1. Prevention of NSAID induced gastropathy by Mucosta

2. Major Pathophysiologic Factors of PUD
Helicobacter pylori
NSAID-induced injury
Acid secretory abnormalities

3. Singh et al.Arch Intern Med.
Most patients are asymptomatic
Peptic ulceration with NSAIDs typically causes no symptoms.
N = 141
N = 1,921
with
Symptoms
19%
with
Symptoms
42%
Without
Symptoms
81%
Without
Symptoms
58%
Asymptomatic GI complications have been reported to be at 58% to 81% in patients taking NSAIDs
Singh et al.Arch Intern Med.
1996; 156:
Armstrong, Blower.
Gut. 1978; 28:
* Bleeding, perforation, and gastric outlet obstruction
Ref.> Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 8th edition. Vol p

4. Cause of death: NSAIDs Toxicity
US mortality data in 1997
15th cause of death in USA
20,197
25,000
20,000
15,000
10,000
5,000
Number of deaths
16,685
16,500
10,503
5,338
4,441
1,437
NSAIDs toxicity
AIDS
Leukemia
Asthma
Multiple myeloma
Cervical cancer
Hodgkin’s disease
Singh G et al., The Journal of Rheumaotology ;26(56):18-24.

5. Hospitalizations and Deaths for GI events
Approximately 10% of hospitalizations for upper GI bleeding result in death.
Estimated Annual NSAIDs-Associated
GI Hospitalizations and Deaths in the United States
Diagnosis
NSAIDs Exposure(n)
Hospitalizations
Deaths
Incidence(%)
Patients(n) RA
2,000,000
1.5
30,000
0.22
4,400
Probable RA*
3,000,000
0.7†
21,000
0.11‡
3,300 OA
8,000,000
0.7
56,000
8,800
Total
13,000,000
107,000
16,500
* Estimated in the Community, not under a rheumatologist’s care
† Estimated to be half; presumed milder disease as they are not under a rheumatologist’s care
‡ Estimated from ratio of GI hospitalizations.
Ref.> Singh G et al., Am J Med 1998;105:31S-38S

6. Risk of ulcer complications associated
with varying dose Aspirin and NSAIDs
7.7( )
4.9 ( )
Odds ratio (95% CI)
3.9 ( )
3.2 ( )
2.3 ( )
The data suggest that even low dose aspirin has 2.3 times chances of acquiring ulcer complications and has increased to 3 times the risk of having complication if you combine ASA with NSAID.
Ref.> Weil J et al., BMJ Apr 1;310(6983):827-30

7. NSAIDs-induced GI mucosal injury
Most NSAIDs inhibit the activity of the COX-1 and COX-2 and thereby the synthesis of thromboxane and prostaglandins. It is thought that by inhibiting the COX-2 leads to anti inflammatory, analgesic and antipyretic effect and those inhibiting COX-1 may cause gastrointestinal bleeding and ulcers.
Ref.> Schoen RT et al., Am J Med 1989;86:449-58

8. Neutrophil activation Free-radical production
NSAIDs-induced GI mucosal injury
NSAIDs
Direct damaging
effect on mucosa
Accumulation in cells
Liposoluble
H+ dependent
pathway
Stimulation of
ICAM-1 expression?
Neutrophil activation
Free-radical production
Inhibition of
growth factor
production
Cox-2 Inhibition
epithelial repair
mechanism
Microvascular injury
Inhibition of mucous
Bicarbonate barrier
Decrease mucosal
defense
Epithelial injury
Cox-1 Inhibition
Let us analyse the damage mechanism of NSAID induced GI mucosal injury in details:
Ulcer formation
Systemic effect
local effect
Ref.> Gudis K et al., Dig Dis Sci Oct;50 Suppl 1:S16-23
Ref.> Hiraishi H et al., Mebio 1994;11(19):86

9. Gastric mucosal injury
Free Radicals Play an Important Role
In NSAIDs-induced GI mucosal injury
NSAIDs
Gastric mucosal injury
PGs
LTs
・OH
O2-
Free radicals
Activation of neutrophils
O2-
XOD
hypoxanthine
＋O2
Elastase
Endothelial cell damage
Adhesion Molecule
infiltration
Inflammation caused by ASA and NSAID is due to the release of free radicals from activated neutrophils
Ischemia-reperfusion
Microcirculation damage
Ref.> Data on file

10. Prevention of NSAIDs-related ulcer complications
Summary of recommendations for prevention
of NSAIDs-related ulcer complications
Gastrointestinal risk
Low
Moderate
High
Low CV risk
NSAIDs alone
(the least ulcerogenic
NSAIDs at the lowest effective dose)
NSAIDs + PPI/misoprostol
Alternative therapy if possible or
COX-2 inhibitor
+ PPI/misoprostol
High CV risk
(low-dose
aspirin required)
Naproxen +
PPI/misoprostol
Naproxen + PPI/misoprostol
Avoid NSAIDs or
COX-2 inhibitors.
Use alternative therapy
Gastrointestinal risk is stratified into low (no risk factors), moderate (presence of one or two risk factors),
and high (multiple risk factors, or previous ulcer complications, or concomitant use of corticosterolds or anticoagulants).
High CV risk is arbitrarily defined as the requirement for low-dose aspirin for prevention of serious CV events.
All patients with a history of ulcers who require NSAIDs should be tested for H.pylorl, and if the infection is present, eradication therapy should be given.
The ACG guidelines recommends the prevention of NSAID induced ulcer complication by:
GI risk와 CV risk를 모두 고려하여 위험군에 따라
PPI와 misoprostol을 NSAIDs와 병용 투여하거나 NSAIDs 중에서 선택적 Cox-2 억제제를 사용하도록 추천하고 있습니다.
하지만 저용량 아스피린이 요구되는 CV 위험이 높은 환자의 경우,
심혈관계보호 작용의 가능성이 보고된 naproxen을 NSAID 중에서 첫번째 선택약으로 추천하고 있으며 GI risk가 낮은 환자라도 PPI와 misoprostol을 병용투여하도록 추천하고 있습니다.
GI risk와 CV risk가 모두 높은 고위험군 환자에서는 선택적 Cox-2 억제제를 비롯한 모든 NSAID 사용을 피하고 다른 대체요법을 사용하도록 권하고 있습니다.
Ref.> Lanza FL et al., Am J Gastroenterol Mar;104(3):

11. Treatment of NSAIDs enteropathy
Mainstay of treatment: Discontinuation of NSAIDs
even if temporary cessation of the NSAIDs is possible,
long-term cessation of NSAIDs is frequently impossible for
patients with chronic pain or anti-platelet therapy.
However
Metronidazole, Sulfasalazine, and Misoprostol
However
Their effectiveness has not yet been fully confirmed.
NSAID enteropathy를 치료하기 위해서는 NSAID 투여를 중단하는 것이 가장 중요하지만,
일시적인 중단은 가능할 수 있어도 만성적인 통증 환자 또는 항혈소판 치료를 받는 환자의 경우 NSAID의 장기간 투여 중단은 불가한 경우가 많습니다.
또한 metronidazole, sulfasalazine, misoprostol이 NSAID enteropathy 치료 시 사용되고 있지만, 아직 그 효능이 확실하게 증명되지는 않았기 때문에
NSAID enteropathy 치료에는 아직 한계점이 있습니다.
It is not clear what kind of drug is appropriate to heal NSAID-induced enteropathy.
Several reports showed the preventive effect of prostaglandin analogue or inducer using healthy subjects who took NSAIDs.
However, there was no report for healing effect and for patients.
Ref.> Higuchi K et al., J Gastroenterol 2009;44:879–888

12. Serious GI complication requiring
hospitalization
Antacid/H2RA in ulcer complications
Antacid/H2RA may relieve NSAIDs-related dyspepsia but not ulcer risk
(%)
3.7
1.4
제산제와 H2RA의 경우 NSAID와 관련된 dyspepsia는 감소시켜도 ulcer의 위험은 감소시키지 못했다는 연구결과가 있습니다.
Prophylactic treatment
with antacid and H2RA
No GI medication
GI medication group N=489 / No GI medication N=1141 / Total 1,921 patients
with rheumatoid arthritis from 8 ARAMIS (Arthritis, Rheumatism, and Aging Medical Information System centers)
Singh G et al., Arch Intern Med. 1996;156: 12

13. Safety Concerns of PPI June 2015 Aug 2010 Nov 2009 Jul 2009 May 2009
C difficile infection: Ailment Pharmacol Ther
PPI related Rebound for Acid Reflux:: Journal of Gastroenterology
Possibility of Reducing antiplatelet effect: US FDA
Possibility of increasing risk of fractures: US FDA
Increase risk for Heart Attack : PLOS ONE
Aug 2010
Nov 2009
Jul 2009
May 2009

14. (derived from STRIDE data)
Proton pump inhibitor use is associated with an increased risk for heart attack
Proton pump inhibitor
Odds ratio (95% CI)
(derived from STRIDE data)
Pantoprazole
1.34 ( )
Omeprazole
1.26 ( )
Lansoprazole
1.24 ( )
Rabeprazole
1.12 ( )
Esomeprazole
1.08 ( )

15. Events per 100 patients-year
Selective COX-2 inhibitor still have
GI events in lower GI complications
There were no benefits of etoricoxib over diclofenac when looking at the
incidence of lower GI complications.
Selective Coxibs improved upper and lower GI safety according to results of clinical trial,
but coxibs are still capable of triggering GI adverse events and are still concerned to be
associated with cardiovascular toxicity issues.
Events per 100 patients-year
NSAID 중에서 upper GI complication의 위험이 상대적으로 낮은 선택적 Cox-2 억제제 역시,
현재까지의 data에 근거하면 아직까지 lower GI tract에서도 안전성이 입증되지는 않았습니다.
diclofenac과 etoricoxib의 GI events를 비교한 결과, upper 나 lower GI event 역시 두 군 모두 유사하였습니다.
Any GI
adverse events
Upper
GI events
Lower
GI events
Re.f.> Lanas A. et al., Gastroenterol Clin North Am Jun;38(2):333-52

16. What other option are available for prevention of NSAIDs/ASA induced gastropathy?
X Other pharmacokinetics of PPIs?
X Modified COX2 selectivity?
Mucoprotective agents?

17. Clinical Study of Mucosta
As of March 2014, Results in Pubmed :
Rebamipide + NSAID/ASA 65 studies
Kurokawa S, et al. J Gastroenterol 2013
A randomized, double-blinded, placebo-controlled, multicenter trial, healing effect of rebamipide in patients with low-dose aspirin and/or non-steroidal anti-inflammatory drug induced small bowel injury (PRIME Study)
Rebamipide compared with Misoprostol for NSAIDs associated Gastrointestinal Toxicity Prevention: Multi-nation study
Park et al, J.Clin. Biochem.Nutr., , March 2007
World J Gastroenterol Dec 14;17(46):
Aspirin-induced small bowel injuries and the preventive effect of rebamipide. .
World J Gastroenterol Jan 14;17(2):
Evaluation of small bowel blood flow in healthy subjects receiving low-dose aspirin.
J Clin Biochem Nutr Nov;47(3): Epub 2010 Oct 29.
Small bowel tissue concentration of rebamipide: study of two dosages in healthy subjects.
J Gastroenterol Jan;46(1): Epub 2010 Oct 6.
Rebamipide has the potential to reduce the intensity of NSAID-induced small intestinal injury: a double-blind, randomized, controlled trial evaluated by capsule endoscopy.
Efficacy of rebamipide for diclofenac-induced small-intestinal mucosal injuries in healthy subjects: a prospective, randomized,
double-blinded, placebo-controlled, cross-over study.
Niwa Y. et al., J Gastroenterol. 2008;43(4):270-6
Digestion. 2010;82(3): Epub 2010 Jun 25.
Prevention of traditional NSAID-induced small intestinal injury: recent preliminary studies using capsule endoscopy.
.Clin. Biochem. Nutr., 47, 27–31, July 2010
Gastroduodenal Mucosal Injury in Patients Taking Low-Dose Apirin and the Role of Gastric
Mucoprotective Drugs: Possible Effect of Rebamipide .
Biochem Pharmacol Jun 1;79(11): Epub 2010 Feb 2.
Protective effect of rebamipide against celecoxib-induced gastric mucosal cell apoptosis.
J Clin Biochem Nutr Sep;45(2):248-53
Preliminary trial of rebamipide for prevention of low-dose aspirin-induced gastric injury in healthy subjects: a randomized, double-blind, placebo-controlled, cross-over study
J Med Assoc Thai Sep;92(9):
Effect of rebamipide on gastric ulcer healing caused by Helicobacter pylori and/or NSAIDs or non NSAIDs-non H.pylori.
A randomized, double-blinded, placebo-controlled, multicenter trial, healing effect of rebamipide in patients with low-dose aspirin and/or non-steroidal anti-inflammatory drug induced small bowel injury. (PRIME Study)
J Gastroenterol. 2008;43(4): Epub 2008 May 6.
Efficacy of rebamipide for diclofenac-induced small-intestinal mucosal injuries in healthy subjects: a prospective, randomized, double-blinded, placebo-controlled, cross-over study.
J Pharmacol Sci Mar;106(3):
Prophylactic effect of rebamipide on aspirin-induced gastric lesions and disruption of tight junctional protein zonula
occludens-1 distribution.
J Clin Biochem Nutr Mar;40(2):
Comparison of Prevention of NSAID-Induced Gastrointestinal Complications by Rebamipide and Misoprostol: A Randomized, Multicenter, Controlled Trial-STORM STUDY.
Kurokawa S, et al. J Gastroenterol Feb;49(2):
- 2007~2013 : Rebemipide studies related to NSAID/ASA-

18. Mucosta
Ref.>Arakawa T. et al., Dig Dis Sci Oct;50 Suppl 1:S3-S11

19. Rebamipide Compared with Misoprostol for
NSAIDs-associated Gastrointestinal Toxicity
Prevention: Multi-nation study : STORM STUDY
Park et al, J.Clin Biochem.Nutr.,40, , March 2007

20. NSAIDs + Rebamipide 100mg t.i.d
Methods
Study Design : Randomized, multicenter, controlled, open-label
Objective: To compare NSAIDs-induced gastrointestinal complications (peptic ulcer)
in rebamipide and misoprostol treated group.
The Primary end point: The cumulative incidence of gastric or duodenal ulceration at 12 weeks.
The Secondary end point: The cumulative incidence of adverse events.
410 patients who required
Continuous NSAIDs therapy
Washout period : 4 weeks S
NSAIDs + Rebamipide 100mg t.i.d
NSAIDs + Misoprostol 200µg t.i.d
Dyspepsia assessment
Endoscopy
n=207
n=203
weeks
Park et al, J.Clin.Biochem.Nutr.,40, , March 2007

21. Demographic Characteristics of Enrolled Patients
Results
Demographic Characteristics of Enrolled Patients
Rebamipide
Misoprostol
P-value
Number
207
86 (China)
203
88 (China)
76 (Korea)
77 (Korea)
45 (Thailand)
38 (Thailand)
Sex (M:F)
54:153
67:136
0.1244
Age (Mean±SE)
48±11
46±12
0.3754
Hp positive(%)
48.5
41.7
0.2342
Pre-MLS
128
137
0.2633 1 38 29 2 27 17 3 12 15 4 5
Park et al, J.Clin.Biochem.Nutr.,40, , March 2007

22. Incidence of peptic ulcer after 3 month
Results
Incidence of peptic ulcer after 3 month
NSAID administration
100 80 60 40 20
Rebamipide
Misoprostol
Percent of patients (%)
p = n.s
p = n.s
p = n.s
4.5
4.4
3.9
1.9
2.5
0.5
Gastric ulcer
Duodenal ulcer
Peptic ulcer
n.s : not significant
Park et al, J.Clin.Biochem.Nutr.,40, , March 2007

23. Cumulative incidence of dyspeptic symptom, GI complications
Results
Cumulative incidence of
dyspeptic symptom, GI complications
100
p = 80
70.2
64.1
Rebamipide
Misoprostol
cumulative symptoms (%)
Percent of 60
p <
p =
p = 40
21.2
20.7
14.8 20
10.1
7.7
1.9
Dyspepsia
incidence
Diarrhea
Low
abdominal pain
Bloating
Park et al, J.Clin.Biochem.Nutr.,40, , March 2007

24. Percent of patients (%)
Results
Adverse Events
p = 25 20 15 10 5
22.8
(n=39)
Rebamipide
Misoprostol
Percent of patients (%)
14.4
(n=24)
Rebamipide
Misoprostol
Park et al, J.Clin.Biochem.Nutr.,40, , March 2007

25. A randomized, double-blinded, placebo-controlled, multicenter trial, healing effect of rebamipide in patients with low-dose aspirin and/or non-steroidal anti-inflammatory drug induced small bowel injury (PRIME Study)
Kurokawa S, et al. J Gastroenterol Feb;49(2): Impact factor: 4.16
This study is a randomized, double-blinded, placebo-controlled study and
The aim of this study was to evaluate the healing effect of rebamipide in patients with NSAIDs-induced enteropathy.

26. Methods Study design Objective:
To evaluate the healing effect of rebamipide in patients with NSAIDs-induced enteropathy
Subjects : Patients with LDA and/or NSAID more than 3 months (n=62)
The Primary end point : Changes in the number of the small intestinal mucosal breaks
The Secondary end point : Changes in the total protein and hemoglobin
Study design
Informed
Consent
NSAIDs and/or Aspirin + Rebamipide (300mg/day, tid)
NSAIDs and/or Aspirin + Placebo
Patients with LDA and/or NSAID more than 3 months were enrolled.
Patients with enteropathy were divided into the placebo and the rebamipide groups.
Rebamipide100 mg three times daily was administered during 4 weeks.
Capsule endoscopies were performed at 0 and 4 week.
The number of small intestinal ulcer and erosion were evaluated.
Total protein was analyzed as nutritional parameter.
0 week
4 week
Capsule
Endoscopy
Ref.> Kurokawa S, et al. J Gastroenterol Feb;49(2):

27. Demographic data
There were no differences in patients’ demographic data and characteristics between the placebo
group and the rebamipide group.
Some patients with anemia in the rebamipide group and placebo were observed.
Ref.> Kurokawa S, et al. J Gastroenterol Feb;49(2):

28. Flow Chart Informed consent (n=67) Capsule endoscopy (n=67)
Dropped out(n=5)
Not observed injury
Enrollment
(n=62)
Randomization
(n=62)
Sixty-two patients were divided into the placebo group and the rebamipide group.
Placebo
(n=31)
Rebamipide
(n=31)
Dropped out (n=1)
By Hypertension
Completion
(n=30)
Completion
(n=31)
Ref.> Kurokawa S, et al. J Gastroenterol Feb;49(2):

29. Results
The healing effect of Rebamipide in patients with small bowel injuries at 4 weeks
CI, confidential interval
Placebo
(n=30)
Rebamipide
(n=31)
Absolute Difference
95% CI
P value
Erosion
2.1±3.9
-3.2±4.1
-4.6
-6.5 to -2.7
<0.0001
Ulcer
0.1±0.7
-0.5±1.6
-0.6
-1.4 to -0.1
0.024
Reddened lesion
-0.2±3.7
-2.3±3.8
-2.1
-4.1 to -0.2
0.003
Complete remission
5.3%
(n=1)
37.5%
(n=9)
0.018
Rebamipide was superior to placebo in the improvement of small intestinal mucosal break including erosion, ulcer.
Complete remission was achieved for 37.5 % of patients in the rebamipide group. It had statistical
significant difference in comparison with 5.3 % of remission rate in the placebo group.
* Complete remission was defined as an improvement of small intestinal condition that showed the
disappearance of mucosal break by observation of CE at final evaluation time point.
Rebamipide was superior to placebo in the improvement
of small intestinal mucosal break.
Ref.> Kurokawa S, et al. J Gastroenterol Feb;49(2):

30. Changes in hemoglobin and total protein
Results
Changes in hemoglobin and total protein
CI, confidential interval
Placebo
(n=30)
Rebamipide
(n=31)
Absolute Difference
95% CI
P value
Total protein (g/dL)
-0.3±0.3
0.06±0.4
0.3
0.2 to 0.5
0.0005
Hemoglobin (g/dL)
-0.6±1.6
0.01±0.9
0.6
-0.04 to 1.3
0.066
* Chronic small intestinal damage by taking LDA and/or NSAID may impair this function.
Long-term use of LDA and/or NSAID leads to hyper-permeation of small intestinal mucosa. Moreover, chronic hyper-permeation
in the small intestinal mucosa leads to rhexis of tight junction.
On the other hand, reducing prostaglandin leads to decreasing of blood flow.
Although these reactions are invisible, this condition occurs all over the small intestinal mucosa.
As the result, function of small intestine such as absorption of nutritional elements may be lost.
In this study, baseline of serum total protein of patients was lower rather than normal levels.
Rebamipide improved serum total protein.
Namely, this result might also show avoidance from decrease of serum protein level by reparatory action of rebamipide.
Serum total protein was also improved by
taking rebamipide compared with placebo.
Ref.> Kurokawa S, et al. J Gastroenterol Feb;49(2):

31. PRIME study conclusion
PRIME study was the first report to proof the healing
effect of a drug in patients with LDA and/or NSAID related
small intestinal injuries by double-blinded, randomized, placebo-controlled trial.
Rebamipide has not only a healing effect for NSAID and/or LDA-induced small intestinal injuries compared with placebo, but also improves the nutritional condition.
Our present study was the first report to proof the healing effect of a drug in patients with LDA and/or NSAID related
small intestinal injuries by double-blinded, randomized, placebo-controlled trial.
Rebamipide has not only the healing effect for LDA and/or NSAID-induced small intestinal injuries compared with placebo,
but also the improvement of nutritional condition.
This therapeutic strategy is clinically meaningful for chronic LDA and/or NSAID users.
This result might be one of appropriate goal as the management of small intestine in patients with LDA.
Ref.> Kurokawa S, et al. J Gastroenterol Feb;49(2):

32. Reducing the Risk of Entire GI Complications : Two basic strategies
Stevens-Johnson
Not working
Efficacy on IBD
Pneumonia
Renal toxicity↑(?)
Rebamipide
Cox2 selective
Aggravates IBD
◁ Acid production of osteoclast ￬
◁ Vitamin B12 ￬ >homocysteine ￪
◁ Ca dissolution ￬
Hip fracture X2.6/yr
하지만 무코스타는 PPI의 장기 부작용과 같은 심각한 부작용이 보고된 바 없으며
CV risk에도 영향을 미치지 않습니다.오히려 혈관확장물질인 NO 생성 증가도 보고된 바 있습니다.
또한 무코스타는 위 점막과 마찬가지로 소장의 점막 방어인자를 증가시켜 소장 점막의 손상 예방 효과 뿐 아니라
항염증 효과를 통해 IBD에서도 효과를 나타냈습니다.
따라서 무코스타는 상부 및 하부 전체 위장관의 합병증 위험을 감소시킬 수 있는 유효한 약물입니다.
Small Bowel
Nitric oxide ↑
Clopidogrel effect ￬
CV risk ↑

33. Conclusion
Mucosta prevented NSAID-induced peptic ulcer as effectively as misoprostol in patients on long-term NSAID therapy.
Mucosta were proven the preventive effect in healthy subjects
and healing effect in patients with LDA and/or NSAID-induced small intestinal injuries.
Current evidences show rebamipide is effective and safe for defending against NSAID-induced gastroduodenal and lower-gastrointestinal injuries.
Ref.> 1) Park et al, J.Clin Biochem.Nutr.,40, , March 2007
2) Kurokawa S, et al. J Gastroenterol Feb;49(2):
3) Dig Dis Sci. Volume 58, Issue 7 , pp

34. SAMPLE Patient case report:
TS, 54y/o male, known hypertensive, non diabetic, history of GERD, S/P EGD 2015 came in due to hematemesis
Chief complain: 30 mins PTA. nausea and bloatedness, sudden onset of hematemesis (2x episodes, approx. 200ml/episode) with intake of NSAIDs/ Aspirin 80mg OD
SAMPLE
VS: BP- 150/110, HR- 95, RR- 20, temp- 36.6c.
No neck engorgement, no retractions, bronchovesicular breath sounds, no crackles, no wheezes
Abdomen: soft, mild tenderness on deep palpitation of the epigastric area, bipedal edema.
Rectal exam: good sphinteric tone, rectal vault not collapsed, (-) blood per examining ginfer
Please input your MD case report

35. SAMPLE Patient case report:
NGT insert noted coffee ground per NGT, 200ml initial
Meds: Pantoprazole drip 80mg IV then 40mg in soluset to run at 8mg/hr, Tranexamic acid
SAMPLE
Impression: UGIB prob secondary to Drug Induced Gastropathy
1st hd, Bleeding stoppedand was started on soft diet.
PPI continued, NGT was removed. Started on Rebamipide 100mg TID 1hr after meals.

36. THANK YOU