Malcolm Freeman Sim

Cardiovascular effects of the novel arteriovenous dilator agent, flosequinan in conscious dogs and cats

1 Flosequinan (BTS 49 465, 7‐fluoro‐l‐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 l.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 < 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 < 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.

Assessment of flosequinan's direct effect on human arterial, venous, and cardiac muscle: comparison with other classes of agents used to treat heart failure.

Summary: 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 μM, respectively. At higher concentrations, flosequinan also produced a positive inotropic effect on human cardiac muscle (EC25 = 32 μM). 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.

Relationship between inotropic activity and phosphodiesterase inhibition for flosequinan and milrinone

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.

Investigation of the effects of BTS 67 582, a novel antidiabetic agent, in the beagle dog

BTS 67 582 stimulates insulin release and causes dose‐dependent glucose‐lowering activity in the conscious beagle dog. Plasma glucose levels were lowered within 1 h and were maximally reduced by 53.2± 2.7% 2–3 h after oral dosing with 90 μmol/kg BTS 67 582 (equivalent to 22.5 mg/kg as the free base). A dose of BTS 67 582 causing a 25% (ED25) reduction of plasma glucose was calculated as 24.7 μmol/kg. No effect on the urinary excretion of glucose was observed (except for a marginal increase at the highest dose tested, 90 μmol/kg BTS 67 582). Insulin‐stimulated glucose disposal is, therefore, the most likely cause of the glucose‐lowering effect of BTS 67 582. BTS 67 582 significantly increased urine flow by 1.9‐ and 2.2‐fold and sodium excretion by 2.8‐ and 2.9‐fold by BTS 67 582 at 30 and 90 μmol/kg, respectively, without increased potassium excretion. In separate studies, increases in the urinary clearance of both creatinine and p‐aminohippuric acid were observed with BTS 67 582 at 90 μmol/kg, indicating that changes in glomerular filtration rate and renal blood flow, respectively, may have contributed to this diuretic effect. BTS 67 582 had no effect on blood pressure or heart rate. In conclusion, in the conscious beagle dog BTS 67 582 stimulates insulin secretion, causes dose‐dependent lowering in plasma glucose, and also possesses mild eukalemic diuretic properties. Drug Dev. Res. 47:137–143, 1999.