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A Glass of Water Immediately Increases Gastric pH in HealthySubjects George Karamanolis Æ Ioanna Theofanidou Æ Marina Yiasemidou ÆEvangelos Giannoulis Æ Konstantinos Triantafyllou Æ Spiros D. Ladas Received: 18 February 2008 / Accepted: 10 April 2008 / Published online: 13 May 2008Ó Springer Science+Business Media, LLC 2008 Onset of action of antisecretory agents is of pivotal importance for patients with gastroesophagealreflux disease (GERD) treated ‘‘on-demand.’’ Aim To study Up to 20% of the general population has heartburn at least the acute effect of acid-inhibiting drugs and water admin- twice a week while 1–4% of the Western population istration on gastric pH. Method A cross-over study was consumes acid-suppressive drugs, most often for gastro- performed in 12 H. pylori (-), healthy subjects (6 men; esophageal reflux disease (GERD) [].
mean age: 26 years). A single oral dose of the following The majority of symptomatic GERD patients have non- agents was received with a wash-out period between each erosive reflux disease (NERD) and require treatment with study: a glass of water (200 ml), antacid, ranitidine, ome- acid suppressive drugs for symptom relief However, prazole, esomeprazole, and rabeprazole. Gastric pH was GERD is a chronic disease, and relapse of symptoms recorded for 6 h after drug intake. Results Water increased occurs frequently. Studies have shown relapse rates in up to gastric pH [4 in 10/12 subjects after 1 min. The time 70–80% in patients with NERD after they finish an initial (median) needed to pH [4 was for: antacid 2 min, raniti- course of therapy [Therefore, maintenance therapy is dine 50 min, omeprazole 171 min, esomeprazole 151 min, often required for ongoing symptom control.
and rabeprazole 175 min. Gastric pH [4 lasted for 3 min Treatment to relieve symptoms as they occur may be the after water and for 12 min after antacids; it remained [4 best way to manage NERD patients. In the on-demand until the end of recording in: 4/12 subjects with ranitidine, approach, symptoms are allowed to recur, and patients take 11/12 with rabeprazole, and all with omeprazole and an acid-suppressing drug when symptoms arise Since esomeprazole. Conclusion Water and antacid immediately reflux symptoms are often transient, medication for on- increased gastric pH, while PPIs showed a delayed but demand therapy should have a rapid onset of action for prolonged effect compared to ranitidine.
prompt symptom relief and act long enough to preventrecurrent symptoms. Many agents are currently available for the treatment of heartburn, including antacids, H2- receptor antagonists (H2RAs), and proton pump inhibitors(PPIs) []. PPIs have been established to be potent inhib-itors during chronic administration however, H2RAs G. Karamanolis Á I. Theofanidou Á M. Yiasemidou Á are reported to have a faster onset of antisecretory activity Hepatogastroenteroly Unit, 2nd Department of Internal We have observed that many patients with heartburn Medicine-Propaedeutic, ‘‘Attikon’’ University General Hospital, report immediate relief after drug administration. The majority of patients take acid-suppressive drugs with tap water, which usually has an alkaline pH. Thus, we Hepatogastroenteroly Unit, First Department of Internal hypothesized that the water could be the putative factor of Medicine-Propaedeutic, ‘‘Laikon’’ General Hospital, Athens the early post-administartion effect, whereas the active University, Ag. Thoma 17, 11527 Athens, Greecee-mail: sdladas@otenet.gr drug results in the later and prolonged action.
The aims of our prospective study on healthy subjects location of LES was determined by stationary esophageal were: (1) to compare the acute effects (onset and the duration) on intragastric pH of antacids and acid-inhibiting Values for intragastric pH were recorded on a Digitr- drugs (H2RAs and PPIs) and (2) to investigate the effect of apper Mk III (Synectics Medical, Stockholm, Sweden) every 5 s. At the end of pH monitoring, the recorded datawere uploaded from the data logger to a computer and wereanalyzed using a commercially available software program Subjects were 12 (6 men; mean age: 26 years, range 21– Gastric juice was obtained from one healthy fasting vol- 30) healthy volunteers with no symptoms of gastrointesti- unteer. In 20 ml of the sample of gastric juice (pH 1.3), we nal or other disease. None of the subjects was receiving any added different volumes (50, 100, and 200 ml) of tap acid-suppresive medications or medication likely to inter- water, distilled water, and two commercially available act with acid secretion. Volunteers with a negative 13C- bottled mineral waters (Table ). The pH of the used bot- urea breath test for Helicobacter pylori infection were tled water is into the range (from 6.0 to 7.9) of that included in the study. All subjects were doctors or nurses of characterizing nearly all the worldwide bottled mineral our unit and medical students who volunteered to partici- pate in the experiments. Written informed consent wasobtained from each volunteer, and the study was carried Further Experiments with Water Administration out in accordance with the Helsinki Declaration.
Further intragastric pH studies were performed in five subjects. This ancillary study was performed to clarify theearly effect of water volume on the gastric pH. Each vol- The study was an open-label, randomized, crossover trial.
unteer drank 50, 100, and 200 ml of water in a random The volunteers were fasted overnight before treatment, and order with a washout period of 60 min between each study.
study medications were randomly given in the morning. Asingle oral dose (swallowed with 15 ml of water) of each of the following medications was received with a washoutperiod of at least 2 days between each study [ The effects of each medication and of water were com- aluminium hydroxide plus magnesium oxide 400 mg, pared for the time (in minutes) required for pH to increase ranitidine 150 mg, omeprazole 20 mg, rabeprazole 20 mg, to [4 after their ingestion. The time for which intragastric and esomeprazole 40 mg. Moreover, administration of pH remained above 4 during the 6-h monitoring period 200 ml (a glass) of water was studied in all subjects. All after taking the study drug and water was also measured.
subjects underwent pH monitoring on 6 separate days, andthey were blinded for the administered drug.
Each study drug was administered 5 min after an intragastric pH value of 1–3 was continuously recorded for Results in the text and tables are expressed as median with 5 min. Gastric pH monitoring was continued for 6 h after ranges. Statistical analysis of paired data was performed intake of the medication. Smoking and ingestion of food orliquids were prohibited during the pH recording periods.
In vitro experiment: effect of different volumes of various Gastric pH data were collected using an antimony pH catheter with external reference (Synectics Medical Inc.), which was inserted transnasally under local anesthesia (xylocaine spray 2%). The catheter was calibrated before insertion using standard buffer solutions of pH 1.0 and 7.0 at room temperature. It was positioned 10 cm below the proximal border of the lower esophageal sphincter (LES), and a pH value of 1–3 was recorded for 5 min. The using non-parametric tests as appropriate. A P-value \0.05 time to pH [4 (median: 50 min) compared to omepra- zole (median: 171 min, P \ 0.05), rabeprazole (median:175 min, P \ 0.05), and esomeprazole (median: 151 min,P \ 0.05). No significant difference was found among omeprazole, rabeprazole, and esomeprazole.
Figure shows the median time taken for gastric pH to Administration of water and of antacids provided a short increase [4 for all study drugs. Water administration duration of pH control (median: 3 and 12 min, respectively).
immediately increased gastric pH [4 in 10/12 subjects.
Figure shows median time that gastric pH remained[4. A Antacids increased gastric pH [4 within 2 min (Fig. sustained pH [4 was observed until the end of the 6-h study The onset of antisecretory action of the remaining study period in 4/12 subjects on ranitidine, in 11/12 subjects on drugs occured in the majority of subjects within 2 h of drug rabeprazole, and in all subjects on omeprazole and administration. Ranitidine provided faster increase in esomeprazole. The pH was maintained [4 for shorter peri-ods with ranitidine when compared with omeprazole,rabeprazole, and esomeprazole (median: 65 vs. 189, 185,209 min, respectively; P \ 0.05). No significant diffe-rence was found among omeprazole, rabeprazole, andesomeprazole.
Changes of fasting gastric juice pH after administration ofdifferent volumes of tap, distilled, and mineral bottledwater are shown in Table . We observed that byincreasing the volume of added water, intragastric pHincreased. This increase also depended on the initial pH ofthe type of added water (Table Fig. 1 Time taken until pH rise [4 (median, 25th–75th percentileand 9th–95th percentile) Fig. 2 Intragastric pH after administration of a glass of water and of Fig. 3 Duration for which pH remained [4 (median, 25th–75th Intragastric pH after Water Administration that observed after antacids intake. A putative mechanismfor such a phenomenon is that the water as a substance with Gastric pH remained below 4 after administration of 50 and alkaline pH eliminates gastric acid similarly to the action 100 ml of water in all volunteers. In contrast, administra- of antacids. Moreover, water could increase the total vol- tion of 200 ml of water induced increase of pH [4 in all ume of gastric fluid, decreasing the concentration of acid in subjects after a median time of 1.5 min (range: 1–3). The the gastric fluid. In other words, water administration pH remained above 4 for a short period of time (median: 2, seems to have a dilution effect on H+ ions. The latter is supported by the in vitro experiments and our ancillarystudy. We showed that only the administration of a glass ofwater (200 ml) induced an increase of gastric pH above 4, whereas the smaller water volumes usually used duringdrug consumption are inadequate to induce an effect on Our study investigated the acute effect on intragastric pH gastric pH. Although a dilution effect could be an impor- of water and of the early phase following an oral single tant factor for gastric pH increase, other factors might also dose of antisecretory drugs. Water intake and antacids be involved. Indeed, in our in vitro studies, we observed a showed an immediately increase of gastric pH that lasted large increase of pH (e.g., from 1.4 to 5.4) with the addition for a few minutes. Ranitidine showed a faster onset of of 200 ml of tap water to 20 ml of gastric juice sample.
action than did PPIs (omeprazole, rabeprazole, and Thus, on the basis of dilution alone, one would predict that esomeprazole). In contrast, maintenance of a gastric pH the [H+] of the sample would decrease 11-fold, the dilution above 4 was longer with all PPIs compared to ranititidine factor, from 40 mM to 3.6 mM, or to pH 2.4. The finding that water increased the pH to 5.4 suggests that the tap and Although PPIs are the antisecretory drugs of choice for mineral water used also had a high buffering capacity. This GERD, they are not considered good candidates for treat- buffering effect might be partly explained from the pres- ment of very short episodes because of the rather long lag ence of component elements, such as ions, acting as bases.
time needed to increase intragastric pH [4 ]. Indeed, our Keeping in mind that antacids are provided as rescue study showed that PPIs required longer time to increase therapy in patients receiving on-demand PPI therapy [ gastric pH above 4 compared to ranitidine, and this finding administration of a glass of water is likely to be clinically is compatible with results reported by others [– – meaningful. Water had a rapid onset of action comparable However, our results are in contrast to studies showing that to antacids and should be efficacious in relief of symp- gastric pH failed to rise above 4 in the majority of subjects tomatic heartburn episodes. Our study has a preliminary after PPI treatment during a 6-h period [, We found nature as it was performed in healthy subjects. Therefore, that although PPIs required more time to start being effec- further studies in patients with heartburn are needed to tive, gastric pH above 4 was achieved in all subjects within confirm the effect of water on gastric acidity and to support a period of approximately 3 h after drug administration. Our a potential role of water as rescue therapy for episodic results support the findings of a previous study showing that reflux symptoms during non-continuous treatment for the onset of antisecretory action for PPIs occured within 2 h In conclusion, we showed that in healthy subjects, We also found that high intragastric pH with PPIs was similarly to antacids, a glass of water (200 ml) increases maintained for a longer period of time than with ranitidine.
gastric pH immediately. Although heartburn is usually Gastric pH remained above 4 at the end of the study in all associated with acidic esophageal pH and not with intra- subjects with omeprazole and esomeprazole and in all gastric drop in pH \4, we could hypothesize that an except one with rabeprazole, while only four subjects with increase of intragastic pH [4 is likely to contribute to the ranitidine sustained a pH [4. This finding was unexpected improvement of heartburn. Thus, patients who with ‘‘on- because previous studies have shown that during the early demand’’ therapy for episodic heartburn should swallow postadministration period, H2RAs had a greater long- the pill with at least a glass of water, as this may imme- standing effect on gastric pH compared to PPIs , – All studies were carried out in healthy, H. pylori (-)subjects; thus, we can speculate that differences either indoses and formulations of the drugs or in fasting status of the subjects could explain this discrepancy.
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