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Home , Etodolac, Naproxen, Prostaglandin E, Prostaglandin E2, Salicylic acid

354 Annals ofthe Rheumatic Diseases 1990; 49: 354-358

Effect on gastric and duodenal mucosal of repeated intake of therapeutic Ann Rheum Dis: first published as 10.1136/ard.49.6.354 on 1 June 1990. Downloaded from doses of and in

A S Taha, S McLaughlin, P J Holland, R W Kelly, R D Sturrock, R I Russell

Abstract Etodolac is a member of a new class of The synthesis ofgastric and duodenal mucosal NSAIDs, the pyranocarboxylic acids; it has E2, prostaglandin I2, and been reported to be better tolerated by the B2 during a 60 minute incubation than naproxen," a of biopsy specimens, the degree of endoscopic derivative with established efficacy in arthritis, and histological damage, and the anti- but both agents were reported to have a inflammatory response were all studied after a comparable anti-arthritic activity.'2 An animal four week, double blind study of therapeutic study suggested that the different effect of these doses of two non-steroidal anti-inflammatory two agents on the gastric mucosa might be due drugs, naproxen and etodolac, received by 27 to the sparing of gastric prostaglandin synthesis patients with active rheumatoid arthritis (13 by etodolac. 3 receiving naproxen, 14 etodolac). Prosta- The purpose of this prospective, double glandin values after treatment did not differ blind, single centre study was to assess the from the baseline levels when all the patients effect of four weeks' treatment with therapeutic were analysed as one group. Subgroup analysis doses of naproxen or etodolac in patients with showed that naproxen suppressed gastric active rheumatoid arthritis on gastroduodenal from a median of 29 to 9 mucosal prostaglandin synthesis, anti-inflam- ng/mg protein, duodenal prostaglandin E2 matory activity, and endoscopic and histological from 34 to 11 ng/mg, and duodenal prosta- changes. glandin I2 from 62 to 15 ng/mg protein. No overall suppression occurred with etodolac. Also, on the second assessment patients Subjects, materials, and methods receiving naproxen had lower gastric and PATIENTS WITH RHEUMATOID ARTHRITIS duodenal prostaglandin E2 and prostaglandin The patients studied were 18-70 years with http://ard.bmj.com/ I2, but higher values ofduodenal thromboxane active rheumatoid arthritis according to the B2, than patients receiving etodolac. Both criteria of the American Rheumatism Associa- drugs had comparable anti-arthritic activity tion. Patients receiving second line agents-gold, and caused microscopic gastritis in similar penicillamine, or hydroxychloroquine but not proportions of patients. No correlation was sulphasalazine-were included if the drug treat- detected between prostaglandin values and ment had been started six or more months the mucosal damage which developed in before the start of the study and the doses had on September 25, 2021 by guest. Protected copyright. seven patients receiving naproxen (54%) and been unchanged for the last two months. three receiving etodolac (21%). Sulphasalazine was excluded because 5-10% of These findings indicate that, unlike its 5-aminosalicyclic acid component is ab- naproxen, etodolac does not seem to affect sorbed, which might affect prostaglandin pro- gastric or duodenal prostaglandin synthesis; duction, although there is no evidence for this. other mechanisms of injury need to be con- Subjects receiving NSAIDs underwent a wash- sidered. out period of at least five to seven days before receiving the study drugs, during which time Gastroenterology Unit, was used as an agent. Glasgow Royal Infirmary A S Taha It has been increasingly recognised that non- Preliminary work at our units showed that there S McLaughlin steroidal anti-inflammatory drugs (NSAIDs) was no significant difference in gastric or R I Russell and prostaglandins have opposite effects on the duodenal mucosal prostaglandin synthesis Centre for Rheumatic defensive mechanisms of the gastric mucosa. ' 2 between arthritic patients who had stopped Diseases, Glasgow Royal One theory suggests that NSAID induced receiving NSAIDs for four days and controls Infirmary R D Sturrock damage is due to suppression of mucosal prosta- who were not receiving NSAIDs. Patients with glandin Most knowledge in this abdominal complaints, a history of peptic ulcer- MRC Unit for synthesis.3' Reproductive Biology, field has come from animal work,3 5-7 or from ation, or any systemic diseases were excluded. Edinburgh studies of young, healthy, human volunteers Those taking cytotoxic agents, steroids, or ulcer P J Holland given single doses or short term courses of healing drugs were also excluded. R W Kelly or indomethacin.8 9 When patients with Correspondence to: were studied'0 basal values Dr A S Taha, rheumatic disorders Gastroenterology Unit, of the ability of gastroduodenal mucosa to STUDY DRUGS Royal Infirmary, Glasgow were not and Naproxen 500 mg twice daily and etodolac 300 G31 2ER, Scotland. synthesise prostaglandins known, was in Accepted for publication the precise nature of their disease not mg twice daily were given a double blind, 18 July 1989 adequately described. randomised design for a period of four weeks, Effect ofnaproxen and etodolac on prostaglandins in RA 355

with paracetamol used as a baseline analgesic. prostaglandin F ,, and respec- Compliance was checked by a tablet count. tively. Intra-assay variations were 14 8% for prosta- Ann Rheum Dis: first published as 10.1136/ard.49.6.354 on 1 June 1990. Downloaded from glandin E2, 11-0% for 6-oxo-prostaglandin F(, ASSESSMENTS and 5 0% for thromboxane B2. Inter-assay Assessments were made on two visits-just variations were 13 5-26% for prostaglandin E2, before the start of the study and on completion 13-0% for 6-oxo-prostaglandin Fl((, and 5-6% four weeks later. They included a general for thromboxane B2. Cross reactions of the anti- medical history and examination, assessment of sera were as follows: prostaglandin E2 (methyl- the activity of the rheumatoid arthritis, and oximation agent) antiserum with prostaglandin endoscopy. Rheumatoid disease activity was El 53%, prostaglandin E3 31%, prostaglandin assessed by measuring the erythrocyte sedi- B2 0-2%, 15-oxo-prostaglandin E2 0-25%. mentation rate, grip strength (mmHg), Ritchie 6-Oxo-prostaglandin Fl,, (methyloximation articular index, duration of morning stiffness, agent) antiserum with thromboxane B2 0-02%, and both the patients' and investigators' evalu- prostaglandin E2 0 01%, prostaglandin El ation of the global condition. Endoscopy was 0-01%. Thromboxane B2 antiserum with performed after giving 5-15 mg diazepam intra- 0-02%, 6-oxo-prostaglandin venously. Endoscopic abnormalities were graded El 0-02%, prostaglandin E2 0-02%. The sensi- according to a (0-5) scale modified from Lanza tivity of prostaglandin assays (as defined by the et al'4: 0= normal; 1 =any erythematous changes; amount distinguishable from zero with 95% 2 = submucosal haemorrhage; 3= single erosion; confidence limit) was 2 pg in all assays. Other 4=multiple erosions; and 5=frank ulceration. details of prostaglandin cross reactions, the Patients showing abnormal endoscopic find- sensitivity of prostaglandin assays, intra-assay ings at the initial visit were not admitted to the and interassay precisions have been described study. On both visits biopsy specimens weigh- previously.'8 The protein content of each ing 5-10 mg were taken from healthy looking biopsy specimen was measured,'9 and the mucosa in the gastric antrum and the first part results of prostaglandin synthesis are expressed of the duodenum for prostaglandin assays and in ng prostaglandin/mg protein after a total of for histology. All assessments were done under 60 minutes' incubation. double blind conditions. Suitable patients were given the study drugs within 12 hours of completing the initial assessment. STATISTICAL ANALYSES Statistical analyses were carried out with the Wilcoxon signed ranks and the Mann-Whitney HISTOLOGY tests, where appropriate. p Values of less than Specimens were fixed in formalin buffered 0-05 were regarded as significant. Correlation saline, embedded in paraffin wax, and S ,tm between prostaglandin values and endoscopic http://ard.bmj.com/ sections prepared for light microscopy. Sections scores was tested using Spearman's rank corre- were stained with haematoxylin and eosin. lation coefficient. Histological appearances were broadly divided Informed consent was obtained from patients, into mild or severe : mild inflam- and the study was approved by the local ethical mation referred to the presence of few inflam- committee. matory cells in the lamina propria, while severe inflammation meant that there was extensive inflammatory infiltration of the lamina propria, Results on September 25, 2021 by guest. Protected copyright. glands, and crypts.'5 Twenty seven patients completed the study; 13 (nine women, four men), median age 60 years, were found to have been receiving naproxen, PROSTAGLANDIN ASSAYS and 14 (10 women, four men), median age 50, Biopsy specimens were taken and immediately etodolac. Three furtherpatients were not entered frozen in liquid nitrogen and stored at -700C. into the study because their initial endoscopy Each specimen was later thawed, weighed, and was abnormal and two other patients dropped washed in 0 5 ml of phosphate buffer for five out before completing the study owing to minutes at room temperature to remove debris protocol violations. In the group receiving and prostaglandins induced by trauma. The naproxen six patients smoked, nine were receiv- supernatant was removed and specimens were ing second line drugs, and 10 had previous incubated at 200C for 30 minutes and at 37°C for exposure to NSAIDs, compared with seven, another 30 minutes. Fresh phosphate buffer eight, and 11 patients in the etodolac group (0 5 ml) was added at the start ofeach incubation respectively. Compliance was good and compar- step, and the supernatant removed at the end of able in both groups (median of 89% of naproxen each stage was mixed with an equal volume tablets and 87% of etodolac tablets provided (1: 1) of methyloximation agent,'6 left overnight were taken), though patients receiving etodolac at room temperature, and stored at 4°C until used less paracetamol. needed for radioimmunoassay. After incubation at 20°C the biopsy specimens were incubated at 37°C to stimulate further prostaglandin synthe- PROSTAGLANDIN SYNTHESIS sis. Prostaglandins were assayed in both in- Baseline values were similar in both groups. cubates separately and their values summated. When all rheumatoid patients were considered Prostaglandin I2 and were as one group there was no significant change in measured as their stable metabolites 6-oxo- gastric or duodenal prostaglandin values before 356 Taha, McLaughlin, Holland, Kelly, Sturrock, Russell

Table 1: Gastric and duodenal ,, median (interquartile ranges), nglmg protein, at baseline and after non-steroidal anti-inflammatory drug treatment

Subjects Baseline 4 Weeks Ann Rheum Dis: first published as 10.1136/ard.49.6.354 on 1 June 1990. Downloaded from Gastric Duodenal (Gastric Duodenal All rheumatoid patients (n=27) 29 28 20 19 (23-41) (17-39) (9-76) (10-33) Patients receiving naproxen (n=13) 29 34 9 11 (24-65) (21-39) (4-17) (6-16) Patients receiving etodolac (n= 14) 29 18 64 29 (16-35) (15-35) (21-101) (20-42) Significant drop: p

Table 2: Gastric and duodenal prostaglandin I2 (6-oxo-prostaglandin F,,), median (interquartile range), nglmg protein, at baseline and after non-steroidal anti-inflammatory drug treatment Subjects Baseline 4 Weeks Gastric D)uodenal Gastric D)uodenal All rheumatoid patients (n=27) 12 50 18 28 (8-17) (28-84) (2-37) (11-42) Patients receiving naproxen (n=13) 11 62 2 15 (7-14) (34-86) (1-27) (2-32) Patients receiving etodolac (n=14) 15 39 23 40 (9-18) (16-63) (13-42) (29-44) Significant drop: kp

Table 3: Gastric and duodenal thromboxane B,, median (interquartile ranges), nglmg protein, at baseline and after non-steroidal anti-inflammatory drug treatment Subjects Baseline 4 Weeks Gastric Duodenal Gastric Duodenal All rheumatoid patients (n=27) 33 36 38 31 (23-61) (21-41) (24-48) (20-41) Patients receiving naproxen (n=13) 35 36 40 35: (23-60) (28-45) (28-45) (27-42) Patients receiving etodolac (n=14) 33 27 34 22 (21-61) (21-38) (22-48) (14-41) Significant rise: 'p<0O05 (compared with etodolac). http://ard.bmj.com/ or after NSAID treatment. Significant differ- of rheumatoid disease activity; all variables ences became noticeable when patients were improved after treatment but not necessarily to classified according to whether they had received a significant degree, apart from the duration of naproxen or etodolac (tables 1-3); gastric prosta- morning stiffness (p<0001) and the articular glandin E2, duodenal prostaglandin E2 and index (p<005). The overall results indicate prostaglandin '2 were all suppressed by naproxen. that in this small group of patients naproxen Etodolac seemed to have no effect on prosta- and etodolac had similar anti-inflammatory on September 25, 2021 by guest. Protected copyright. glandin concentrations. In addition, compared efficacy. with etodolac patients on the second assessment, naproxen patients had lower gastric and duo- denal prostaglandin E2 and prostaglandin '2 but ENDOSCOPIC AND HISTOLOGICAL CHANGES higher values of duodenal thromboxane B2. The second endoscopy was abnormal in seven patients receiving naproxen (54%) with a median score of2 (0-4), (interquartile ranges), compared ANTI-ARTHRITIC ACTIVITY with three patients receiving etodolac (21%) and Table 4 shows the improvement in the indices a score of 0 (0-1) (p<0 05). Lesions developed

Table 4: Duration of morning stiffness, grip strength, articular index, and ervthrocvte sedimentation (ESR) bejore and after treatment: median and interquartile ranges Indices of activitv All rheumatoid patients Naproxen grroup Etodolac group (n=27) (n= 13) (n= 14) Baseline 4 Weeks Baseline 4 Weeks Baseline 4 Weeks Duration of morning stiffness (min) 60 30* 90 50* 60 30 (60-120) (5-60) (60-150) (17-90) (48-105) (12-55) Grip strength (mmHg) Right hand 74 83 74 102 76 81 (60-105) (65-135) (60-102) (60-154) (59-126) (71-120) Left hand 80 94 77 93 88 96 (68-116) (72-144) (65-129) (67-174) (67-130) (70-139) Articular index 13 8' 16 10 13 6 (10-19) (5-11) (10-22) (7-12) (9-18) (3-11) ESR 22 17 23 17 I 16 (7-39) (8-33) (10-36) (9-34) (7-41) (5-35) Significant improvement: *p

in the stomach in all 10 cases (seven naproxen, of this gastritis is unclear; it was not evident on three etodolac) but one patient receiving endoscopic examination and was only shown by naproxen had them in both the stomach and the histology. Ann Rheum Dis: first published as 10.1136/ard.49.6.354 on 1 June 1990. Downloaded from duodenum. Only three patients (naproxen) Possibly, agents like etodolac may be selec- developed upper abdominal complaints, and the tive in their effects on various tissues and rest were all asymptomatic. Prostaglandins were different types of prostaglandins. Such an effect not suppressed in the three patients with was previously described with , endoscopic abnormalities due to etodolac. As which caused preferential reduction in prosta- mentioned above, comparable numbers of glandin E2 in sheep vesicular tissue, whereas patients took other NSAIDs before receiving indomethacin suppressed all classes of prosta- either naproxen or etodolac. Prior exposure to glandins. NSAIDs did not seem to affect the side effects The fact that prostaglandins were not sup- due to the study drugs, possibly because of the pressed in patients who developed endoscopic washout period. Only seven patients (five abnormalities due to etodolac may mean that naproxen, two etodolac) out of 21 (33%) the mucosa recovered its capacity to synthesis previously receiving NSAIDs developed endo- prostaglandin before full healing of erosions, scopic damage on completion of the study. though we have not shown that such capacity Prostaglandin values in such patients were not was lost to begin with, or that mechanisms other significantly different from those of other than prostaglandin deficiency were involved in members of their respective groups. The causing gastric damage: in theory, these could number of patients with severe inflammation in include increased mucosal permeability,22 inter- their gastric biopsy specimens rose from three ference with active transport,23 redistribu- (23%) to 10 (77%) after taking naproxen, and tion of mucosal blood flow,24 capillary stasis,25 from four (29%) to 11 (79%) after etodolac or interference with the mucus layer.26 treatment. There was no correlation between Little is known about the duodenal mucosal prostaglandin values and the degree of gastric prostaglandin response to the intake of NSAIDs endoscopic damage (r=-013196 for prosta- as most studies have concentrated on their effect glandin E2, -013793 for prostaglandin 12, and on the gastric mucosa,3 5 6 8 9 possibly owing to -0-2339 for thromboxane B2 in the entire the fact that the stomach is more commonly population of rheumatoid patients). Also, no affected by NSAIDs than the duodenum as significant correction was found between the shown by this study and by others.27 Like one prostaglandin E2/thromboxane B2 ratio and the of the previous studies on patients with duo- endoscopic scores (r=-0-2495). Both gastric denal ulcers,28 our results may suggest that the and duodenal prostaglandin E2/thromboxane B2 duodenal mucosal potential to synthesise prosta- ratios were significantly higher in patients glandin I2 becomes limited in the presence of receiving etodolac than in those who took ulceration or when subjected to naproxen.

naproxen (p<0005). From these results it Duodenal prostaglandin E2 was also suppressed http://ard.bmj.com/ seems that there should be some form of in our patients taking naproxen, but not in negative correlation between endoscopic scores those of Hillier et al,28 the difference probably and prostaglandin E2/thromboxane B2 ratios as being due to the fact that their patients did not patients receiving naproxen appear to have take NSAIDs. It is also interesting to find that lower ratios and higher scores. This cannot be patients who took naproxen had higher values proved, however, as no correlations were signi- of thromboxane B2 (the stable metabolite of thromboxane than receiving etodolac. ficant. A2) those on September 25, 2021 by guest. Protected copyright. Animal studies have suggested that vaso- constriction with thromboxane A2 induces Discussion ulceration of the gastric mucosa,29 and that the This study shows that, unlike naproxen, etodolac selective inhibition of its synthesis results in does not suppress gastric or duodenal prosta- gastric mucosal protection.30 The effect of glandin synthesis. In this respect these results thromboxane A2 on the duodenal mucosa was disagree with most of the available data obtained not clarified by those studies. We found that from studies on gastric prostaglandins in patients both gastric and duodenal prostaglandin E2/ with rheumatic diseases or those receiving thromboxane B2 ratios were higher in patients regular NSAID treatment; such studies have taking etodolac than in those receiving shown that the NSAIDs tested do suppress naproxen. The significance of this is not fully gastric prostaglandins.'0 20 The effects of indi- clear but it may explain, at least in part, the vidual NSAIDs were not known in those greater damaging effects of naproxen, though reports, however, baseline prostaglandins were we could not show a significant correlation not measured, and the number of patients between the prostaglandin E2/thromboxane B2 taking the same agent was small. ratio and the endoscopic scores. Patients receiving naproxen had both a greater In conclusion, after four weeks of regular number of endoscopic abnormalities and lower intake in therapeutic doses, naproxen suppres- prostaglandin values. Possibly, these two events sed gastric prostaglandin E2, duodenal prosta- were interrelated, but we, like others, were glandin E2 and prostaglandin I2, while etodolac unable to show a correlation between the did not. At the same time etodolac caused a endoscopic scores and prostaglandin values. lesser degree of endoscopic damage than Gastritis20 does not adequately explain the naproxen; this may be related to their different sparing of prostaglandin by etodolac as inflam- effects on prostaglandins, though there was no mation was present in similar numbers of correlation between prostaglandin values and patients who took either agent. The significance endoscopic scores. If it is assumed that more 358 Taha, McLaughlin, Holland, Kelly, Sturrock, Russell

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