CURRICULUM VITAE

Education background
• 1984-1991 : Medical Doctor, University of Brawijaya
•Name
1997-2002 :: Internist specialist,
Hery Djagat Purnomo,Faculty
MD,ofSp.PD-KGEH
medicine University
of Diponegoro, Semarang)
• 2003-2008 : Gastroentero-hepatology consultant
• 2009-now : Program of Doctor (S-3), Faculty of medicine
University of Diponegoro Semarang.
Fellowship
• 2005 YCP World Congres Gastro, Montreal, Canada
• 2006 Observer Gastroenterology, Santo Thomas Hospital, Manila
• 2009 Training of Advanced Endoscopic Therapeutic, AIG,
Hyderabad, India
Work experiences
• 1992-1995 : Head of Puskesmas Ropang- Moyohulu,
Sumbawa NTB
• 1995-1996 : Medical Doctor in Jombang hospital
• 1997-2002 : Internist in Dr.Kariadi Hospital, Semarang
• 2003-now : Gastroentero hepatology Staff, Internal medicine
department, Dr.Kariadi hospital, Faculty of
medicine University of Diponegoro
• 2009-now : Secretary 0f Program Sp-2 Internist,In Dr Kariadi
Hospital, Diponegoro University.
Organization
• 1997-now : Member of IDI in Semarang
• 2002-now : Member of PAPDI in Semarang
• 2004-2007 : Secretary of PAPDI in Semarang
• 2010-now : Head of Indonesia probiotic study club.
 MANAGEMENT
GASTROPATHY NSAID:UPDATED

Hery djagat purnomo

Sub bagian gastroentero-hepatologi
Bagian Penyakit Dalam RSUP Dr Kariadi-FK UNDIP
Semarang

PIT PAPDI Semarang, 28 September 2012

Introductions
Causes of UGI bleeding
RS.Dr.Kariadi (2004-2005)

Causes Frequency Percentage

Variceal 44 65
Non Variceal 35
Esofagitis 8 12
Gastritis erosive 7 10.4
Chronic gastritis 1 1.5
Duodenitis erosive 2 3.0
Tumor
Esofagus 1 1.5
Gaster 4 6.0

Presented Poster,YCP WGO, Montreal Canada 2005

Etiology UGIB in Dr Kariadi Hospital
with different Ages (2008-2011)

14-45 years old 46-60 years old >60years old

Elderly had higher rate for ulcer than other groups (p=0.001)
Elyana, Hery Djagat P, Hirlan ,Proceeding Konas PGI-PEGI 2011
RISK FACTORS
 Risk factors for upper GI bleeding associated with NSAID use [13–15].

Risk factors for upper GI bleeding associated with NSAID use

Lanas A Rheumatology 2010;49:ii3-ii10

© The Author(s) 2010. Published by Oxford University Press on behalf of The British Society for
Rheumatology.
Patients at increased risk for NSAID GI toxicity
High risk
1. History of a previously complicated ulcer, especially recent
2. Multiple (>2) risk factors

Moderate risk (1 – 2 risk factors)

1. Age >65 years
2. High dose NSAID therapy
3. A previous history of uncomplicated ulcer
4. Concurrent use of aspirin (including low dose) corticosteroids
or anticoagulants

Low risk
1. No risk factors
H. pylori is an independent and additive risk factor and needs to be
addressed separately (see text and recommendations).
Am J Gastroenterol 2009; 104:728 – 738
H. Pylori infection increases the risk of NSAID –
related GI complication

Meta-analysis of 16 studies consisting of 1633 patients

100
OR 3.55
80
OR 3.53 HP+, NSAID+
60 OR 19.4
HP-, NSAID+
OR 18.1 HP+, NSAID-
40
HP-, NSAID-
20

0
HP+, HP-, HP+, HP-,
NSAID+ NSAID+ NSAID- NSAID-

Huang et al. Lancet 2002

10
Risk upper GI bleeding with NSAID’s and Coxib’s
Adjusted relative risk and 95% Cls
Drug 0.5 1 2 3 4 5 6 7 8 9 10 27
COXIBS 1.6
Celecoxib
Rofecoxib
1.6
Paracetamol
1.7
Metamizole

Diclofenac 2.5
Ibuprofen 3.8
Meloxicam 8.3
Naproxen 10.5
Ketorolac 10.5
Piroxicam 12.7

Lanas & Garcia Rodriguez, Gastroenterology 2003 (Abst)

PATHOGENESIS
Cellular and molecular pathogenesis NSAI
induced ulcer
The proposed pathophysiology of NSAID –induced
small intestinal mucosa injury
Clinical Diagnosis
 CLINICAL MANIFESTATION OF
NSAID GASTROPATHY

• No symptom
• Dyspepsia: epigastric pain, epigastric
discomfort, bloating, early satiety,
vomitus, nausea, belching etc
• Upper GI bleeding
• Stricture/stenosis
• Acute abdomen: perforation
• Fatigue, Anaemia
16
GI Lesions due to NSAID
(GASTROPATHY NSAID)
 Incidence of small bowel mucosal breaks, assessed by video capsule endoscopy, in two
randomized, placebo-controlled studies comparing celecoxib, 200 mg twice daily, with the
combination of a non-selective NSAID and omeprazole in healthy volunteers [32, 33].

Lanas A Rheumatology 2010;49:ii3-ii10

© The Author(s) 2010. Published by Oxford University Press on behalf of The British Society for
Rheumatology.
ASA-Induced small intestinal
mucosal breaks (ulcers).
Traditional NSAIDs-induced
diaphragm-like stricture
Most patient with nonselective NSAID-related
GI complication are asymptomatic
Symptomatic
Asymptomatic

58%
81%

Amstrong, Blower, 1987 Sing et al, 1966

UK Epidemiologic study (1) US cohort study (2)

Please Remember!
More than 25% Peptic Ulcer due to NSAID are painless
1. Gut, 1987: 28:527-532: 2. Arch Intern Med 1966156:1530-1536
21
 Gastrointestinal Side Effects
due to non-selective NSAID’s
Complications
1-2%

Ulcers
Dispepsia 15-30%
No Lession 25-50%

Graham, Ann Intern Med 1993; 119: 257

Langman et al, Lancet 1994; 343: 1075
Gastropathy NSAID in Elderly Larkal et al, J Clin Gastroenterol 1989; 11: 158
* 30-40% asymtomatic acute lessions Silverstein, Ann Intern Med 1995; 123: 241

* 60% asymtomatic ulcer bleeding

Management
 Advantages and disadvantages of different
pharmacological approaches
Regiment Principle Advantage Disadvanted
Mechanism
A) Prostaglandin Effective GI adverse event,
Classical NSAID substitution Inefective prevent
+Misoprostol dyspepsia
Dosis 3x/day
Classical NSAID + PH >> Effective Possibly acc
PPI (antioxidant, (dyspepsia, ulcer, corpus gastritis in
antiapoptosis) ass complic) HP pts
Min adv event -
PPI
Selective Cox -2 Sparing Effective in redc Lack
inhibtr gastroprotective dyspepsia, ulcer gastroprotective +
and ass cmplc aspirin
Lack anti platelet
effect/
protrombotic
effect
Regiment Principle Advantage Disadvanted
Mechanism
B) Abrogation of cheap Benefit not
Enteric coating topical damage proven
form effect
Classical NSAID + Antioxidant No adverse effect No data large
Vit C properties Cheap studies outcome
available
C) Slow release Physiology Lack of clin data
Non NSAID gastroprotective concept, GI event,
NO (antiapoptosis anti inflam, anti
effect) trombotic Effect
Cox/ 5 –Lox inhib Inhib leukotrien Maintenance GI, Lack of clin data
even + aspirin,
anti trmbotic efect
 Novel therapeutic approach againts NSAID
induced gastrointestinal mucosal injuries
should include agents that prevent the
uncoupling oxidative phosphorylation of
mitochondria in epithelial cells.
Diagrammatic representation of gastric mucosal defen

Gastroenterologia Polska 2010,

17 (3): 171-179
 Biological Effect of Prostaglandin
(PGE & PGI) in Gastric Mucosal

  blood supply in gastric/duodenal mucosal.

  mucous secretion.
  bicarbonate secretion.
 Decreases back diffusion of hydrogen Ion (H+).
  cell proliferation & gastric mucosal
regeneration

28
 PREVENTION OF GASTROPATHY NSAID

• The best: avoid NSAIDs

• Change to non-opiate analgetic (paracetamol) or
COX-2 selective NSAID
• Combination classical NSAID + Cytoprotector
• Prophylactic therapy especially in high risk
patient
• If the H. pylori infection present, eradicating
therapy should be given
29
 “Prevention of NSAIDs-induced ulcer”

 Misoprostol
PPI

- Attention : interaction with clopidogrel
Selective COX-2 inhibitors

- Attention : CV risk
H2RA ( not recommended)
×
- should be double dose
- attention: masking effect
Sucralfate ( not recommended)
×
- For short term used only

- Attention : Interaction

× Antacids ( not recommended)

- For short term used only

- Attention : Interaction
Frank L. Lanza MD FACG. The American Journal of Gastroenterology, 2009
Jan C. Becker et all. British Journal Clinical Pharmacology, 2004
30
 Role of REBAMIPIDE ???
Rebamipide, an amino acid derivative of
2(1H)-quinolinone, is used for mucosal
protection, healing of gastroduodenal ulcers,
and treatment of gastritis

Gastroprotector with GI Anti-Oxidative & Anti-Inflammatory

Properties

31
 Rebamipide Mechanisms of Action
 prostaglandin synthesis
Kleine A, et al：Dig Dis Sci 1993；38：1441-9
 mucus glycoprotein synthesis
Ishihara K, et al：Arzneim-Forsch/Drug Res 1992；42
oxygenfree radicals
Naito Y, et al：Free Radical Biol Med 1995；18：117-23
Yoshikawa T, et al：Arzneim-Forsch/Drug Res 1993；43
Han BG, et al：Pharmacol Res 1995；32：201-7
 neutrophil activity
Yoshida N, et al：Dig Dis Sci 1996；41：1139-44
Murakami K, et al：Dig Dis Sci 1997；42：319-25
 inflammatory cytokines
Aihara M, et al：Dig Dis Sci, in press
Fukuda T, et al：J Gastroenterol Hepatol 1997；12(suppl.)
Tetsuo Arakawa, MD, DMSc, FACG, AGAF. 2008, Professor and Chairman, Dpt. of
Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
32
 Classical NSAID

Inhibition of cyclo-oxygenase

Altered inflammatory mediator production

COX 2 COX 1
 
5-LOX 2

Proinflammatory PG  Gastroprotective PG 
Leukotrienes  Proinflammatory Mediators 
Inflammation  Mucus production  (TNF , ----)
Pain  Bicarbonase release 
Gastric acid secretion 
Blood flow  Apoptosis 
Leukocyte adherence activation  Inflammation 
Vasocontriction  Inflammation 
others........... Leukocyte adherence activation 
Leukocyte adherence activation 
Post-capilary venule leakage others...........
others...........

Microvascular pertubation
& free radical release

G A S T R I C M U C O S A L I N J U RY

Rebamipide Jan C. Becker et al. British Journal Clinical Pharmacol.2004

33
Publication Paper Related Efficacy Rebamipide in
Prevention of NSAID Gastro-Enteropathy

34
All Subjects Rebamipide Misoprostol OR (95%CI) p value
n = 176 n = 156

Gastric Ulcer 7 (3.9%) 3 (1.9%) 0.47 (0.10-1.73) 0.2847

Duodenal Ulcer 1 (0.5%) 4 (2.5%) 4.60 (0.67-90.54) 0.1741
All Peptic Ulcer 8 (4.5%) 7 (4.4%) 0.98 (0.33-2.81) 0.9796
MLS 0/1/2 99/25/23 (83.5%) 102/26/12 (89.7%) 0.2284
MLS 3/4/5 18/4/7 (16.5%) 13/0/3 (10.3%

High-risk Rebamipide Misoprostol OR (95%CI) p value

Subjects n = 151 n = 154

Gastric Ulcer 5 (3.3%) 3 (1.9%) 0.38 (0.05-1.81) 0.2574

Duodenal Ulcer 1 (0.7%) 4 (2.6%) 4.60 (0.58-78.68) 0.2174
All Peptic Ulcer 6 (4.0%) 6 (3.9%) 0.98 (0.30-3.19) 0.9723

Park, S-H et al. J Clin Biochem Nutr, 2007;40:148-15535

 STORM Study: Study of Rebamipide Vs Misoprostol

Rebamipide and Misoprostol are equally effective, but better safety profile
in the prevention of NSAID Gastropathy

Classic NSAID MLS 0/1/2 MLS 3/4/5

+ Rebamipide 83.5% 16.5% Statistically
100 mg tid, 12 wk’s
Peptic Equal
Ulcer 4.5% p = 0.22
+ Misoprostol
200 ug tid, 12 wk’s
83.5% 10.3% CI 95%
Peptic
Ulcer 4.4%
P=0.0001 P=0.0228 P=0.0029

21.2 20.7
20%
14.8
Better
10.1 Safety
10%
7.7 Profile
1.9

Diarrhea Lower Abdominal Pain Abdominal Bloating

Park, S-H et al,,J Clin Biochem Nutr, 2007;40:148-155
36
 How to prevent NSAIDs-ulcer
Old fashion
Prevention of GU (& DU)
•acid-related: PPI
•PG-deficiency: PG derivatives

New fashion
Prevention of ulcers in whole GI tract
•PG-deficiency: PG derivatives
•inflammation-related: Rebamipide)
Tetsuo Arakawa, MD, DMSc, FACG, AGAF. Professor and Chairman,
Dpt. of Gastroenterology Osaka City University Graduate School of Medicine, Osaka, Japan

37
Yamamoto , J Clin Biochem Nutr. 2010 July; 47(1): 27–31.
In conclusion,
These results show the possible gastroprotective
effects of rebamipide, suggesting that it may be
a good choice in aspirin users with
gastroduodenal toxicity that is not suppressed by acid
suppressants alone.
Rebamipide, a mucoprotective drug, inhibits
NSAIDs-induced gastric mucosal injury: possible
involvement of the downregulation of 15-
hydroxyprostaglandin dehydrogenase

Tetsuya Tanigawa,1* Toshio Watanabe,1

Fumikazu Ohkawa,2 Yuji Nadatani,1 Koji
Otani,1 Hirohisa Machida,1 Hirotoshi
Okazaki,1 Hirokazu Yamagami,1 Kenji
Watanabe,1 Kazunari Tominaga,1 Yasuhiro
Fujiwara,1 Koji Takeuchi,2 and Tetsuo
Arakawa1

J Clin Biochem Nutr. 2011 March; 48(2): 149–153.

The effect of rebamipide on Cox1-Cox-2 and
15 –PGDH mRNA expression on the gastric tissue

Mice were given rebamipide 30 0r 100 mg/kg/oral and kill 4 h later .

Data as presented as mean  SD for 4-6 mice

Tanigawa, J Clin Biochem Nutr March 2011 vol 48 no 2, 149-153

The effect of rebamipide on a) PGE2 synthesis
and b) PGE2 levels in the gastric tissue

Tanigawa, J Clin Biochem Nutr March 2011 vol 48 no 2, 149-153

Small Bowel Tissue Concentration of Rebamipide: Study of
Two Dosages in Healthy Subjects
Taiji Akamatsu,1* Tadanobu Nagaya,2 Shinya Ichikawa,2 Takamori Sudo,2 Ryutaro
Takeda,2 Kazuhiro Takenaka,1,2 Ryo Kodama,2 Tetsuya Ito,2 Norikazu Arakura,2 and Eiji
Tanaka2

In conclusion, the COR level in the jejunum was sufficient to

protect for NSAID-induced gastrointestinal complications.

J Clin Biochem Nutr. 2010 November; 47(3): 256–260.

 Take home message
• Some of GI lesion due to NSAIDs was asymptomatic
• NSAID induced GI mucosal injury, not only in stomach and
duodenum, but in small intestinal as well
• Identification of risk-factors and initiation of appropriate
preventive therapy are the keys to minimizing the societal burden
of this disease.
• Clinical approach in the management of Gastroenteropathy
involving non pharmacological and pharmacological approach
such as select more tolerable NSAID, risk factors management (ie
Hp eradication), prophylactic with gastroprotective agents
• Rebamipide is one of the effective drugs for management of GI
lesion due to NSAID
45