Comparative evaluation of five-day and seven-day eradication regimens using rabeprazole in patients with Helicobacter pylori-associated duodenal ulcer disease

The dissertation is devoted to a comparative clinical evaluation of five-day and seven-day eradication regimens that include the proton pump inhibitor rabeprazole in patients with duodenal ulcer disease associated with Helicobacter pylori. The work investigates the antisecretory properties of rabeprazole and omeprazole using 24-hour intragastric pH-metry, compares the effectiveness of regimens of different durations in terms of relief of the pain syndrome, the rate of epithelialization of ulcer defects, and the degree of H. pylori eradication, and also analyzes the tolerability and safety of therapy, including adverse reactions and changes in the colon microbiocenosis. The author proposes parameters for an individual chronometric approach to the selection of an eradication regimen that takes into account the severity of infection and the pharmacological characteristics of the antisecretory component.

The practical significance of the work is associated with the introduction of the results into the clinical practice of gastroenterology departments and into the educational process of the relevant departments, as well as with the substantiation of the optimal duration of anti-Helicobacter therapy in this category of patients.

Relevance of the problem

Peptic ulcer disease (PUD) is among the most common pathologies of the gastrointestinal tract, and the selection of adequate treatment regimens for it is among the most topical problems. Over the past 15 years, the majority of studies in the field of peptic ulcer disease have been devoted to investigating the role of the microorganism Helicobacter pylori, the significance of which in the genesis of this disease is considered proven. According to multicenter studies conducted in different countries, the persistence of H. pylori is associated with more than 90% of duodenal ulcers and more than 60% of gastric ulcers, and Helicobacter infection itself is recognized by most authors as one of the most widespread human infections [1,3,6,7,13,18,21,54,74,76,77,79,123].

Current standards of PUD treatment provide for three- or four-component anti-Helicobacter therapy, including drugs with antisecretory and antibacterial actions. According to the Maastricht Consensus Report adopted in 2000, the treatment of H. pylori-associated diseases includes first-line therapy (three-component anti-Helicobacter regimen) and second-line therapy (four-component regimen). Both regimens include proton pump inhibitors (PPIs) and two or three antibiotics [20,75,94].

The positive aspects of multicomponent therapy are the rapid achievement of clinical improvement and a sustained effect of H. pylori eradication. However, the frequency of adverse reactions with various combinations of drugs varies widely depending on the choice of evaluation criteria and the thoroughness of recording their unfavorable effects [98,73]. Intensive antibacterial therapy causes allergic, toxic, and dysbiotic changes in the human body, which raises a legitimate question regarding the tolerability and safety of anti-Helicobacter drugs. In addition, the widespread use of antibacterial drugs for the purpose of H. pylori eradication has led to the emergence of H. pylori strains resistant to antibiotics, which has created new problems in the therapy of Helicobacter infection [1,31,32]. According to data from a number of researchers, the frequency of adverse events (AE) during anti-Helicobacter therapy can reach 63%, and in 3-10% of patients it becomes the reason for premature discontinuation of treatment [88,90,91]. Meanwhile, in most works devoted to the study of drugs used in treatment, only mentions of AE are encountered.

The questions of effective doses and combinations of drugs, as well as the frequency of adverse reactions depending on sex, age, and the presence of underlying and concomitant pathology, remain relevant and not fully resolved. The discussion continues regarding the choice of drugs that make it possible to shorten the time of ulcer defect healing and to overcome H. pylori resistance to the antibacterial agents used [1,18,21,31,32,33,54,88,98]. Undoubtedly, the introduction into practice of optimal regimens of antisecretory therapy and the resolution of the question of the duration of anti-Helicobacter courses are of great importance.

Aim of the study

The aim of our work was to compare the clinical effectiveness of eradication regimens of different durations that include proton pump inhibitors in patients with duodenal ulcer disease associated with H. pylori infection.

Objectives of the study:

1. To evaluate the antisecretory effect of the proton pump inhibitors rabeprazole and omeprazole during pharmacological probes.

2. To evaluate the effectiveness of five-day and seven-day anti-Helicobacter therapy regimens based on omeprazole and rabeprazole in duodenal ulcer disease.

3. To evaluate the tolerability and safety of five-day and seven-day anti-Helicobacter therapy regimens based on omeprazole and rabeprazole in duodenal ulcer disease.

4. To determine parameters that help implement a chronometric approach when prescribing an anti-Helicobacter regimen in patients with duodenal ulcer disease associated with H. pylori.

Scientific novelty of the work

For the first time, a regular relationship has been revealed between the indicators of the antisecretory action of proton pump inhibitors and the degree of eradication. New parameters for evaluating antisecretory agents by means of pH-metry have been proposed, taking into account the interaction of drugs used in anti-Helicobacter regimens.

For the first time, a comparative evaluation of standard eradication regimens of different durations has been carried out — their antisecretory effect and influence on the dynamics of the pain syndrome, the rate and frequency of epithelialization of ulcer defects, as well as the degree of H. pylori eradication in patients with duodenal ulcer disease associated with H. pylori.

For the first time, criteria for an individual chronometric approach to the choice of a regimen aimed at H. pylori eradication in patients with duodenal ulcer disease have been determined.

Practical significance of the work

For a more predictable successful effect of eradication therapy when selecting the antisecretory component of a regimen, pharmacological probes with the aid of 24-hour intragastric pH-metry come to the rescue, along with the assessment of such parameters as the latent period, the total time of antisecretory action of the drug, and the time with pH above 6.

It has been shown that the use in patients with H. pylori-associated duodenal ulcer disease of 5- and 7-day eradication regimens with the basic drug represented by a new-generation proton pump inhibitor, rabeprazole, as well as a 7-day regimen based on omeprazole, which include amoxicillin and clarithromycin as the antibacterial components, make it possible to achieve H. pylori eradication rates that exceed the acceptable threshold.

The 7-day regimen based on rabeprazole, compared with the others, appears to be the most advantageous for use in clinical practice, since this regimen has demonstrated a high rate of H. pylori eradication and at the same time allows reducing the duration of treatment of H. pylori-associated duodenal ulcer disease to 1 week.

It has been revealed that shortening the duration of the anti-Helicobacter course, even when using rabeprazole with a pronounced antisecretory action as a constituent component, does not make it possible to achieve complete H. pylori eradication in patients with a significant degree of infection.

Ways of implementation of the study results

The results of the study have been introduced into the everyday practice of the gastroenterology departments of the Main Clinical Hospital of the Ministry of Internal Affairs of Russia and the Central Clinical Hospital No. 1 of JSC Russian Railways; they have been incorporated into the educational and practical work of the Department of Propaedeutics of Internal Diseases and Gastroenterology of the State Educational Institution of Higher Professional Education Moscow State University of Medicine and Dentistry of the Russian Health Ministry and are used in lecture courses, seminars, and practical classes with students and listeners of the certification courses of the Faculty of Postgraduate Additional Education.

Main propositions of the dissertation submitted for defense

1. In studying the indicators of the antisecretory action of the investigated proton pump inhibitors — omeprazole and rabeprazole — a more pronounced inhibitory secretory action of the latter has been revealed. However, both drugs possess a pronounced antisecretory effect and make it possible to maintain the intragastric pH level above 4 on average for 13 to 17 hours, which is considered sufficient for achieving a high degree of epithelialization of gastric and duodenal ulcer defects.

2. The eradication therapy regimens based on omeprazole and rabeprazole, used for the treatment of gastric and duodenal ulcer disease, have shown comparably high results with respect to the rate of relief of the pain syndrome, the frequency of epithelialization, and the degree of H. pylori eradication. However, the seven-day therapy of duodenal ulcer disease with the inclusion in the regimen of rabeprazole 20 mg twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1000 mg twice daily provides earlier scarring and a higher frequency of effective eradication, and therefore appears optimal. In patients with a significant degree of infection, the use of anti-Helicobacter treatment regimens based on rabeprazole with a reduction in duration to 5 days does not make it possible to achieve complete H. pylori eradication.

3. Anti-Helicobacter regimens based on rabeprazole are characterized by better tolerability and a lower percentage of adverse events compared with regimens based on omeprazole. Moreover, when using the 5-day regimen based on rabeprazole, the frequency of undesirable adverse events is significantly lower and their earlier relief is noted.

4. To achieve a higher percentage of H. pylori eradication, when selecting an adequate anti-Helicobacter regimen, it is necessary to carry out pharmacological probes with the antisecretory drug by means of 24-hour intragastric monitoring. The data of this study have shown that the evaluation of the antisecretory action of PPIs when used in eradication regimens should be performed according to the following indicators: the time of the latent period, the total duration of action of the drug, the time with pH above 6 and its percentage ratio to the total time of action of the drug, as well as the time required to reach a pH of 6 units.