ISSN:
1432-1041
Keywords:
Renal function
;
Prostaglandins
;
Flosulide
;
non-steroidal anti-inflammatory drug
;
renin-angiotensin-aldosterone
;
healthy volunteers
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
,
Medicine
Notes:
Abstract Two double-blind, placebo-controlled, balanced cross-over studies were carried out successively in 8 male normotensive volunteers to investigate the acute and chronic effects of two doses of a novel non-steroidal anti-inflammatory drug flosulide (5 mg b.d. and 25 mg b.d.), on the renin-angiotensin-aldosterone system, linking this to changes in the urinary excretion of prostaglandins. Plasma renin and aldosterone were determined on Days 2 and 9, with the subject supine, after 1 h of rest in the sitting position following 1 h of walking, and 3 h after oral intake of 40 mg furosemide, also in the sitting position. Twenty-four hour urine samples were collected on Days 1 and 8 for the measurement of the electrolytes, aldosterone pH1 and the urinary prostaglandins PGE2, PGF2α, 6-keto-PGF1α and TxB2. Results: After the first day of treatment with 25 mg b.d. flosulide, the increase in body weight was close to significance (0.86 vs -0.08 kg with placebo). A dose-and time-dependent decrease in both active and inactive plasma renin were observed, whereas the fall in plasma and urinary aldosterone was statistically significant only after the higher dose of flosulide. These changes in the renin-angiotensin-aldosterone system were observed in the absence of oedema. Two out of eight volunteers experienced a strong and immediate reduction in the excretion of prostaglandins but overall the two doses tested did not produce a statistically significant inhibition in renal prostaglandins, especially following repeated dosing. The inhibitory effect of flosulide on renal prostaglandin synthesis was found to be less pronounced after repeated treatment, as documented on Day 9 by the lower inhibition of 6-keto-PGF1α and TxB2. Conclusion: These two studies in normal volunteers, in spite of some methodological limitations, were helpful in order to select doses of flosulide which should be effective and safe in patients during Phase II trials, by examining the inhibitory effect of the drug on renin synthesis and renal prostaglandin synthesis.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00192379
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