Dyspepsia is common, with an estimated prevalence in Canada of 28.6%. It is unclear whether NSAID therapy causes dyspepsia or simply worsens a pre-existing condition. Studies indicate that 15% to 25% of patients taking NSAIDs experience dyspepsia and that, due to intolerance, treatment is discontinued or medication is changed in about 10% of patients. Clinical trials enroll highly selected patient populations and exclude patients with co-morbidity and extensive use of comedication; therefore, estimates of NSAID-related dyspepsia rates may be biased. A recent telephone survey reported that 48% of patients with arthritis and 30% of patients suffering from hypertension who were taking NSAIDs experienced dyspepsia. These findings are consistent with those of a previous metaanalysis demonstrating a positive association between NSAID use and dyspepsia. Learn how to save money – buy antibiotics online to enjoy your shopping and your treatment.
Gastrointestinal complications of conventional NSAID therapy
The adverse effects of NSAIDs in the upper gastrointestinal tract include erosions, ulceration, bleeding and perforation, while in the small and large intestine, ulcers, strictures and fibrous diaphragms have been reported. In addition, diverticular bleeding and relapse of inflammatory bowel disease have been described.
Endoscopic studies of users of conventional NSAIDs indicate a prevalence of gastric or duodenal ulcers of 15% to 30%, with 15% to 20% of patients having gastric ulcers and 5% to 8% having duodenal ulcers. Studies conclude that NSAID use is associated with an approximate fourfold increase in the risk of gastrointestinal complications, which are reported to have an annual incidence of 1% to 4%. Your most trusted pharmacy offering asthma inhalers and giving you very fast shipping.
There is an increasing awareness of the need to consider ulcers according to their site, with duodenal ulcer considered to be a Helicobacter pylori-related condition and gastric ulcer an NSAID-related condition. However, due to their effects on COX-1, conventional NSAIDs may cause the ulcer to either bleed or perforate.
Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are effective anti-inflammatory and analgesic drugs, but their use is accompanied by an enhanced risk of upper gastrointestinal complications. The management of these events, which range from mild to potentially life-threatening, is an important and practical clinical issue.
Cyclooxygenase (COX) exists in two isoforms — COX-1 and COX-2. COX-1 is important for the protection of the gastric and duodenal mucosa, and the gastrointestinal toxicity resulting from nonselective NSAIDs is mediated by inhibition of COX-1. COX-2 is highly expressed at sites of inflammation, which has led to the development of selective COX-2 inhibitors (coxibs), which control pain and inflammation while sparing the protective effects of COX-1. Initial studies provided evidence of a reduced incidence of endoscopic ulcers and gastrointestinal bleeding with coxibs compared with conventional NSAIDs — a finding that has been confirmed subsequently in clinical outcome studies.
Three of the most often reported adverse events were expected, because taste disturbance and nausea are known adverse effects of metronidazole, and diarrhea is a known adverse effect of tetracycline. Adverse event was the reason to discontinue treatment in only one patient. They were limited in time to the period of treatment. Moreover, no serious adverse event or clinically significant laboratory abnormalities were reported in the trial.
The efficacy of this regimen in metronidazole-resistant strains remains a limiting step to its use and should be improved. Published preliminary results have shown more promising efficacy with a new 10-day treatment with a single triple-capsule containing colloidal bismuth subcitrate 120 mg plus metronidazole 375 mg plus tetracycline 375 mg given qid with omeprazole 20 mg given with the morning and evening meals. Updated results (data on file) with this capsule have shown, in 125 patients with active or history of duodenal ulcer, an MITT eradication rate of 91.9% in metronidazole-sensitive and 80.4% in metronidazole-resistant strains respectively.
We conclude that the OBMT regimen used in the present study is effective against metronidazole-sensitive H pylori strains. However, longer duration of treatment (10 days) with higher doses of metronidazole and tetracycline (1.5 g daily each) seems better as suggested by the preliminary results of a more recently completed study.
The overall eradication rate by MITT analysis was 80%. The rates varied greatly from site to site, and this difference is likely explained, in part, by the small sample size seen in some investigative sites. If the site where only three patients were included in the per protocol analysis is not considered, the range becomes 66% to 100%.
In the MITT population, the combination of colloidal bismuth subcitrate 120 mg plus metronidazole 250 mg plus tetracycline 250 mg qid given with omeprazole 20 mg bid successfully eradicated H pylori in 82.5% and 66.7% of metronidazole-sensitive and metronidazole-resistant strains, respectively. Compared with the previously reported values of 88.5% and 69% in a survey of 1639 patients treated with a bismuth-based regimen, the actual rates were a little lower in sensitive strains and as low as those in resistant ones. The regimen used in the present study is, therefore, effective and safe for the eradication of metronidazole-sensitive H pylori strains, but is less effective than the 14-day triple therapy with 2 g daily of tetracycline given without a proton pump inhibitor.
In the present study, the overall prevalence of resistance to metronidazole in Canada was 30%. It varies greatly from site to site, and part of this variation is likely explained by the small sample sizes in some of the investigative sites. Nonetheless, this 30% figure compares favourably with the previously reported prevalence of 33%. The differences between the eradication rates in metronidazole-sensitive and metronidazole-resistant strains were statistically significant for the per protocol population but not for the MITT protocol; this is likely due to a type 2 error in the latter group. Actually, these tests were exploratory, and the sample size was not estimated based on these comparisons.
A sample size of 140 patients was estimated a priori for the 95% confidence interval based on the assumptions that expected eradication rate of BMT plus omeprazole (OBMT) would be 90%, alpha-error 5% and length of the confidence interval 95%. With an eradication rate of 80%, 161 patients give the power to compute the 94% confidence interval.
The metronidazole sensitivity was successfully documented in strains from 90 patients and showed an average resistance rate of 30.0%. The results by city and site are presented in Table 3. Eighteen of 27 resistant strains (66.7%) and 52 of 63 sensitive strains (82.5%) were eradicated in the MITT population (P=0.105). Seventeen of 24 resistant strains (70.8%) and 51 of 57 sensitive strains (89.55%) were eradicated in the per protocol population (P=0.045). Detailed results are shown in Table 2.
H pylori was successfully eradicated in 128 patients in the MITT population, for a rate of 80%, and in 123 patients in the per protocol population, for a rate of 84% (Table 2). The individual eradication rates by study sites varied between 40% and 100%, and 67% and 100%, in the MITT and per protocol populations, respectively (Figure 1).
Helicobacter pylori eradication rates in the modified intent-to-treat (MITT) and per protocol study populations
||H pylori sensitive
||H pylori resistant
Figure 1) Individual Helicobacter pylori eradication rates in the modified intent-to-treat (MITT) and per protocol (PP) study popula-tions
Two hundred thirty-eight patients were screened for the study. Sixty-eight were found to be H pylori negative at entry, four withdrew before starting the medication, one was included in violation of the upper age limit and was discontinued, and four were included despite the presence of a concomitant condition precluding participation (gastrointestinal bleeding, thyroid disease and elevated transaminase levels at baseline) and were discontinued, leaving 161 patients in the MITT population. Fifteen patients were subsequently withdrawn (six protocol violations, six lost to follow-up, one adverse event and two voluntary withdrawals), leaving 146 patients in the per protocol population. Their demographics are presented in Table 1.
Demographics of the modified intent-to-treat (MITT) and per protocol study populations
|History of gastric ulcer (n)*
|History of duodenal ulcer (n) *
|History of nonulcer dyspepsia (n)
Values are means ± SD. *A given patient may be in both groups
Within four days following completion of the treatment, physical examination and clinical laboratory tests were repeated and adverse events recorded. Not less than 28 and 84 days after the end of treatment, patients returned for 13 carbon urea breath tests. Eradication was defined as two negative 13 carbon urea breath test results at least one and three months after completion of therapy.
All medications for dyspepsia were prohibited throughout the study as well as nonsteroidal anti-inflammatory drugs and acetylsalicylic acid. The occasional use of acetaminophen was, however, permitted, and antacids were allowed as rescue medication if the dyspepsia symptoms were severe.
All patients were, a priori, advised to refrain from alcohol during the seven-day treatment period. Female patients using oral contraceptives were informed about the risk of interaction between tetracycline and oral contraceptives, and advised to use an additional means of contraception. Patients were also warned to avoid exposure to direct sunlight and/or ultraviolet light during the seven-day treatment period because of the photosensitizing effect of tetracycline.
This was an open-label, multicentre study of H pylori-positive patients with or without a history of peptic ulcer. The local ethics committee of each of the participating centres approved the study. Males and females, aged 18 to 75 years, found positive for H pylori by both 13carbon urea breath test and histology at entry were eligible after giving informed written consent.
The following main exclusion criteria were applied: macroscopic esophagitis, previous gastric surgery, dysphagia, vomiting, hematemesis, melena, recent documented gastrointestinal bleeding, iron-deficiency anemia, inability to abstain from alcohol, significantly impaired renal or hepatic function, contraindication to the use of bismuth, metronidazole or tetracycline, chronic use of nonsteroidal antiinflammatory drugs, use of antibiotics within 30 days before enrollment, regular use of bismuth compounds in the past 30 days, a previous attempt to eradicate H pylori infection and use of antiulcer drugs (including H2 receptor antagonists [seven days] or proton pump inhibitors [30 days]) preceding enrollment.