outline definition epidemiology impact and burden of disease pathophysiology treatment: what is the...
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OutlineOutline
• Definition• Epidemiology• Impact and burden of disease• Pathophysiology• Treatment: What is the evidence?• Novel therapies• Concluding Remarks
• Definition• Epidemiology• Impact and burden of disease• Pathophysiology• Treatment: What is the evidence?• Novel therapies• Concluding Remarks
What is IBS?What is IBS?• A common functional GI disorder
manifested by a group of symptoms– Abdominal pain/discomfort– Bloating/distention – Constipation and/or diarrhea
• No known structural or biochemical abnormalities
• Symptoms may be exacerbated by eating, stress and some pharmacologic agents
• Significantly affects quality of life
• A common functional GI disorder manifested by a group of symptoms– Abdominal pain/discomfort– Bloating/distention – Constipation and/or diarrhea
• No known structural or biochemical abnormalities
• Symptoms may be exacerbated by eating, stress and some pharmacologic agents
• Significantly affects quality of life
12 weeks in the last 12 months of abdominal discomfort or pain that has 2 out of 3 features
– Relieved with defecation– Onset associated with a in frequency of stool– Onset associated with a in consistency of stool
The following symptoms are not essential, but the more of them that are present, the more confident is the diagnosis
– Abnormal stool frequency (>3/day or <3/week)– Abnormal stool form or abnormal stool passage – Passage of mucus – Bloating or feeling of abdominal distention
12 weeks in the last 12 months of abdominal discomfort or pain that has 2 out of 3 features
– Relieved with defecation– Onset associated with a in frequency of stool– Onset associated with a in consistency of stool
The following symptoms are not essential, but the more of them that are present, the more confident is the diagnosis
– Abnormal stool frequency (>3/day or <3/week)– Abnormal stool form or abnormal stool passage – Passage of mucus – Bloating or feeling of abdominal distention
THE ROME CRITERIATHE ROME CRITERIA
• Anemia
• Fever
• Persistent diarrhea
• Rectal bleeding
• Severe constipation
• Weight loss
• Anemia
• Fever
• Persistent diarrhea
• Rectal bleeding
• Severe constipation
• Weight loss
• Nocturnal symptoms ofpain and abnormal bowel function
• Family history of GI cancer, inflammatory bowel disease, or celiac disease
• New onset of symptoms in patients 50+ years of age
• Nocturnal symptoms ofpain and abnormal bowel function
• Family history of GI cancer, inflammatory bowel disease, or celiac disease
• New onset of symptoms in patients 50+ years of age
RED FLAGS!RED FLAGS!
WORLDWIDE PREVALENCE OF IBSWORLDWIDE PREVALENCE OF IBS
0
10
20
30
40
50
60
70
Pre
vale
nce
(%
)
0
10
20
30
40
50
60
70
Pre
vale
nce
(%
)
1Heaton K et al. 1992; 2Longstreth G, Wolde-Tsadnik P 1993; 3Welch G, Pomare W 1990; 4Bommalaer G et al. 19865Bi-zhen W, Qi-Ying P 1988; 6Olubuyide O et al. 1995; 7Kay L et al. 1994
1Heaton K et al. 1992; 2Longstreth G, Wolde-Tsadnik P 1993; 3Welch G, Pomare W 1990; 4Bommalaer G et al. 19865Bi-zhen W, Qi-Ying P 1988; 6Olubuyide O et al. 1995; 7Kay L et al. 1994
UK1 USA2 New France4 China5 Nigeria6 Denmark7
Zealand3
UK1 USA2 New France4 China5 Nigeria6 Denmark7
Zealand3
Rome II = 5%Rome II = 5%
IBS versus Other Important Disease States
IBS versus Other Important Disease States
• US prevalence of IBS/functional bloating up to 20%1
• US prevalence rates for other common diseases2
– Diabetes 3%– Asthma 4%
– Heart disease 8%– Hypertension 11%
• US prevalence of IBS/functional bloating up to 20%1
• US prevalence rates for other common diseases2
– Diabetes 3%– Asthma 4%
– Heart disease 8%– Hypertension 11%
1Camilleri M et al. Aliment Pharmacol Ther 1997;11:3–152Adams P, et al. Vital Health Stat 10 1991;181:1–212
1Camilleri M et al. Aliment Pharmacol Ther 1997;11:3–152Adams P, et al. Vital Health Stat 10 1991;181:1–212
Drossman DA et al. Dig Dis Sci 1993; AGA Teaching Unit in IBS, 1997Drossman DA et al. Dig Dis Sci 1993; AGA Teaching Unit in IBS, 1997
0
1
2
3
4
5
6
IBS Non-IBS
Num
ber
of v
isits
per
yea
r
GI
Non-GI
0
1
2
3
4
5
6
IBS Non-IBS
Num
ber
of v
isits
per
yea
r
GI
Non-GI
PHYSICIANS VISITS PER YEARPHYSICIANS VISITS PER YEAR
0
5000
10000
15000
20000
25000
Direct Indirect
The Burden of Gastrointestinal Diseases. AGA 2001The Burden of Gastrointestinal Diseases. AGA 2001
COST OF IBS (in millions)COST OF IBS (in millions)
3030
4040
5050
6060
7070
8080
9090
Role-Physical
Role-Physical
Bodily Pain
Bodily Pain
VitalityVitality Social Functioning
Social Functioning
Role-Emotional
Role-Emotional
Mental HealthMental Health
Me
an
SF
-36
sc
ore
Me
an
SF
-36
sc
ore
US NormUS Norm
IBSIBS
Adapted from Wells et al. Aliment Pharmacol Ther. 1997;11:1019-1030. Adapted from Wells et al. Aliment Pharmacol Ther. 1997;11:1019-1030.
Impact of IBS on Quality of Life Compared with US Norms
Impact of IBS on Quality of Life Compared with US Norms
General Health
General Health
PhysicalFunctioning
PhysicalFunctioning
100100
3030
4040
5050
6060
7070
8080
9090
Me
an
SF
-36
sc
ore
Me
an
SF
-36
sc
ore
US NormUS Norm
Diabetes type IIDiabetes type II
IBSIBS
Clinical depressionClinical depression
Adapted from Wells et al. Aliment Pharmacol Ther. 1997;11:1019-1030. Adapted from Wells et al. Aliment Pharmacol Ther. 1997;11:1019-1030.
Impact of IBS on Quality of Life Compared with Other Medical Conditions
Impact of IBS on Quality of Life Compared with Other Medical Conditions
Role-Physical
Role-Physical
Bodily Pain
Bodily Pain
VitalityVitality Social Functioning
Social Functioning
Role-Emotional
Role-Emotional
Mental HealthMental Health
General Health
General Health
PhysicalFunctioning
PhysicalFunctioning
100100
Abnormal motility2Abnormal motility2
Visceral hypersensitivity2Visceral hypersensitivity2
Brain-gut interaction2Brain-gut interaction2
5-HT mediated visceralsensitivity and gut motility1
5-HT mediated visceralsensitivity and gut motility1
19501950 20002000
1Prior A, Read N. Aliment Pharmacol Ther 19932Drossman D. Aliment Pharmacol Ther 1999
1Prior A, Read N. Aliment Pharmacol Ther 19932Drossman D. Aliment Pharmacol Ther 1999
EVOLUTION OF MECHANISTIC HYPOTHESES IN IBS
EVOLUTION OF MECHANISTIC HYPOTHESES IN IBS
Small bowel bacterial overgrowthSmall bowel bacterial overgrowth
% REPORTING PAIN
IBS PATIENT
H. Mertz, 2000.H. Mertz, 2000.
ABERRANT ACTIVATION OF CNS PAIN CENTERS IN IBS
ABERRANT ACTIVATION OF CNS PAIN CENTERS IN IBS
2.83.4
3
4.6
8.48.6
10.29.4
0
2
4
6
8
10
12
Relaxing sounds Conflicting sounds Relaxing sounds Conflicting sounds
2.83.4
3
4.6
8.48.6
10.29.4
0
2
4
6
8
10
12
Relaxing sounds Conflicting sounds Relaxing sounds Conflicting sounds
Unpleasentness at 45 mm Hg (cm)Unpleasentness
at 45 mm Hg (cm)
Dickhaus et al. Am J Gastroenterol 2003;98:135-43Dickhaus et al. Am J Gastroenterol 2003;98:135-43
Anger ratingAnger rating
***p<0.05*p<0.05
***p<0.05*p<0.05
AUDITORY STRESS ALTERS PERCEPTUAL AND EMOTIONAL RATINGS OF VISCERAL STIMULI
AUDITORY STRESS ALTERS PERCEPTUAL AND EMOTIONAL RATINGS OF VISCERAL STIMULI
ControlsControls
IBSIBS
CNS – 5%CNS – 5%
– Enterochromaffin cells– Neuronal– Enterochromaffin cells– Neuronal
GI tract – 95% GI tract – 95%
Gershon MD. Aliment Pharmacol Ther 1999;13(Suppl. 2):15–30Gershon MD. Aliment Pharmacol Ther 1999;13(Suppl. 2):15–30
PHYSIOLOGIC DISTRIBUTION OF 5-HTPHYSIOLOGIC DISTRIBUTION OF 5-HT
5-HT5-HT
Excitatorymotor neuron(contraction)
Excitatorymotor neuron(contraction)
5-HTreceptors5-HTreceptors
Inhibitorymotor neuron (relaxation)Inhibitorymotor neuron (relaxation)
Enterochromaffin cellsEnterochromaffin cells
InterneuronsInterneurons
SensoryneuronSensoryneuron
MOTOR ACTIVITY IN IBSMOTOR ACTIVITY IN IBS
5-HT45-HT4 5-HT35-HT3
IBSIBSIBSIBS
Gas retention
Genetic polymorphism: SERT/Cytokines
Inflammation
Social stress
?Foodhypersensitivity
Altered ANS
Sleep dysfunction
Colonic flora
?Small bowel bacterial
overgrowth
Heightened visceral
nociception
Gut-Brain Axis dysfunction
Post-Infectious IBS
Altered serotonergic
function
• Education/reassurance
• Dietary modification
• Focus on health
• Set realistic goals
• Pharmacotherapy of GI symptoms
• Monitoring and modification
• Psychological treatments
• Referral to pain management
• Education/reassurance
• Dietary modification
• Focus on health
• Set realistic goals
• Pharmacotherapy of GI symptoms
• Monitoring and modification
• Psychological treatments
• Referral to pain management
KEYS TO TREATMENT OF IBSKEYS TO TREATMENT OF IBS
• 27 studies: Median placebo response 47% (range 5 – 84%)
• REASONS:
– On-going attention and care
– Expectation of “treatment” response
– Placebo response may represent, in part, natural fluctuations in symptoms
– Chance
• 27 studies: Median placebo response 47% (range 5 – 84%)
• REASONS:
– On-going attention and care
– Expectation of “treatment” response
– Placebo response may represent, in part, natural fluctuations in symptoms
– Chance
HIGH PLACEBO RESPONSE RATES IN IBS
HIGH PLACEBO RESPONSE RATES IN IBS
Anticholinergics
SM relaxants
• mebeverine
• cimetropium
• pinaverium
• otilonium
• trimebutine
• zamifenacin
• darifenacin
Anticholinergics
SM relaxants
• mebeverine
• cimetropium
• pinaverium
• otilonium
• trimebutine
• zamifenacin
• darifenacin
inhibiting
gut
spasms
inhibiting
gut
spasms
modulating
visceral pain
pathway &
anti-nociceptive
effect
modulating
visceral pain
pathway &
anti-nociceptive
effect
5-HT3-antagonists
• Alosetron , cilansetron
5-HT4-agonist
• tegaserod
Antidepressants• Tricyclics, SSRI
NK2-receptor antagonist
• nepadutant
kappa-opioid agonist
• fedotozine
5-HT3-antagonists
• Alosetron , cilansetron
5-HT4-agonist
• tegaserod
Antidepressants• Tricyclics, SSRI
NK2-receptor antagonist
• nepadutant
kappa-opioid agonist
• fedotozine
TREATMENT OF IBSTREATMENT OF IBS
Pain &Pain &bloatingbloating Pain &Pain &bloatingbloating
• Meta-analysis of 23 RCTs with comparable outcomes (1888 pts)
• 5 superior to placebo: mebeverine , pinaverium, otilium, trimebutine, cimetropium
• Meta-analysis of 23 RCTs with comparable outcomes (1888 pts)
• 5 superior to placebo: mebeverine , pinaverium, otilium, trimebutine, cimetropium
Poynard et al. Aliment Pharmacol Ther 2001;15:355-61.Poynard et al. Aliment Pharmacol Ther 2001;15:355-61.
EFFICACY OF ANTISPASMODIC AGENTSEFFICACY OF ANTISPASMODIC AGENTS
5653
44
3841
35
0
20
40
60
80
Global Improvement Pain Improvement Abdominal DistentionImprovement
Active
Placebo56
53
44
3841
35
0
20
40
60
80
Global Improvement Pain Improvement Abdominal DistentionImprovement
Active
Placebo
****** ******
****
*** p<0.001 ** p=0.008 *** p<0.001 ** p=0.008
Anticholinergics
SM relaxants
• mebeverine
• cimetropium
• pinaverium
• otilonium
• trimebutine
• zamifenacin
• darifenacin
Anticholinergics
SM relaxants
• mebeverine
• cimetropium
• pinaverium
• otilonium
• trimebutine
• zamifenacin
• darifenacin
inhibiting
gut
spasms
inhibiting
gut
spasms
modulating
visceral pain
pathway &
anti-nociceptive
effect
modulating
visceral pain
pathway &
anti-nociceptive
effect
5-HT3-antagonists
• Alosetron , cilansetron
5-HT4-agonist
• tegaserod
Antidepressants• Tricyclics, SSRI
NK2-receptor antagonist
• nepadutant
kappa-opioid agonist
• fedotozine
5-HT3-antagonists
• Alosetron , cilansetron
5-HT4-agonist
• tegaserod
Antidepressants• Tricyclics, SSRI
NK2-receptor antagonist
• nepadutant
kappa-opioid agonist
• fedotozine
TREATMENT OF IBSTREATMENT OF IBS
Pain &Pain &bloatingbloating Pain &Pain &bloatingbloating
• 7 trials: Only 1 met high quality criteria1
• 4 reported significant improvement in:
– Abdominal pain
– diarrhea1
• 7 trials: Only 1 met high quality criteria1
• 4 reported significant improvement in:
– Abdominal pain
– diarrhea1
LOW-DOSE TRICYCLIC ANTIDEPRESSANTS
LOW-DOSE TRICYCLIC ANTIDEPRESSANTS
1Jailwala et al. Ann Intern Med 2000; 2 Jackson et al. Am J Med 20001Jailwala et al. Ann Intern Med 2000; 2 Jackson et al. Am J Med 2000
A Randomized Double-Blind Placebo-Controlled Trial of
Imipramine in IBS
A Randomized Double-Blind Placebo-Controlled Trial of
Imipramine in IBSSharara A et al.
Oral presentation at the Annual Scientific Meeting of the American College of Gastroenterology 2006
and Winner of ACG/Novartis Research Award
Sharara A et al. Oral presentation at the Annual Scientific Meeting of the American College of Gastroenterology 2006
and Winner of ACG/Novartis Research Award
NS15 (31.3%)14 (23.7%)Mixed (alternating)
NS7 (14.6%)11 (18.6%)Diarrhea (D)
NS100%100%Prior medical Rx
NS15 (31.3%)17 (28.8%)Constipation (C)
NS40 (83.3%)45 (76.3%)Flatulence
NS47 (97.9%)58 (98.3%)Pain
NS46 (95.8%)57 (96.6%)Bloating/Distention
NS29 (60.4%) referrals 38 (64.4%) referralsType of recruitment
NS29 (60.4%)33 (55.9%)Sex (% Male)
NS45.3±13.8 42.6±12.4Mean Age
p-valuePlacebo(n=48)
Imipramine(n=59)
Patient Characteristics
Drop-outs
Imipramine* Placebo
Premature withdrawal 6 14
Lost to follow-up 3 3
Protocol violation 5 1
Side-effects 14 5
58.1%
28.0%
80.6%83.3%85.4%
0%
48.0%51.4%52.5%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
0 4 8 12 16
Weeks
Imipramine Placebo
Patient Global Relief (Per Protocol)
p<0.05
Sharara A et al. Oral presentation ACG 2006. Winner of ACG/Novartis Research AwardSharara A et al. Oral presentation ACG 2006. Winner of ACG/Novartis Research Award
14.6%
30.5%
42.4%
50.8%
59.3%
0%
25.0%
37.5%
43.8%
0%
10%
20%
30%
40%
50%
60%
70%
0 4 8 12 16
Weeks
Imipramine Placebo
Patient Global Relief (intent-to-treat)
p=0.053
Sharara A et al. Oral presentation ACG 2006. Winner of ACG/Novartis Research AwardSharara A et al. Oral presentation ACG 2006. Winner of ACG/Novartis Research Award
Sweating1
Genitourinary symptoms
2
Dizziness3
Dry mouth1
Disturbed sleep
1
Palpitations 2
GI disturbance
3 Anxiety1
Imipramine-Associated Side Effects
3.0%
12.1%
0.0%
5.0%
10.0%
15.0%
Placebo Imipramine
Mean % Change in SF36 Scores
p<0.01
Anticholinergics
SM relaxants
• mebeverine
• cimetropium
• pinaverium
• otilonium
• trimebutine
• zamifenacin
• darifenacin
Anticholinergics
SM relaxants
• mebeverine
• cimetropium
• pinaverium
• otilonium
• trimebutine
• zamifenacin
• darifenacin
inhibiting
gut
spasms
inhibiting
gut
spasms
modulating
visceral pain
pathway &
anti-nociceptive
effect
modulating
visceral pain
pathway &
anti-nociceptive
effect
5-HT3-antagonists
• Alosetron , cilansetron
5-HT4-agonist
• tegaserod
Antidepressants• Tricyclics, SSRI
NK2-receptor antagonist
• nepadutant
kappa-opioid agonist
• fedotozine
5-HT3-antagonists
• Alosetron , cilansetron
5-HT4-agonist
• tegaserod
Antidepressants• Tricyclics, SSRI
NK2-receptor antagonist
• nepadutant
kappa-opioid agonist
• fedotozine
TREATMENT OF IBSTREATMENT OF IBS
Pain &Pain &bloatingbloating Pain &Pain &bloatingbloating
Effect of Alosetron on Relief of Abdominal Pain and Discomfort and Stool Consistency (D-IBS)Effect of Alosetron on Relief of Abdominal Pain and Discomfort and Stool Consistency (D-IBS)
Camilleri M et al. Lancet 2000;355:1035–40Camilleri M et al. Lancet 2000;355:1035–40
With
rel
ief (
%)
With
rel
ief (
%)
1 2 3 4 5 6 7 8 9 10 11 12 +1 +2 +3 +41 2 3 4 5 6 7 8 9 10 11 12 +1 +2 +3 +4
LOCFLOCF
Placebo b.i.d.Placebo b.i.d.
Alosetron 1mg b.i.d.Alosetron 1mg b.i.d.
*p<0.05*p<0.05
70
60
50
40
30
20
10
0
70
60
50
40
30
20
10
0
12 weeks treatment12 weeks treatment 4 weeks follow-up4 weeks follow-up
**
**
** **** ** **
**** ** ****
Sto
ol c
onsi
sten
cy s
core
Sto
ol c
onsi
sten
cy s
core
Alosetron 1mg b.i.d.Alosetron 1mg b.i.d.
PlaceboPlacebo
LOCFLOCF
**p<0.001**p<0.001
Har
dH
ard
Ver
y ha
rdV
ery
hard
For
me
dF
orm
ed
0 1 2 3 4 5 6 7 8 9 10 11 12 +1 +2 +3 +40 1 2 3 4 5 6 7 8 9 10 11 12 +1 +2 +3 +4
12 weeks treatment12 weeks treatment 4 weeks follow-up4 weeks follow-up
4
3
2
1
4
3
2
1Lo
ose
Loo
se
******** **** **** **** **** ******** **** ******** ****
TegaserodTegaserod
• Aminoguanidine indole derivative of serotonin• Specific 5-HT4 partial agonist• Actions:
– Stimulates small and large intestinal motility– Accelerates whole oro-cecal transit time– Stimulated peristalsis and gastric emptying– Stimulates intestinal chloride secretion– Inhibits visceral hypersensitivity
• Aminoguanidine indole derivative of serotonin• Specific 5-HT4 partial agonist• Actions:
– Stimulates small and large intestinal motility– Accelerates whole oro-cecal transit time– Stimulated peristalsis and gastric emptying– Stimulates intestinal chloride secretion– Inhibits visceral hypersensitivity
TEGASEROD in C-IBSSatisfactory relief by week (ITT)
TEGASEROD in C-IBSSatisfactory relief by week (ITT)
*p<0.05; **p<0.01 vs placebo*p<0.05; **p<0.01 vs placebo
0
10
20
30
40
50
60
70
80
Week
Pat
ien
ts (
%)
0
10
20
30
40
50
60
70
80
Week
Pat
ien
ts (
%) **** ****
****
**** **** ******** **** ******** ****
**
****
–1 2 4 6 8 10 12 WD2 WD4–1 2 4 6 8 10 12 WD2 WD4
placeboplacebo tegaserodtegaserod
Melatonin and the GutMelatonin and the Gut
Barajas-Lopez C et al 1996; Storr M et al 2000; Roberts-Thomson IC 1988; Lu WZ et al 2005Barajas-Lopez C et al 1996; Storr M et al 2000; Roberts-Thomson IC 1988; Lu WZ et al 2005
• Melatonin exerts both excitatory & inhibitory effects on the gut but mechanism unclear
• ? blockade of nicotinic channels and/or interaction with Ca2+-activated K+ channels
• ?mediating gut visceral sensation
• Melatonin exerts both excitatory & inhibitory effects on the gut but mechanism unclear
• ? blockade of nicotinic channels and/or interaction with Ca2+-activated K+ channels
• ?mediating gut visceral sensation
RCT of Melatonin in IBSRCT of Melatonin in IBS
Song, G H et al. Gut 2005;54:1402-1407Song, G H et al. Gut 2005;54:1402-1407
Melatonin in IBSMelatonin in IBS
• Melatonin did not change rectal pressures during squeezing, pushing, or resting states indicating that melatonin did not influence gut motility
• 3 mg melatonin at bedtime for two weeks did not improve subjective or objective sleep parameters
• Melatonin did not change rectal pressures during squeezing, pushing, or resting states indicating that melatonin did not influence gut motility
• 3 mg melatonin at bedtime for two weeks did not improve subjective or objective sleep parameters
Song, G H et al. Gut 2005;54:1402-1407Song, G H et al. Gut 2005;54:1402-1407
Probiotics in IBSProbiotics in IBS
• 77 patients with IBS randomized to Lactobacillus salivarius or Bifidobacterium infantis (1 x 1010 live bacterial cells) for 8 weeks
• Symptoms, QoL, stool microbiologic studies, and PBMC release of IL-10 and IL-12 done at beginning and end of study
• 77 patients with IBS randomized to Lactobacillus salivarius or Bifidobacterium infantis (1 x 1010 live bacterial cells) for 8 weeks
• Symptoms, QoL, stool microbiologic studies, and PBMC release of IL-10 and IL-12 done at beginning and end of study
O’Mahoney L et al. Gastroenterology 2005;128:541-551O’Mahoney L et al. Gastroenterology 2005;128:541-551
Probiotics in IBSProbiotics in IBS
O’Mahoney L et al. Gastroenterology 2005;128:541-551O’Mahoney L et al. Gastroenterology 2005;128:541-551
1Balsari A et al. Microbiology 1982;5:185-94 2King TS et al. Lancet 1998;352:1187-9
1Balsari A et al. Microbiology 1982;5:185-94 2King TS et al. Lancet 1998;352:1187-9
Probiotics in IBSProbiotics in IBS
Which of the following do you find as the most disturbing-and difficult to treat-
symptom in IBS?
Which of the following do you find as the most disturbing-and difficult to treat-
symptom in IBS?
1. Abdominal pain2. Constipation3. Diarrhea4. Bloating5. Feeling of incomplete evacuation6. Alternating diarrhea & constipation
1. Abdominal pain2. Constipation3. Diarrhea4. Bloating5. Feeling of incomplete evacuation6. Alternating diarrhea & constipation
• The colon is the major site of intestinal H2 formation (>99% in fasting state and after lactose)
• H2 production depends upon delivery of non-absorbable CHO to colon bacteria (1014 bacteria)
• Large quantities can be liberated with relatively small amounts of CHO (85 mL over 90-min period1)
• Symptoms of gaseous distention after certain foods are temporally related to breath H2 concentration2
• The colon is the major site of intestinal H2 formation (>99% in fasting state and after lactose)
• H2 production depends upon delivery of non-absorbable CHO to colon bacteria (1014 bacteria)
• Large quantities can be liberated with relatively small amounts of CHO (85 mL over 90-min period1)
• Symptoms of gaseous distention after certain foods are temporally related to breath H2 concentration2
Hydrogen Gas in ManHydrogen Gas in Man
1Levitt MD. N Engl J Med 1969;281:122-7 2Calloway D. Gastroenterology 1966;51:383-9
1Levitt MD. N Engl J Med 1969;281:122-7 2Calloway D. Gastroenterology 1966;51:383-9
RifaximinRifaximin• Rifamycin derivative: inhibits bacterial RNA
synthesis
• Non-absorbable & free of side-effects
• Good activity against aerobic & anaerobic bacteria1
• Low level of resistance strains with chronic use2, 3
• Causes significant in H2 production in GI tract4
• Shown in open-label studies to reduce symptoms of flatulence and bloating4, 5
• Rifamycin derivative: inhibits bacterial RNA synthesis
• Non-absorbable & free of side-effects
• Good activity against aerobic & anaerobic bacteria1
• Low level of resistance strains with chronic use2, 3
• Causes significant in H2 production in GI tract4
• Shown in open-label studies to reduce symptoms of flatulence and bloating4, 5
1Drugs 1995;49:467-84; 2Drugs Exp Clin Res 1986;12:979-81;3Chemotherapy2000;46:253-66;4Aliment Pharmacol Ther 2000;14:551-6; 5Int J Colorectal Dis 2003;18:55-62
1Drugs 1995;49:467-84; 2Drugs Exp Clin Res 1986;12:979-81;3Chemotherapy2000;46:253-66;4Aliment Pharmacol Ther 2000;14:551-6; 5Int J Colorectal Dis 2003;18:55-62
Global Assessment of ReliefGlobal Assessment of Relief
*
*
Sharara AI et al. Am J Gastroenterol 2006Sharara AI et al. Am J Gastroenterol 2006
* p < 0.05
*
*
IBS patients
Sharara AI et al. Am J Gastroenterol 2006Sharara AI et al. Am J Gastroenterol 2006
* p < 0.05
Global Assessment of ReliefGlobal Assessment of Relief
Symptom score vs. LHBTSymptom score vs. LHBT
Rifaximin Placebo
Bloating score vs. LHBTBloating score vs. LHBT
Rifaximin Placebo
Constipation With IBS
Constipation With IBS
Diarrhea pred.IBS
Diarrhea pred.IBS
Pain pred.IBS
Pain pred.IBS
Fiber, exercise
Fluid intake
Osm. LaxativeAntispasmodic
agents
Serotonin-4 agonist
? Low-doseTCA
Trial diet excluding
lactose/caffeine
Loperamide, Antispasmodic
agent
Serotonin-3 antagonist
Serotonin-3 antagonist if
diarrhea occurs
Co
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oth
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reev
alu
atio
n
mildmild
Antispasmodic agent
moderatemoderate severesevere
Modified from Mertz HR. N Engl J Med 2003;349;2136-46.
Low-dose TCA
Ed
uc
atio
n,
reas
sura
nc
e, s
tres
s m
ana
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ent
Low-dose TCA
Proposed AlgorithmProposed Algorithm