Optimal treatment of peptic ulcer: Perspectives beyond the year 2000

Abstract

Key Words: Peptic ulcer/therapy; Helicobacter infections; Helicobacter pylori; Stomach diseases

INTRODUCTION

Helicobacter pylori (H. pylori) infection is the most common chronic disease afflicting humans. It is estimated that around 50% of the world’s population suffers from this infection. The prevalence of H. pylori infection is low in developed countries (20%-40% of healthy adults), but it is much higher in developing countries. In China, epidemiological studies have shown that the prevalence of H. pylori infection varies from 50% to 90% in different cities and villages[1]. The prevalence is higher in aged individuals, and in those with low socioeconomic status and living under poor sanitation and crowded living conditions. Many studies have shown that H. pylori is closely related with gastritis, peptic ulcers, gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. It has also been suggested that H. pylori may be a causative agent of Ménétrier′s disease.

Several years ago, the principal treatment of patients with duodenal and gastric ulcer included the use of various H₂-receptor blockers and proton pump inhibitors. Although these agents are able to heal a high percentage of ulcers, the recurrence rate is very high after cessation of treatment[2]. Since the discovery of H. pylori by Warren and Marshall in 1982, innumerable basic and clinical studies have been carried out over the past 14 years. Many of these studies have indicated that H. pylori plays an important etiological role in the pathogenesis of peptic ulcer. Now, nearly all cases of duodenal ulcer and the majority of cases of gastric ulcer can be regarded as infectious diseases and the strategy for treatment of peptic ulcer has completely changed.

It is believed that the proverb “no acid, no ulcer” will still be valid beyond the year 2000, but it should be modified to: “no H. pylori and no acid, no ulcer”. Peptic ulcer has a recurrent course. If a patient received no treatment after the ulcer was healed, duodenal ulcer recurrence rate was reportedly 72% within 12 mo, but dropped to 25% following maintenance therapy with H₂-receptor antagonist. It was a very exciting finding that showed the duodenal ulcer recurrence rate was only 2%-3% when H. pylori was eradicated, and that this rate was maintained for at least 7 years after treatment with a low incidence of reinfection. It was thus concluded that peptic ulcer can be cured if the associated H. pylori is eradicated. The follow-up study of patients with bleeding peptic ulcer showed that the relapse rate of bleeding was 33% in those with persistent H. pylori, and 0% in those with eradicated H. pylori.

In February 1994[3], the National Institute of Health in the United States organized a consensus development conference on H. pylori in peptic ulcer disease. This effort brought together specialists in gastroenterology, surgery, infectious diseases, epidemiology and pathology, as well as members of the public, to discuss many questions related to H. pylori and peptic ulcer disease. Finally the consensus panel concluded that ulcer patients with H. pylori infection require treatment with antimicrobial agents in addition to antisecretory drugs, whether the administration begins upon first presentation of the illness or upon recurrence. It is doubtless that nearly all patients with peptic ulcer, except for those suffering from Zollinger-Ellison syndrome and NSAID-induced peptic ulcer, should be treated with antimicrobial agents and acid suppressants, such as H₂-receptor blocker or proton pump inhibitor.

How to eradicate H. pylori has emerged as a hot topic that is under investigation all over the world. In 1990[4] the Working Party of the 9th World Congress of Gastroenterology in Sydney recommended a triple therapy [colloidal bismuth subcitrate (CBS) at 120 mg q.i.d., tetracycline hydrochloride at 500 mg q.i.d. or amoxicillin at 500 mg q.i.d., and metronidazole at 400 mg t.i.d. given for 2 wk] as the standard therapy for H. pylori infection, giving an eradication rate of 80%-90%. However, many patients are intolerant to this treatment because of its related side effects and poor compliance. In addition, development of metronidazole-resistance is an important factor influencing the efficacy of the standard triple therapy.

Many other regimens have been reported in the literature for eradication of H. pylori, and these may be categorized into two main groups: bismuth-based therapies and proton pump inhibitor-based therapies. In China, both are used for eradication of H. pylori. We would like to mention that furazolidone is an anti-ulcer agent that has been in routine use in China for more than 20 years[5]. In the early 1970′s, many doctors in Shanghai, Beijing and other cities prescribed furazolidone for refractory peptic ulcer and achieved consistently good results. In 1978, healing of ulcer by treatment with furazolidone was confirmed with evidence. Then, in 1982 and 1983, open controlled studies and double-blind controlled studies were carried out in China. The ulcer healing rates were 73%-75% or 80%-83% after 2 wk or 4 wk of treatment with furazolidone. At that time nobody knew why furazolidone was effective for peptic ulcer, and particularly for the refractory peptic ulcer, and only a few patients relapsed after the ulcer was healed (Figure 1).

Figure 1 Professor Shu-Dong Xiao.

In 1989, we used furazolidone monotherapy (furazolidone at 100 mg t.i.d. for 21 d) to treat H. pylori-associated dyspepsia[6] and the eradication rate was 55.5%. The minimal inhibitory concentration (MIC) of furazolidone for H. pylori was found to be < 0.2 mg/L. Furazolidone is not expensive and is also very effective for eradication of H. pylori and ulcer healing. Serious side effects, such as skin rashes and polyneuritis, may occur occasionally if furazolidone is used in high doses and for long-term. However, if we use furazolidone at a low dose and for several days, development of serious side effects is uncommon. It is important to remember, though, that furazolidone is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency.

In 1994, a multi-center collaborative study was carried out in Shanghai. We used dual and triple therapies with furazolidone and the bismuth compound to treat H. pylori-associated dyspepsia and peptic ulcer[7]. The dual therapy consisted of CBS at 120 mg and furazolidone at 100 mg q.i.d. for 14 d, and the triple therapy consisted of CBS at 120 mg, furazolidone at 100 mg, and metronidazole at 200 mg q.i.d. for 10 d. The results showed that with the dual therapy, the healing rates of duodenal ulcer and gastric ulcer were 80% and 77.7%, respectively. With the triple therapy, the healing rates of duodenal ulcer and gastric ulcer were 86.1% and 77.3%, respectively. There was no significant difference in the healing rates of duodenal ulcer or gastric ulcer achieved with either the dual therapy or the triple therapy. With the dual therapy, the overall eradication rate of H. pylori was 73%, and with the triple therapy, the overall eradication rate of H. pylori was 77.8%. The difference was not statistically significant between the two groups, but there were milder side effects in the patients who received the triple therapy.

Now many studies have shown that some regimens are able to achieve a high eradication rate of H. pylori. Sung et al reported that a 1-wk regimen of the triple therapy (bismuth subcitrate, tetracycline and metronidazole) produced a successful eradication of H. pylori in 95% of patients. In a prospective randomized trial, H. pylori-associated duodenal ulcer patients were treated with either the triple therapy alone or in further combination with omeprazole. Four weeks after cessation of the treatment, duodenal ulcers were healed in 92% of patients who received the triple therapy alone and 95% of patients who received the triple therapy plus omeprazole. Bazzoli reported on a 1-wk treatment regimen composed of omeprazole at 20 mg once daily or b.i.d., clarithromycin at 250 mg b.i.d., and tinidazole at 500 mg b.i.d. or metronidazole at 400 mg b.i.d., and showed that this regimen eradicated H. pylori infection in > 90% of treated patients. Unpublished data from our group have demonstrated that a 1-wk triple therapy (CBS at 240 mg b.i.d., or lansoprazole at 30 mg q.d., clarithromycin at 250 mg b.i.d., and furazolidone at 100 mg b.i.d.) achieved an eradication rate of H. pylori of > 90%. In addition, our clinical trial has also demonstrated that a bismuth-based dual therapy (CBS at 240 mg b.i.d. plus josamycin at 1000 mg b.i.d.) achieved a 69.9% eradication rate of H. pylori. Josamycin and clarithromycin are macrolide antibiotics. Similar to clarithromycin, josamycin possesses high activity against H. pylori, even in an acidic environment. Our study showed that when H. pylori strains developed resistance to clarithromycin or josamycin, they might not be eradicated with clarithromycin or josamycin-based dual or triple therapy.

H. pylori is relatively easy to suppress, but much more difficult to eradicate. New regimens for eradication of H. pylori are still under investigation. An ideal H. pylori eradication therapy has not been found yet. Hopefully, the use of low-dose, short-term triple therapy (consisting of one antisecretory agent and two antibiotics) with high efficacy (90% eradication rate), low incidence of side effects and convenient administration (twice daily for only 7 d) will be acceptable as an optimal treatment for peptic ulcer associated with H. pylori infection. We are confident that optimal treatment of peptic ulcer will be found beyond the year 2000, and we predict that peptic ulcer might not run a chronic and recurrent course any more. Peptic ulcer is a disease that can be cured if the associated H. pylori is eradicated.