GASTROENTEROLOGY 2008; 134 :688–695 소화기내과 R4 이 재 연

PPARc AS A NEW THERAPEUTIC TARGET IN INFLAMMATORY BOWEL DISEASES Gut 2006;55:1341–1349.

Background  Thiazolidinedione (TZD) : anti-diabetic drugs, ligands for the PPARγ  Available evidence suggests a potential anti-inflammatory effect of PPAR ligands, Including TZDs, particularly in the colon  Tx with PPAR ligands (synthetic agonist) :  ↓  ↓ inflammatory cytokine production (eg, IL-1 & TNF-α)  ↓  ↓ inflammatory cell proliferation  ↓  ↓ expression of selected adhesion molecules

 OBJECTIVES  Previous research ~ ligands for PPARγ reduce inflammation in two different murine models of colitis   potential efficacy of rosiglitazone, as a Tx for active UC  METHODS  15 pts with mild to moderately active UC despite therapy with 5-ASA,an open-label study of rosiglitazone (4 mg b.i.d. p.o.) for 12 wks 13/15 pts were receiving concomitant therapy with corticosteroids and/or immunomodulator medications  RESULTS  clinical remission - 4 (27%)  endoscopic remission - 3(20%)  clinical response without achieving remission - 4(27%)  hospitalized with worsened disease activity- 2(13%)  withdrawn for nephrotic syndrome - 1 (7%)

Materials and Methods  Design  randomized, double-blind, placebo-controlled clinical trial  compared the efficacy of rosiglitazone (Avandia) 4 mg or placebo p.o. bid for 12 wks in 105 pts with mild to moderately active UC  Participants  Mild to moderate dis. activity was defined as a Mayo score of 4–10, inclusive  Evaluation Schedule  flexible sigmoidoscopy (or colonoscopy) within 30 days before randomization (90% within 3 days before randomization) and again at the week 12 f/u visit  Patients were seen at the clinical centers for f/u evaluation after randomization at weeks 2, 4, 8, 12, and 14

primary outcome Decrease ≥ 2- point in the Mayo score from baseline at week 12 Secondary clinical outcome decrease of ≥ 3 points in the Mayo score clinical remission (week 12 Mayo score, ≤ 2) endoscopic remission (week 12 Mayo score, <2; endoscopic score, 0)

Eligible patients mesalamine compounds at a dose of ≥ 2000 mg/day for at least 4 wks immediately before randomization or to have documented intolerance to such Tx Steroids : prednisoprednisone ≤ 20 mg/day, budesonide ≤ 9 mg/day, or the equivalent  permitted if the dose was stable for a minimum of 4 wks before randomization azathioprine or 6-mercaptopurine  permitted if the dose was stable for a minimum of 2 month before randomization Rectally administered corticosteroids or mesalamine  permitted if the dose was stable for a minimum of 2 wks before randomization The dose of concomitant medications could not be increased above baseline during the study. Steroid tapering was not allowed. Use of antidiarrheal medications was not permitted. Exclusion Infectious colitis pregnant or breast feeding liver disease, abnormal LFT CIx to flexible sigmoidoscopy or Bx NYHA class III or IV heart failure active malignancy other than nonmelanoma skin cancer DM requiring medications

Result

primary and secondary outcomes at week 12 *P.03; †P.01 improvement in the partial Mayo score (decrease, ≥ 2 points from baseline) *P.03; †P.049; #P.06 Improvement in QOL (IBD Questionnaire Increase, ≥ 16 points) after Tx ‡P.04 Improvement(> 1 points) in the individual Components of the Mayo score *P.04; †P.03; ‡P.01

> <

Discussion Rosiglitazone : most common side effects were weight gain and edema -some Wt gain could result from improvement in dis. Activity -average Wt gain in 12 weeks of rosiglitazone Tx was less than 2 kg Other than worsening UC, serious adverse events were uncommon anti-diabetes mechanism of Rosiglitazone : increased sensitization to insulin rather than increased insulin secretion, in the absence of other diabetes Tx, hypoglycemia is not anticipated from treatment with TZD PPARγ ligands No cases of symptomatic hypoglycemia were reported as adverse events

Discussion Pts in this study received only 12 weeks of Tx. As such, these data cannot be considered to establish long-term safety among patients with UC who may have an increased risk of colon cancer and fracture in animal models, TZDs may either promote or inhibit the development of colonic neoplasia  but, to date, 2 epidemiologic studies in non-UC pts with T2DM suggest that TZDs do not increase the risk of colon cancer in human beings Mesalamine (5-aminosalicylic acid) induced PPARγ expression  The greater affinity to PPARγ of rosiglitazone than mesalamine potentially could allow for efficacy among pts treated inadequately with mesalamine

PPARc AS A NEW THERAPEUTIC TARGET IN INFLAMMATORY BOWEL DISEASES Gut 2006;55:1341–1349.

Conclusions  Short-term Tx with rosiglitazone 4 mg twice daily for 12 weeks was well tolerated and resulted in higher rates of clinical response and clinical remission than placebo for patients with mild to moderately active UC  Tx with rosiglitazone should be limited to pts who have either failed or are intolerant of standard Tx  Tx with rosiglitazone should not be used in patients with liver disease, CHF, or in those at particularly high risk for MI