Effects of flurbiprofen on renal function in patients with moderate renal insufficiency

Transcription

1 Br. J. lin. Phrm. (1992), 33, ffets of fluriprofen on renl funtion in ptients with moderte renl insuffiieny M. D. MURRAY12, P. K. GRN', D. C. BRATR', A. K. MANATUNGA' & S. D. HALL' 'Division of Clinil Phrmology, Deprtment of Mediine, Indin University Shool of Mediine nd 2Deprtment of Phrmy Prtie, Purdue University Shool of Phrmy nd Phrml Sienes, Indinpolis, IN, USA 1 Renl funtion ws ssessed in eight ptients with hroni renl insuffiieny following the dministrtion of fluriprofen 50 mg s single dose nd fter hroni dministrtion of 50 mg four times dily for 8 nd 27 dys. Diet nd fluid intke were ontrolled. 2 Inulin nd retinine lernes nd urinry exretion of sodium were mesured t seline nd every 20 min for t lest 3 h fter dosing. The time of the men pek onentrtion of (S)-fluriprofen ws used to guide the nlysis of the lernes. Cretinine lerne, urinry exretion of sodium, nd serum sodium nd potssium were lso ssessed for 24 h fter the dose nd on dily sis. Body weight nd lood pressure were mesured on dily sis. 3 Derements in inulin nd retinine lernes were smll nd reversile within 3 h of n orl dose of fluriprofen. Comprison of seline lernes for the three study periods (first dose nd t 8 nd 27 dys of hroni dosing) reveled lk of hroni effet on glomerulr filtrtion rte. 4 In ontrst, fluriprofen used sustntil (73 to 86%) nd progressive derese in the urinry exretion of sodium tht rehed ndir within 4-5 h fter drug dministrtion. However, omprison of seline vlues did not differ, inditing tht lne onditions hd een re-estlished. 5 Results of 24 h ssessments were in greement with the lerne study results. Redued urinry exretion of sodium ppered to e limited to the first few dys of fluriprofen dministrtion. Serum potssium onentrtion inresed y 0.44 mq 1-1 ± 0.14 within the first week fter hroni fluriprofen dosing, ut then deresed to seline despite ontinued dministrtion of the drug. Body weight nd systoli nd distoli lood pressures remined reltively stle while ptients reeived fluriprofen in onjuntion with ontrolled sodium diet ut in the sene of the ontrolled diet they inresed y 2.8 ± 0.4 kg, 26.7 ± 7.5 mm Hg, nd 12.1 ± 4.6 mm Hg, respetively. 6 Fluriprofen dministrtion t this dosge ppers to use no overll hroni dverse effets on renl funtion in ptients with moderte renl insuffiieny. Serum potssium onentrtion, ptient weight nd lood pressure inrese to minor degree ut to n extent likely to e linilly importnt in some ptients. Keywords fluriprofen dverse renl effets glomerulr filtrtion ntriuresis Introdution Non-steroidl nti-inflmmtory drugs (NSAIDs) re renl funtion re linil onditions tht render renl known to ffet renl funtion in suseptile ptients y funtion prostglndin-dependent suh s irrhosis inhiiting the synthesis of vsodilting renl pros- (Zipser et l., 1979), ongestive hert filure (Cnnon, tglndins (Brter, 1988; Clive & Stoff, 1984). Among 1986; Oliver et l., 1981), nd hroni renl insufthe risk ftors for NSAID-ssoited redutions in fiieny (Berg & Tlseth, 1985; Brter et l., 1985, 1987; Correspondene: Dr Mihel D. Murry, Clinil Phrmology Division, Wishrd Memoril Hospitl, OPW 320, 1001 West 10th Street, Indinpolis, IN 46202, USA 385

2 386 M. D. Murry et l. Cittoni et l., 1984; riksson et l., 1990; Swinson & Griffiths, 1985; Toto et l., 1986; Whelton et l., 1990). Upon dministrtion of NSAIDs to ptients with these disorders, glomerulr filtrtion rte (GFR) dereses nd independent of this effet, urinry exretion of sodium nd potssium lso derese (Brter, 1988; Clive & Stoff, 1984). In ptients with hroni renl insuffiieny, numerous reports hve doumented these effets upon exposure to vriety of NSAIDs (Berg & Tlseth, 1985; Brter et l., 1985, 1987; Cittoni et l., 1984; riksson et l., 1990; Swinson & Griffiths, 1985; Toto et l., 1986; Whelton et l., 1990). However, studies hve lso doumented tht n ute dverse effet n e oserved without umultive effet over time (Berg & Tlseth, 1985; Brter et l., 1985; Swinson & Griffiths, 1985; Toto et l., 1986). Beuse the renl effets my vry mong the ville NSAIDs, newly mrketed NSAIDs nd those not previously studied must e studied individully. Fluriprofen, n rylpropioni id NSAID, ws mrketed in the United Sttes in 1989 ut hs een ville in other ountries sine the lte 1970s (Brogden et l., 1979). Its effets on renl funtion in ptients with hroni renl insuffiieny hve not een exmined systemtilly. We therefore studied the ute nd hroni effets of fluriprofen on renl funtion in ptients with moderte hroni renl insuffiieny. Methods Originlly, this study ws designed to ssess the effets of orl fluriprofen (Ansid Tlets, The Upjohn Compny) on renl funtion in ptients with renl insuffiieny using indomethin s positive ontrol. However, it eme pprent fter severl ptients were rndomized to reeive indomethin tht this NSAID hd intolerle dverse effets in two of the three ptients to whom it ws dministered. For ethil resons nd euse indomethin hd previously een studied in ptients with renl insuffiieny, the protool ws modified to delete the indomethin rm of the study. ight ptients, ge 49 to 68 yers, ompleted the fluriprofen study rm ut only one ptient reeived the full ourse of indomethin therpy. Two other ptients hd indomethin stopped premturely owing to dverse effets. Ptient hrteristis pper in Tle 1. Tle 1 Chrteristis of ptients with hroni renl insuffiieny Age Weight ntry CLr Ptient numer (yers) Sex (kg) (ml min-) Dignoses Conomitnt meditions Fluriprofen S Indomethin M M M M M F M M CLr = retinine lerne M M M Polyysti kidney disese, hypertension 29 Hypertension Peripherl vsulr disese, hypertension, oronry rtery disese 27 Hypertension, emphysem 47 Hypertension, oronry rtery disese, peripherl vsulr disese 29 Hypertension, oronry rtery disese, gout 20 Fol segmentl glomerulr nephritis, hypertension 41 Dietes mellitus 43 Hypertension 37 Dietes mellitus, ongestive hert filure, hypertension, peripherl vsulr disese 41 Dietes mellitus, oronry rtery disese, hroni pnretitis nlpril, frusemide, metoprolol Clonidine, enlpril Cptopril, frusemide, isosoride dinitrte, nifedipine, quinidine, nitroglyerine pth Aluterol inhler, hydrohlorothizide, reserpine, propoxyphene, theophylline Clonidine, isosoride dinitrte, nifedipine, nitroglyerine nlpril, ferrous sulphte, frusemide, minoxidil, verpmil Diltizem, frusemide, przosin, nifedipine nlpril, frusemide, insulin, nifedipine Frusemide, proprnolol Cptopril, frusemide, insulin Diltizem, fludroortisone, insulin, isosoride dinitrte, nitroglyerine, pnreti enzymes, rniditine

3 Fluriprofen effets on renl funtion 387 The eight ptients who reeived fluriprofen hve een desried previously (Kndler et l., 1992). Ptients Prior to enrollment medil history ws tken, nd physil exmintion, eletrordiogrm, vitl signs, nd endogenous retinine lerne nd other lortory studies were otined. Informed onsent ws otined from eh ptient. The study ws pproved y the Indin University Medil Center Institutionl Review Bord. Inlusion riteri required tht ptients e yers of ge with moderte renl insuffiieny (retinine lerne ml min-'). Ptients were exluded if ny of the following were present: known hypersensitivity or intolerne to ny NSAID or spirin; history of pepti uler disese, gstrointestinl leeding or frequent dyspepsi; nemi over nd ove tht whih would e expeted from the ptient's renl insuffiieny; use of ortiosteroids, NSAIDs, spirin or spirin-ontining produts unless the ptient ould refrin from tking these meditions for 1 month prior to enrollment in the study nd for the durtion of the study. Also exluded were women of hildering ge who were not surgilly sterile or not tively prtiing ontreption (IUD in ple or tking orl ontreptive). Ptients remined on stle regimens of their hroni meditions s shown in Tle 1. Smokers nd nonsmokers were permitted to prtiipte in the study. However, onsumption of loholi everges ws not permitted during the study period. Ptients were sked to void strenuous exerise immeditely efore nd during the study. Study design nd linil protool This ws rndomized open-lel, prllel study lsting 47 dys with oth inptient nd outptient phses (Figure 1). Ptients were dmitted to the Generl Clinil Reserh Center (GCRC) for dietry equilirtion throughout dys 1 to 14. Sodium nd potssium intke were 150 mq nd mq per dy, respetively, nd dietry fluids were 3 1 per dy. On dy 6, ptients were rndomised to reeive their first dose of either fluriprofen or indomethin 50 mg, nd the first of iil 21 3A 47 5 L6 7 nter Study 1 study Diet NSAID _ 8 A 9 10 [ii 12 i13 14 Study 2 Diet i [:3:: Out- Out- Study 3 ptient ptient Stop visit 1 visit 2 NSAID 46i 47 xit / ~~~study Figure 1 Study lendr. Letters in the upper, left orner of eh lok represent either inptient (i) or outptient (o) dys. Hthed loks represent vrile extended time periods. three renl lerne studies (vide infr) ws performed. Ptients were ontinued on either fluriprofen 50 mg orlly four times per dy (with mels nd edtime snk) or indomethin 50 mg orlly three times per dy with mels throughout dys 7 to 13 nd dys 15 to 32. The seond renl lerne study (dy 14) ws performed fter ptients hd reeived their ssigned study NSAID for 8 dys. On dy 15, ptients hd vitl signs ssessed nd were then dishrged from the GCRC ut returned for evlution s outptients on dys 19 nd 26 to hek for dverse symptoms nd to ssess serum eletrolytes nd retinine onentrtion. On dy 32, ptients returned to the GCRC for the study diet nd third renl lerne study on dy 33 fter hving reeived hroni dosing of their ssigned study NSAID for 27 dys. Study NSAIDs were disontinued fter this third renl lerne study following whih ptients returned to the GCRC on dys 46 nd 47 for finl mesurement of retinine lerne. Vitl signs were lso ssessed on dys 46 to 48. Ptients kept dily reords of their medition reording ll doses tken nd ll tht were missed. Compline ws lso heked with tlet ounts whih reveled tht >90% of the doses of study NSAID were tken. Clerne studies Inulin nd retinine lerne nd sodium exretion rte were ssessed on dys 6, 14, nd 33 representing studies of the effets of NSAID following the first dose (study 1), nd fter 8 dys (study 2) nd 27 dys (study 3) of ontinuous drug dministrtion. Brekfst ws withheld on these dys. At the end of 24 h urine olletion tht egn the previous dy, ptients hd n intrvenous theter inserted in eh rm: one for the infusion of inulin nd the other for lood smpling. A loding dose of inulin ws dministered s 10% w/v solution t dose of 50 mg kg-' of ody weight followed y ontinuous infusion t rte of 0.25 mg times the estimted glomerulr filtrtion rte in ml min-'. Following the inulin loding dose 45 min equilirtion period egn during whih ptients ingested distilled wter lod of 20 ml kg-' to ensure dequte urine output. At the end of the equilirtion period ptients voided urine. Beginning with the equilirtion smple, urinry output ws mthed with n equl volume of intrvenous 5% w/v dextrose nd wter. After the equilirtion period, three 20 min ontrol urine olletions with midpoint serum smples were otined. After ompletion of the ontrol olletions, the ptients were given single 50 mg dose of either fluriprofen or indomethin y mouth. Following drug ingestion nine 20 min urine olletions with midpoint serum smples were otined. After ompletion of the 180 min olletion period the inulin infusion nd the intrvenous fluid replement were stopped. Ptients were then llowed lunh. Urine smples were then olleted hourly to 8 h nd t 10, 12, nd 24 h fter dosing. Serum smples were lso olleted t 8, 10, 12 nd 24 h. Blood nd urine smples were nlyzed for inulin, retinine, potssium, sodium, nd fluriprofen nd its metolites. The phrmokineti dt re reported seprtely (Kndler et l., 1992).

4 388 M. D. Murry et l. Blne studies During inptient dys nd outptient dys 19 nd 26, 24 h urine olletions nd serum smples were otined nd nlyzed for sodium, potssium, nd retinine. Anlytil proedures Serum nd urine onentrtions of inulin nd retinine were mesured with n utonlyzer (Tehnion Instruments Corportion, Terrytown, NY, USA). The method for inulin in serum nd urine ws sed upon the stndrd test for mesuring rohydrtes using the nthrone method (Wright & Gnn, 1966), wheres retinine ws mesured using the Jffe retion. Individul stndrd urves were prepred for ssy of eh ptient's smples. If the predited onentrtion of externl stndrds differed y more thn 5% from their tul vlues, the ssy ws rerun. Sodium nd potssium were mesured simultneously with n IL943 Automti Flme Photometer (Allied Instrumenttion Lortory, Lexington, MA, USA). Commeril stndrds were mesured every 10 to 15 smples, nd if their predited vlue vried y more thn 5% from the tul vlue, the smples were renlyzed. Dt nlysis Clerne studies Previous studies of the effets of severl NSAIDs in ptients with hroni renl insuffiieny hve reveled tht redutions in renl funtion, s refleted y glomerulr filtrtion nd sodium exretion rtes following NSAID dministrtion, re reversile. For lerne tehniques, this trnsient effet results in proli response-time urve. We therefore used the time of the pek onentrtion of (S)- fluriprofen, the tive enntiomer, to mrk the eginning of the liner desent to the ndir of renl funtion, tht is, the mximl drug effet. This method ssumes no hysteresis etween the serum onentrtion of the NSAID nd its renl effet, n ssumption tht seems resonle in view of other studies tht hve ssessed onordne of onentrtions with renl effets (Brter et l., 1985, 1987; Toto et l., 1986). We first lulted the men ontrol vlue s the men of two to three stle prmeter vlues otined prior to fluriprofen dministrtion for eh ptient. Stle vlues were those with onsistent urine volume. Using phrmokineti dt from Kndler et l. (1992), we then determined the men time of the mximum onentrtion of (S)-fluriprofen (men tmx). Resoning tht the mximum renl effet of fluriprofen would our t or shortly fter the men tmx, we ompred the men ontrol with ll experimentl smples tht ourred one 20 min olletion period eyond the men tmx. For study 1, the men tmx ± s.e. men fter the first dose ws 145 ± 43 min. Therefore, experimentl smples up to 160 min were ompred with the men ontrol. Similrly, the men tmx for study 2 ourred t 113 ± 16 min so ll experimentl smples up to 1 min were sumitted for nlysis wheres the men tmx for study 3 ourred t 136 ± 22 h so ll experimentl smples up to 160 min were nlyzed. We lulted the hnge from seline y sutrting the vlue for eh of the experimentl mesurements from the men ontrol. Fisher's lest signifint differene multiple omprison proedure ws then used to determine the signifine of the effets of fluriprofen on renl lerne prmeters (inulin nd retinine lerne, nd sodium exretion rte) from seline (Winer, 1971). We lso ssessed the redution in renl funtion with time using repeted mesures nlysis of vrine. One-wy nlysis of vrine ws used to ompre men ontrol mesurements of inulin nd retinine lerne, nd sodium exretion rte etween studies 1, 2, nd 3. Doing so, we ssessed the hroni effets of fluriprofen on these prmeters in omprison to seline renl funtion in the sene of fluriprofen (study dy 6), fter 8 dys (study dy 14), nd fter 27 dys (study dy 33). Blne studies Pired t-tests were used to ssess the effets of fluriprofen on dily serum sodium nd potssium onentrtions, totl urinry sodiuml24 h, nd retinine lerne. For these nlyses, the men ontrol vlue ws lulted s the men of the vlues for dys four nd five (immeditely prior to first fluriprofen dministrtion) y whih time dietry equilirtion hd ourred. We lulted the hnge from seline y sutrting the vlue for eh of the mesurements for dys 7-13, 19, 26, nd 32 from the men ontrol. We then tested the hypothesis tht the hnge from seline did not differ from zero. Results re expressed s men ± s.e. men. Sttistil nlyses were onsidered signifint if P < Results ffets of indomethin Of the three ptients rndomized to reeive indomethin, only ptient 10 ompleted the study. Two ptients (9 nd 11) were removed from the study premturely owing to dverse effets from indomethin. Ptient 9 ws removed on dy 12 euse of 3 kg weight gin, peripherl oedem, nd rise in serum retinine onentrtion from 1.6 to 1.9 mg%. Upon disontinution of indomethin, this ptient's weight nd serum retinine onentrtion returned to seline vlues, nd the oedemtous ondition resolved. Ptient 11 ws removed from the study on dy 15 euse of derese in hemogloin from 9.3 g dl-1 to 7.7 g dl-1 ompnied y hemtest positive stools. This ptient ws symptomti nd thought to hve hd n upper gstrointestinl leed or gstritis. This prolem resolved fter indomethin ws disontinued. Beuse of erly disontinution of indomethin therpy owing to dverse effets in tht study rm nd susequent disontinution of tht rm fter only three ptients hd een enrolled, there were insuffiient dt to nlyze for indomethin effets. Thus, the remining results fous upon fluriprofen.

5 Fluriprofen effets on renl funtion 389 ffets offluriprofen Clerne studies Renl hemodynmis Clerne dt for ptients reeiving fluriprofen pper in Figures 2 nd 3. Differenes etween the inulin lerne men ontrols (time 0) nd experimentl olletions were smll nd not sttistilly signifint for studies 1 nd 2 (Figure 2, nd ). In study 3, however, derements in inulin lerne of 27.4% nd 25.4% ourred t experimentl olletions of 60 nd 100 min, respetively (Figure 2). These redutions were trnsient nd fully reversile y the men tmx (P > 0.05). Comprison of the men ontrols for inulin lerne mong study 1, study 2, nd study 3 reveled smll inrements tht were not sttistilly signifint inditing no umultive effet of fluriprofen on inulin lerne with repeted dosing (F= 1.05, P = 0.37). A pttern similr to tht for inulin lerne ws oserved for retinine lerne (Figure 3 to ). For study 1, signifint ut reversile derements in retinine lerne of 19.4% nd 18.0% ourred t 60 nd 80 min, respetively (Figure 3). For study 2, derements of 24.8% nd 18.2% ourred t 80 nd 100 min, respetively (Figure 3). Agin the derements were trnsient. For study 3, derements ourred erlier nd were more prolonged (Figure 3). Derements from the men ontrol for this ltter study rnged from 25.0% to 41.6% ut hd egun inresing y 180 min. It ppers tht ontrol vlues in this study re inordintely high; therefore, the derements deteted my hve little mening. It is importnt to note tht if the men ontrol for study 1 (prior to fluriprofen use) hd een used for omprison of the study 3 experimentl olletions, none of the derements oserved in study 3 would hve rehed sttistil signifine Time (min) Figure 2 Men (± s.e. men) inulin lerne vlues fter the first fluriprofen dose (study 1, pnel ), nd fter 8 dys (study 2, pnel ) nd 27 dys (study 3, pnel ) of ontinuous dosing. Time 0 is the men ontrol (see text). The vertil dshed line represents the men time of the mximum serum onentrtion of S-fluriprofen. P < 0.05 ompred with the ontrol vlue for tht study dy j u Time (min) Figure 3 Men (± s.e. men) retinine lerne vlues fter the first fluriprofen dose (study 1, pnel ), nd fter 8 dys (study 2, pnel ) nd 27 dys (study 3, pnel ) of ontinuous dosing. Formt s in Figure 2.

6 390 M. D. Murry et l. Differenes mong the men ontrols for studies 1, 2, nd 3 were not signifint (F = 1.26, P = 0.) inditing no umultive effet of fluriprofen on retinine lerne. Renl sodium exretion In ontrst to the ute, trnsient effets of fluriprofen on renl hemodynmis, there ws lerly progressive effet of fluriprofen on sodium resorption (Figure 4 to ). During studies 1, 2, nd 3, sustntil numer of olletion periods showed signifint derese in sodium exretion. For study 1, derements rehed sttistil signifine t 60 min nd hd not returned to seline throughout the period of oservtion (Figure 4). The ndir ourred t 4 h when exretion diminished to 75.0% of the men ontrol (dt not shown in Figure 4). As suh, these results indite time effet of fluriprofen on sodium exretion up until the men tmx (F = 3.53, P = 0.004). However, this time effet ws not oserved during study 2 owing to inresed vriility used y one outlier (Figure 4). For this study, ptient 8 hd n inordintely high sodium exretion (73% greter thn the men for the other ptients), pprently due to dietry indisretion. This resulted in loss of the time effet (F = 1.75, P = 0.13). Removl of this ptient from nlysis resulted in return of the time effet despite fewer degrees of freedom (F = 3.58, P = 0.007). As with study 1, the ndir ourred 4 h fter dministrtion of fluriprofen. Similr effets were oserved for study 3 (Figure 4). In this study derements rehed ndir 85.6% less thn the men ontrol ourred t 5 h (F = 3.10, P = 0.009). Comprison of the men ontrols for urinry sodium exretion mong studies 1, 2, nd 3 reveled signifint inrement etween study 1 nd study 3 (F = 5.50, P < 0.02). This higher urinry sodium exretion with hroni therpy my e the result of ompenstory mehnism preventing umultive sodium retention with repeted fluriprofen dministrtion. More likely, however, it is due to the shorter dietry equilirtion period (one dy) in study 3 s ompred with studies 1 nd 2 (5 nd 13 dys, respetively). In summry, these dt re entirely onsistent with the known redution of renl tuulr sodium resorption used y NSAIDs. Blne studies The results of the dily studies of retinine lerne, urinry sodium exretion, nd serum sodium nd potssium pper in Figure 5 to d. Vlues for dily serum retinine onentrtion (dt not shown) were onsistent with the findings from the lerne studies inditing no umultive derement in renl funtion throughout 28 dys of fluriprofen therpy (Figure 5). Although dily exretion of sodium ws signifintly redued on dys 7, 9, nd 11 throughout the period of dietry ontrol, urinry exretion ws modertely elevted on outptient dys 19, 26, nd inptient dy 32 when no speil diet ws used (Figure S). There were no sttistilly signifint hnges in serum sodium onentrtion while ptients reeived fluriprofen (Figure S). In ontrst to the lk of effets of fluriprofen on serum sodium onentrtion, serum potssium onentrtion ws signifintly elevted on study dys 8, 10, nd 12 (Figure Sd). Serum potssium onentrtion inresed from men ontrol vlue of 4.31 ± 0.20 to 4.75 ± 0.23 mq l-1 on dy 12 ( ± 0.14). Only one ptient's inrese in serum potssium onentrtion from the men ontrol exeeded 1.0 mq 1-1 (Ptient 12); this ptient's men ontrol ws the lowest (3.3 mq 1-1). No ptients' serum potssium onentrtion exeeded 6.0 mq 1-1. In two ptients serum potssium onentrtions rose ove 5.0 mq 1-1 ut returned to seline vlues in oth despite ontinued fluriprofen dministrtion. ffet on weight nd lood pressure Weight nd lood pressure were inresed, prtiulrly in the sene of the ontrolled diet, whih is onsistent with the effets noted of sodium retention (Figure 6). As n e seen in Figure 6, ptient weights were slightly elevted from the men ontrol vlue (73.5 kg ± 4.1) throughout inptient dys 7 to 15. However, men weight inresed :5 0n 'I, 0 0.)_ X x C.._ s 0 v-x w I ±. L I rv! -. +-L I Time (min) Figure 4 Men (± s.e. men) urinry exretion of sodium fter the first fluriprofen dose (study 1, pnel ), nd fter 8 dys (study 2, pnel ) nd 27 dys (study 2, pnel ) of ontinuous dosing. mq min-' = mmol min-. Formt s in Figure 2.

7 Fluriprofen effets on renl funtion r r - CN w i J 1- + z L.. 20 t 50 L-, MC r d 55 r UJ w + r w 5.0 z ) U) (1HI"i 4 ~ ~ ~ ~ 1 11" i4 I I- I 4jH Study dy MC Figure 5 Men (± s.e. men) effets of hroni fluriprofen dosing on dily ptient retinine lernes (pnel ), urinry exretion of sodium (pnel, mq/24 h = mmol/24 h), serum sodium onentrtion (pnel, mq 1-1 = mmol 1-1), nd serum potssium onentrtion (pnel d, mq 1-1 = mmol 1-1). The men ontrol (MC) is the men result of mesurements mde on dys 4 nd 5, immeditely prior to the ptient's first fluriprofen dose. + ) further following ptient dishrge from the GCRC to mximum vlue of 76.3 ± 4.2 kg (+ 2.8 ± 0.4 kg) on dy 26, presumly refleting n inrese in dietry sodium intke in onjuntion with fluriprofen dministrtion. Following the disontinution of fluriprofen dministrtion on dy 33, ptient weights remined slightly ut signifintly higher thn the men ontrol vlue (dys 46 to 48.). Similrly, systoli nd distoli lood pressures were elevted in the outptient phse of the study (Figure 6 nd ). Systoli lood pressure rose from men ontrol vlue of mm Hg to pek of ± 6.5 mm Hg ( mm Hg) on dy 26 (pnel B) wheres distoli lood pressure rose from men ontrol of mm Hg to pek of 91.5 ± 3.5 mm Hg ( mm Hg) on dy 26 (Figure 6). Systoli nd distoli lood pressure diminished fter fluriprofen ws withdrwn (dys 46 to 48). Disussion Chroni renl insuffiieny my render renl hemodynmis nd eletrolyte homeostsis prostglndindependent. Upon dministrtion of NSAIDs to suseptile ptients with pre-existing renl disese, synthesis of renl prostglndins is redued or olished resulting in derements in renl funtion nd, independent of this hemodynmi effet, redued exretion of sodium nd potssium (Brter, 1988; Clive & Stoff, 1984). In suh ptients, NSAIDs my use ute ishemi insult to the kidney tht eomes linilly mnifest y inreses in serum retinine nd ure nitrogen. The effet on sodium resorption my use weight gin, oedem, nd inresed lood pressure. Lstly, the hyporeninemi-hypoldosterone effet my use hyperklemi (Tn et l., 1979). The degree to whih ptients with renl insuffiieny re suseptile to the effets of NSAIDs my depend upon sodium lne, the type nd extent of renl disese, nd the type of NSAID dministered. rlier studies ssessed the renl effets of NSAIDs in sodium deplete ptients with renl diseses therey onfounding the effet of the disese per se (Dunn & Zmrski, 1980). Reent studies hve employed ontrolled diet in whih ptients reeived fixed intkes of modest mounts of sodium (100 to 150 mq dy-1) nd potssium (60 to 80 mq dy-'). In severl suh studies of ptients with systemi lupus erythemtosus (SL) nd other hroni glomerulr diseses there ws liner orreltion etween glomerulr filtrtion rte nd prostylin synthesis (s determined using urinry exretion of 6-keto prostglndin Fl,) (Cittoni et l., 1984; Ptrono et l., 1985; Ptrono & Pierui, 1986). Renl funtion my lso deline with NSAID dministrtion to ptients with renl diseses used y hypertension or dietes suh s those in this study suggesting tht prostglndins re needed to mintin renl perfusion in this setting (Berg & Tlseth, 1985; Brter et l., 1985, 1987; riksson et l., 1990; Toto et l., 1986; Whelton et l., 1990.

8 392 M. D. Murry et l. - ) I m.2 n I 0- m n o ) 85 r F 1 f T go9t H1 _ MC MC MC Study dy Figure 6 Men (± s.e. men) effets of hroni fluriprofen dosing (dys 7 through 33) on dily ptient weights (pnel ), nd systoli nd distoli lood pressures (pnels nd ). The men ontrol (MC) ws lulted s in Figure 5. Fluriprofen used smll nd inonsistent derements in inulin nd retinine lerne mesurements tht were reversile within 3 h of dministrtion. Furthermore, omprison of the men ontrol lerne mesurements for studies 1, 2, nd 3 reveled lk of umultive derements with up to 27 dys of ontinuous fluriprofen dministrtion. These results re in greement with those of similr studies in whih the dministrtion of other NSAIDs ws 2 to 11 dys (Berg & Tlseth, 1985; riksson et l., 1990; Toto et l., 1986; Whelton et l., 1990) nd one study in whih the GFR of six ptients with hroni renl disese ws unffeted following 27 dys of ontinuous sulind dministrtion (Swinson & Griffiths, 1985). As suh, the results provided dded ressurne tht hroni dministrtion of fluriprofen up to 28 dys does not use umultive derements in GFR in ptients with moderte hroni renl insuffiieny. In ontrst to the modest effet of fluriprofen on GFR, sustntil redution in urinry exretion of sodium ws oserved tht rehed ndir t 4-5 h fter dosge dministrtion. Renl prostglndins re ntriureti, loking sodium resorption in the nephron y interfering with hloride trnsport ross the thik sending lim of Henle nd inresing renl medullry lood flow (Ikhikw & Brenner, 1980; Kojrern et l., 1983; Kirhner, 1985; Kokko, 1981). Upon dministrtion of NSAIDs, the ntriureti effet of prostglndins is diminished. Sodium retention nd/or redued response to diuretis re well desried result. Although none of the ptients who reeived fluriprofen experiened inresed oedem, net sodium umultion nd mild inreses in weight nd lood pressure ourred. In summry, dt from the lerne studies indite modest, reversile effet on renl hemodynmi prmeters, ut onsistent effet of fluriprofen in using deresed sodium exretion nd its ttendnt linil effets. Interestingly, there were different timeresponse profiles for the hemodynmi prmeters ompred with tht oserved for urinry exretion of sodium. This is presumly due to the existene of seprte omprtments for prostglndin effets, s hs een previously suggested y MGiff et l. (1979). The hemodynmi effet is proly due to vsulr endothelil prodution of PGI2, whih would e redily essed y irulting NSAID. In ontrst, the renl tuulr effet on sodium resorption is proly due to PG2, whih my e more remote from irulting NSAID. In terms of hroni effets of fluriprofen (Figures 5 nd 6), retinine lerne ws deresed y 18 to 24% on dy 7 nd 8 ompred with ontrol, inditing tht with hroni therpy there my e slight derement in retinine lerne. It is of interest tht on susequent dys there ws no deline in retinine lerne ompred with ontrol, inditing reovery of renl funtion with persistent dosing. Urinry sodium exretion ws deresed on dys 7, 9, nd 11 ompred with ontrol vlues nd this effet ws onsistent with tht oserved in the lerne studies, nmely, mild sodium retentive effet of the NSAID ssoited with the susequent weight gin nd lood pressure inrese with inresed dietry sodium (Figure 6). There were no signifint hnges in serum sodium onentrtion throughout the study. Lstly, serum potssium onentrtions were found to e slightly ut signifintly higher on dys 8, 10, nd 12 ompred with ontrol vlues. This effet is undoutedly due to the hyporeninemi-hypoldosterone syndrome known to our with NSAIDs (Brter, 1988; Clive & Stoff, 1984). The mgnitude of this elevtion ws not linilly relevnt. In onlusion, this study of the effets of fluriprofen in eight ptients with moderte renl insuffiieny indites trnsient effets on renl hemodynmis. There ws lso redution in urinry exretion of sodium with first nd susequent doses ssoited with weight gin nd inrese in lood pressure. An inrese in serum potssium lso ourred, whih returned to seline despite ontinued dosing. Thus, there ppered to e no overll hroni dverse effet of fluriprofen on renl funtion in these ptients. These findings re

9 Fluriprofen effets on renl funtion 393 onsistent with the lk of umultion of fluriprofen in suh ptients (Kndler et l., 1992). Additionlly, the effets were qulittively similr though somewht less thn those tht we hve oserved in similr studies of suh ptients dministered indomethin nd ketoprofen (Toto et l., 1986) nd etodol (Brter et l., 1985, 1987). This work ws supported in prt y NIH grnt DK37994, AG07631 nd grnt from the Upjohn Compny. Referenes Berg, K. J. & Tlseth, T. (1985). Aute renl effets of sulind nd indomethin in hroni renl filure. Clin. Phrm. Ther., 37, Brter, D. C. (1988). Clinil spets of renl prostglndins nd NSAID therpy. Semin. Arth. Rheum., 17 (Suppl. 2), Brter, D. C., Anderson, S. A., Brown-Crtwright, D., Toto, R. D., Chen, A. & Jo, G. B. (1985). ffet of etodol in ptients with moderte renl impirment ompred with norml sujets. Clin. Phrm. Ther., 38, Brter, D. C., Brown-Crtwright, D., Anderson, S. A. & Umnuihi, M. (1987). ffet of high-dose etodol on renl funtion. Clin. Phrm. Ther., 42, Brogden, R. N., Heel, R. C., Speight, T. M. & Avery, G. (1979). Fluriprofen: A review of its phrmologil properties nd therpeuti use in rheumti diseses. Drugs, 18, Cnnon, P. J. (1986). Prostglndins in ongestive hert filure nd the effets of nonsteroidl nti-inflmmtory drugs. Am. J. Med., 81 (Suppl. 2B), Cittoni, G., Cinotti, G. A., Pierui, A., Simonetti, B. M., Mnzi, M., Pugliese, F., Brsotti, P., Pei, G., Tggi, F. & Ptrono, C. (1984). ffets of sulind nd iuprofen in ptients with hroni glomerulr disese: evidene for the dependene of renl funtion on prostylin. New ngl. J. Med., 310, Clive, D. M. & Stoff, J. S. (1984). Renl syndromes ssoited with nonsteroidl nti-inflmmtory drugs. New ngl. J. Med., 310, Dunn, M. J. & Zmrski,. J. (1980). Renl effets of drugs tht inhiit prostglndin synthesis. Kidney Int., 18, riksson, L., Sturfelt, G., Thysell, H. & Wollheim, F. A. (1990). ffets of sulind nd nproxen on prostglndin exretion in ptients with impired renl funtion nd rheumtoid rthritis. Am. J. Med., 189, Ikhikw, I. & Brenner, B. M. (1980). Importne of efferent rteriolr vsulr tone in regultion of proximl tuulr fluid resorption nd glomerulotuulr lne in the rt. J. lin. invest., 65, Kojrern, S., Chennvsin, P., Anderson, S. & Brter, D. C. (1983). Nephron site of effet of nonsteroidl ntiinflmmtory drugs on solute exretion in humns. Am. J. Physiol., 244, F134-F139. Kirhner, K. A. (1985). Prostglndin inhiitors lter loop segment hloride uptke during furosemide diuresis. Am. J. Physiol., 248, F698-F704. Kndler, M. P., Hll, S. D. & Brter, D. C. (1992). Stereoseletive disposition of fluriprofen in uremi ptients. Br. J. lin. Phrm., 33, Kokko, P. (1981). ffet of prostglndins on renl epithelil trnsport. Kidney Int., 19, MGiff, J. C. & Wong, P. Y. (1979). Comprtmentliztion of prostglndins nd prostylin within the kidney: implitions for renl funtion. Fed. Pro., 38, Oliver, J. A., Si, R. R., Pinto, J. & Cnnon, P. J. (1981). Prtiiption of the prostglndins in the ontrol of renl lood flow during ute redution of rdi output in the dog. J. lin. Invest., 67, Ptrono, C., Cittoni, G., Remuzzi, G., Gotti,., Bomrdieri, S., Di Munno 0., Trtrelli G., Cinotti, G. A., Simonetti, B. M. & Pierui, A. (1985). Funtionl signifine of renl prostylin nd thromoxne A2 prodution in ptients with systemi lupus erythemtosus. J. lin. Invest., 76, Ptrono, C. & Pierui, A. (1986). Renl effets of nonsteroidl nti-inflmmtory drugs in hroni glomerulr disese. Am. J. Med., 81 (Suppl. 2B), Swinson, C. P. & Griffiths, P. (1985). Aute nd hroni effets of sulind on renl funtion in hroni renl disese. Clin. Phrm. Ther., 37, Tn, S. Y., Shpiro, R., Frno, R., Stokrd, H. & Mulrow, P. J. (1979). Indomethin-indued prostglndin inhiition with hyperklemi: A reversile use of hyporeninemi-hypoldosteronism. Ann. Intern. Med., 90, Toto, R. D., Anderson, S. A., Brown-Crtwright, D., Kokko, J. P. & Brter, D. C. (1986). ffets of ute nd hroni dosing of NSAIDs with renl insuffiieny. Kidney Int.,, Whelton, A., Stout, R. L., Spilmn, P. S. & Klssen, D. K. (1990). Renl effets of iuprofen, piroxim, nd sulind in ptients with symptomti renl filure. Ann. Intern. Med., 112, Winer, B. J. (1971). Sttistil priniples in experimentl design, 2nd edition. New York: MGrw Hill. Wright, H. K. & Gnn, D. S. (1966). An utomti nthrone method for the determintion of inulin in plsm nd urine. J. l. lin. Med., 67, Zipser, R. D., Hoefs, J. C., Spekrt, P. F., Zi, P. K. & Horton, R. (1979). Prostglndins: modultors of renl funtion nd pressor resistne in hroni liver disese. J. lin. ndorinol. Met., 48, (Reeived 16 July 1991, epted 1 Novemer 1991)