Pharmacodynamic studies on PPIs: look carefully at the country of origin.

The 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.