1,721,185 research outputs found
The use of artificial neural network in gastroenterology : the experience of the first 10 years
No full text
Proton pump inhibitor failure: why does it occur and how can it be managed?
No full textProton pump inhibitors (PPIs) are the best medical
therapy for patients with gastro-oesophageal reflux disease
(GORD), as they control symptoms and heal oesophagitis
in about 80% of the cases [1] . Despite this high
degree of efficacy, a substantial part of the patients remains
symptomatic on once-daily PPI, and this is particularly
true for those with non-erosive reflux disease
(NERD). Although there is no universal agreement on
the definition of PPI failure in terms of frequency and
severity of symptoms, an incomplete or unsatisfactory response
of them to a full course of PPIs can be empirically
accepted as ‘refractory GORD’
Pharmacodynamic studies on PPIs: look carefully at the country of origin.
No full textThe pharmacodynamic effect of proton pump inhibitors
(PPIs) given in single daily dose is characterised by a complete
control of gastric acid secretion during the daytime and
a relatively lower activity during the nighttime [1]. Doubling
and fractioning the standard dosage of PPIs is generally associated
with a more uniform and constant increase of gastric pH over the whole 24-h period [2,3]. Among the various
factors capable of affecting the pharmacodynamic profile of
PPIs, Helicobacter pylori infection harbouring in the stomach
has been documented as a cause of increased gastric pH
in many studies [4,5]. The mechanism is not clear, but the
production of ammonia buffering gastric acid as result of bacterial
urease activity seems to play the most important role [6].
In this issue of the journal, Shimatani et al. [7] have
evaluated, in a prospective cross-over study, 24 CYP2C19 extensive metaboliser individuals from Japan, who were
subdivided into 13 H. pylori-negative healthy volunteers
and 11 asymptomatic H. pylori-positive subjects. They were
administered sequentially placebo, rabeprazole 10 mg twice
daily and 20 mg twice daily for 7 days, in a randomised
manner, and underwent three 24-h intragastric pH measurements
on the 7th day of each treatment in order to assess
the influence of H. pylori infection on the acid-suppressant
effect of the two doses of PPI. The Authors selected a group
of extensive metabolisers to assimilate as much as possible
their study population to people living in Western countries.
It is well known that there is a genetic polymorphism of
CYP2C19 which allows us to subdivide subjects roughly
into two categories: extensive or rapid metabolisers and poor
or slow metabolisers. The latter group, however, is much
more frequent in Asian than in Caucasian populations [8]
and therefore the Authors excluded them from the study in
order to avoid a possible bias.
The results they obtained show that the two rabeprazole
dosages had a much greater acid suppressive effect than
placebo, without significant difference between them. As to
the status of H. pylori infection, intragastric pH was significantly
higher in infected than in non-infected subjects.
Accordingly, nocturnal acid breakthrough (NAB) occurred
less in the former group. The only difference between the
two dosages of rabeprazole was the lower number of NAB
episodes achieved with 20 mg than 10 mg twice daily in H.
pylori-negative subjects, although a statistical significance
was not reached. However, the clinical relevance of NAB
episodes has been overemphasised in the past, because most
patients with gastro-oesophageal reflux disease (GORD) do
not present this phenomenon and especially patients with Barrett’s
oesophagus are more likely to have acid reflux during
NAB [9].
The significantly higher acid inhibition of rabeprazole
than placebo and the increased intragastric pH in H. pyloripositive
compared with H. pylori-negative subjects are
expected according to the previous medical literature in this
field [1–6]. Moreover, the impact of H. pylori eradication in
the management of patients with acid-related diseases is only
marginal, because there is no need of PPI dose adjustment to
maintain the therapeutic benefit in GORD patients whose
infection has been eliminated [6,10]. Lastly, if we look at a
recent study also coming from Japan [11], it has been shown
that the presence of H. pylori infection potentiates the symptomatic
response of GORD patients to famotidine and not to
low-dose lansoprazole.
An important drawback of this study is that PPIs were
administered after meals, while it is well known that these
drugs achieve their maximal acid-lowering effect when
given approximately half an hour before breakfast [3,8,12].
Although the Authors quote some papers showing the lack
of influence by meals on the pharmacodynamic properties of
PPIs in Asiatic populations, many studies carried out inWestern
countries confirm that the antisecretory action of these
drugs is greatly affected by meals [13–15] and a once daily
morning dosage regimen is generally recommended in the
treatment of acid-related diseases. In addition, a very recent
paper [16] has also shown that more than 50% of patients taking
PPIs and referred for persistent GORD symptoms were
suboptimal dosers, in that the intake of the drug occurred
>60 min before meals, after meals, at bedtime or as needed.
Accordingly, the therapeutic successwas lower than expected
in these cases.
It is also reasonable to think that the unusual administration
time of PPIs in this study may be responsible for
the surprising finding of a similar acid inhibition by the two
different dosages of rabeprazole. Many studies have clearly
shown a dose-dependent effect of PPIs [17,18] and this is
the reason for which doubling the dosage of PPIs can be the
simplest and most convenient measure to transform a therapeutic
failure with standard doses into a success [19,20]. It
cannot be excluded, however, that the similar pharmacodynamic
profiles of the two doses of rabeprazole, 10 mg and
20 mg twice daily, are due to the well known lower gastric
acid secretion of Asian than Caucasian populations [21] and
this reduced acid output can be adequately controlled even
by the smaller dose of PPI.
In conclusion, the study by Shimatani et al. is well done
from a methodological point of view and the Authors must be
congratulated for choosing Japanese patients with a genetic
polymorphism of CYP2C19 which is similar to that found
in Western populations. However, on one hand, the results
they achieved confirm previous studies on the influence of
H. pylori infection on the antisecretory effect of PPIs and,
on the other hand, seem to be greatly affected by the peculiar
physiologic background of Asian people. Therefore, their
findings cannot be easily extrapolated to ourWestern patients
and it must be acknowledged that the Authors themselves
have emphasised this point by making clear in the title of
the paper that the study was performed in Japanese subjects
The reason for failure of on-demand PPI therapy in NERD patients.
No full textTo The Editors:
We read with interest the paper by Wu et al (1) showing that concomitant irritable bowel syndrome, in addition to functional dyspepsia, is associated with failure of on-demand Proton Pump Inhibitors (PPI) therapy in reflux patients. The Authors performed a large study in which all patients underwent conventional manometry and pH monitoring in order to be characterized. They included in the group with non-erosive reflux disease (NERD) patients with abnormal acid exposure and those with normal acid and a strong correlation between symptoms and acid reflux events (SI>75%). They classified patients with negative symptoms association as having functional heartburn (FH) and excluded them from the study.
The separation of FH from NERD represents a very important point, because the former sub-group is likely to be associated more frequently with other functional GI disorders and this can influence the therapeutic PPIs response. Indeed, in a recent study (2), we have shown that sub-grouping the complex population of endoscopy-negative reflux patients by means of impedance-pH testing led us to demonstrate that several dyspeptic symptoms, such as those pertaining to the postprandial distress syndrome (3), overlap significantly more with FH than with NERD. This sustains the concept that FH may be part of functional GI disorders, in which other factors (i.e. visceral hypersensitivity, psychological factors, etc.) rather than acid seem to play a major role. Therefore, the response to PPI therapy, given in whatever modality in these patients, is very poor.
However, the fact that NERD patients had higher failure rate of on-demand PPI therapy than those with Erosive Esophagitis (EE), even after Wu et al had excluded FH from their study, may depend on additional factors. For instance, the use of traditional pH-metry alone allowed the Authors to detect only NERD patients with an esophagus hypersensitive to acid, while those with a positive symptom association with weakly acidic reflux were necessarily missed. The modern impedance-pH technique has the merit to distinguish acid from weakly acidic reflux events and this allowed us to demonstrate that there is a subgroup of endoscopy-negative patients who have a clear association between heartburn and weakly acidic reflux episodes (4). The presence of patients pertaining to this last subgroup among those with NERD and normal acid in their esophagus represents one of the main causes of non response to PPIs (5) and could explain why in the above study the failure rate to these drugs was higher in NERD than in EE
The relevance of reflux monitoring off therapy.
No full textTo The Editors:
We read the recent article by Vaezi MF. (1) with interest. The Author discussed on the opportunity to evaluate patients with symptoms suggestive of gastro-oesophageal reflux (GERD) by means of 24-h pH or impedance-pH monitoring On or Off therapy. He concluded that, after an empiric trial with twice-daily PPI therapy, in case of refractoriness, patients should undergo reflux monitoring On therapy in order to exclude reflux disease, while testing Off therapy has a limited value, because in this group it results only in an additional test proving what is already established by patients’ lack of response to aggressive PPI therapy.
We agree that an empiric treatment with a twice daily PPI trial is the correct initial approach to patients with suspected GERD and testing should be reserved only to those with persisting symptoms despite antisecretory drugs. However, we believe that a particular attention must be taken when considering the endoscopy-negative population. We have recently observed that patients with non-erosive reflux disease (NERD) evaluated using impedance-pH monitoring Off therapy (2) have frequently symptoms related to weakly acidic reflux, mainly in case of normal esophageal acid exposure. This appears a relevant point, in that we are now able to subtract this subgroup of patients with weakly acidic reflux disease from those without any reflux underlying their symptoms (functional heartburn, FH). These two subgroups require completely different therapeutic approaches (surgery or pain-modulators), although limited outcome data are available in this field (3,4). On the other hand, a recent study (4) has shown that NERD patients refractory to PPIs can equally respond to surgery. In the endoscopy-negative population the risk of including FH in NERD is rather high and we have shown that PPI therapy may cause an underestimation of GERD patients (inability to identify weakly acidic reflux patients) and an overestimation of FH patients (placebo effect) (5). These findings have been confirmed in a recent investigation, in which the analysis of PPIs response in a large number of endoscopy-negative patients with heartburn revealed that those patients with normal acid exposure and positive symptom association had a 50% response to PPIs (6). Therefore, we confirmed that the negative response to PPI therapy does not mean immediately that reflux can be excluded.
Overall, in our opinion, impedance-pH testing On therapy is more indicated in patients with proven reflux disease (erosive esophagitis, Barrett’s esophagus, previous abnormal pH-metry), while endoscopy-negative patients not responding to PPIs should be better assessed Off antisecretory therapy in order to be sure that they have GERD or not
Is acid relevant in the genesis of dyspeptic symptoms associated with nonerosive reflux disease?
No full textAbstract:
A consistent subset of patients with NERD suffers from symptoms centered in the upper part of the abdomen that are more characteristic of functional dyspepsia than reflux disease. The cause of this overlap is still unclear, but acid has been implicated as one of the possible common pathophysiological factors responsible for these two categories of upper gastrointestinal (GI) symptoms. Many physiological investigations and the modest success of proton pump inhibitors in resolving dyspeptic symptoms associated with typical reflux syndrome seem to support the concept that functional dyspepsia and NERD are two separate entities, which need to be treated with different drugs
Functional heartburn and non-erosive reflux disease.
No full textAbstract: Gastroesophageal reflux disease ( GERD) is a common disorder in Western countries. For many years our attention has been focused on patients with erosive esophagitis, but in recent times we have realized that endoscopy-negative reflux disease is the most common presentation of this illness, affecting up to 70% of these individuals. Patients with the non-erosive form (NERD) are a heterogeneous group including various subpopulations with different mechanisms for their main symptom of heartburn: reflux of acidic and non-acidic gastric contents, mucosal hypersensitivity, intra-esophageal distension by gas, intraduodenal infusion of fat, muscle contractions and psychological abnormalities. As to esophageal acid exposure, patients with NERD can be subdivided into those with abnormal and normal pH testing. The latter group includes patients with a positive correlation between symptoms and reflux events, in whom heartburn can be controlled by proton pump inhibitor ( PPI) therapy. According to the recent Rome III criteria, they are still in the realm of GERD. An additional group is called functional heartburn, because this typical symptom is associated neither with an abnormal pH test nor with a positive symptom index. Their response to PPIs is very disappointing. Therefore, there is an increasing consensus on the fact that they do not have GERD and should be treated with drugs other than PPIs
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