Pharmacology of flosequinan.

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.

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

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.

Prostaglandin production in arthritis.

Inflammatory cell populations from synovial effusions or synovial villi in rheumatoid arthritis have been cultured in vitro. Prostaglandin productive capacity, measured by radioimmunoassay, showed the polymorphonuclear leucocyte rich populations from synovial effusions to be poor sources of PGE production whereas the synovial fragments produced substantial amounts of PGE activity. It is suggested that the macrophage is the major source of local prostaglandin formation both in gout and rheumatoid arthritis.

Nuclei of cultured synovial fibroblasts studied by immunofluorescence and microdensitometry.

Two techniques which might be expected to detect alterations in DNA have been used in a comparison of cultured non-rheumatoid and rheumatoid synovial fibroblasts. Microdensitometry showed no alteration in staining affinity for methyl green when two pairs of cultures were compared. There was, however, a minor difference in the predominant staining pattern to a fluorescein conjugated anti-IgM serum when five rheumatoid cultures were compared with five non-rheumatoid cultures after exposure to a serum containing anti-nuclear antibodies.

Inhibition of prostaglandin synthesis and leucocyte migration by flurbiprofen.

The carrageenan air pouch technique in the rat was used to investigate the effects of flurbiprofen, a non-steroidal anti-inflammatory agent, on prostaglandin production and leucocyte migration. tthere is a suggestion that flurbiprofen was capable of inhibiting prostaglandin synthesis at doses lower than those which were effective in reducing leucocyte migration. Therefore, these two effects may reflect independent actions of the drug. The possible clinical relevance of these experiments has been noted since the effects of flurbiprofen on prostaglandin synthesis and leucocyte migration are produced in the rat at peak plasma concentrations which are less than those found in man after a single dose of 50 mg.

Cardiac valvular disease in chronic inflammatory disorders of connective tissue. Factors influencing survival after surgery.

Three cases of cardiac valvular disease complicating chronic inflammatory disorders of connective tissue are described. Each underwent surgical valve replacement. The outcome in the first case, a patient with aortitis complicating Reiter's syndrome and in good health otherwise, has been excellent. The other two patients, one with rheumatoid arthritis and vasculitis, the other with systemic lupus erythematosus and nephritis, died after operation as the result of their systemic disease. The importance of systemic features in assessing this type of patient is emphasized.

Rheumatoid synovitis and joint disease. Relationship between arthroscopic and histological changes.

Arthroscopic and histological synovial features have been studied in forty-two patients with classical or definite rheumatoid arthritis. A total index of disease activity as judged arthroscopically correlates significantly with a total index of histological activity. In those patients who have dense, waxy looking villi, the intensity of the villus-proliferation is associated with lymphocytic infiltration of the synovium. No relationship between synovial lining cell proliferation and cartilage disease nor between sparsity of lymphocyte infiltration and cartilage disease could be established.