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ppis in gastric acid–related diseasesDuring the past two decades, enormous changes occurred in the management of gastric acid–related diseases. First, the histamine2–receptor antagonists were introduced, offering patients the first single–agent therapy that effectively reduced gastric acid secretion. Since the introduction of PPIs, most physicians now use them as first–line treatment for patients with acid–peptic disorders, including erosive gastro–oesophageal reflux disease (GERD), nonerosive reflux disease (NERD) and duodenal and gastric ulcers.1

Proton pump inhibitors (PPIs) act selectively on the final stage of the process of gastric acid secretion, namely the H+/K+ –ATPase or proton pump. This enzyme represents an essential step in the process of secretion of H+, and PPIs exert a very specific action on the parietal cell, as they need an environment with very low pH levels, which only exist in this cell. After two decades of use, PPIs have proved to be very effective and safe drugs. The significant inhibitory capacity of gastric acid secretion of PPIs makes them the drugs of choice for treating acid–related diseases.2

metabolism and efficacy of ppis: focus on rabeprazoleAlthough all proton pump inhibitors are highly effective, the antisecretory effects of different drugs in this class are not completely consistent across patients. An important reason for interpatient variability of the effects of proton pump inhibitors on acid secretion involves genetically determined differences in the metabolism of these drugs.

Results reviewed indicate that the metabolism and pharmacoki–

Rabeprazole fast-release (NaHCO3 buffer) as first-line treatment for acid-peptic disorders

A Passi Publication

ADvANTAGEs of soDIum bIcARboNATE buffER

• Although PPIs are stable at alkaline pH, they are destroyed rapidly as pH falls (e.g., by gastric acid). Therefore, if the micro-encapsulation or the enteric coating is disrupted (e.g., trituration to compound a liquid, or chewing the capsule), the dosage forms of the prior PPIs will be exposed to degradation by the gastric acid in the stomach. Hence, previously all oral PPIs were delayed-release, enteric-coated formulations designed to prevent degradation of the drug by gastric acid.

• The enteric dosage forms of the prior PPIs were employed because they are acid labile; thus, it is important that these drugs not be exposed to low pH gastric acid prior to absorption. unfortunately, enteric coatings delay absorption and initial acid suppression.

• RAbIfINE fR tablets contains sodium bicarbonate, which protects the drug from gastric acid degradation. This provides the benefits of the proton pump inhibitor without the drawbacks of the current enteric-coated solid dosage forms.

• moreover, this built–in sodium bicarbonate buffer protects RAbIfINE fR from acid degradation by raising intragastric pH. No enteric coating of capsules or powder for oral suspensions are thus required. In this form, the drug is faster acting and may also be useful for patients who are unable to swallow and have nasogastric (NG) tubes in place.3

rabifine fr

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netics of rabeprazole differ significantly from those of other proton pump inhibitors. most importantly, the clearance of rabeprazole is largely non enzymatic and less dependent on cYP2c19 than other drugs in its class. This results in greater consistency of pharmacokinetics for rabeprazole across a wide range of patients with acid–related disease, particularly those with different cYP2c19 genotypes.

The pharmacodynamic profile for rabeprazole is also characterized by more rapid suppression of gastric acid secretion than with other proton pump inhibitors, which is also independent of cYP2c19 genotype. The favorable pharmacokinetic/pharmacodynamic profile for rabeprazole has been shown to result in high eradication rates for H. pylori in both normal and poor metabolizers. Pharmacodynamic results have also suggested that rabeprazole may be better suited than omeprazole as on–demand therapy for symptomatic gastro–oesophageal reflux disease. finally, the use of rabeprazole is not complicated by clinically significant drug–drug interactions of the type that have been reported for omeprazole.4

role of rabeprazole treatment in acid–related disorderscontrol of gastric acid secretion by antisecretory agents has been the cornerstone of therapy in the successful management of all acid–related disorders, including gastro–oesophageal reflux disease (GERD), and duodenal and gastric ulcer. Treatment efficacy has been strongly correlated with degree and duration of acid suppression within the 24–h period and with total duration of therapy.

All PPIs have closely similar mechanisms of action, yet important pharmacological differences exist, which can significantly impact certain aspects of their clinical efficacy. Rabeprazole’s has an early onset of effective acid inhibition compared with other proton pump inhibitors such as omeprazole, lansoprazole and pantoprazole. Like rabeprazole, esomeprazole is also a potent inhibitor of gastric acid at steady state, although it is thought that rabeprazole may provide enhanced first–day acid suppression compared with esomeprazole.

first–day antisecretory efficacy should produce faster symptom relief, a hypothesis supported by clinical data. moreover, drugs with pharmacological profiles that include both rapid onset and potent antisecretory effects should help control healthcare costs by reducing the need for otherwise commonly used twice–daily proton pump inhibitor administration.5 Rabeprazole which has been further enhanced with sodium bicarbonate buffer provides even better results.

acid inhibition on the first day of dosing: comparison of four ppis To compare the antisecretory activity and onset of action of single doses of rabeprazole, lansoprazole, pantoprazole, omeprazole capsule, omeprazole multiple unit pellet system (muPs) tablet and placebo in healthy Helicobacter pylori–negative subjects, this cross–over, double–blind, randomized study was performed in 18 H. pylori–negative subjects.

The intragastric pH (3.4) and time at pH > 4 during the 24 h post–dose (8.0 h) were significantly greater with rabeprazole than

with lansoprazole, pantoprazole, omeprazole capsule, omeprazole muPs tablet or placebo (P ≤ 0.04 for rabeprazole vs. the others). Daytime and night–time pH values were higher with rabeprazole and lansoprazole than with pantoprazole, omeprazole capsule and omeprazole muPs tablet (P ≤ 0.04). Rabeprazole was the most potent acid inhibitor of all the proton pump inhibitors tested during the first day of dosing.6 Rabeprazole which has been further enhanced with sodium bicarbonate buffer will provides even better results because of raised pH.

rabeprazole, amoxicillin, and gatifloxacin after treatment failure of H. pylori eradicationEligible patients with persistent infection following one or more conventional clarithromycin–containing triple therapies were enrolled in this open–label trial. A total of 45 patients (22 females:23 males; mean age 44.5 ± 13 years) were enrolled. Eradication occurred in 38 patients [both per–protocol (PP) and intention–to–treat analysis: 84.4%; 95% cI: 74–95%]. No significant adverse effects were reported. in vitro susceptibility testing showed no secondary resistance to gatifloxacin or amoxicillin in any of the seven non responders. A 7–day regimen of gatifloxacin, rabeprazole, and amoxicillin is effective after failed eradication therapy for H. pylori and does not appear to result in secondary resistance. This combination is simple, well tolerated, and may lead to higher compliance and lower costs.7

comparison of four ppis for the treatment of esophagitis A total of 320 patients over 65 years with endoscopically diagnosed esophagitis were randomly assigned to one of the following treatments for 8 wks: (1) omeprazole 20 mg/d; (2) lansoprazole 30 mg/d; (3) pantoprazole 40 mg/d, or (4) rabeprazole 20 mg/d. major symptoms, compliance, and adverse events were recorded. After 8 wks, endoscopy and clinical evaluation were repeated.

Per protocol and intention to treat healing rates of esophagitis were: omeprazole = 81.0% and 75.0%, lansoprazole = 90.7% (P = 0.143 vs omeprazole) and 85.0%, pantoprazole = 93.5% (P = 0.04 vs omeprazole) and 90.0% (P = 0.02 vs omeprazole), rabeprazole = 94.6% (P = 0.02 vs omeprazole) and 88.8% (P = 0.04 vs omeprazole).

Dividing patients according to the grades of esophagitis, omeprazole was significantly less effective than the three other PPIs in healing grade 1 esophagitis (healing rates: 81.8% vs 100%, 100% and 100%, respectively, P = 0.012).

Pantoprazole and rabeprazole (100%) were more effective vs omeprazole (89.6%, P = 0.0001) and lansoprazole (82.4%, P = 0.0001) in decreasing heartburn. Pantoprazole and rabeprazole (92.2% and 90.1%, respectively) were also more effective vs lansoprazole (75.0%, P < 0.05) in decreasing acid regurgitation. finally, pantoprazole and rabeprazole (95.2% and 100%) were also more effective vs lansoprazole (82.6%, P < 0.05) in decreasing epigastric pain.

In elderly patients, pantoprazole and rabeprazole were significantly more effective than omeprazole in healing esophagitis and than omeprazole or lansoprazole in improving symptoms. H. pylori

drug composition packing administrationRAbIfINE fR Rabeprazole sodium 20mg (sodium bicarbonate as buffer) 10 Tablets 1 oD

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infection did not influence the healing rates of esophagitis after a short–term treatment with PPI.8 Rabeprazole which has been further enhanced with sodium bicarbonate buffer will provides even better results.

oral rabeprazole vs. intravenous pantoprazoleIntravenous pantoprazole is often administered inappropriately to hospitalized patients who can take oral medications. In a double–blind, double–dummy, two–way crossover study, 38 H. pylori–negative volunteers were randomized to oral rabeprazole 20 mg or intravenous pantoprazole 40 mg daily for 3 days followed, after a 14–day washout period by the comparator treatment.

The mean (95% cI) percentage of the 24–h recording with gastric pH >4 was higher with rabeprazole than with pantoprazole on day 1: 37.7% (30.6–44.8%) vs. 23.9% (20.0–27.8). The mean percentage times with pH >3 and >4 for all intervals assessed were greater and the median 24–h intragastric pH values were higher with rabeprazole than with pantoprazole on days 1 and 3. The mean acidity index was lower with rabeprazole on days 1 and 3.

In conclusion, oral rabeprazole 20 mg produced greater acid suppression than intravenous pantoprazole 40 mg. Therefore, it may be an appropriate and effective alternative in patients who can take

highlights• Sodium bicarbonate added as a buffer to rabeprazole provides

prolonged yet immediate effect because it prevents rabeprazole from acid degradation by raising pH due to which tablets are not enteric coated

• In 8-week studies, among patients with gastro-esophageal reflux disease (GERD), rabeprazole 20 mg/day or 10mg twice daily was as effective as omeprazole and superior to ranitidine in the healing of GERD. symptom relief with rabeprazole was superior to that provided by placebo and ranitidine and similar to omeprazole

• In long-term trials rabeprazole 10 mg/day was similar to omeprazole 20 mg/day in a 2-year study and superior to placebo in 1-year studies, in both the maintenance of healing and prevention of symptoms in patients with healed GERD

• In nonerosive GERD, 4-week studies have shown rabeprazole to be more effective than placebo in relieving heartburn and various other gastrointestinal symptoms

• Data among patients with barrett’s oesophagus suggest ra-beprazole 20 mg/day may be more effective than placebo in maintaining healing of associated oesophagitis after 1 year of treatment.

• As monotherapy for peptic ulcer healing and symptom relief, 4- to 8-week studies have shown rabeprazole 10 to 40 mg/day to be superior to placebo and ranitidine and have similar efficacy to omeprazole

• Preliminary 1-year data among 16 patients with Zollinger-Ellison syndrome suggest rabeprazole 60 to 120 mg/day can resolve and prevent the recurrence of symptoms and endoscopic lesions associated with this condition.

oral medication.9 Rabeprazole which has been further enhanced with sodium bicarbonate buffer gives even better results.

effects of 5 years of treatment with rabeprazoleProlonged gastric acid suppression leads to hypergastrinaemia, which promotes hyperplasia of the enterochromaffin–like (EcL) cells of the oxyntic mucosa. Two hundred and forty–three patients received rabeprazole (20 mg or 10 mg) or omeprazole (20 mg) once daily for up to 5 years, for gastro–oesophageal reflux disease and 51% completed the whole 5 year period. Gastric biopsy specimens were taken and examined for gastritis, H. pylori infection, and EcL cell status.

Findings revealed that H. pylori infection in the gastric corpus was more common than in the antrum, and remained constant, whereas antral H. pylori infection became less common as the study progressed. H. pylori infection was a highly significant predictor of higher gastritis scores, which were similar among the three treatment groups. EcL cell hyperplasia occurred in a minority of patients, and was associated with serum gastrin concentrations. No EcL cell dysplasia or tumours were observed. There were no significant differences among the treatment groups in gastritis or EcL cell hyperplasia grades. This study has confirmed the link between EcL cell hyperplasia and elevated serum gastrin concentrations, but has found no evidence that this progresses to high grades of hyperplasia during 5 years of treatment with rabeprazole.10

references1. Robinson m. Review article: the pharmacodynamics and pharmacokinetics of proton

pump inhibitors––overview and clinical implications. Aliment pharmacol Ther. 2004 Nov; 20 suppl 6:1–10.

2. Esplugues Jv, martí–cabrera m, Ponce J. [safety of proton pump inhibitors] med clin (Barc). 2006 Nov 25; 127(20):790–5.

3. No authors listed Zegerid–immediate–release omeprazole. med Lett Drugs Ther. 2005 Apr 11; 47(1206):29.

4. Horn J. Review article: relationship between the metabolism and efficacy of proton pump inhibitors––focus on rabeprazole. Aliment pharmacol Ther. 2004 Nov; 20 suppl 6:11–9.

5. Robinson m. Review article: pH, healing and symptom relief with rabeprazole treatment in acid–related disorders. Aliment pharmacol Ther. 2004 Nov; 20 suppl 6:30–7.

6. Pantoflickova D, Dorta G, Ravic m, Jornod P, blum AL. Acid inhibition on the first day of dosing: comparison of four proton pump inhibitors. Aliment pharmacol Ther. 2003 Jun 15; 17(12): 1507–14.

8. Pilotto A, franceschi m, Leandro G, scarcelli c, D’Ambrosio LP, Paris f, Annese v, seripa D, Andriulli A, Di mario f. comparison of four proton pump inhibitors for the short–term treatment of esophagitis in elderly patients. World J Gastroenterol. 2007 sep 7; 13(33): 4467–72.

9. Armstrong D, James c, camacho f, chen Y, Horbay GL, Teixeira b, Husein–bhabha fA. oral rabeprazole vs. intravenous pantoprazole: a comparison of the effect on intra-gastric pH in healthy subjects. Aliment pharmacol Ther. 2007 Jan 15; 25(2): 185–96.

10. Rindi G, fiocca R, morocutti A, Jacobs A, miller N, Thjodleifsson b; European Rabe-prazole study Group. Effects of 5 years of treatment with rabeprazole or omeprazole on the gastric mucosa. Eur J Gastroenterol Hepatol. 2005 may; 17(5): 559–66.

Doctor opines...Adding sodium bicarbonate as a buffer makes for better science since it protects rabeprazole from premature degradation in the gastric acidic environment. The improved PK/PD

translates into better clinical efficacy and this has been very evident from the patients' feedback.

dr. Jayant thakuria, mdconsultant, Department of medicine, fortis Escorts Hospital, faridabad