apd presentation by prof.javed akram
TRANSCRIPT
New Perspectives in The Management of Peptic Ulcer Disease.
New Perspectives in The Management of Peptic Ulcer Disease.
Professor Javed Akram.
Mb, MEE(Can), MRCP(UK), FRCP(Glasg), FRCP(Edin), FRCP(London), FACP(USA), FASIM(USA), FACC(USA).
Professor Javed Akram.
Mb, MEE(Can), MRCP(UK), FRCP(Glasg), FRCP(Edin), FRCP(London), FACP(USA), FASIM(USA), FACC(USA).
Peptic Ulcer DiseasePeptic Ulcer Disease
A peptic ulcer is a break (an ulceration) in the protective mucous lining (mucosa) of the lower esophagus, stomach or duodenum
A peptic ulcer is a break (an ulceration) in the protective mucous lining (mucosa) of the lower esophagus, stomach or duodenum
Common MisconceptionsCommon Misconceptions
A peptic ulcer is NOT: A stress ulcer Chronic gastritis (a symptom as well as a disease state
that may lead to peptic ulcers) Dyspepsia (the symptoms that may or may not be
diagnosed as an ulcer)
Peptic Ulcers cannot be diagnosed solely on the basis of clinical presentation (Werdmuller et al. 1996)
A peptic ulcer is NOT: A stress ulcer Chronic gastritis (a symptom as well as a disease state
that may lead to peptic ulcers) Dyspepsia (the symptoms that may or may not be
diagnosed as an ulcer)
Peptic Ulcers cannot be diagnosed solely on the basis of clinical presentation (Werdmuller et al. 1996)
Dyspepsia.Dyspepsia.
Dyspepsia - Definition
A group of symptoms which alert clinicians to consider disease of the upper gastrointestinal tract
(British Society of Gastroenterology, 1996)(British Society of Gastroenterology, 1996)
Symptoms of Functional Dyspepsia
Nocturnal Nocturnal pain painLocalized Localized epigastric epigastric burning burning
BetterBetter with food with food
HeartburnHeartburn
RetrosternalRetrosternal burningburning
NauseaNausea
BloatingBloating
Early satietyEarly satiety
WorseWorse with food with food
Ulcer-like DominantUlcer-like Dominant Dysmotility-like Dominant Dysmotility-like Dominant
Quick Stats:Peptic UlcerQuick Stats:Peptic Ulcer
5-10% lifetime incidence 1-2% of people have ulcer at any given time $5.65 billion industry
5-10% lifetime incidence 1-2% of people have ulcer at any given time $5.65 billion industry
Peptic Ulcer Hospitalization RatesPeptic Ulcer Hospitalization Rates
Kurata JH. Kurata JH. Semin Gastrointest DisSemin Gastrointest Dis 1993:4 1993:4
RateRate per per
100,000100,000
Gastric UlcerGastric Ulcer Duodenal UlcerDuodenal Ulcer
70 75 80 85 900
20
40
60
80
100
Uncomplicated Uncomplicated
HemorrhageHemorrhage
Perforation Perforation
70 75 80 85 900
20
40
YearYear YearYear
30
10
Uncomplicated Uncomplicated
HemorrhageHemorrhage
Perforation Perforation
TypesTypes
Gastric Slightly more common in men and way more
common in elderly Most commonly located in the stomach’s lesser
curvature, antrum 1-3% associated with gastric carcinomas Basic defect is disruption of gastric mucosal
barrier (gastritis, duodenal reflux, H. pylori, NSAIDS)
Gastric Slightly more common in men and way more
common in elderly Most commonly located in the stomach’s lesser
curvature, antrum 1-3% associated with gastric carcinomas Basic defect is disruption of gastric mucosal
barrier (gastritis, duodenal reflux, H. pylori, NSAIDS)
TypesTypes
Duodenal Almost always located in the duodenal bulb More likely culprit in chronic disease No association with cancer
Duodenal Almost always located in the duodenal bulb More likely culprit in chronic disease No association with cancer
Risk FactorsRisk Factors
Smoking 33-100% more likely to develop duodenal ulcers Retards healing of identified ulcers J Akram& Colleagues ..E.J.of Gastrenterology.Nov2003)
Age and Sex Alcohol Diet
Milk Stress Ramadan fasting
Smoking 33-100% more likely to develop duodenal ulcers Retards healing of identified ulcers J Akram& Colleagues ..E.J.of Gastrenterology.Nov2003)
Age and Sex Alcohol Diet
Milk Stress Ramadan fasting
Risk FactorsRisk Factors
NSAIDS Responsible for majority of ulcers not caused
by H.pylori Greater risk for complications once ulcer
identified Risk of GU increases sixfold when taking
>three aspirin/day. Buffered coat has no advantage
NSAIDS Responsible for majority of ulcers not caused
by H.pylori Greater risk for complications once ulcer
identified Risk of GU increases sixfold when taking
>three aspirin/day. Buffered coat has no advantage
Prevalence of EndoscopicNSAID-Induced UlcerationPrevalence of Endoscopic
NSAID-Induced Ulceration
Mean Range Gastric Ulcer 15 % 10 to 30% Duodenal Ulcer 5 % 4 to 10 % Clinically Significant Ulcers 2% 1 to 4%
Mean Range Gastric Ulcer 15 % 10 to 30% Duodenal Ulcer 5 % 4 to 10 % Clinically Significant Ulcers 2% 1 to 4%
Risk Factors forSerious GI Adverse Events with NSAIDs: Relative Risks
Risk Factors forSerious GI Adverse Events with NSAIDs: Relative Risks
Rodriguez. Lancet. 1994; Guttham. Epidemiology. 1997; Shorr. Arch Intern Med. 1993; Piper. Ann Intern Med. 1991.
0 5 10 15
4.4 (2.0-9.7)
12.7 (6.3-25.7)
2.9 (2.2-3.8)
5.8 (4.0-8.6)
5.6 (4.6-6.9)
3.1 (2.5-3.7)
1.6 (1.4-2.0)
13.5 (10.3-17.7)
Corticosteroid use
Anticoagulant use
Low dose NSAIDLow dose NSAID
High dose NSAID
Age 70-80
Age 60-69
Age 50-59
Prior bleed
Relative RiskRelative Risk
NSAID
↑ Leukocyte-EndothelialInteractions
Capillary Obstruction
IschemicCell Injury
Proteases +Oxygen Radicals
Endo/EpithelialCell Injury
Mucosal Ulceration
Loss o
f PG
E 2 an
d PG
I 2 m
edia
ted in
hibiti
on
of ac
id se
cret
ion an
d cyto
prote
ctiv
e effe
ct
Loss of PGI2 induced inhibition of LTB4 mediated endothelial adhesion and activation of neutrophils
Peptic Ulcers and StressPeptic Ulcers and Stress
Experimental stress results in decreased upper gastrointestinal blood flow in animals
(Kauffman, 1997; Livingston 1993)
Effect of stress seems to be reversible (Levenstein et al., 1996)
Experimental stress results in decreased upper gastrointestinal blood flow in animals
(Kauffman, 1997; Livingston 1993)
Effect of stress seems to be reversible (Levenstein et al., 1996)
Peptic Ulcer and PersonalityPeptic Ulcer and Personality
Studies have found a strong association between dependency and peptic ulcers
Patients with peptic ulcer have significantly more personality disturbances than control subjects (Feldman et al.)
Ulcer patients also more inclined to pessimism and excessive dependence (Akram et al.)
Studies have found a strong association between dependency and peptic ulcers
Patients with peptic ulcer have significantly more personality disturbances than control subjects (Feldman et al.)
Ulcer patients also more inclined to pessimism and excessive dependence (Akram et al.)
Helicobacter pyloriHelicobacter pylori
Gram-negative spiral organism Most common and important risk factor for
duodenal ulcer Variable risk factor for gastric ulcers 10% healthy people under 30, 60% healthy
people over 60. Will cause disease in 15-20% of infected Eradication is the key
Gram-negative spiral organism Most common and important risk factor for
duodenal ulcer Variable risk factor for gastric ulcers 10% healthy people under 30, 60% healthy
people over 60. Will cause disease in 15-20% of infected Eradication is the key
Diagnosis of Peptic UlcerDiagnosis of Peptic Ulcer
DiagnosisDiagnosis Vague discomfort and feeling of gnawing hunger Duodenal usually has predictable food relationship (1-3 hrs after meal) Gastric ulcer relationship with food more variable Gastric ulcer-weight loss Duodenal ulcer-weight gain Watch for peptic ulceration/bleeding: melena, radiation of pain to
back/shoulder
Vague discomfort and feeling of gnawing hunger Duodenal usually has predictable food relationship (1-3 hrs after meal) Gastric ulcer relationship with food more variable Gastric ulcer-weight loss Duodenal ulcer-weight gain Watch for peptic ulceration/bleeding: melena, radiation of pain to
back/shoulder
Physical ExamPhysical Exam
Epigastric tenderness Rectal exam!!
Epigastric tenderness Rectal exam!!
StudiesStudies Radiography
Barium swallow with double contrast Duodenal-detects 40-80% Gastric-detects 65-80%
Endoscopy Gold standard Detects up to 95% gastroduodenal ulcers Generally considered the study of choice esp. for
large ulcers or those not clearly benign
Radiography Barium swallow with double contrast Duodenal-detects 40-80% Gastric-detects 65-80%
Endoscopy Gold standard Detects up to 95% gastroduodenal ulcers Generally considered the study of choice esp. for
large ulcers or those not clearly benign
Diagnosis of H. pyloriDiagnosis of H. pylori
Invasive (if patient requires endoscopy) Histologic testing (50-90% sensitive, 100%
specific) Rapid urease (CLO) test (95% sensitive and
95% specific)* Noninvasive
IgG antibody* Urea breath test (96% sensitive, 98% specific)
Invasive (if patient requires endoscopy) Histologic testing (50-90% sensitive, 100%
specific) Rapid urease (CLO) test (95% sensitive and
95% specific)* Noninvasive
IgG antibody* Urea breath test (96% sensitive, 98% specific)
ComplicationsComplications
Perforation Reoccurrence Obstruction Bleeding Cancer
Perforation Reoccurrence Obstruction Bleeding Cancer
Upper GI BleedingUpper GI Bleeding
A common medical conditionA common medical condition
250,000 – 500,000 admissions/year in US UGI bleeding incidence 100/100,000 adults
Incidence increases 20-30 fold from third to ninth decade of life
GI bleeding stops spontaneously in 80 %
250,000 – 500,000 admissions/year in US UGI bleeding incidence 100/100,000 adults
Incidence increases 20-30 fold from third to ninth decade of life
GI bleeding stops spontaneously in 80 %
Bleeding Stats:Mayo J.Akram etal 2001PJGEBleeding Stats:Mayo J.Akram etal 2001PJGE
TherapyTherapy
Goal is to heal the ulcer and prevent recurrence
Both can be accomplished by eradicating H. pylori if present
Treat the acute pain if necessary
Goal is to heal the ulcer and prevent recurrence
Both can be accomplished by eradicating H. pylori if present
Treat the acute pain if necessary
NonpharmacologicNonpharmacologic
There is no evidence that dietary modifications changes the course of the disease
Quit smoking Milk intake Faster healing, lower recurrence, lower
complications Discontinue NSAIDS COX2 Inhibitors?
There is no evidence that dietary modifications changes the course of the disease
Quit smoking Milk intake Faster healing, lower recurrence, lower
complications Discontinue NSAIDS COX2 Inhibitors?
Treatment of ulcersTreatment of ulcers Eradicate H. pylori Single antibiotic therapy does not work Compliance is key
More than 60% of the doses must be taken to ensure eradication
If eradicated, maintenance therapy not needed. If recurs, check for H. pylori again
If H. pylori not found, check again and treat with H2-receptor antagonists, PPI’s and sucralfate
Document healing of gastric ulcers with endoscopy
Eradicate H. pylori Single antibiotic therapy does not work Compliance is key
More than 60% of the doses must be taken to ensure eradication
If eradicated, maintenance therapy not needed. If recurs, check for H. pylori again
If H. pylori not found, check again and treat with H2-receptor antagonists, PPI’s and sucralfate
Document healing of gastric ulcers with endoscopy
ULCOCID(Sucralfate)
ULCOCID(Sucralfate)
Chemical Structure of Sucralfate Chemical Structure of Sucralfate
Sucrose Octasulphate Poly aluminum Hydroxide
Sucralfate
C12 H6 O11 [SO3 Al2 (OH)5] n H2 O
Sucrose Octasulphate Poly aluminum Hydroxide
Sucralfate
C12 H6 O11 [SO3 Al2 (OH)5] n H2 O
ULCOCID(Sucralfate)
ULCOCID(Sucralfate)
1. Non systemic
2. Cytoprotective
3. Acid related disorders
1. Non systemic
2. Cytoprotective
3. Acid related disorders
PHAMACOKINETICSPHAMACOKINETICS
ABS0RPTION Minimal absorption by GIT 3-5%
ABS0RPTION Minimal absorption by GIT 3-5%
EXCRETION Approximately 90% is excreted in the stool, very
small amount is excreted in the urine.
EXCRETION Approximately 90% is excreted in the stool, very
small amount is excreted in the urine.
INDICATIONS OF ULCOCIDINDICATIONS OF ULCOCID
Duodenal ulcers Gastric ulcers treatment of reflux and peptic oesophagitis H.pylori treatment of NSAID & aspirin induced GI symptoms and
mucosal damage. Prevention of stress ulcers and GI bleeding in critically ill
patients. Treatment of oral and oesophageal ulcers due to radiation
chemotherapy & sclerotherapy. Sucralfate enemas in ulcerative colitis & colonic
carcinomas
Duodenal ulcers Gastric ulcers treatment of reflux and peptic oesophagitis H.pylori treatment of NSAID & aspirin induced GI symptoms and
mucosal damage. Prevention of stress ulcers and GI bleeding in critically ill
patients. Treatment of oral and oesophageal ulcers due to radiation
chemotherapy & sclerotherapy. Sucralfate enemas in ulcerative colitis & colonic
carcinomas
AVAILABILITY OF DRUGAVAILABILITY OF DRUG
1. ULCOCID tablets ( containing 500 mg Sucralfate per tablet ).
2. ULCOCID tablets ( containing 1 g Sucralfate per tablet ).
3. ULCOCID Susp. 60 ml
( containing 1 g Sucralfate per 5ml).
1. ULCOCID tablets ( containing 500 mg Sucralfate per tablet ).
2. ULCOCID tablets ( containing 1 g Sucralfate per tablet ).
3. ULCOCID Susp. 60 ml
( containing 1 g Sucralfate per 5ml).
DOSAGE RECOMMENDATION OF ULCOCIDDOSAGE RECOMMENDATION OF ULCOCID
For Ulcer Patients Morning 2g Ulcocid Evening
For Non Ulcer Patients Morning 1 g Ulcocid Evening
For Ulcer Patients Morning 2g Ulcocid Evening
For Non Ulcer Patients Morning 1 g Ulcocid Evening
ULCOCIDULCOCIDULCOCID should always be
taken 1 hour before meals at bed time (Monotherapy)
Do not take antacids 1/2 hour before or after taking ULCOCID (Polytherapy).
ULCOCID should always be taken 1 hour before meals at bed time (Monotherapy)
Do not take antacids 1/2 hour before or after taking ULCOCID (Polytherapy).
ANTACIDS Vs ULCOCDANTACIDS Vs ULCOCDANTACIDS
Just symptomatic therapy. Intense antacid regimen required
for healing. Not safe for hypertensive or
cardiac patients. Non-Palatable. Not suitable for working class
because of frequent dose taken.
ANTACIDS Just symptomatic therapy. Intense antacid regimen required
for healing. Not safe for hypertensive or
cardiac patients. Non-Palatable. Not suitable for working class
because of frequent dose taken.
ULCOCID Ulcer healing occurs.
None
Palatable
Dosage is convenient.
ULCOCID Ulcer healing occurs.
None
Palatable
Dosage is convenient.
Ulcocid Vs H2- Receptor AntagonistsUlcocid Vs H2- Receptor Antagonists
Ulcocid Less side effects Can be administered to elderly. Smokers can use it. Does not effect hepatic
metabolism of drugs. Does not effect pulmonary
functions in patients with pre-existing broncho- pulmonary diseases.
Ulcocid Less side effects Can be administered to elderly. Smokers can use it. Does not effect hepatic
metabolism of drugs. Does not effect pulmonary
functions in patients with pre-existing broncho- pulmonary diseases.
H2-Receptor Antagonists More side effects Causes hallucination and delirium
in elderly Only for non- smokers. Does effect the metabolism of
drugs metabolized by Cytochrome P-450 path-way.
H2 – blockers may worsen the condition.
H2-Receptor Antagonists More side effects Causes hallucination and delirium
in elderly Only for non- smokers. Does effect the metabolism of
drugs metabolized by Cytochrome P-450 path-way.
H2 – blockers may worsen the condition.
Human Studies.Human Studies.Comparative evaluation of Sucralfate &
Cimetidine efficacy in treatment of chronic erosive gastritis.
The results of patients with chronic erosive gastritis treated with Sucralfate & Cimetidine were compared. The result of examinations indicate that chronic erosive gastritis is difficult to be heal; Sucralfate proved to be more efficient than Cimetidine.
Ref: Au:Kula-Z:Walasek-L So:Pizegl-Lek 1998; 51(2): 73-6
Comparative evaluation of Sucralfate & Cimetidine efficacy in treatment of chronic erosive gastritis.
The results of patients with chronic erosive gastritis treated with Sucralfate & Cimetidine were compared. The result of examinations indicate that chronic erosive gastritis is difficult to be heal; Sucralfate proved to be more efficient than Cimetidine.
Ref: Au:Kula-Z:Walasek-L So:Pizegl-Lek 1998; 51(2): 73-6
Meta-analysis:Human Studies.Meta-analysis:Human Studies.
Comparative evaluation of Sucralfate & Cimetidine efficiency in treatment of chronic erosive gastritis proved that Sucralfate is more efficient than Cimetidine.
Ref: Au: Kula-Z:Walasek-L So:Pizegl-Lek 1999; 51(2): 73-6
Comparative evaluation of Sucralfate & Cimetidine efficiency in treatment of chronic erosive gastritis proved that Sucralfate is more efficient than Cimetidine.
Ref: Au: Kula-Z:Walasek-L So:Pizegl-Lek 1999; 51(2): 73-6
ULCOCID Vs ACID PUMP INHIBITORS
ULCOCID Vs ACID PUMP INHIBITORS
Acid Pump Inhibitors Jaundice has been reported.
Hypoglycaemia, Wt. Gain.
Increased intragastric concentrations of viable bacteria during the T/M.
Acid Pump Inhibitors Jaundice has been reported.
Hypoglycaemia, Wt. Gain.
Increased intragastric concentrations of viable bacteria during the T/M.
Ulcocid No jaundice reported
None
None
Ulcocid No jaundice reported
None
None
Anti Helicobacter effects
Omeprazole Vs Ulcocid(With Clarithromycin and Metronidazole)
Anti Helicobacter effects
Omeprazole Vs Ulcocid(With Clarithromycin and Metronidazole)
75
80
85
90
95
100
4 WeeksHealing
H.Pylorieradication
OmeprazoleUlcocid
75
80
85
90
95
100
4 WeeksHealing
H.Pylorieradication
OmeprazoleUlcocid
Ulcocid Counters the Effect of H.Pylori on Gastric Mucosa
Ulcocid Counters the Effect of H.Pylori on Gastric Mucosa
H.PYLORI Mucus viscosity Glycoproteins & lipids Na+/H+ exchange of mucus Mucosal bicarbonate secretion Cell desquamation Mucosal microvessel
permeability Mucosal blood flow? Surface hydrophobicity Cell membrane permeability H+ Back diffusion.
H.PYLORI Mucus viscosity Glycoproteins & lipids Na+/H+ exchange of mucus Mucosal bicarbonate secretion Cell desquamation Mucosal microvessel
permeability Mucosal blood flow? Surface hydrophobicity Cell membrane permeability H+ Back diffusion.
ULCOCID Mucus viscosity Glycoproteins & lipids Na+/H+ exchange of mucus Mucosal bicarbonate secretion
Mucosal PGE2, Mucosal renewal Mucosal blood flow Surface hydrophobicity Cell membrane permeability H+ Back diffusion.
ULCOCID Mucus viscosity Glycoproteins & lipids Na+/H+ exchange of mucus Mucosal bicarbonate secretion
Mucosal PGE2, Mucosal renewal Mucosal blood flow Surface hydrophobicity Cell membrane permeability H+ Back diffusion.
HUMAN AND ANIMAL STUDIESHUMAN AND ANIMAL STUDIES
Invitro and clinical data suggest that triple therapy with SUCRALFATE is effective in eradicating HELICOBACTER PYLORI and reducing duodenal ulcer relapse.
Ref: Louw- Ja So:Scand-J-Gastroenterol-Suppl. 1998; 191:28-31
Invitro and clinical data suggest that triple therapy with SUCRALFATE is effective in eradicating HELICOBACTER PYLORI and reducing duodenal ulcer relapse.
Ref: Louw- Ja So:Scand-J-Gastroenterol-Suppl. 1998; 191:28-31
Human StudiesHuman Studies
Glycosulfatase activity of H. Pylori towards human gastric mucin; effect of Sucrafate.
Results demonstrate that H. Pylori, through its Glycosulfatase activity affects the sulphated mucin & glycero-gluco-lipid content of the protective mucous layer & that anti-ulcer drug Sucralfate is able to counteract the detrimental action of this enzyme.
Ref: Slomiany-BL; Piotrowski-J; Grabska-M; SLOMIANY-a So: Am-j-Gastroenterol. 1999 Sep; 87(9); 1132-7
Glycosulfatase activity of H. Pylori towards human gastric mucin; effect of Sucrafate.
Results demonstrate that H. Pylori, through its Glycosulfatase activity affects the sulphated mucin & glycero-gluco-lipid content of the protective mucous layer & that anti-ulcer drug Sucralfate is able to counteract the detrimental action of this enzyme.
Ref: Slomiany-BL; Piotrowski-J; Grabska-M; SLOMIANY-a So: Am-j-Gastroenterol. 1999 Sep; 87(9); 1132-7
ULCOCID INHIBITS THE EFFECT OF H.Pylori on gastric mucins
ULCOCID INHIBITS THE EFFECT OF H.Pylori on gastric mucins
0
200
400
600
800
1000
1200
Specific binding (dpm/assay)
Control 10 40 80
ULCOCID (mg/ml)
0
200
400
600
800
1000
1200
Specific binding (dpm/assay)
Control 10 40 80
ULCOCID (mg/ml)
ULCOCIDULCOCID Direct binding to ulcer
crater
Stimulates prostaglandin production
Enhances the surface active phospholipid mucosal barrier.
Direct binding to ulcer crater
Stimulates prostaglandin production
Enhances the surface active phospholipid mucosal barrier.
Stimulates growth factors
. Epidermal
. Transforming
. Fibroblast
Anti-helicobacter effects.
Stimulates growth factors
. Epidermal
. Transforming
. Fibroblast
Anti-helicobacter effects.
Recurrent Aphthous Stomatitis (RAS)Recurrent Aphthous Stomatitis (RAS)
Minor apthae Minor apthae
Recurrent Aphthous Stomatitis (RAS)Recurrent Aphthous Stomatitis (RAS)
Major apthae Major apthae
Sucralfate in apthous ulcers.F.Khan,A.Awan,J.Akram SMJ,Jun,2003
Sucralfate in apthous ulcers.F.Khan,A.Awan,J.Akram SMJ,Jun,2003
Statistically significantly better pain relief Earlier ulcer healing rates Better QOL
Statistically significantly better pain relief Earlier ulcer healing rates Better QOL
Sucralfate EnemaSucralfate Enema
Ulcerative Colitis Ca.Colon
Ulcerative Colitis Ca.Colon
HUMAN STUDIES HUMAN STUDIES
Management of bleeding in a patient with colorectal cancer:
SUCRALFATE an oral cytoprotective, used topically in a patient with colo-rectal cancer resulting in control of bleeding, less localized pain and more freedom & independence for the patient.
Ref: Au: Famcombe-M So: Support-care-cancer, 1993 May;1(3):159-60.
Management of bleeding in a patient with colorectal cancer:
SUCRALFATE an oral cytoprotective, used topically in a patient with colo-rectal cancer resulting in control of bleeding, less localized pain and more freedom & independence for the patient.
Ref: Au: Famcombe-M So: Support-care-cancer, 1993 May;1(3):159-60.
WHY ULCOCID ?WHY ULCOCID ?
Fast pain relief. Excellent healing rate. Equal good for smokers and non - smokers. Good for elderly. Equally good for ulcer and non - ulcer
patients. Economical
Fast pain relief. Excellent healing rate. Equal good for smokers and non - smokers. Good for elderly. Equally good for ulcer and non - ulcer
patients. Economical
Thank You.Thank You.