Effects of Ibuprofen, Naproxen, and Sulindac on Prostaglandins in Men

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Kidney International, Vol. 27 (1985), pp. 66—73

Effects of ibuprofen, naproxen, and sulindac on prostaglandins in men

D. CRAIG BRATER, SHIRLEY ANDERSON, BECKY BAIRD, and WILLIAM B. CAMPBELL

Departments of Pharmacology and Internal Medicine, The University of Texas Health Science Center at Dallas, Southwestern Medical School, Dallas, Texas, USA

Effects of ibuprofen, naproxen, and sulindac on prostaglandins in men. ischemic mechanism and is most frequently exhibited in dis- in contrast to other nonsteroidal anti-inflammatory drugs (NSAIDs), eases in which the local synthesis of vasodilatory prosta- sulindac has been reported to inhibit systemic prostaglandins (PGs) while not affecting renal PGs. We studied 11 normal volunteers who glandins (PUs) is a critical determinant of renal perfusion. received placebo, ibuprofen, naproxen, or sulindac in a randomized, Animal models of congestive heart failure, cirrhosis, sodium double-blind fashion. After control periods assessing the effect of the depletion, and hemorrhage demonstrate increased activity of NSAIDs alone, 40 mg of furosemide were administered. Overall, each the sympathetic nervous and renin-angiotensin systems. The of the drugs appeared similar. Renal function, plasma renin activity resultant increase in vasoconstricting autocoids is matched by (PRA) and urinary PGs were not affected during control collections, while all three NSATDs decreased thromboxane B2 (TxB2). Afterthe synthesis of PGs, thereby maintaining renal perfusion. furosemide, all NSAIDs decreased fractional excretions of Na andInhibition of renal PG synthesis results in unopposed renal Cl, PRA, and TxB2 by equivalent degrees (P <0.05).Sulindac and vasoconstriction which may lead to acute ischemic renal failure ibuprofen decreased urinary PGE2 (P <0.05)while naproxen had no [16—191. In humans, sodium-deprived normal subjects [14, 15] effect. None of these drugs affected the excretion of furosemide, but all decreased the pharmacodynamics of response to furosemide. In conclu- and patients with heart failure, cirrhosis, and intrinsic renal sion, the effects of these NSAIDs depended on the conditions of the disease appear to be most susceptible to this effect [1—13, 201, study. In the basal state there were no renal effects but all decreased the and caution must be exercised when administering NSAIDs in renal response to furosemide. these clinical settings. Recently, sulindac has been reported to differ from other NSAIDs by sparing renal but inhibiting Effets de l'ibuprofène, du naproxène, et du sulindac sur lessystemic PGs as reflected by the lack of effect on urinary prostaglandines che les hommes. A l'opposé d'autres médicamentsprostaglandin E2 (PGE2) excretion and on other putative end anti-inflammatoires non stéroidiens (NSAIDs), il a été rapporté que Ic sulindac inhibe les prostaglandines systémiques (PUs), mais n'affecte points of renal PG synthesis such as renin release and response pas les PUs rénales. Nous avons étudié II volontaires sains qui ant recu to furosemide while inhibiting systemic PGs as reflected by the du placebo, de l'ibuprofène, du naproxène, ou du sulindac d'unedecreased production of thromboxane by platelets [20—22]. maniêre randomisée, en double insu. Apres les périodes contrôles étudiant l'effet des NSAIDs seuls, 40 mg de furosémide ont étéOther preliminary studies report disparate findings [23—26]. A administrés. Globalenient, chacun des mCdicaments apparaissait sembl- differential effect of sulindac would considerably improve its able. La fonction rénale, l'activité rénine plasmatique (PRA) et les PGs therapeutic index relative to other NSAIDs. We felt that any urinaires n'étaient pas modiflées pendant les collections contrôles, alors putative advantage required closer scrutiny, for heretofore que les trois NSAIDs diminuaient le thromboxane B2 (TxB2). AprCs published studies have been conflicting [20—261. Consequently, furosémide, tous les NSAIDs diminuaient les excretions fractionnelles we performed the current randomized, double-blind, placebo- de Na et C1, PRA et TxB2 de facon equivalente (P <0,05).Le sulindac et l'ibuprofène diminuaient la PGE2 urinaire (P <0,05),alors controlled study in normal subjects. Our data do not support an que Ic naproxène était sans effet. Aucun de ces médicaments n'affectait overall renal sparing effect of sulindac. l'excrétion du furosémide. mais tous diminualent Ia pharniacodyna- mique de Ia réponse au furosémide. En conclusion, les effets de ces Methods NSAIDs dependaient des conditions de l'étude. A l'état basal, il ny avait pas d'effet renal, mais tous diminuaient La rCponse rénale au Study protocol furosémide. We studied eleven healthy men, 23 to 34 years old, and asked them to refrain from sexual activity throughout the duration of the study to avoid contamination of urine samples with seminal fluid PGs [27]. Prior to the study, the subjects were asked to Nonsteroidal anti-inflammatory drugs are well known toprovide a complete medical history, and they were given decrease renal function [1—15]. The most common type of acutephysical examinations including a screening of blood chemis- renal failure caused by these drugs appears to occur by antries, blood counts, and urinalysis to verify their lack of disease. The study was of double-blind, four-way crossover, balanced block design with random assignment to four treatments: pla- Received for publication December 28, 1983, cebo, ibuprofen, naproxen, and sulindac. All subjects com- and in revised form August 8, 1984 pleted all phases of the study. Each treatment period consisted © 1985 by the International Society of Neprhology of 5 days during which the subjects ingested a metabolic diet of NSAIDs and rena/function 67

Table 1. Assignment of drug given to subjects on day 5 of the study Assays Time drug ingested Sodium and potassium were measured with ion-specific elec- —12 hr —6hr —1 hr trodes, chloride by potentiometric titration, and creatinine by the Jaffe reaction with an autoanalyzer (Beckman Astra 8, Placebo Placebo Placebo Beckman Instruments, Inc., Fullerton, California, USA); inulin Naproxen, 375 mg Placebo Naproxen, 375 mg and PAH were measured with an autoanalyzer (Technicon Sulindac, 200 mg Placebo Sulindac. 200 mg Ibuprofen, 600 mg Ibuprofen, 600 mg Ibuprofen, 600 mg Instruments Corporation, Tarrytown, New York, USA) [29—3 1]; osmolality was measured by freezing point depression with a micro-osmometer (Precision Systems); phosphate as 10 mEq Na/day. All meals were eaten on the General Clinicaltotal phosphorus by the method of Fiske and Subbarow [321; Research Center (GCRC). Urinary electrolytes were measuredand furosemide by high performance liquid chromatography as previously described [33, 341. Plasma renin activity was mea- on a 24-hr urine sample collected from 8 P.M. of day 3 to 8 P.M. of day 4 to determine compliance with the diet. Urinary sodiumsured by radioimmunoassay using the antibody trapping proce- dure of Poulson and Jorgensen [351. Urinary PGE2 and 6 excretion in this sample was 17 4, and 17 4, 14 4, 17 keto-PGF1 and serum and plasma TxB2 were measured by 4 mEq/24 hr before placebo, ibuprofen, naproxen, and sulindac, respectively. Subjects were asked to withhold food and fluidsradioimmunoassay by the method of Dray, Charbonnel, and Maclouf [361 as modified by Campbell et al [37, 38]. Briefly, 2 ml after midnight of day 4, for the clearance study conducted on of urine or 4 ml of plasma were acidified to pH 3.0 with glacial day 5. A drug, randomly assigned, was ingested at —12, —6,acetic acid and passed through a 6 ml Baker C18 extraction and —1hr in the order shown in Table 1. We felt this regimen would approximate "normal" dosing of these drugs albeitcolumn that had been previously washed with ethanol and water [39]. The column was washed successively with 5 ml of acute. Though argument could be made for the need for more chronic dosing, it is important to note that the ischemic renal15% ethanol in water and toluene and the PGs were eluted with 2 ml of ethyl acetate. This eluate was evaporated to dryness insult observed with NSAIDs occurs quickly. Elevations of under a stream of nitrogen and further purified by silicic acid serum creatinine occur within 24 hr of exposure to the NSAID indicating that the deleterious effect probably occurs with initialchromatography [39]. The PG containing fraction was assayed by radioimmunoassay. One-tenth milliliter of the reconstituted exposure to the drug [281. Treatment periods were separated byfraction was mixed with 0.1 ml of 3H-PG and 0.1 ml of the at least 14 days. At time 0, the subjects received priming doses diluted antiserum. After incubation overnight at 4°C, the bound of inulin and para-aminohippurate (PAH) through an intra-and free PGs were separated with dextran-coated charcoal and venous catheter placed in one forearm followed by a main- the bound counts were estimated by liquid scintillation spec- tenance infusion throughout the duration of the clearance studytrometry. The results were corrected for recovery and ex- calculated to maintain serum concentrations of inulin and PAH pressed as nanograms of picograms per milliliter. With each of 25 and 1.5 mg%, respectively. These markers of renalassay a water blank is assessed. To avoid any artifact of hemodynamics were administered by an infusion pumpincreased urinary volumes, if a water blank is elevated, the (Harvard) at a rate of approximately 1 ml/min. During a 45-mm assay is discarded and repeated. equilibration period, the subjects drank a water load of 5 mI/kg of body wt to assure sufficient urinary output so spontaneously voided urine samples could be collected. At the end of the Data analysis 45-mm equilibration period, subjects voided and three 20-mm Effects of the different NSAIDs were assessed during both collection periods ensued, during which midpoint blood sam-the control periods and after furosemide. In the former, values ples were obtained for measurement of electrolytes, creatinine,for each of the three control collections in an individual subject inulin, PAH, plasma renin activity (PRA), and osmolality. Atwere averaged; in the latter, values encompassing the peak the midpoint of the third collection period, blood samples wereresponse to furosemide (invariably the first three collections) also obtained for measurement of serum and plasma throm-were averaged. Global renal handling of water was assessed as boxane (TxB2). The latter samples were collected in glass tubesurinary flow rate (V); global renal handling of solute as sodium containing 100 U/mI of heparin and 1 g/ml of indomethacin.and chloride excretion rates (Na and Cl) and as their fractional After the three baseline collection periods, 40 mg of furosemideexcretions (FENa and FEc1); glomerular filtration rate (GFR) as were administered as an intravenous bolus over 2 to 3 mm afterclearances of creatinine and of inulin (Cc. and C1) [40]; and which six 20-mm collection periods ensued. At the midpoint ofrenal plasma flow (RPF) as clearance of PAH (CPAH) [28, 29]. Since the accuracy of this measure depends on the secretion of the second collection period, blood samples were again col-PAH into urine, the presence of furosemide and/or NSAIDs lected to measure TxB2. For the duration of the study, urinarycould obviate using CPAH as a measure of RPF. Though Bartha losses were replaced intravenously with 5%dextroseand waterand Hably [411 have shown that indomethacin does not affect including 1 mI/mm for insensible water loss. All urine samplessecretion of PAH, similar data do not exist for the drugs used in were measured for volume, creatinine, electrolytes, P04,this study. Consequently, these data should he interpreted with inulin, PAH, PGE2, 6 keto-PGF1 osmolality, and furosemide,these caveats in mind. Phosphate excretion rate (P04) was used the latter where appropriate. On the 2 days following the periodas a nonspecific index of proximal tubular function [42, 43]. of observation, blood urea nitrogen (BUN), serum creatinine, The pharmacodynamics of fuorsemide were assessed as and urinalysis were obtained as a safety follow-up. No adverse"dose-response" curves by plotting the logarithm of urinary effects occurred. furosemide excretion rate (sg/min) versus Na excretion rate 68 Brater et al

Table 2. Effect of NSAIDs on renal function (mean sEM) Placebo Ibuprofen Naproxen Sulindac

V, mI/mm 2.97 0.70 2.97 0.61 3.28 0.80 3.24 0.73 Na, mEqimin 0.022 0.005 0.017 0.003 0.17 0.004 0.021 0.004 FENa, % 0.16 0.03 0.11 0.02 0.13 0.03 0.18 0.03 Cl, mEqlmin 0.014 0.003 0.007 o.oola 0.013 0.003 0.014 0.002 FE1, % 0.14 0.03 0.07 0.Ola 0.14 0.03 0.15 0.02 P04, mg/mm 0.52 0.08 0.42 0.05 0.38 0.06 0.41 0.04 C1,, mI/mm 105 6 111 9 106 5 98 10 Car, mI/mm 155 7 164 12 157 7 153 8 CPAH, mI/mm 635 46 657 56 655 50 674 69

Abbreviations: V, urinary flow rate; a and a,globalrenal handling of solute as sodium and chloride excretion rates; FENaandFEc1, fractional excretions of sodium and chloride; P04, phosphate excretion rate; C1,, clearance of inulin; Car,clearanceof creatinine; CPAH,clearanceof PAH. aTheeffects of ibuprofen were significantly more than the placebo.

Table 3. Effect of NSAIDs on plasma renin activity, urinary prostaglandins, and circulating thromboxane (mean sEM) Placebo Ibuprofen Naproxen Sulindac

PRA ngAl/mI/mm 2.7 0.3 2.7 0.2 2.5 0.2 2.6 0.1

Urinary PGE2 ng/min 0.21 0.05 0.17 0.02 0.16 0,03 0.14 0.03

Urinary 6 keto-PGF1, ng/min 0.24 0.09 0.14 0.02 0.20 0.05 0.12 0.02

Serum TxB2 ng/mI 0.94 0.26 0.04 o.ola 0.06 0.03a 0.43 010a,b

Plasma TxB2 ng/ml 0.049 0.012 0.015 0.008a 0.010 0.002a 0.016 o.oo4 a Theeffects were significantly more than the placebo. bTheeffects were significantly less than ibuprofen or naproxen.

(mEq/min) for all six collection periods. These sigmoid-shapedPRA or urinary excretion of PGE2 or 6 keto-PGF1,,, though the curves were analyzed using the ALLFIT computer program toPGs tended to decline (Table 3). In contrast, TxB2 was de- fit the curve to a standard format [44]: creased by all three agents whether assessed as plasma concentration or as production in serum (Table 3). Interestingly, with Y= a-d the latter assay, though sulindac significantly decreased TxB2 X b compared to the placebo (P < 0.025), this effect was less than 1+ (—) that of either ibuprofen (P < 0.025) or naproxen (P < 0.05). c Each of the latter markedly decreased TxB2 compared to the placebo (P < 0.001). This difference among agents was not The model used is the four parameter logistic equation where Yapparent with measures of plasma TxB2 concentration, where and X are response and dose, respectively, and a, b, c, and deach NSAID had similar quantitative effects (P < 0.01). Over- are the four derived parameters where a is the response at zeroall, then, during the control periods, each of these drugs dose, b is the "slope factor," c is the dose causing half maximalsuppressed systemic PGs as assessed by effects on TxB2 while response (ED50), and d is the response at infinite dose orall had negligible effects on renal PGs or function. maximal response. Response at zero dose, a, was fixed as the sodium excretion rate during the appropriate control period. Effect of NSAIDs on response to furosemide Differences among groups were tested using analysis of In contrast to the control collections, each of the NSAIDs variance. We used Bartlett's test to assess the equality ofdecreased response to furosemide (Table 4). Naproxen tended variances. If they were equal, we used a Newman-Keulsto have the least effect and ibuprofen the greatest, although multiple comparison; if variances were not equal, we used adifferences among drugs were not significant. Neither GFR nor Welch's approximation of nonparametric analysis. Values areRPF was affected. Phosphate excretion tended to decrease but expressed as mean SEM. not significantly. Each of these drugs could potentially affect response to Results furosemide by inhibiting its active secretion to its intraluminal site of action. Neither total amounts of furosemide nor the time Effect of NSAIDs alone course of its delivery into urine were affected by the NSAIDs Neither ibuprofen, naproxen, nor sulindac appreciably af-(Fig. 1). Consequently, the effect on the response to furosemide fected renal function during the control period, except theis not a pharmacokinetic interaction, but instead is pharmaco- decrease in chloride excretion caused by ibuprofen (P < 0.03;dynamic in nature, causing a shift in the relationship between Table 2). Similarly, none of these NSAIDs significantly affectedamounts of furosemide at its urinary site of action and natriu- NSAIDs and rena/function 69

Table 4. Effect of NSAIDs on the renal effects of furosemide (mean SaM) Placebo Ibuprofen Naproxen Sulindac V, mi/mm 25.8 1.3 20.6 l.i 23.8 1.6 20.3 i.4 Na, rnEq/min 2.30 0.08 1.56 0.13 1.97 0.14 1.70±0.13 FENa,% 16.8 0.9 12.7 1.2k 14.0 1.2 13.2 l.4a Cl,mEqlmmn 2.61 0.09 1.88 0.l3a 2.34 0.14 1.97 0.l1 FE1,% 26.7 1.4 21.1 1.8 23.5 2.0k 20.9 2.0k P04,mg/mm 1.10± 0.11 0.90 0.06 0.90 0.06 0.82 0.08 C1,,, mi/mm 109 4 96 5 106 4 102 6 Ccr, rn//rn in 159 136 8 132 6 137 9 CPAH,mi/mm 622 483 620 598 Abbreviations are the same as those used for Table 2. aTheeffects were significantly more than the placebo.

1000 3.0 800 •Furosemide alone 600 o F+Sulindac F+Naproxen 400 o F+lbuprofen

C 2.0 0 200 E •,,/f ai a C .2 100 80 a ax 1.0 60 E E a,a Furosemide o ./1 o 40 = N excretion, mg • Furosemide alone 9 21±1.0 o F+Sulindac 11 20±1.0 20 F+Naproxen 9 24±1.0 o F+lbuprofen 10 21±1.0 028T20 40 60 100 200 400 600

10 I Furosemide excretion rate, g/min 10 30 50 70 90 110 Fig.2. "Dose" response curves tofurosemide relating the logarithm of Time, mm urinary furosemide excretion rate (gImin) to response quantj/ied as Fig. 1. Time course of delivery of furosemide into urine with the total sodium excretion rate (mEqimmn). amount of diuretic excreted quantified in the figure.

and sulindac decreased serum production of TxB2 compared to retic response (Fig. 2). Table 5 presents derived parameters ofthe placebo (P < 0.001, P < 0.001, P < 0.025), the effects of these "dose' '-response curves. Basal sodium excretion, theibuprofen (P < 0.025) and naproxen (P < 0.05) were greater slope factor of the dose-response curve, and the dose causingthan that of sulindac. A similar qualitative effect was seen when half-maximal response (ED50) were not affected by any ofassessing plasma TxB2 concentration where both ibuprofen and the NSAIDs. In contrast, all significantly decreased maximalnaproxen caused tenfold decreases (P < 0.001) whereas the response (P < 0.005) with ibuprofen (P < 0.001) and sulindacdecrease with sulindac escaped significance (P =0.078). (P < 0.025), being significantly more potent than naproxen and ibuprofen being more potent than sulindac (P < 0.025). This Discussion pattern of effect is similar to that which we have previously One clinical problem with the use of NSAIDs is the nonselec- described with indomethacin [34]. tive nature of their inhibition of PG synthesis. Consequently, All three agents blunted fuorsemide-stimulated increases inpotential salutory effects of inhibiting PGs in one organ system PRA (P < 0.025) whereas only ibuprofen (P < 0.01) andcan be offset by adverse effects elsewhere. This drawback has sulindac (P < 0.03) suppressed urinary excretion of PGE2been particularly evident with respect to the acute renal failure (Table 6). Effects on urinary 6 keto-PGF1,,, were qualitativelythat has occurred with these agents [1—151. Recent data have similar to those on PGE2 although differences were not sig-indicated that sulindac might differ from other NSAIDs by nificant (Table 6). Similar to effects of these drugs on solutesparing renal PGs while inhibiting synthesis of those elsewhere excretion, ibuprofen appeared to be most potent and naproxen[20—22]. Because the mechanism of acute renal failure with the least. Effects of the NSAIDs on TxB2 were similar to thoseNSAIDs appears in most cases to occur by inhibition of during the control collections. Although ibuprofen, naproxen,vasodilatory renal PGs allowing vasoconstriction mediated by 70 Brater et a!

Table 5. Derived parameters of furosemide dose-response curves (mean SEM) Placebo Ibuprofen Naproxen Sulindac Basal response, mEq/min 0.022 0.017 0.017 0.021

Slope factor, mEq/p.g 3.34 1.14 3.45 1.91 3.10 -'-1.24 3.31 1.50

ED50, j.g/min 84.2 +9.7 80.6 12.9 90.7 12.7 94.9 15.2

Maximal response, tnEqlmin 2.43 0.20 1.60 0.20c 2.08 0,21a,h 1.84 0.22" a The effects were significantly more than the placebo. bTheeffects were significantly less than ibuprofen or sulindac. The effects were significantly more than sulindac.

Table 6. Effect of NSAIDs on plasma renin activity, urinary prostaglandins, and circulating thromboxane after furosemide (mean SEM) Placebo Ibuprofen Naproxen Sulindac

PRA, ng Al/mi/mm 5.5 0.6 34 3.6 0.4 3.6 0.5'

Urinary PGE2, nglmmn 1.28 +0.20 0.66 o.06 1.21 0.29 0.88 0.13 Urinary 6 keto-PGF1, nglmin 0.98 0.30 0.46 0.04 1.19 0.29 0.66 0.12

Serum TxB2, ng/mi 0.88 0.19 0.06 0.03u 0.03 +0.02 0.38 0•09a.b

Plasma TxB2, ng/m! 0.078 0.029 0.007 ÷ 0.00l 0.008 0.002" 0.025 0006b a The effects were significantly more than the placebo. bTheeffects were significantly less than ibuprofen or naproxen. the sympathetic nervous system and angiotensin to be un-affected renal function or urinary PGs (Tables 2 and 3). On one opposed [16—19], a renal sparing NSAID would offer consider-hand, these data do not support a difference between sulindac able advantages. It would be expected to cause less, if any,and either ibuprofen or naproxen, but on the other, they differ nephrotoxicity and might thereby be safer than other NSAIDsfrom the findings cited above of Muther and Bennett [14] and in patients at risk for this type of ischemic acute renal failure.Muther, Potter, and Bennett [15]. Two factors probably ac- Unfortunately, recent preliminary reports have not substanti-count for this difference: (1) Though the amounts of NSAIDs ated a renal sparing effect of sulindac 123—261. Consequently,we used were "average" doses used clinically, they were we felt the need for a more rigorous study. insufficient to inhibit renal PGs in this model and (2) our Certain patient groups are at a higher risk for the adversesubjects did not appear to have been as sodium-depleted as renal effects of NSAIDs including those with congestive heartwere those of the Muther and Bennett study, as reflected by a failure, cirrhosis with ascites, and probably various forms ofPRA in our subjects of 2.7 compared to 6.4 in theirs and by intrinsic renal disease [1—13, 20]. In these settings, the main-values for urinary PGE7 excretion in our subjects similar to tenance of renal perfusion appears to depend on local synthesisthose in sodium-replete patients. of PGs. One might argue that our study should have been Despite a lack of effect on renal PGs, however, these doses of conducted in a susceptible patient group. However, we felt thatNSAIDs were sufficient to inhibit TxB2 whether measured as such patient groups most likely encompass a wide range ofproduction in an incubate of serum or as plasma concentration pathophysiologies, even within one diagnostic category.(Table 3). Interestingly, this observation implies that synthesis Hence, we sought a model in which potential variables could beof thromboxane is more sensitive to NSAIDs than is renal PG more rigidly controlled, realizing that our findings might notsynthesis. When assessed as serum production of TxB2, but not extrapolate directly to clinical settings. On the other hand, theyas plasma concentration, sulindac had less effect than ibuprofen would serve as a valid starting point. Consequently, we choseor naproxen. We cannot explain this difference or speculate as to study a model in normal subjects which amplifies the role ofto its clinical implications. renal PGs, thereby better enabling us to detect renal effects of Do these data imply that ibuprofen and naproxen might also NSAIDs or a lack thereof. Muther and Bennett [141 andbe renal sparing? Strictly speaking, in this model, at these Muther, Potter, and Bennett [151 showed that GFR decreased indoses, both ibuprofen and naproxen spared renal PGs. How- normal subjects who had equilibrated on a 10 mEq/day sodiumever, we think these data are more appropriately interpreted to diet when they were given sufficient aspirin to inhibit renal PUs,imply that different NSAIDs have different potencies and that These data implied that the sodium-deprived state in normaldifferent sites of PG synthesis (for example, renal interstitium subjects in some respects mimicked clinical conditions such asversus vascular endothelium versus platelet) probably have heart failure in which the local synthesis of vasodilatory PGs isdiffering sensitivites to PG inhibition. Large doses of any required to maintain renal perfusion [19]. NSAID will probably inhibit all PGs whereas differences among In the current study, none of the NSAIDs appreciablydrugs will become manifest at lower doses and in different NSAIDs and renal function 71

conditions or models as a function of the PG source beingpressed TxB2. No comparison was made with other NSAIDs monitored. and effects on renal function were not reported. Administration of furosemide stimulates renal PGs and, in Recently, this same group studied 20 women with chronic fact, Nies et al [451haveshown that the hemodynamic compo-glomerular diseases comparing 1 week of treatment with 1.2 nent of response to furosemide is mediated by PGs. We felt itg/day of ibuprofen to 400 mg/day sulindac [20]. Sulindac did not might be reasonable to presume that this PG-mediated vascularaffect urinary excretion of PGE2 or 6 keto-PGF1a or cause renal effect is analagous to the PG-mediated vasodilation in patientsfunction to deteriorate while serum TxB2 decreased 85%. In susceptible to the adverse renal effects of NSAIDs. Conse-contrast, ibuprofen caused approximately 80% decreases in quently, we used furosemide as an additional test of effects ofboth urinary PGs, a 30% decrease in Ccr, and a 35% decrease in the various NSAIDs on renal function. Ibuprofen, naproxen,CPAH. and sulindac all had similar effects whether assessing renal A preliminary report from another group support function (Tables 4 and 6) or the pharmacodynamics of responseCiabottoni's findings. Twelve cirrhotic patients with ascites to furosemide (Fig. 2 and Table 5). In the doses used in thisreceived acute administration of 150 mg of sulindac or 50 mg of study, ibuprofen seemed to be most potent and naproxen theindomethacin [26]. The latter significantly decreased basal least in terms of effects on the kidney. In contrast, just as in thesodium and volume excretion and Ccr fell from 99 19 to 45 control periods, in terms of effects on TxB2, ibuprofen and11 mI/mm. Sulindac had no effect. naproxen were of comparable potency while sulindac was less Lastly, a recent case report described three patients who so. These data again demonstrate differences in sensitivity ofsuffered acute renal failure with ibuprofen or naproxen but were thromboxane as opposed to renal PG synthesis. able to tolerate sulindac [231. We attempted to use the clearance of PAH as an indirect On the other hand, the current study and other reports offer measure of renal blood flow. Although furosemide and otherconflicting data [23—26]. In the same study in cirrhotics cited loop diuretics have clearly been shown to increase renal bloodabove [26], although sulindac spared basal renal function, its flow when using electromagnetic flow probes, PAH clearanceeffects to inhibit response to furosemide were identical to those has proven to be a less reliable marker. In fact, in most studiesof indomethacin. In three additional studies, sulindac has been in humans in which high basal urinary flow rates are attainedcompared to 5 to 6 days of treatment with indomethacin [23], (water loading) which minimizes any "wash out" phenomenonnaproxen [24], or ibuprofen [25] in normal subjects. In these associated with acute administration of the diuretic, PAHstudies, sulindac had no effect on basal renal function but clearance has not increased with furosemide administration [46,inhibited response to furosemide in a similar qualitative but 47]. Furosemide can compete for tubular secretion of PAH,different quantitative fashion than the other NSAIDs. perhaps accounting for these observations. Although averaging Lastly, it is important to note that acute renal failure has also three collections after furosemide could conceivably have ob-occurred with large doses of sulindac in an elderly patient [13]. scured a transient increase in clearance of PAH, analysis of theAlso, in the original description of aspirin causing decrements data showed no such brief effect. in renal function in patients with lupus nephritis, the two signal Presumably, prostacyclin (PGI2) mediates the vascular ef-patients were successfully switched to 2.0 and 2.4 g/day of fects of furosemide [48]. Consequently, patterns of effects onibuprofen [11]. urinary excretion of 6 keto-PGF1 might be more informative Our bias is that all available NSAIDs can inhibit renal PGs than those on PGE2. Unfortunately, however, it is not knownand can cause acute ischemic renal failure if given in sufficient whether changes in urinary 6 keto-PGF1 reflect renal ordoses. The renal sparing effect of sulindac may simply reflect systemic synthesis of PGI2 (or more likely, a combination) [49,that common clinical doses are at the "low end" of the 50]. Consequently, we are reluctant to interpret the patterns ofdose-response curve in terms of inhibition of renal PGs while 6 keto-PGF1a excretion observed in this study other than theirrelatively higher doses of other NSAIDs are used. In addition, qualitative similarity to those of PGE2, thereby confirming adifferent pathologies and models probably have different sus- potency heirarchy of these drugs on PGI2 similar to that onceptibilities to inhibit PG synthesis. Our data demonstrate PGE2. differences in susceptibility of different PG systems within a Our data do not support an overall renal sparing effect ofnormal individual. Indeed, in the doses we used, the potency sulindac, which are findings which differ from the original and aheirarchy for renal effects of ibuprofen > sulindac > naproxen subsequent report of Ciabattoni et al [20, 21]. In their firstdiffered from the heirarchy for effects on TxB2 of ibuprofen report [21], these authors performed several different protocols.equal naproxen > sulindac. One would predict similar, if not In one study, they assessed the effects of 300 mg/day of sulindac on basal 24 hr urinary PG excretion and on serum TxB2greater, differences among patients. Although an overall renal- production in three healthy women. In one of these subjects,sparing NSAID would be a welcome advantage to our thera- after sulindac had been discontinued, the patient was re-peutic armamentarium, we do not feel that sulindac totally evaluated on 150 mg/day of indomethacin. At these doses,fulfills this criterion, and we urge that cautions be exercised in sulindac did not affect urinary PGs or PRA while in the patientits use similar to those with other NSAIDs. Our findings should who received indomethacin both decreased. A similar patternbe tested in other suscpetible patient groups because the was observed in one patient with Bartter syndrome. The lastfindings of Ciabottoni et al [20] in patients with glomerular protocol involved measurement of PRA and serum TxB2 pro-diseases may not extrapolate to other clinical settings. In duction in four men administered furosemide with and withoutaddition, when using NSAIDs as a research tool to inhibit PGs, pretreatment with 800 mg of sulindac. Sulindac had no effect onone cannot make a priori assumptions as to which PGs will be either basal or furosemide-stimulated PRA but markedley sup-inhibited and to what degree. 72 BraterCtal

Acknowledgments reduction of cardiac output in the dog. J Gun in vest 67:229—237, 1981 This study was supported by grants from the National Institutes of 20. CIABOTTONI G, CINOTTI GA, PIERUCCI A, SIMONETTI GM, MANZI Health (AM27059), General Clinical Research Center (1-MOl- M, PUGLIESE F, BAR50TTI P, Pacci G, TAGGI F, PATRONO C: RR00633), and a grant from Merck, Sharp & Dohme. Dr. D. C. Brater Effects of sulindac and ibuprofen in patients with chronic glomer- is a recipient of a Research Career Development Award (AM00705), ular disease. Evidence for the dependence of renal function on and Dr. W. B. Campbell is also the recipient of a Research Career prostacyclin. N EngI J Med 3 10:279—283, 1984 Development Award (HLOO8OI). The authors thank Dr. A. N. Chremos 21. CIABATTONI G, PUGLIESE F, CINOTTI GA, PATRONO C: Renal and M. A. Tupy-Visich of Merck Sharp & Dohme for suggestions and effects of anti-inflammatory drugs. 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