INTESTINAL DISEASE MEETING BERLIN Topical steroids rectal application

Transcription

1 INTESTINAL DISEASE MEETING BERLIN 2006 Topical steroids rectal application Prof. Dr. med. T. Andus Department of Internal Medicine, Gastroenterology, Hepatology, and Oncology Krankenhaus Bad Cannstatt, Prießnitzweg 24, Stuttgart

2 Topical steroids rectal application 1. Why topical steroids? 2. What are topical steroids? 3. Efficacy of rectal topical steroids 4. Topical steroids rectal application: How?

3 Corticosteroids Pleiotropic actions Anti-inflammatory actions Cortisol ACTH Metabolic actions Cortisol Inflammatory cells 90% bound to transcortin receptos / cell Affinity: 30 nmol/l (~ conc. in blood) Neg. feed back receptor-regulation Andus-T: Corticosteroids in Gastroenterology In: Kaiser: Corticosteroids 2002

4 Corticosteroids Side effects Doctors view Tromm-A et al. In: Möllmann & May. Glucocorticoid Therapy in Chronic IBD 1996

5 Corticosteroids side effects Patients view Sometimes the treatment can be worse than the disease itself! J Minchew: Patients view, Falk Symposium 132, Freiburg 2002

6 Ulcerative colitis - Localisation of disease 7.3% 22.5% 70.2%. Proctosigmoiditis (70.2%) Left-sided colitis (22.5%) Pancolitis (7.3%) Jiang-XL, et al. World J Gastroenterol. 2002:

7 Topical steroids rectal application 1. Why topical steroids? Side effects of systemic steroids Lokalisation of disease 2. What are topical steroids? Pharmacological mechanisms 3. Efficacy of rectal topical steroids 4. Topical steroids rectal application: How?

8 Glucocorticoids Chemical modifications Cortisone 2 O O 1 A HO H 11 C H B H H O C CH 3 D C H OH 2 O H Cortisole 11β, 17α, 21-Trihydroxypregn-4-en-3, 29-dion Prednisolone O O 2 1 HO H H 6 H CH 3 C CH 3 H CH OH 2 OH 6-Methyl-Prednisolone Dexamethasone O HO 9 H F H H O C CH 3 CH OH 2 OH CH 3 Kaiser: Kortisontherapie 2002

9 Topical steroids used in IBD Budesonide Budenofalk, Entocort Edsbäcker-S et al.: Drug Metab Dispos 1983: 590

10 Budesonide Biotransformation to inactive metabolites First pass effect (Similiar mechanisms for fluticasone, and tixocortol) Cytochrome P450 3A Ryrfeldt-A 1982, Jönsson-G 1995, Möllmann-HW 1996

11 Topical steroids used in IBD Fluticasone proprionate Tixocortol pivalate

12 Topical steroids used in IBD Beclomethasone dipropionate Clipper Cleaved to active metabolite beclomethasone monopropionate by esterases Edsbäcker-S et al.: Drug Metab Dispos 1983: 590

13 Rectal treatment by enemas How far do they reach? Hydrocortisone acetate Colifoam Budesonide Budenofalk Jay-M et al. Dig Dis Sci 1986 Brunner-M et al. Aliment Pharmcacol Ther: 2005

14 Topical steroids rectal application 1. Why topical steroids? Side effects of systemic steroids Lokalisation of disease 2. What are topical steroids? Pharmacological mechanisms 3. Efficacy of rectal topical steroids 4. Topical steroids rectal application: How? Foam versus enema

15 Rectal Budesonide enemas in active distal UC Dose response 2 mg and 8 mg are effective > 90% had normal ACTH-test Hanauer-SB et al.: Gastroenterology 1998

16 Budesonide versus Conventional Steroids Rectally Meta-Analysis Comparable efficacy to conventional corticosteroids Less endogenous cortisol suppression Marshall-JK & Irvine-EJ: Gut 1997 Hammond-A et al.: Hepatogastroenterology 2004

17 Budesonide versus mesalamine rectally Budesonide (Entocort ) enema 2 mg/100 ml versus 5-ASA enema 1 g/100 ml (n=97) Rate of remission: 38% vs. 60% (p=0.03) No difference: endoscopy, histopathology and side effects Budesonide (Budenofalk ) foam 1 mg/50 ml versus 5-ASA enema 4 g/60 ml (n=33) Total response: 67% vs. 71% (n.s.) No difference: endoscopy, histopathology side effects Lemann-M et al. Aliment Pharmacol Ther 1995: Rufle-W et al. Z. Gastroenterol 2000:

18 Topical Treatment of Distal UC Beclomethasone Dipropionate 3 mg (n=111) or Mesalamine 1g (n=106) A Single-blind Randomized Controlled Trial Gionchetti-P et al.: J Clin Gastroenterol 2005

19 Beclomethasone dipropionate (3mg) versus 5-ASA (2 g) versus both as retention enemas in active distal UC MRDB Placebo-controlled study: 60 pat.; <20 cm disease, 4 wks. 120% 100% 80% 60% 40% 20% 0% Clinical improvement in % of patients 70% 76% 100% Clinical improvement steroid 5-ASA both CJ Mulder: Eur J Gastroenterol Hepatol 1996;8:549-53

20 Topical steroids rectal application 1. Why topical steroids? Side effects of systemic steroids Lokalisation of disease 2. What are topical steroids? Pharmacological mechanisms 3. Efficacy of rectal topical steroids 4. Topical steroids rectal application: How? Foam versus enema

21 Budesonide vs. Hydrocortisone Acetate Foam for Active Distal UC Randomized, open, parallel-group, active-controlled, multicenter clinical trial (n=251) Budenofalk 2 mg / 20 ml versus Colifoam 100 mg / 15 ml Remission: 53% vs. 52%; Low plasma cortisol in 3% and 0% Even successful in mesalamine failures: 52% (Bud) vs. 37% (HC) Bar-Meir-S et al.: Dis Colon Rectum 2003

22 Budesonide foam versus enema in active distal UC Double-blind, double-dummy, randomized, multicentre study (n=533) Budenofalk foam 2 mg / 25 ml vs. Entocort enema 2 mg / 100 ml Remission: 60% vs. 66% 84 % vs. 6% of patients preferred Budenofalk foam Gross-V et al.: Aliment Pharmcol Ther 2006

23 Topical steroids rectal application Summary 1 1. Why topical steroids? Because of the side effects of systemic steroids Lokalisation of disease 2. What are topical steroids? Low bioavailability: Beclomethasone High first pass effect: Budesonide, Tixocortol, Fluticasone

24 Topical steroids rectal application Summary 2 3. Efficacy of rectal topical steroids As effective as mesalamine and systemic steroids Less side-effects than systemic steroids Due to cost and efficacy: first choice for 2 nd line 4. Topical steroids rectal application: How? Foam and enema similar efficacy Foam preferred by 84% of patients

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