Effects of sulindac and naproxen on prostaglandin excretion in patients with impaired renal function and rheumatoid arthritis.
OBJECTIVE
The purpose of the current investigation was to study the influence of sulindac and naproxen on renal function and urinary excretion of the stable hydration product of prostacyclin, 6-keto-PGF1 alpha, in patients with arthritis and impaired renal function.


METHODS
In a placebo-controlled, double-blind, cross-over design, the effects of 7 days of oral sulindac 200 mg twice a day were compared with naproxen 500 mg in the morning and 250 mg in the evening in 10 patients with polyarthritis and stable impaired renal function. Inulin and para-amino-hippurate sodium were used to calculate glomerular filtration rate and renal plasma flow. The excretion rate of 6-keto-PGF1 alpha was measured in urine collected overnight. After patients ingested drugs in the morning, urine was collected in fractions by spontaneous voiding. Venous blood samples were drawn repeatedly for assay of electrolytes, creatinine, proteins, hormones, and drugs. Grip strength and Ritchie articular index were recorded as indicators of symptomatic antiarthritic effectiveness.


RESULTS
Naproxen decreased urine levels of 6-keto PGF1 alpha by 59% (p less than 0.01). Sulindac had no effect on renal prostaglandin excretion. Naproxen reduced the glomerular filtration rate and renal plasma flow by 18% (p less than 0.05) and 13% (p less than 0.05), respectively, while no significant change was observed during the sulindac treatment periods. Serum levels of creatinine and complement factor D were unaffected by either drug. Plasma renin activity decreased during naproxen and sulindac treatments by 38% (p less than 0.05) and 22% (p less than 0.05). No significant change in plasma aldosterone was observed during the two drug treatments, but urinary aldosterone declined significantly (p less than 0.05) by 34% with naproxen. Albuminuria decreased (p less than 0.05) during both naproxen (41%) and sulindac treatment (72%), while the albumin/creatinine clearance ratio decreased by 59% (p less than 0.05) only during treatment with sulindac. N-acetyl-beta-D-glucosaminidase in urine was not changed by either drug. Sulindac and naproxen had no discernible effects on base excess, excretion of water, sodium, or potassium, or on osmolal clearance. However, serum potassium increased slightly but significantly (p less than 0.01) during treatment with naproxen. Sulindac sulfide, the active metabolite of sulindac, could not be traced in the urine from any of the patients. Mean arterial blood pressure declined significantly (p less than 0.05) during sulindac treatment but did not change during treatment with naproxen. Both drugs produced equal clinical improvement as measured by grip strength and the Ritchie articular index.


CONCLUSIONS
The results suggest that when sulindac and naproxen are given in clinical equipotent doses to patients with impaired renal function, sulindac does not affect renal prostaglandin synthesis or renal function, whereas naproxen induces suppression of renal prostaglandin synthesis and a further decrease in renal function.
Department of Clinical Pharmacology, Lund University Hospital, Sweden.
L O
LO
Eriksson
G
G
Sturfelt
H
H
Thysell
F A
FA
Wollheim
D015121:6-Ketoprostaglandin F1 alpha / Q000652:urine*; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D002908:Chronic Disease; D002986:Clinical Trials as Topic; D004311:Double-Blind Method; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007674:Kidney Diseases / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D008297:Male; D008875:Middle Aged; D009288:Naproxen / Q000627:therapeutic use*; D010919:Placebos; D011188:Potassium / Q000652:urine; D012079:Renal Circulation / Q000187:drug effects; D012083:Renin / Q000097:blood; D012964:Sodium / Q000652:urine; D013467:Sulindac / Q000627:therapeutic use*
D010919:Placebos; D013467:Sulindac; D009288:Naproxen; D015121:6-Ketoprostaglandin F1 alpha; D012964:Sodium; D012083:Renin; D011188:Potassium