Fondazione Rosa Gallo
“Attualità chirurgiche nelle
malattie del colon-retto”
Verona, 14 giugno 2012
Simposio
“La stipsi severa attualità terapeutiche”
“Novità nella terapia medica”
Gabriele Riegler
Seconda Università di Napoli
STIPSI E LASSATIVI
CAMPIONE INTERVISTATO
ETA’
20 - 40
41 - 60
>60
Riegler G. et al.: Clin. Ter. 1986
M.
F.
TOT.
403
408
811
213
113
77
159
138
111
372
251
188
STIPSI E LASSATIVI
330/811 (40.7%)
ASSUMEVANO LASSATIVI
Riegler G. et al.: Clin. Ter. 1986
STIPSI E LASSATIVI
USO DEI LASSATIVI
ASSUNZIONE VS.PRESCRIZIONE
ASSUNZIONE
SETTIMANALE
3-7 VOLTE
1-2 “
<1 “
Riegler G. et al.: Clin. Ter. 1986
PRESCRITTI
SI
NO
67%
52%
29%
33%
48%
71%
STIPSI E LASSATIVI
EFFICACIA TERAPEUTICA
BUONA
MEDIOCRE
NULLA
58%
14%
28%
EFFETTI COLLATERALI
14%
Riegler G. et al.: Clin. Ter. 1986
STIPSI E LASSATIVI
CATEGORIE DI FARMACI
• DA CONTATTO
• OSMOTICI
• DETERGENTI
• LUBRIFICANTI
• FIBRE
Riegler G. et al.: Clin. Ter. 1986
57%
36%
28%
16%
4%
229 pazienti con stipsi funzionale: terapie
Consigli dietetici
Fibre
Lassativi
Clistere
Supposte
Probiotici
Antispastici
Antidepressivi
Ansiolitici
Antibiotici intestinali
Psicoterapia
Riabilitazione pav.pelvi
0
Bellini M. et al.
20
40
60
80
100 %
FIBRE
IDROSOLUBILI
• PHGG
• FOS
• INULINA
• GUAR
• PSYLLIUM
• ALGINATI
• PECTINA
FIBRE
NON IDROSOLUBILI
• EMICELLULOSA
• CELLULOSA
• LIGNINA
MECCANISMO D’AZIONE DELLE FIBRE
insolubili
solubili
< svuotamento gastrico
+
< transito tenue
+
> transito tenue
+
> transito colon
+
< assorbimento
+
< assorbimento colesterolo
+
> peso & volume feci
+
+
> fermentazione
+
++
> acidi grassi a catena corta
++
+
Effect of fibre on global symptom improvement
SOLUBLE FIBRE
Arthurs and Fielding, 1983
Jalihal and Kurian, 1999
Longstreth et al., 1981
Nigam et al., 1984
Prior and Whorwell, 1987
Toskes et al., 1993
Ritchie and Truelove, 1979
Ritchie and Truelove, 1980
Subtotal (95%CI) (41% pla vs 64% treatment)
Test for heterogeneity chi square=13.44; P=0.062
Test for overall effect z=6.31; P<0.0001
INSOLUBLE FIBRE
Cook et al., 1990
Fowlie et al., 1992
Snook and Shepherd, 1994
Soltoft et al., 1976
Subtotal (95%CI) (56% pla vs 50% treatment)
Test for heterogeneity chi square=0.68; P=0.88
Test for overall effect z=-1.01; P=0.3
Total (95%CI) (45% pla vs 60% treatment)
Test for heterogeneity chi square=27.97; P=0.0033
Test for overall effect z=4.93; P<0.00001
-1 -2
Favours control
Bijkerk et al, Aliment Pharmacol Ther 2004;19:245
1
5
10
Favours treatment
500 g / die
200 g / die
+
= 25 g. di fibre
Long term efficacy of PEG
(17.5 gr. bid) vs placebo
% pts with normal bowel movements
on bowel movement frequency in 70 patients with constipation
90
75
RUN IN
PEG
PLA
60
* p < 0.001
45
30
15
0
4
8
Corazziari et al, Gut 2000;46:522-6
12
16
20
24
wks
Effect of PEG vs. Lactulose on Stool Frequency / Wk
PEG better than Lactulose for the following outcomes:
- stool frequency / wk
- form of stools
- relief of abdominal pain
- need for additional products
Lee-Robichaud et al., Cochrane Database Syst Rev. 2010 Jul 7;(7):CD007570
IBS: profile of an ideal drug
• Active in all IBS patients
• Efficacy for the multiple aspects of the IBS symptom
complex
• Devoid of significant side effects
• Sustained activity over time
• Rapid onset of action
• Aimed at underlying pathophysiology
• Improves socio-economic impact of IBS
IBS: Evolving understanding
5-HT mediated visceral
hypersensitivity and
gut motility
Brain-gut interaction
Visceral hypersenstivity
Abnormal motor function
1950
1960
Drossman et al, 1999
1970
1980
1990
2000
Distribution of
5-hydroxytryptamine (5-HT)
CNS - 5%
GI tract - 95%
enterochromaffin cells
neuronal
Gershon, 1999
Serotonin (5-HT): key mediator of
gut motility and visceral sensitivity
CNS – 5%
Activation of 5-HT4 receptors
regulates
GI function:
– increases motility
throughout the GI tract
(peristalsis)
GI tract – 95%
– enterochromaffin cells
– neuronal
Gershon. Aliment Pharmacol Ther 1999;13:15–30
Crowell. Am J Managed Care 2001;7(Suppl):S252–S260
Lacy, Yu. J Clin Gastroenterol 2002;34:27–33
– inhibits visceral sensitivity
(pain)
– stimulates intestinal
secretion
Pharmacological Classes of
Prokinetics
Motilin receptor agonists
Erythromycin
Mitemcinal
Alemcinal
Dopamine receptor
antagonists
Domperidone
Metoclopramide
Levosulpiride
Itopride
Cholinesterase inhibitors
Pyridostigmine
Itopride
5-HT4 agonists
Cisapride
Tegaserod
Renzapride
Clebopride
Mosapride
Prucalopride
Velusetrag
Naronapride
Linaclotide
…
Prucalopride targets the receptors involved
in the underlying impaired motility
Selective and
specific
stimulation of
5-HT4 receptors
on intrinsic
sensory neurons1,2
Triggers
peristaltic
reflex and
colonic mass
movement3
1Briejer
& Bosmans. Eur J Pharmacol 2001;423:71
et al. Gastroenterology 1998;115:370 Rectum
3Prins et al. Br J Pharmacol 2000;131:927
4Bouras et al. Gut 1999;44:682
2Grider
Prucalopride
significantly
accelerates overall
colonic transit (p<0.05)
and proximal colonic
emptying t1/2 (p<0.05)4
Three pivotal prucalopride trials:
Main inclusion criteria
• Adult patients (≥18 years) of either gender
• History of chronic constipation, defined as:
– ≤2 spontaneous complete bowel movements/week
for
a minimum of 6 months
– ≥1 of the following symptoms for at least
a quarter of stools:
• Very hard or hard stools
• A sensation of incomplete evacuation
• Straining during defaecation
The 3 studies had identical inclusion criteria and endpoints so the results can be pooled and analysed together
1Camilleri
3Quigley
et al. N Engl J Med 2008;358:2344. 2Tack et al. Gut 2009;58:357
et al. Aliment Pharmacol Ther 2008;29:315
Efficacy in chronic constipation:
≥3 SCBM/week (primary endpoint)
(SCBM = spontaneous complete bowel movements)
35
30.9 28.4
*** ***
% over 12 weeks
30
23.6 24.7
*** ***
25
19.5
**
20
15
11.3
10
23.9 23.5
**
**
23.6
***
12.1
12.0
9.6
5
0
Camilleri11
(n=1924)
Tack2
(n=713) (91% F)
Placebo
Quigley3
(n=641) (87% F)
Prucalopride 2 mg
Camilleri4
(n=620) (88% F)
Prucalopride 4 mg
**p≤0.01 vs. placebo
***p≤0.001 vs. placebo
1Camilleri
et al. Gastroenterology 2008;134:A548. 2Tack et al. Gut 2009;58:357
3Quigley et al. Aliment Pharmacol Ther 2008;29:315. 4Camilleri et al. N Engl J Med 2008;358:2344
Efficacy in chronic constipation:
Increase of ≥1 SCBM/week (secondary endpoint)
60
47.0
43.1 ***
***
% over 12 weeks
50
38.1
***
40
30
44.1
***
27.5
24.6
47.3 46.6
*** ***
46.6
42.6 ***
***
25.8
20.9
20
10
0
Pooled data1
(n=1924)
Placebo
INT–62
(n=713)
USA–133
(n=641)
Prucalopride 2 mg
USA–114
(n=620)
Prucalopride 4 mg
***p≤0.001 vs. placebo
1Camilleri
et al. Gastroenterology 2008;134:A548. 2Tack et al. Gut 2009;58:357
3Quigley et al. Aliment Pharmacol Ther 2008;29:315. 4Camilleri et al. N Engl J Med 2008;358:2344
Efficacy in chronic constipation:
Quality of life
% subjects with an average increase of ≥1 point on PAC-QOL
satisfaction subscale at Week 12
60%
47.1*** 47.8***
45.8***
50%
45.6***
44.0*** 43.3***
43.5*** 44.4***
40%
26.0
30%
25.2
22.2
21.8
20%
10%
0%
Pooled
INT-6
Placebo
USA-13
PRU 2mg
USA-11
PRU 4mg
***p<0.001 vs. placebo
Tack et al. Gut 2009;58:357
Quigley et al. Aliment Pharmacol Ther 2008;29:315. Camilleri et al. N Engl J Med 2008;358:2344
Efficacy in chronic constipation:
Onset of response
Median time (range) to first “SBCM” (hours:minutes)
Placebo
(n=645)
26.5 (5–98)
Prucalopride 2 mg
(n=640)
2.5 (1–13) *
Prucalopride 4 mg
(n=639)
2 (1–7) *
* p < 0.001 prucalopride vs. placebo
SBM: spontaneous bowel movement
Camilleri et al. Gastroenterology 2008; 134: A548
Pooled data: Response maintained
over the 12-week treatment period
50
% over 12 weeks
40
*
*
*
30
*
*
*
*
*
*
*
*
20
10
0
Placebo
Prucalopride 2 mg
*p<0.001 vs. placebo for both doses of prucalopride
Stanghellini et al. Gut 2009 Abstract [2891]
Prucalopride 4 mg
*
Pooled safety and tolerability:
Adverse events
Most common drug-related adverse events
30
Patients (%)
25
20
15
10
5
0
Placebo (n=661)
Prucalopride 2 mg (n=659)
Tack et al. Gastroenterology 2008;134:A530
Prucalopride 4 mg (n=657)
Summary
• Prucalopride has been evaluated extensively (~2700 patients)
– Normalisation of bowel function (≥3 SCBM/week) compared with
placebo
– An improvement in bowel function (≥1 SCBM/week) compared with
placebo
– Adverse events occurred primarily on Day 1
– No indication of QT prolongation
– Efficacy maintained in the long-term
• Prucalopride (1‒2 mg) is authorised in Europe for the symptomatic
treatment of chronic constipation in women in whom laxatives fail to
provide adequate relief
• Recommendation by an expert panel is to use this drug when 2 different
laxatives have failed to provide relief
*P≤ 0.001, vs. PLA
**P≤ 0.01, vs. PLA
1276 patients;
Linaclotide od for 12 wks
Primary endpoint:  3CSBM
Lembo et al., N Engl J Med 2011;365:527-36
ERNST E.
ABDOMINAL MASSAGE THERAPY FOR
CHRONIC CONSTIPATION: A SYSTEMATIC
REVIEW OF CONTROLLED CLINICAL TRIALS
Forsch. Komplementarmed, 1999