Mais les résultats doivent être attendus longtemps et il n'y a généralement pas de temps doxycycline prix L'autre cas, c'est que l'achat d'un ou d'un autre antibiotique dans une pharmacie classique nécessite des dépenses matérielles considérables et pas toutes les personnes ne peuvent acheter des produits pharmaceutiques aussi coûteux.

061396 effect of an enteric-coated fish-oil

Copyright, 1996, by the Massachusetts Medical Society EFFECT OF AN ENTERIC-COATED FISH-OIL PREPARATION ON RELAPSES
the 39 patients in the placebo group, 27 (69 percent) had may have periods of remission, interrupted by relapses.
relapses, 1 dropped out because of diarrhea, and 1 with- Because fish oil has antiinflammatory actions, it could re- drew for other reasons (difference in relapse rate, 41 per- duce the frequency of relapses, but it is often poorly tol- centage points; 95 percent confidence interval, 21 to 61; erated because of its unpleasant taste and gastrointesti- PϽ0.001). After one year, 23 patients (59 percent) in the fish-oil group remained in remission, as compared with 10 We performed a one-year, double-blind, pla- (26 percent) in the placebo group (Pϭ0.003). Logistic- cebo-controlled study to investigate the effects of a new regression analysis indicated that only fish oil and not sex, fish-oil preparation in the maintenance of remission in 78 age, previous surgery, duration of disease, or smoking sta- patients with Crohn’s disease who had a high risk of re- tus affected the likelihood of relapse (odds ratio for the pla- lapse. The patients received either nine fish-oil capsules cebo group as compared with the fish-oil group, 4.2; 95 containing a total of 2.7 g of nϪ3 fatty acids or nine pla- percent confidence interval, 1.6 to 10.7).
cebo capsules daily. A special coating protected the cap- In patients with Crohn’s disease in re- sules against gastric acidity for at least 30 minutes.
mission, a novel enteric-coated fish-oil preparation is ef- Among the 39 patients in the fish-oil group, 11 fective in reducing the rate of relapse. (N Engl J Med 1996; (28 percent) had relapses, 4 dropped out because of diar- rhea, and 1 withdrew for other reasons. In contrast, among 1996, Massachusetts Medical Society.
CROHN’S disease is characterized by remission and creases, and long-term treatment becomes feasible for relapse. The relapses are most likely to occur soon after patients enter remission and are more frequent in In this study, we investigated the effects of the new, those with abnormalities in serum concentrations of enteric-coated fish-oil preparation in the maintenance acute-phase proteins.1-3 Because fish oil has antiinflam- of remission in patients with Crohn’s disease.
matory actions, its use has been proposed in patients with several inflammatory diseases, including inflamma-tory bowel disease.4-8 However, its unpleasant taste and Between May 1992 and September 1993, patients treated in our outpatient clinic who had an established diagnosis of Crohn’s disease its side effects, which include flatulence, heartburn, hal- and were in clinical remission were evaluated for eligibility for this itosis, belching, and diarrhea, make it unacceptable to study with use of the Crohn’s Disease Activity Index.13 This index in- corporates eight items — the daily number of liquid or very soft We have found that the rate of absorption of the com- stools, abdominal pain, general well-being, extraintestinal manifesta-tions of Crohn’s disease, use of opiates to treat diarrhea, abdominal ponent nϪ3 fatty acids in fish oil is high when they are mass, hematocrit, and body weight — to yield a composite score administered in the form of a new, enteric-coated prep- ranging from 0 to 600. Higher scores indicate more disease activity.
aration, so that the dose needed to achieve the incorpo- Patients with scores of 150 or less are considered to have inactive dis- ration of fish-oil fatty acids into phospholipid mem- ease. The criterion for eligibility for our study was a score that had branes is one third of that used previously.12 As a result, been below 150 for at least three months but less than two years.
In addition to having a score below 150 on this index, the patients the frequency of side effects is reduced, compliance in- had to have at least one of the following: a serum a1-acid glycopro-tein concentration above 130 mg per deciliter (normal referencerange, Ͻ120 mg per deciliter), a serum a -globulin concentration From the Institute of Clinical Medicine and Gastroenterology (A.B., C.B., above 0.9 g per deciliter (normal reference range, Ͻ0.8 g per deci- M.C., M.M.) and the Department of Clinical Pharmacology (S.B.), University ofBologna, Bologna; and the Department of Gastroenterology, S. Giovanni Battista liter), or an erythrocyte sedimentation rate of more than 40 mm per Hospital, Turin (A.P.) — both in Italy. Address reprint requests to Dr. Belluzzi at hour (normal reference range, Ͻ20 mm per hour). Patients were ex- cluded if they were less than 18 or more than 75 years old, had re- Supported by Tillotts Pharma, Ziefen, Switzerland.
ceived mesalamine, sulfasalazine, or corticosteroids in the previous Downloaded from on January 9, 2008 . For personal use only. No other uses without permission. Copyright 1996 Massachusetts Medical Society. All rights reserved. three months or immunosuppressive drugs in the previous six months, Table 2. Clinical Results during Treatment with Fish or had undergone resection of more than 1 m of bowel in the past; Oil or Placebo in Patients with Crohn’s Disease in patients who had undergone less extensive resection were eligible only if they had had clinical and endoscopic or radiologic evidence of re-currence after surgery, with subsequent remission.
Of 89 potentially eligible patients, 78 were enrolled in the one-year study. The reasons for exclusion were a decision by the patient not to participate in the study (five patients), pregnancy or a desire to be- Outcome*
come pregnant (three patients), and inability to keep follow-up ap- The patients were randomly assigned to receive either three enter- ic-coated capsules of fish oil three times daily (Purepa, Tillotts Phar- ma, Ziefen, Switzerland) or three enteric-coated capsules of identical appearance containing 500 mg of placebo three times daily. The pla- Major symptoms in patients with
cebo used was Miglyol 812 (Dynamit Nobel Chemicals, Witten, Ger- many), a mixed-acid triglyceride of fractionated fatty acids made up of 60 percent caprylic acid and 40 percent capric acid. The fish-oil capsules each contained 500 mg of a new marine lipid concentrate in free-fatty-acid form (40 percent eicosapentaenoic acid and 20 percent docosahexaenoic acid; the remaining 40 percent was a mixture of nϪ7 fatty acids [17 percent], nϪ9 fatty acids [16 percent], and nϪ6 fatty acids [7 percent]), resulting in daily doses of 1.8 g of eicosapen-taenoic acid and 0.9 g of docosahexaenoic acid.
*Because of rounding, percentages do not total 100 for the placebo The capsules were specially coated (Eudragit NE 30D, Röhm, Darm- stadt, Germany) to resist gastric acid for at least 30 minutes but todisintegrate within 60 minutes, thus allowing the release of fish oil the fatty-acid phospholipid profile of the cells by gas chromatography, into the small intestine. The study medications were packed identical- ly and labeled with each patient’s code number according to a bal- The study was conducted in accordance with the Declaration of anced-block randomization scheme. There was no difference in odor Helsinki and approved by the ethics committee of the University of between the fish-oil and placebo preparations, provided the capsules Bologna and the clinical boards of the hospitals; all the patients gave were not broken. During treatment the patients took no other medi- All the patients were examined by two physicians on entry into the Statistical Analysis
study and at 3, 6, 9, and 12 months, or earlier if their symptoms wor- The differences in the rates of relapse and the proportions of pa- sened. Relapse was defined as an increase in the score on the Crohn’s tients remaining in remission in the fish-oil and placebo groups were Disease Activity Index to at least 100 points more than the base-line analyzed with the chi-square test. Differences between the groups in value and a score above 150 for more than two weeks. Compliance clinical findings and changes in laboratory results during the study was assessed by pill counts. At each visit, routine laboratory tests were were analyzed with the Mann–Whitney U test. Kaplan–Meier life- performed, including a blood count; measurement of the erythrocyte table curves were calculated for patients remaining in remission who sedimentation rate and serum creatinine, a1-acid glycoprotein, and were assigned to the two treatments.14 Differences in the curves were a -globulins; and liver-function tests. Before and at the end of the tested by log-rank analysis. Multivariate logistic-regression analysis study, 2 ml of packed red cells was obtained for the determination of was performed with treatment, sex, age, previous surgery, duration ofdisease, and smoking status as independent variables and with clinicalrelapse as the outcome variable.15 SOLO-BMDP Statistical Software Table 1. Base-Line Characteristics of 78 Patients with Crohn’s (version 3.0, BMDP, Los Angeles) was used for statistical analysis. All The characteristics of the 78 patients are shown in Ta- ble 1. There were no significant differences between the groups at base line. Among the 39 patients in the fish- oil group 11 (28 percent) had relapses, 1 patient moved away, and 4 dropped out because of diarrhea. Among the 39 patients in the placebo group, 27 (69 percent) had relapses, 1 patient moved away, and 1 dropped out be- cause of diarrhea (difference in relapse rates, 41 percent- age points; 95 percent confidence interval, 21 to 61; PϽ0.001) (Table 2). In all five patients who had diar- rhea, symptoms began within the first month of treat- ment and did not improve when the daily intake of cap- sules was reduced. There were no other side effects. The distribution of disease in the intestines of the patients who had relapses was similar to that in the group as a whole at base line. All patients who had relapses were treated with 0.75 to 1 mg of methylprednisolone per kil- Score on Crohn’s Disease Activity Index ogram of body weight daily for at least three weeks.
After one year of treatment, 23 of the 39 patients in the fish-oil group (59 percent) were still in remission, Downloaded from on January 9, 2008 . For personal use only. No other uses without permission. Copyright 1996 Massachusetts Medical Society. All rights reserved. ENTERIC-COATED FISH-OIL PREPARATION AND RELAPSES IN CROHN’S DISEASE ment of Crohn’s disease, since treatment with nϪ3 fat-ty acids decreases platelet responsiveness in patientswith this disorder.23 Fish oil may also induce enterocyte hyperplasia, thereby increasing the mucosal surface ar-ea, with a corresponding increase in enteral absorptionof nutrients and improvement of nutrition.24 There have been only two reported trials of fish oil in patients with Crohn’s disease. Matè et al.7 reportedthat remissions were more prolonged in patients who received a diet rich in fish oil for two years. By contrast,Lorenz et al.8 found that 1.8 g of eicosapentaenoic acid daily did not affect the clinical activity of the disease.
In our study, the patients receiving the fish-oil formulawere significantly less likely to have relapses than the patients receiving placebo. The patients had been in clinical remission for less than 24 months before the study, and all had some laboratory evidence of inflam-mation. Patients with these characteristics have about a Figure 1. Life-Table Curves Showing the Percentage of All Ran- 75 percent greater risk of relapse than those who have domized Patients Who Remained in Clinical Remission during been in remission longer and have normal laboratory- There were 39 patients in each group. Pϭ0.006 for the compar- ison of the two groups by log-rank analysis.
The coated fish-oil preparation we used has few gas- tric side effects, and patients’ level of compliance was as compared with only 10 of the 39 patients in the pla- high. Furthermore, the degree of absorption of the nϪ3 cebo group (26 percent, Pϭ0.003). Figure 1 shows the free fatty acids and of their incorporation into phospho- Kaplan–Meier life-table curves for patients remaining lipid membranes was high (Table 4); with other fish-oil in clinical remission (Pϭ0.006 by log-rank analysis).
preparations, in contrast, triglycerides and ethyl esters The multivariate logistic-regression analysis indicated require lipase activity for absorption.12,26,27 that only fish-oil treatment affected the likelihood of re- Ten percent of the patients in the fish-oil group lapse (odds ratio for relapse in the placebo group vs.
dropped out because they had diarrhea. This may have the fish-oil group, 4.2; 95 percent confidence interval, been due to the slower breakdown of the capsules and 1.6 to 10.7); sex, age, previous surgery, duration of dis- the resulting delivery of the contents to the distal part of ease, and smoking status were not significant determi- the gut. Disintegration of the coating requires 30 to 60 minutes; therefore, if the transit time is short, the cap- With regard to the laboratory tests for indicators of sules would remain intact further along the intestine.
inflammation, there was a significant decrease in all In several trials, treatment with mesalamine decreased such markers in the fish-oil group as compared with the the frequency of clinical relapse in patients with Crohn’s placebo group at the end of the study (Table 3). The disease.3,28-30 In these trials, mesalamine reduced the analysis of the main fatty acids in red cells from the pa- rate of relapse by 25 to 30 percent, as compared with tients who were still in remission at the end of the study placebo.31 In most of the trials, the rate of relapse in indicated the incorporation of nϪ3 fatty acids into the the placebo group ranged from 25 to 55 percent at 12 phospholipid membranes of patients given fish oil, dis-placing arachidonic acid almost completely (Table 4).
Table 3. Changes in Laboratory-Test Results during the Study, DISCUSSION
Fish oil has been suggested as a treatment for a vari- ety of chronic inflammatory disorders. Its antiinflamma-tory effect may be due to reduced production of leuko- triene B and thromboxane A ,16 which are elevated in the inflamed intestinal mucosa of patients with Crohn’s disease,17 or inhibition of the synthesis of cytokines such as interleukin-1b and tumor necrosis factor.18 It can In addition to inflammation, multifocal gastrointesti- nal infarction has been suggested as an early pathogen- ic event in Crohn’s disease20; its presence may indicate a pivotal role in the pathogenesis of platelets and pos- *Plus–minus values are means ϮSE. CI denotes confidence interval. The normal reference sibly thromboxane A , a powerful platelet-aggregating ranges are as follows: erythrocyte sedimentation rate, Ͻ20 mm per hour; serum a -globulins, Ͻ0.8 g per deciliter; serum a1-acid glycoprotein, Ͻ120 mg per deciliter.
agent.21 The capacity of fish oil to inhibit22 the produc- †PϽ0.001 for the comparison of the changes in the two groups.
tion of thromboxane A could be relevant to the treat- ‡Pϭ0.02 for the comparison of the changes in the two groups.
Downloaded from on January 9, 2008 . For personal use only. No other uses without permission. Copyright 1996 Massachusetts Medical Society. All rights reserved. Table 4. Changes in the Levels of Major Fatty Acids in Red Cells 6. Aslan A, Triadafilopoulos G. Fish oil fatty acid supplementation in active ulcerative colitis: a double-blind, placebo-controlled, crossover study. Am J from Patients Remaining in Remission at the End of the Study, 7. Matè J, Castaños R, Garcia-Samaniego J, Pajares JM. Does dietary fish oil maintain the remission of Crohn’s disease (CD): a study case control. Gas- troenterology 1991;100:Suppl:A228. abstract.
8. Lorenz R, Weber PC, Szimnau P, Heldwein W, Strasser T, Loeschke K. Sup- plementation with n-3 fatty acids from fish oil in chronic inflammatory bow- el disease — a randomized, placebo-controlled, double-blind cross-over tri- al. J Intern Med Suppl 1989;225:225-32.
9. Appel LJ, Miller ER III, Seidler AJ, Whelton PK. Does supplementation of diet with “fish oil” reduce blood pressure? A meta-analysis of controlled clinical trials. Arch Intern Med 1993;153:1429-38.
10. O’Connor GT, Malenka DJ, Olmstead EM, Johnson PS, Hennekens CH. A meta-analysis of randomized trials of fish oil in prevention of restenosis fol- lowing coronary angioplasty. Am J Prev Med 1992;8:186-92.
11. Donnelly SM, Ali MA, Churchill DN. Effect of n-3 fatty acids from fish oil on hemostasis, blood pressure, and lipid profile of dialysis patients. J Am 12. Belluzzi A, Brignola C, Campieri M, et al. Effects of new fish oil derivative on fatty acid phospholipid-membrane pattern in a group of Crohn’s disease patients. Dig Dis Sci 1994;39:2589-94.
13. Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn’s disease activity index: National Cooperative Crohn’s Disease Study. Gas- 14. Kaplan EL, Meier P. Nonparametric estimation from incomplete observa- tions. J Am Stat Assoc 1958;53:457-81.
*Plus–minus values are means ϮSE. Fatty-acid levels are expressed as relative percentages 15. Hosmer DW Jr, Lemeshow S. Applied logistic regression. New York: John of total fatty acids. CI denotes confidence interval.
†PϽ0.001 for the comparison of the changes in the two groups.
16. Lee TH, Hoover RL, Williams JD, et al. Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil andmonocyte leukotriene generation and neutrophil function. N Engl J Med months, but these percentages are not comparable to that in our study because of differences in the charac- 17. Rampton DS, Collins CE. Thromboxanes in inflammatory bowel disease — teristics of the patients. In a study of patients similar to pathogenic and therapeutic implications. Aliment Pharmacol Ther 1993;7:357-67.
ours, the relapse rate was 83 percent in the placebo 18. Endres S, Ghorbani R, Kelley VE, et al. The effect of dietary supplementation group and 62 percent in the mesalamine group after 12 with n–3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tu- mor necrosis factor by mononuclear cells. N Engl J Med 1989;320:265-71.
19. Fisher M, Upchurch KS, Levine PH, et al. Effects of dietary fish oil supple- Our results indicate that the new coated fish-oil prep- mentation on polymorphonuclear leucocyte inflammatory potential. In- aration is an effective, well-tolerated treatment that pre- 20. Wakefield AJ, Sawyerr AM, Dhillon AP, et al. Pathogenesis of Crohn’s dis- vents clinical relapses in patients with Crohn’s disease ease: multifocal gastrointestinal infarction. Lancet 1989;2:1057-62.
in remission. Its efficacy in relation to that of me- 21. Webberley MJ, Hart MT, Melikian V. Thromboembolism in inflammatory salamine, currently the standard treatment for the main- bowel disease: role of platelets. Gut 1993;34:247-51.
22. MacIntyre DE, Hoover RL, Smith M, et al. Inhibition of platelet function tenance of remission in patients with Crohn’s disease, by cis-unsaturated fatty acids. Blood 1984;63:848-57.
23. Jaschonek K, Clemens MR, Scheurlen M. Decreased responsiveness of platelets to a stable prostacyclin analogue in patients with Crohn’s disease: We are indebted to Marco Astegiano, M.D., Fernando Rizzello, reversal by n-3 polyunsaturated fatty acids. Thromb Res 1991;63:667-72.
M.D., Alessandra Munarini, B.D., Clarissa Belloli, M.D., Giuliana De 24. Vanderhoof JA, Park JHY, Herrington MK, Adrian TE. Effects of dietary Simone, M.D., Loris Pironi, M.D., and Roberta Roberti, M.D., for menhaden oil mucosal adaptation after small bowel resection in rats. Gas-troenterology 1994;106:94-9.
their continuous support of our research and to Professor Lloyd Suth- 25. Brignola C, Iannone P, Belloli C, et al. Prediction of relapse in patients with erland, Professor Alan Bennett, and Dr. Claudio Borghi for their help- Crohn’s disease in remission: a simplified index using laboratory tests, en- hanced by clinical characteristics. Eur J Gastroenterol Hepatol 1994;6:955-61.
26. el Boustani S, Colette C, Monnier L, Descomps B, de Paulet AC, Mendy F.
Enteral absorption in man of eicosapentaenoic acid in different chemicalforms. Lipids 1987;22:711-4.
1. Wright JP, Young GO, Tigler-Wybrandi N. Predictors of acute relapse of 27. Lawson LD, Hughes BG. Human absorption of fish oil fatty acids as tri- Crohn’s disease: a laboratory and clinical study. Dig Dis Sci 1987;32:164- acylglycerols, free acids, or ethyl esters. Biochem Biophys Res Commun 2. Brignola C, Campieri M, Bazzocchi G, Farruggia P, Tragnone A, Lanfran- 28. International Mesalazine Study Group. Coated oral 5-aminosalicylic acid chi GA. A laboratory index for predicting relapse in asymptomatic patients versus placebo in maintaining remission of inactive Crohn’s disease. Ali- with Crohn’s disease. Gastroenterology 1986;91:1490-4.
3. Gendre JP, Mary JY, Florent C, et al. Oral mesalamine (Pentasa) as main- 29. Prantera C, Pallone F, Brunetti G, Cottone M, Miglioli M, Italian IBD Study tenance treatment in Crohn’s disease: a multicenter placebo-controlled Group. Oral 5-aminosalicylic acid (Asacol) in the maintenance treatment of study. Gastroenterology 1993;104:435-9.
Crohn’s disease. Gastroenterology 1992;103:363-8.
4. Hawthorne AB, Daneshmend TK, Hawkey CJ, et al. Treatment of ulcerative 30. Brignola C, Iannone P, Pasquali S, et al. Placebo-controlled trial of oral colitis with fish oil supplementation: a prospective 12 month randomised 5-ASA in relapse prevention of Crohn’s disease. Dig Dis Sci 1992;37:29-32.
controlled trial. Gut 1992;33:922-8.
31. Messori A, Brignola C, Trallori G, et al. Effectiveness of 5-aminosalicylic 5. Stenson WF, Cort D, Rodgers J, et al. Dietary supplementation with fish oil acid for maintaining remission in patients with Crohn’s disease: a meta- in ulcerative colitis. Ann Intern Med 1992;116:609-14.
analysis. Am J Gastroenterol 1994;89:692-8.
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