +/- 1.6 micrograms.h/m:), Cmax (2.43 +/- 0.56 vs 1.30 +/- 0.39 micrograms/mL), and t1/2 (20.7 +/- 16.8 vs 1.7 +/- 0.5 h). The mean systemic clearance decreased (47.3 +/- 46.5 vs 544 +/- 279 mL/min), along with the elimination rate constant (0.066 +/- 0.069 vs 0.44 +/- 0.13 h-1). Mean flosequinoxan AUC0-t and AUC0-infinity values were unaffected by hepatic dysfunction. The mean time to peak was longer (36.4 +/- 27.4 vs 7.0 +/- 3.1 h) and Cmax was less (0.98 +/- 0.52 vs 1.84 +/- 0.26 micrograms/mL) than in normal subjects. These findings are consistent with a decrease in the rate of flosequinan metabolism to flosequinoxan. Five patients reported adverse events, which included headache (three patients) and syncope (one patient).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Biotransformation; Chromatography, High Pressure Liquid; Female; Humans; Liver Diseases; Male; Middle Aged; Quinolines; Quinolones; Spectrophotometry, Ultraviolet

The pharmacokinetic and haemodynamic effects of a 200 mg oral dose of BTS 49 465 (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) were investigated in a double-blind placebo controlled study. BTS 49 465 was rapidly absorbed and cleared from the systemic circulation with a half-life of 1.6 h by oxidation to the sulphone metabolite. The metabolite was cleared with a half-life of 37.6 h. Saliva concentrations of both BTS 49 465 and its metabolite correlated well with the plasma concentrations. Compared to placebo, BTS 49 465 produced statistically significant reductions in blood pressure and increases in heart rate both supine and after a 60 degrees head up tilt. The time course of the haemodynamic changes suggested that the sulphone metabolite contributed to the overall hypotensive response. Plasma Renin Activity was only marginally elevated and there was no evidence of acute fluid retention. BTS 49 465 was well tolerated in terms of haematological and biochemical parameters and subjective side-effects.

Topics: Administration, Oral; Adult; Blood Pressure; Diuresis; Double-Blind Method; Heart Rate; Hemodynamics; Humans; Kinetics; Male; Quinolines; Quinolones; Random Allocation; Renin; Saliva; Vasodilator Agents

Flosequinan (BTS 49465, 7-fluoro-1-methyl-3-methyl-sulphinyl-4-quinolone), a recently direct-acting vasodilator that should cause relatively less reflex tachycardia, was given in a single oral dose of 200 mg to 10 untreated patients with moderate to severe hypertension. Flosequinan caused a fall in blood pressure (BP) from 181/116 +/- 7/4 to 161/102 +/- 5/4 mm Hg (P < 0.05). The proportional decrease of mean arterial pressure (MAP) was 14.6% (P < 0.01). Together with the decrease of BP an increase of heart rate from 79 +/- 5 to 96 +/- 5 beats/min occurred (31 +/- 4%, P < 0.01). Forearm blood flow increased insignificantly (NS) from 3.7 +/- 0.6 to 5.5 +/- 1.5 ml/100 ml/min together with a small decrease in forearm vascular resistance from 47 +/- 7 to 39 +/- 7 arbitrary units (NS). Forearm venous distensibility remained stable around 0.03% mm Hg (NS). Neurohormonal parameters showed the consequences of systemic vasodilation: noradrenaline rose from 1.25 +/- 0.10 to 2.88 +/- 0.34 nmol/l (P < 0.01), adrenaline from 0.16 +/- 0.03 to 0.35 +/- 0.10 nmol/l (NS), plasma renin activity from 2.33 +/- 0.46 to 3.27 +/- 0.73 ng/ml/h (P < 0.05) and aldosterone from 14.31 +/- 2.47 to 26.3 +/- 8.02 ng/ml (P < 0.05). The serum concentrations of flosequinan and its major metabolite were within the therapeutic limits. Nine patients experienced minor side-effects such as headache, nausea and palpitations. We conclude that flosequinan has hypotensive efficacy with signs of systemic counter-regulatory mechanisms but without a clear forearm vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Aldosterone; Epinephrine; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Quinolines; Quinolones; Renin; Vasodilator Agents

Although the potent vasodilating effect of flosequinan is well characterised, the positive inotropic action reported is more varied and less well understood. We examined the contractile and electrophysiologic effects of flosequinan and its metabolite, BTS 53554, in cardiomyocytes from either adult male Sprague-Dawley rats (200-250 g) or New-Zealand White rabbits (2-2.5 kg) and compared the effects with those of sulmazole and enoximone [selective phosphodiesterase (PDE) III inhibitors], Ro 20-1724 and rolipram (selective PDE IV inhibitors) and 3-isobutyl-1-methylxanthine (IBMX, nonselective PDE inhibitor). Flosequinan and BTS 53554 had positive contractile effects (p < 0.05) in both rat and rabbit ventricular cardiomyocytes only at the maximum concentration (10(-3) M). Differences were noted between species, however. Flosequinan 10(-3) M had a greater contractile effect than BTS 53554 (10(-3) M) in rabbit cardiomyocytes, but not in rat cardiomyocytes. We studied the interaction of flosequinan or the metabolite with other PDE inhibitors in rat cardiomyocytes. Contractile amplitudes were not significantly different with equimolar concentrations (3 x 10(-4) M) of Ro 20-1724, flosequinan, or BTS 53554 alone (15 +/- 6, 18 +/- 4, and 32 +/- 10%, respectively, greater than the mean basal dL value of 7.38 +/- 0.12%, mean +/- SE error). However, the combinations of Ro 20-1724 with flosequinan and Ro 20-1724 with BTS 53554 produced synergistic responses: 71 +/- 10 and 72 +/- 14%, respectively, greater than the mean basal dL value (p < 0.05). In contrast, the combinations of either flosequinan or BTS 53554 with IBMX or sulmazole produced no further increase in contractile amplitude. Neither flosequinan nor BTS 53554 produced any detectable increase in cyclic AMP, whereas significant increases were noted with Ro 20-1724, IBMX, and sulmazole (p < 0.05) in rat cardiomyocytes. Flosequinan increased beating frequency in rat isolated right auricles concentration dependently and was significant over the concentration range of 10(-5)-3 x 10(-4) M; flosequinan 3 x 10(-4) M maximally increased the mean frequency of beating by 35% of the predrug value (255 +/- 15 beats/min). Flosequinan had no effect on resting membrane potential, amplitude, or maximum upstroke velocity in rat isolated left ventricular (LV) papillary muscle, but at the maximum concentration (10(-3) M), flosequinan decreased action potential duration (APD) at 10, 50, and 75% of repolarization (p < 0.05). BTS 535

Topics: Adenylyl Cyclases; Animals; Heart; Heart Atria; Heart Rate; Heart Ventricles; Imidazoles; In Vitro Techniques; Male; Myocardial Contraction; Myocardium; Papillary Muscles; Phosphodiesterase Inhibitors; Pyrrolidinones; Quinolines; Quinolones; Rabbits; Rats; Rats, Sprague-Dawley; Rolipram; Stimulation, Chemical; Vasodilator Agents

Flosequinan is a balanced-type vasodilator with a prolonged mode of action due to an approximate 38-hour half-life of its active first metabolite, BTS 53554. As this may lead to tolerance and neurohormonal activation, the acute and long-term pharmacokinetic, hemodynamic, and neurohormonal profile of flosequinan was evaluated. On three consecutive days, 23 patients with heart failure (New York Heart Association classes II-IV), despite digitalis and diuretics, underwent invasive hemodynamic studies after receiving 100 mg oral flosequinan (day 1), placebo (day 2), and 100 mg flosequinan (day 3), followed by repeat invasive evaluation after long-term flosequinan (100 mg daily) for 17 +/- 2 weeks. On each study day, plasma flosequinan levels increased to 1.9 +/- 0.2 mg/L after 1 hour, but returned to baseline levels at 24 hours. In contrast, BTS 53554 increased progressively, reaching relatively high plateau levels (6 mg/L) during chronic therapy. First-dose flosequinan decreased the pulmonary wedge, right atrial pressure, and systemic resistance by 50, 60, and 22%, respectively, whereas the cardiac index was increased by 40%; these effects lasted for 48 hours. During long-term treatment, baseline values of the pulmonary wedge and right atrial pressure were comparable to prestudy values, whereas systemic resistance had decreased by 22%, and the cardiac index and heart rate had increased by 22 and 14%, respectively. Readministration of flosequinan did not further affect hemodynamics, apart from a moderate reduction in the pulmonary wedge and right atrial pressure. Neurohumoral activation did not occur during acute or long-term therapy. Thus, although changes in left and right heart filling pressures are attenuated during long-term treatment, flosequinan induces sustained arterial dilatation and improves cardiac pump function without activation of circulating neurohormones.

Topics: Aged; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Neurotransmitter Agents; Quinolines; Quinolones; Vasodilator Agents

We wished to provide comparative information regarding the direct effects of flosequinan, a novel quinolone under development for treating heart failure, on isolated human arterial, venous, and cardiac muscle. A similar assessment was made for four other agents--milrinone, ouabain, captopril and diltiazem--that have been used to treat heart failure patients, as well as for flosequinoxan, which is the primary metabolite of flosequinan. Flosequinan produced a potent and balanced relaxant effect on norepinephrine (NE)-contracted human arterial and venous smooth muscle, with IC25 values of 0.32 and 0.50 microM, respectively. At higher concentrations, flosequinan also produced a positive inotropic effect on human cardiac muscle (EC25 = 32 microM). A similar pattern of responses was observed with flosequinoxan. The pharmacologic profile obtained for the other agents examined differed from that observed with flosequinan and flosequinoxan in the following ways: Milrinone produced both vascular relaxant and positive inotropic effects, but at comparable concentrations; ouabain produced both vasoconstrictor and positive inotropic effects; diltiazem exerted a vascular relaxant effect at low concentrations and a negative inotropic effect at higher concentrations; and captopril had slight arterial relaxant and negative inotropic effects. These results demonstrate that the pharmacologic profile of flosequinan and flosequinoxan is unique as compared with that of other agents that have been used to treat patients with heart failure.

Topics: Captopril; Diltiazem; Heart Failure; Humans; In Vitro Techniques; Milrinone; Muscle Contraction; Muscle, Smooth, Vascular; Myocardial Contraction; Ouabain; Pyridones; Quinolines; Quinolones; Vasodilator Agents

The goal of this study was to assess the relationship between the positive inotropic response to high concentrations of the vasodilators flosequinan and BTS 53 554 (the sulfone metabolite of flosequinan) and the effect of both compounds on different forms of cyclic nucleotide phosphodiesterase. In addition, the relationship between inotropic activity and phosphodiesterase inhibition for the cardiotonic milrinone was also evaluated. All three agents exerted a positive inotropic effect on human cardiac muscle fibers. The concentration of milrinone required to increase cardiac contractility was comparable to the concentration required to inhibit the milrinone-sensitive subclass of cyclic AMP-specific phosphodiesterase (type III phosphodiesterase). However, no such relationship was observed for flosequinan and BTS 53 554. These results suggest that the cardiac response to high concentrations of flosequinan and BTS 53 554 is not mediated by inhibition of type III phosphodiesterase.

Topics: Humans; In Vitro Techniques; Milrinone; Myocardial Contraction; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pyridones; Quinolines; Quinolones; Vasodilation

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.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Guinea Pigs; Humans; Isoenzymes; Muscle, Smooth; Muscle, Smooth, Vascular; Myocardium; Phosphodiesterase Inhibitors; Quinolines; Quinolones; Vasodilator Agents

1. In right ventricular papillary muscles from control ferrets, flosequinan (10(-7)-10(-4) M) produced a concentration-dependent positive inotropic effect (10(-5) M = 153 +/- 24, 10(-4) M = 198 +/- 44% increase in isometric tension; control tension = 100%; n = 11) associated with a corresponding increase in amplitude of the intracellular Ca2+ ([Ca2+]i) transient recorded with aequorin (10(-5) M = 133 +/- 11, 10(-4) M = 187 +/- 36% increase in [Ca2+]i transient; n = 11). 2. The positive inotropic effect of flosequinan in control ferret ventricular muscle was neither blocked by propranolol (6 x 10(-7) M), nor associated with the abbreviation of the [Ca2+]i transient and contraction that is typical of catecholamines. 3. Neither flosequinan (n = 12) nor BTS 53 554, its sulphone metabolite (n = 6) produced a positive inotropic effect or altered the time course of contraction in myocardium from the hearts of patients with end-stage failure. 4. In contrast to milrinone, which produces a positive inotropic effect via phosphodiesterase inhibition, the unresponsiveness of myopathic human myocardium to flosequinan was not restored after intracellular adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were increased by prior treatment with forskolin (n = 13). 5. Taken together, these data indicate that flosequinan has a direct positive inotropic effect that is Ca(2+)-dependent, but independent of changes in intracellular cyclic AMP concentrations. 6. The positive inotropic effect may be species-dependent or altered by the presence of hypertrophy and/or heart failure. However, when used therapeutically in patients with severe heart failure, our data suggest that flosequinan should not adversely affect myocardial oxygen consumption through direct or catecholamine-mediated actions on the heart.

Topics: Animals; Calcium; Colforsin; Dose-Response Relationship, Drug; Ferrets; Heart Failure; Heart Ventricles; Humans; In Vitro Techniques; Male; Milrinone; Myocardial Contraction; Pyridones; Quinolines; Quinolones; Stimulation, Chemical; Vasodilator Agents

The general pharmacological profile of 7-fluoro-1-methyl-3-(methylsulfonyl)- 4(1H)-quinolone BTS 53 554, CAS 76568-68-8), the main metabolite of a new vasodilator, flosequinan (BTS 49 465), was investigated. 1. The central nervous system: BTS 53 554 at the dose of 30 mg/kg i.v. caused an increase in respiratory rate and a sedation in general behavior in rats. The drug also inhibited acetic acid-induced writhing and slightly decreased normal body temperature in mice. However, the drug at the doses up to 30 mg/kg i.v. had little effect on the spontaneous movement, hexobarbital-induced hypnosis, reserpine-induced hypothermia and motor coordination in mice. The drug showed neither anticonvulsant nor analgesic actions in mice. Furthermore, it had no effect on the spontaneous EEG, sleep-wakefulness cycle and EEG arousal response in rabbits at doses up to 10 mg/kg intravenously. 2. The somatic nervous system: BTS 53 554 induced no muscle relaxation in mice and exerted no local anesthetic action in guinea pigs by corneal reflex method. In addition, it had little effect on the neuromuscular transmission in cats. 3. The autonomic nervous system and smooth muscle: BTS 53 554 showed no effect on the sympathetic ganglionic transmission in cats. In isolated smooth muscles, at doses up to 10(-3) mol/l it showed little effect on the acetylcholine- or barium chloride-induced contraction of guinea-pig ileum, norepinephrine-induced contraction of rat vas deferens or oxytocin-induced contraction of nonpregnant rat uterus. However, it inhibited non-competitively norepinephrine-induced contraction of isolated rat aorta at 10(-4) mol/l or more and serotonin-induced contraction of isolated rat fundus at 3 x 10(-4) mol/l or more. In the isolated guinea-pig ileum, the drug slightly inhibited the histamine-induced maximal contraction at 10(-3) mol/l. These results suggest BTS 53 554 had no specific effect on norepinephrine, serotonin, acetylcholine or histamine. The drug relaxed isolated guinea-pig trachea at 3 x 10(-5) mol/l or more and inhibited the spontaneous movement of isolated pregnant rat uterus at 10(-4) mol/l or more, although these actions were extremely weaker than those of isoproterenol (isoprenaline). BTS 53 554 also showed a slight inhibition of uterus movement in anesthetized rats at 30 mg/kg intravenously. 4. The digestive system: BTS 53 554 tended to inhibit the gastrointestinal propulsion in mice and showed a slight inhibition of gastric and intestinal motilities

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Autonomic Nervous System; Blood Coagulation; Cats; Central Nervous System; Digestive System; Dogs; Female; Guinea Pigs; In Vitro Techniques; Irritants; Male; Mice; Mice, Inbred ICR; Peripheral Nerves; Pregnancy; Quinolines; Quinolones; Rabbits; Rats; Rats, Wistar; Urodynamics