sulindac and Kidney-Failure--Chronic

To evaluate the effects of three chemically distinct nonsteroidal anti-inflammatory drugs (NSAIDs) on renal function in patients with asymptomatic, mild but stable chronic renal failure.. Prospectively randomized, triple-crossover study with at least 1-month washout between each of three treatment periods.. Inpatient and outpatient clinical research center of a university teaching hospital.. Convenience sample of 12 women with serum creatinine levels between 130 and 270 mumols/L (1.5 and 3.0 mg/dL). Mean glomerular filtration rate +/- standard error was 0.36 +/- 0.03 mL/s.m2 (37 +/- 3 mL/min.1.73 m2); mean effective renal plasma flow was 1.6 +/- 0.18 mL/s.m2 (166 +/- 19 mL/min.1.73 m2).. Patients received ibuprofen, 800 mg three times daily; piroxicam, 20 mg daily; and sulindac, 200 mg twice daily for 11 days. Treatment was discontinued if serum creatinine rose by 130 mumols/L (1.5 mg/dL) or serum potassium exceeded 6 mmol/L (6 mEq/L).. Three patients met our criteria for stopping ibuprofen by day 8; however, all patients completed piroxicam and sulindac therapy. When the three patients in whom ibuprofen was withdrawn were rechallenged with ibuprofen, 400 mg three times daily, two again developed evidence of acute renal deterioration. All three regimens suppressed renal prostaglandin production.. These findings indicate that a brief course of ibuprofen, a compound widely used on a nonprescription basis, may result in acute renal failure in patients with asymptomatic, mild chronic renal failure. Additional studies are needed to assess the risk of piroxicam and sulindac in patients with more pronounced renal impairment and in patients receiving longer courses of therapy, which, according to our data, may result in drug accumulation.

Topics: Adult; Aged; Creatinine; Female; Glomerular Filtration Rate; Humans; Ibuprofen; Kidney; Kidney Failure, Chronic; Middle Aged; Piroxicam; Prospective Studies; Prostaglandins; Randomized Controlled Trials as Topic; Renal Circulation; Sulindac; Thromboxane B2

The effects of 2 days of oral dosing with sulindac (200 mg twice a day) or indomethacin (75 mg twice a day) on glomerular filtration rate, urinary excretion of prostaglandin E2, sodium homeostasis, and other renal function parameters were investigated in eight patients with chronic stable impaired renal function. Indomethacin reduced creatinine clearance (from 41.0 +/- 7.9 to 30.3 +/- 6.3 ml/min) and increased serum levels of creatinine and beta 2-microglobulin. Sulindac had no effect on any of these parameters. Both drugs induced depression of urinary prostaglandin E2 excretion; this depression was greater after indomethacin. Urinary sodium excretion fell from 144.4 +/- 18.7 to 85.5 +/- 9.7 mmol/24 hr after indomethacin and from 131.7 +/- 11.6 to 103.4 +/- 13.3 mmol/24 hr after sulindac. Body weight increased 1.2 kg after indomethacin but was not changed by sulindac. Plasma renin activity was reduced from 2.3 +/- 0.8 to 1.7 +/- 0.6 nmol/L/hr by sulindac and from 2.8 +/- 0.8 to 1.5 +/- 0.5 nmol/L/hr by indomethacin. Urinary N-acetyl-beta-glucosaminidase and kallikrein excretion was not changed by either drug. Our data suggest that sulindac affects renal prostaglandin E2 synthesis and sodium excretion in patients with severe renal failure to a lesser extent than does indomethacin. Sulindac still seems to be the drug of choice in this group of patients, but glomerular filtration rate, body weight, and electrolyte balance should be carefully monitored.

Topics: Acetylglucosaminidase; Administration, Oral; Adult; Aged; Aldosterone; beta 2-Microglobulin; Creatinine; Dinoprostone; Female; Humans; Indenes; Indomethacin; Kallikreins; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Potassium; Prostaglandins E; Radioimmunoassay; Random Allocation; Renin; Sodium; Sulindac

Sulindac was administered as a single 300-mg oral dose to six patients with end-stage renal failure and six normal subjects. Plasma concentrations of sulindac and its sulfide and sulfone metabolites were examined over a 48-hour period. As determined by ultrafiltration methods at 37 degrees C, the percentage free of sulindac and sulindac sulfide in plasma was greater, respectively, in the patients with renal failure (10.50 +/- 2.42 and 9.96 +/- 1.21) than in the normal subjects (6.78 +/- 0.45 and 6.01 +/- 0.37). Free sulindac plasma concentrations were not different between the two groups. However, sulindac sulfide, total and free, plasma concentrations were substantially decreased in the group with renal failure. Total area under the curve (AUC) of the sulfide metabolite was 18% in the normal subjects and the free AUC was 29%. In patients with renal failure, the apparent half-lives of sulindac (1.98 +/- 0.76 hours) and sulindac sulfide (15.6 +/- 5.8 hours) were not different from those of normal subjects. Sulindac sulfone half-life was highly variable and longer in the patient group. Studies of dialysis clearance showed that sulindac and its metabolites are poorly dialyzed. A 4-hour dialysis period increased the plasma binding of both sulindac and sulindac sulfide in the patient group. Based on the decreased plasma concentration of the active sulindac sulfide metabolite in the patient group, dosage adjustments may be required in patients with end-stage renal failure.

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; Female; Half-Life; Humans; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Middle Aged; Protein Binding; Renal Dialysis; Sulindac

The purpose of this study was to evaluate the pharmacokinetics of sulindac, a purported "renal sparing" nonsteroidal anti-inflammatory drug, and its effects on renal function and prostaglandin excretion in patients with reduced glomerular filtration rate. Twelve female patients (glomerular filtration rate 37 +/- 4 mL/min) were treated with sulindac 200 mg bid for 11 days. Urinary PGE2, 6-keto-PGF1 alpha and serum thromboxane (TxB2) generation were measured by radioimmunoassay (RIA) following extraction on C-18 columns. Glomerular filtration rate and effective renal plasma flow were measured by 99TC-DPTA and 131I-para-aminohippuric acid clearance. In six patients serum and urine levels of sulindac and its metabolites were measured by high-pressure liquid chromatography (HPLC). Sulindac was rapidly absorbed and converted to sulindac sulfide with peak levels 2 hours after a single dose, but steady state levels were not reached prior to drug discontinuation. Sulindac sulfide AUC (0-5 hours micrograms min/mL) progressively increased from 382 to 3,030 on day 11. It did not appear in the urine. Baseline urinary PGE2 and 6-keto-PGF1 alpha excretion were 23.8 +/- 5.6 and 18.9 +/- 2.7 ng/hr respectively and were reduced by 68% and 47% by day 4 of therapy. TxB2 generation fell by 34% after one dose and by 67% by day 11. There was a significant increase in serum creatinine from 1.88 +/- 0.13 mg/dl before treatment to 2.16 +/- 0.15 mg/dL (P less than .05) after eleven days.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Platelets; Chromatography, High Pressure Liquid; Female; Humans; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Prostaglandins; Sulindac; Thromboxanes

Topics: Humans; Indenes; Kidney Failure, Chronic; Reference Values; Sulindac

In normal humans sulindac, a prodrug, undergoes two major biotransformations: irreversible oxidation to the inactive sulfone metabolite and reversible reduction to the pharmacologically active sulfide metabolite. To assess any effect of end-stage renal failure on sulindac biotransformation, six patients were given 200 mg sulindac orally. Plasma was sampled over 24 hours. Protein binding of sulindac and metabolites was determined by equilibrium dialysis. Results were compared with historic controls. AUC(0-12) for sulindac and the sulfone were similar to controls. AUC(0-12) for the sulfide was significantly reduced to 4.85 micrograms X hr/ml from 13.1 micrograms X hr/ml (P less than 0.02). Protein binding of all three compounds was significantly reduced by renal failure. When corrected for protein binding, the AUC(0-12) for sulindac and the sulfone was twice that of controls whereas that of the sulfide was 42 ng X hr/ml compared with 83 ng X hr/ml in normal individuals (P less than 0.001). This suggests that end-stage renal failure impairs the reduction of sulindac to the active sulfide whereas oxidation to the sulfone is intact.

Topics: Administration, Oral; Adult; Biological Availability; Biotransformation; Chromatography, High Pressure Liquid; Female; Humans; Indenes; Kidney Failure, Chronic; Kinetics; Male; Middle Aged; Sulindac

We have assessed the effects of acute and chronic administration of etodolac, ketoprofen, and indomethacin on renal function in patients with mild to moderate chronic renal insufficiency (CRI). We studied 18 normal volunteers and 24 patients with CRI due to hypertension and/or diabetes mellitus with creatinine clearances between 19 and 83 mL/min/1.73 m2. Clearance studies were performed with the first dose of nonsteroidal antiinflammatory drug (NSAID) to compare acute effects of the agent with a no-drug control. Subjects then received the NSAID for three to five days and, on the last day of study, underwent another clearance study to assess the effects of a single dose of NSAID superimposed on chronic dosing. With each dose of each NSAID, inulin and paraaminohippurate (PAH) clearances and fractional excretion of NA+ decreased. However, the baseline control collections after chronic dosing did not differ from the no-drug control periods. Hence, the decline in renal function with each dose is transient, and no overall adverse effect on renal function occurred with chronic dosing. In five patients with cirrhosis, we assessed the renal sparing effects of sulindac. After equilibration on a fixed sodium intake, they received a 200-mg dose of sulindac. In one patient, no adverse effect occurred; the remaining patients suffered declines in creatinine clearance of 29%, 87%, 37%, and 37%, respectively. This effect was transient and returned to control values six to eight hours after sulindac administration. At the time of maximal depression of renal function, serum concentrations of sulindac sulfide were comparable to those in subjects with normal hepatic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetates; Anti-Inflammatory Agents, Non-Steroidal; Creatinine; Dinoprostone; Etodolac; Humans; Indomethacin; Ketoprofen; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Liver Cirrhosis, Alcoholic; Prostaglandins E; Sulindac

Urinary excretion of two prostacyclin metabolites was investigated in 48 subjects: 8 controls and 40 cirrhotics (9 without ascites, 22 with ascites and preserved renal function, and 9 with functional renal failure). Urinary 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), believed to reflect renal prostacyclin production, was significantly increased in patients without ascites and in ascitic patients with preserved renal function, but cirrhotics with renal failure showed rates similar to controls. Excretion of 2,3-dinor-6-keto-PGF1 alpha (PGI-M), the major urinary metabolite of systemic prostacyclin, was increased in all groups of patients, including those with renal failure. A single dose of sulindac, a renal-sparing prostaglandin synthesis inhibitor, reduced PGI-M but not 6-keto-PGF1 alpha in 5 cirrhotic patients. This would be consistent with the predicted renal origin of the latter and the systemic origin of the former. Ascitic patients with high urinary excretion of PGI-M (above the median value) showed significantly lower mean arterial pressure and higher plasma renin activity and aldosterone than patients with excretion below the median. Urinary 6-keto-PGF1 alpha was higher in patients with low PGI-M. Finally, creatinine clearance corrected excretion of PGI-M, as an estimation of relative plasma levels correlates both with plasma renin activity and plasma aldosterone in the 31 subjects who presented with ascites. It is suggested that enhanced synthesis of systemic prostacyclin may influence hemodynamic changes in patients with liver cirrhosis. Overproduction of systemic prostacyclin in the absence of increased renal prostacyclin synthesis appears to be characteristic of patients with functional renal failure.

Topics: 6-Ketoprostaglandin F1 alpha; Ascites; Chromatography, High Pressure Liquid; Epoprostenol; Humans; Kidney; Kidney Failure, Chronic; Liver Cirrhosis; Radioimmunoassay; Sulindac

The effects of oral sulindac, 600 mg daily, on renal function and plasma hormones were studied in eight subjects with chronic renal failure. Renal function and plasma hormones were measured before drug administration and then after taking sulindac for 28 days. Effective renal plasma flow was reduced in all subjects after 28 days but the glomerular filtration rate did not change. Plasma renin activity, potassium and aldosterone concentrations and urinary sodium excretion did not change but urinary prostaglandin E2 excretion fell significantly. Sulindac may be a relatively renal-sparing drug in its effects on the hormonal control of glomerular function.

Topics: Adult; Aged; Aldosterone; Dinoprostone; Female; Hemodynamics; Humans; Indenes; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Prostaglandins E; Renin; Sulindac

The renal effects of therapeutic doses of sulindac were studied in nine patients with stable renal insufficiency, mean creatinine clearance 37.0 +/- 2.2 ml min-1 1.73 m-2 (range 24.7-54.6 ml min-1 1.73 m-2). Nine days' treatment with sulindac produced a small, but significant, reduction in the mean creatinine clearance (37.0 +/- 2.2 to 34.7 +/- 2.2 ml min-1 1.73 m-2; P less than 0.02) and 99mTc diethylenetriaminepenta-acetate (DTPA) clearance (35.5 +/- 3.4 to 31.4 +/- 3.6 ml min-1 1.73 m-2; P less than 0.02) without altering body weight, effective renal plasma flow [131I]hippuran clearance), plasma renin activity (PRA), 24 h urinary volume or electrolyte excretion. After discontinuation of sulindac, creatinine clearance returned to pretreatment values. In five female patients, pretreatment urinary excretion of the 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), a stable breakdown product of prostacyclin (PGI2), was significantly reduced (P less than 0.02) when compared with four healthy controls, whereas prostaglandin E2 (PGE2) was unchanged. Administration of sulindac did not significantly alter the excretion rate of PGE2 or 6-ketoPGF1 alpha in this group of patients. In chronic renal disease with moderate renal impairment, reduced renal prostacyclin synthesis may be an important predisposing factor to the renal toxicity associated with the use of non-steroidal anti-inflammatory drugs (NSAID). Short term use of sulindac in therapeutic doses does not appear to influence the excretion of prostaglandins and produces only a minor reversible change in renal function; used cautiously it may have advantages over other NSAID in these patients.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Creatinine; Dinoprostone; Female; Glomerular Filtration Rate; Humans; Indenes; Kidney; Kidney Failure, Chronic; Male; Prostaglandins; Prostaglandins E; Renin; Sulindac