flosequinan and Hypertension

The acute and short term antihypertensive effect of flosequinan was determined in 16 hypertensive patients whose blood pressure was inadequately controlled despite treatment with a beta-adrenoceptor blocking agent and a diuretic. Erect and supine systolic and diastolic blood pressure was significantly reduced by flosequinan over the treatment period as compared to placebo. Heart rate was unchanged by flosequinan. Adverse effects were limited to mild headache in 3 patients and taste disturbance in 1 patient, possibly due to salivary excretion of the drug. Flosequinan is a potentially useful vasodilator for the treatment of hypertension.

Topics: Adrenergic beta-Antagonists; Aged; Clinical Trials as Topic; Diuretics; Double-Blind Method; Drug Therapy, Combination; Humans; Hypertension; Middle Aged; Quinolines; Random Allocation

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

1. Flosequinan (BTS 49 465, 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) a novel arteriovenous dilator agent was orally effective in conscious renal hypertensive dogs and normotensive cats. The hypotensive potency of flosequinan was approximately ten times less than that of hydralazine in renal hypertensive dogs, 10 mg kg-1 and 20 mg kg-1 flosequinan causing similar falls in mean blood pressure to 1 mg kg-1 and 3 mg kg-1 hydralazine respectively. In normotensive cats, 5 mg kg-1 flosequinan caused similar falls to 0.5 and 1.0 mg kg-1 hydralazine. The onset of hypotensive effect after flosequinan appeared to be slightly slower than after hydralazine in the dog and slightly faster than hydralazine in the cat. 2. The degree of tachycardia and increase in plasma renin activity (PRA) for equivalent falls in mean blood pressure in both species was significantly less for flosequinan than for hydralazine (P less than 0.05). 3. In normotensive dogs, flosequinan, 10 and 20 mg kg-1 orally, caused a small but non-significant increase in sodium and chloride excretion and had little effect on urine volume whereas hydralazine, 1 and 3 mg kg-1 orally, caused a marked retention of sodium and chloride ions and a reduction in urine volume (P less than 0.01). 4. Neither flosequinan, 10 mg kg-1 orally, nor hydralazine 1 mg kg-1 orally, affected either glomerular filtration rate measured as creatinine clearance or effective renal plasma flow measured as p-aminohippuric acid clearance in normotensive dogs. 5. The lesser degree of tachycardia and increase in plasma renin activity together with a lack of sodium retaining activity associated with flosequinan suggest that this agent may have potential advantages over existing therapy as an antihypertensive in man.

Topics: Animals; Arteries; Blood Pressure; Cats; Chlorides; Dogs; Heart Rate; Hydralazine; Hypertension; Male; Potassium; Quinolines; Renin; Sodium; Vasodilator Agents