Evolution of Helicobacter pylori therapy from a meta-analytical perspective.

Even before the discovery of Helicobacter pylori as their cause, chronic gastritis and peptic ulcer disease were empirically treated with anti-infectious agents. However, it was not until that finding that an antibiotic approach began to be used systematically. The main aim of this article is to review the evolution of H. pylori therapy from a meta-analytical perspective. Initially, antibiotic monotherapy had a minor efficacy on H. pylori. Dual therapy including either bismuth compounds or proton-pump inhibitors (PPI) and one antibiotic also resulted in insufficient cure rates. Bismuth-based triple therapy (the first used) and PPI-based triple therapies (combined with two antibiotics, including amoxicillin, nitroimidazole, or clarithromycin) have been the most widely recommended. PPI-based regimens are superior to H2-antagonist-based ones. The influence of the type of PPI, the dose and the duration of the treatment will be discussed. Among the factors influencing the efficacy of therapy, resistance to clarithromycin and metronidazole are the most important risk factors for eradication failure. Several rescue therapies can be used. Bismuth-based quadruple therapy is effective, but the complexity of the regimen and the associated adverse effects limit the compliance. PPI-based triple therapy with amoxicillin and levofloxacin is at least equally effective and better tolerated.

Thiopurine methyltransferase activity in Spain: a study of 14,545 patients.

We sought to assess the activity of thiopurine methyltransferase (TPMT) in 14,545 Spanish patients with different diseases amenable to treatment with azathioprine/6-mercaptopurine (6-MP), and to evaluate the proportion of patients with low TPMT activity and therefore a higher risk of myelotoxicity with these drugs. TPMT activity in red blood cells (RBCs) was measured by a radiochemical method. The association between several clinical variables and TPMT activity was assessed by multiple linear regression. We included 14,545 patients: autoimmune hepatitis (n=359 patients), inflammatory bowel disease (n=7,046), multiple sclerosis (n = 814), myasthenia gravis (n=344), pemphigus (n=133), and other diseases (n=5,849). Mean TPMT activity was 20.1 +/- 6 U/mL, but differed depending on the disease (P<.001). TPMT distribution was low (<5) in 0.5%; intermediate (5.0-13.7) in 11.9%; or high (>or=13.8) in 87.6%. Only when TPMT activity was considered separately in each disease did it reveal a normal distribution. In the multivariate analysis, gender, hematocrit, and treatment with 5-aminosalicylates/steroids/azathioprine/6-MP statistically influenced TPMT activity, although, probably, in a clinically irrelevant manner. This study shows, in a large sample of 14,545 patients, that 0.5% had low TPMT activity, indicating a higher risk of myelotoxicity with azathioprine/6-MP, a figure similar or slightly higher than that reported in other areas. Nevertheless, the trimodal distribution of TPMT activity varied depending on disease, and the proportion of patients with low activity values ranged from 0-0.8%. The drugs prescribed for the treatment of autoimmune diseases, including azathioprine/6-MP, modified TPMT activity, but the magnitude of this effect was very small and the differences found are probably irrelevant from the clinical point of view.

Levofloxacin- vs. ranitidine bismuth citrate-containing therapy after H. pylori treatment failure.

AIM: Ranitidine bismuth citrate and levofloxacin-based regimen may be an alternative to quadruple therapy after Helicobacter pylori eradication failure. Our aim was to compare two 7-day triple second-line regimens containing ranitidine bismuth citrate or levofloxacin. METHODS: Patients in whom a first eradication trial with omeprazole-clarithromycin-amoxicillin had failed were randomized to receive 7-day treatment with: 1, ranitidine bismuth citrate (400 mg b.i.d.), tetracycline (500 mg q.i.d.), and metronidazole (250 mg q.i.d.), or 2, levofloxacin (500 mg b.i.d.), amoxicillin (1 g b.i.d.), and omeprazole (20 mg b.i.d.). Cure rates were evaluated by (13)C-urea breath test. RESULTS: One-hundred patients were included: 50 received the ranitidine bismuth citrate regimen, and 50 the levofloxacin one. Groups were comparable in terms of demographic variables. Two percent of the patients (one in each group) did not return for follow up. Compliance was similar in both groups (90% took all the medications correctly). Side-effects (only mild/moderate) in the two groups were also comparable (38% with ranitidine bismuth citrate and 36% with levofloxacin). Per-protocol cure rates were 69% (95% CI = 54-80%) in the ranitidine bismuth citrate group, and 71% (57-82%) in the levofloxacin one. Intention-to-treat cure rates were, respectively, 68% (59-79%) and 68% (59-79%) (nonstatistically significant differences). CONCLUSIONS: Both 7-day ranitidine bismuth citrate- and levofloxacin-containing second-line regimens represent alternatives to quadruple therapy in patients with previous omeprazole-clarithromycin-amoxicillin failure.

Clinical trial evaluating amoxicillin and clarithromycin hydrogels (Chitosan-polyacrylic acid polyionic complex) for H. pylori eradication.

AIM: It has been suggested that enhancement of amoxicillin or clarithromycin concentration at the gastric tissue may improve the anti-Helicobacter pylori effect of these drugs. This could be achieved by allowing the drug to remain longer in the stomach using dried hydrogels. Our aim was to evaluate the efficacy of an H. pylori eradication regimen including both amoxicillin and clarithromycin hydrogels. DESIGN: prospective clinical trial. PATIENTS: with peptic ulcer or functional dyspepsia. INTERVENTION: 7-day rabeprazole-amoxicillin-clarithromycin regimen. In addition, amoxicillin and clarithromycin hydrogels were administered twice daily during the 7 days. The polyionic complex hydrogel was prepared with Chitosan and polyacrylic acid. OUTCOME: H. pylori eradication was defined as a negative C-urea breath test 8 weeks after completing therapy. RESULTS: Forty patients were included. One patient did not return for follow-up. Ninety percent of the patients took all the medications correctly. Per-protocol and intention-to-treat eradication rates were 74% (95% CI=58%-86%) and 70% (55%-82%). Mild adverse effects were reported in 4 (10%) patients (diarrhea in 3, and nausea/heartburn in 1). CONCLUSIONS: Although dried polyionic complexes could serve as suitable candidates for amoxicillin and clarithromycin site-specific delivery in the stomach, its addition does not increase the eradication efficacy of the generally prescribed proton pump inhibitor plus amoxicillin and clarithromycin regimen.

Choice of azathioprine or 6-mercaptopurine dose based on thiopurine methyltransferase (TPMT) activity to avoid myelosuppression. A prospective study.

BACKGROUND/AIMS: To prospectively evaluate whether, in patients with inflammatory bowel disease, the choice of azathioprine (AZA) or 6-mercaptopurine (6-MP) dose based on thiopurine methyltransferase (TPMT) activity prevents myelotoxicity. METHODOLOGY: TPMT activity in red blood cells was measured in 99 patients with Crohn's disease and 32 with ulcerative colitis prior to initiating AZA/6-MP treatment. AZA/6-MP dose was chosen based on TPMT activity, which was again determined one month after starting therapy. Incidence of adverse effects was evaluated for at least 6 months of follow-up. RESULTS: Mean basal TPMT value was 21.6 +/- 5 U/mL. No patient had low levels (< 5 U/mL), 6.9% had intermediate levels (5-13.7 U/mL), and 93.1% had high levels (> 13.8 U/mL). In patients with Crohn's disease, mean TPMT activity significantly decreased after AZA/6-MP therapy, while in patients with ulcerative colitis this activity did not change. Among the 4 patients having myelotoxicity, one had intermediate basal TPMT levels, and 3 even had high levels, but no patient had low levels. CONCLUSIONS: In this prospective study we could not confirm that the choice of AZA/6-MP dose based on TPMT activity prevents myelotoxicity in patients with inflammatory bowel disease. Routine analytical controls should be performed in these patients independently of TPMT activity.

Risk assessment and outpatient management in bleeding peptic ulcer.

AIMS: 1) To review clinical and endoscopic variables in patients hospitalized for upper gastrointestinal bleeding (UGIB) due to peptic gastroduodenal lesions over a period of 3 years; 2) to identify factors associated with unfavorable evolution; and 3) to evaluate characteristics of patients discharged immediately after endoscopy. METHODS: A 3-year retrospective analysis of all UGIB episodes was performed. Patients with gastroduodenal ulcer or erosive gastritis/duodenitis at endoscopy were included. The prognostic value of several clinical, endoscopic, and analytical variables was assessed. Persistence or recurrence of bleeding, surgery, and mortality were considered as outcome variables (evolution was classified as "unfavorable" when any of these was observed). RESULTS: A total of 341 patients were identified, with a mean age of 62 years. Melena was the most frequent UGIB presentation (70%). Forty-five percent had associated diseases, and 45% were taking gastroerosive drugs. Duodenal ulcer was the most frequent cause of UGIB (48%), followed by gastric ulcer (32%). The evolution of UGIB was unfavorable in 7% of cases. Variables associated with unfavorable evolution in the multivariate analysis were: systolic blood pressure < or = 100 mm Hg, heart rate > or = 100 bpm, and a Forrest endoscopic classification of severe. Only 10% of patients were immediately discharged, with no subsequent complications. However, if predictive variables obtained in the multivariate analysis had been used, hospitalization could have been prevented in 115 patients (34%) without subsequent complications. CONCLUSIONS: A number of clinical and endoscopic variables (blood pressure, heart rate, and endoscopic stigmata of bleeding) with prognostic value have been identified. These are easy to obtain and apply in clinical practice and allow an accurate estimation of the evolution of UGIB. This diagnostic strategy identifies a relatively high proportion of UGIB patients who can be managed on an outpatient basis.

Helicobacter pylori "rescue" therapy after failure of two eradication treatments.

Nowadays, apart from having to know well first-line eradication regimens, we must also be prepared to face Helicobacter pylori treatment failures. Therefore, in designing a treatment strategy we should not focus on the results of primary therapy alone, but also on the final--overall--eradication rate. After failure of a combination of proton pump inhibitor (PPI), amoxicillin, and clarithromycin, the use of empirical quadruple therapy (PPI-bismuth-tetracycline-metronidazole), has been generally used as the optimal second-line therapy. Even after two consecutive failures, several studies have demonstrated that H. pylori eradication can finally be achieved in almost all patients if several "rescue" therapies are consecutively given. It seems that performing culture even after a second eradication failure may not be necessary, as it is possible to construct an overall strategy to maximize H. pylori eradication, based on the different possibilities of empirical treatment (when antibiotic susceptibilities are unknown). Thus, if one does not want to perform culture before the administration of the third treatment after failure of the first two, different empirical treatments exist, including regimens based on: 1, amoxicillin (amoxicillin-PPI at high doses); 2, amoxicillin plus tetracycline (PPI-bismuth-tetracycline-amoxicillin, or ranitidine-bismuth-citrate-tetracyline-amoxicillin); 3, rifabutin (rifabutin-amoxicillin-PPI); 4, levofloxacin (levofloxacin-amoxicillin-PPI); and 5, furazolidone (furazolidone-bismuth-tetracycline-PPI).

[Thiopurine methyltransferase activity in inflammatory bowel disease. A study on 7046 Spanish patients]. / Actividad de la tiopurina metiltransferasa en la enfermedad inflamatoria intestinal. Un estudio en 7.046 pacientes españoles.

BACKGROUND AND OBJECTIVE: Our objective was to assess the activity of thiopurine methyltransferase (TPMT) in a very large number of Spanish patients with inflammatory bowel disease (IBD), to evaluate the influence of several variables (including azathioprine or 6-mercaptopurine) on that activity, and to know the proportion of patients with low TPMT activity and therefore high risk of myelotoxicity when treated with these drugs. PATIENTS AND METHOD: TPMT activity in red blood cells (RBCs) was measured by a radiochemical method. The association between several variables and TPMT values was assessed by multiple lineal regression. RESULTS: 7046 patients were included (mean age: 37 years; 53% males): 70% with Crohn's disease, 22% with ulcerative colitis, and 8% with indeterminate colitis. Mean TPMT value was 20 (6) U/ml RBCs (minimum 0 and maximum 46). TPMT activity distribution was as follows: low levels (< 5 U/ml), 0.5%; intermediate (5-13.7), 11.1%; and high (> or = 13.8), 88.4%. TPMT values did not follow a normal distribution (p < 0.001). In the univariate study, statistically significant differences (p < 0.001), yet of doubtly clinical significance because its minimal magnitude, were demonstrated in TPMT values depending on age, sex, type of disease, and treatment with azathioprine/6-mercaptopurine. In the multivariate study, the variables associated with TPMT activity were: sex, treatment with 5-aminosalicylates, steroids and azathioprine/6-mercaptopurine. CONCLUSIONS: This study shows that 0.5% of the Spanish patients with IBD have low TPMT activity (< 5 U/ml RBCs), a figure similar to that reported in other countries, these patients being at higher risk of myelotoxicity when treated with azathioprine or 6-mercaptopurine. The drugs usually prescribed for the treatment of IBD, including 5-aminosalicylates and azathioprine/6-mercaptopurine, do not seem to modify in a clinically relevant manner TPMT activity.

Actividad de la tiopurina metiltransferasa en la enfermedad inflamatoria intestinal. Un estudio en 7.046 pacientes españoles / Thiopurine methyltransferase activity in the inflammatory bowel disease. A study on 7046 Spanish patients

Fundamento y objetivo: El objetivo del presente estudio es describir la actividad enzimática de la tiopurina metiltransferasa (TPMT) en un grupo muy numeroso de pacientes españoles con enfermedad inflamatoria intestinal (EII), evaluar el efecto de algunas variables sobre dicha actividad y conocer la proporción de pacientes con baja actividad y, por tanto, mayor riesgo de mielotoxicidad por azatioprina/6-mercaptopurina. Pacientes y método: Se determinó la actividad de TPMT mediante un método radioquímico en pacientes con EII. La asociación entre diversas variables y la actividad de TPMT se estudió mediante regresión lineal múltiple. Resultados: Se incluyó a 7.046 pacientes, el 70% con enfermedad de Crohn, el 22% con colitis ulcerosa y un 8% con colitis indeterminada. El valor medio de TPMT fue de 20 U/ml (extremos: 0-46). La distribución de actividad de TPMT fue: un 0,5% con valores bajos (= 13,8). Los valores de TPMT no siguieron una distribución normal (p < 0,001). En el estudio univariante se demostraron diferencias estadísticamente significativas (p < 0,001), aunque de dudosa relevancia clínica al ser mínimos, en los valores de TPMT en función de la edad, el sexo, el tipo de enfermedad y el tratamiento con azatioprina/6-mercaptopurina. En el estudio multivariante, el sexo y el tratamiento con 5-aminosalicilatos, glucocorticoides y azatioprina/6-mercaptopurina se asoció significativamente con la actividad de TPMT. Conclusiones: El 0,5% de los pacientes españoles con EII tiene una baja actividad enzimática de TPMT (< 5 U/ml, lo que indica un mayor riesgo de mielotoxicidad por azatioprina/6-mercaptopurina), una cifra similar a la descrita en otros países. Los diversos fármacos empleados en el tratamiento de la EII, como los 5-aminosalicilatos o la azatioprina/6-mercaptopurina, no parecen modificar de forma clínicamente relevante dicha actividad enzimática

Background and objective: Our objective was to assess the activity of thiopurine methyltransferase (TPMT) in a very large number of Spanish patients with inflammatory bowel disease (IBD), to evaluate the influence of several variables (including azathioprine or 6-mercaptopurine) on that activity, and to know the proportion of patients with low TPMT activity and therefore high risk of myelotoxicity when treated with these drugs. Patients and method: TPMT activity in red blood cells (RBCs) was measured by a radiochemical method. The association between several variables and TPMT values was assessed by multiple lineal regression. Results: 7046 patients were included (mean age: 37 years; 53% males): 70% with Crohn's disease, 22% with ulcerative colitis, and 8% with indeterminate colitis. Mean TPMT value was 20 (6) U/ml RBCs (minimum 0 and maximum 46). TPMT activity distribution was as follows: low levels (= 13.8), 88.4%. TPMT values did not follow a normal distribution (p < 0.001). In the univariate study, statistically significant differences (p < 0.001), yet of doubtly clinical significance because its minimal magnitude, were demonstrated in TPMT values depending on age, sex, type of disease, and treatment with azathioprine/6-mercaptopurine. In the multivariate study, the variables associated with TPMT activity were: sex, treatment with 5-aminosalicylates, steroids and azathioprine/6-mercaptopurine. Conclusions: This study shows that 0.5% of the Spanish patients with IBD have low TPMT activity (< 5 U/ml RBCs), a figure similar to that reported in other countries, these patients being at higher risk of myelotoxicity when treated with azathioprine or 6-mercaptopurine. The drugs usually prescribed for the treatment of IBD, including 5-aminosalicylates and azathioprine/6-ercaptopurine, do not seem to modify in a clinically relevant manner TPMT activity

Effect of ibuprofen on cyclooxygenase and nitric oxide synthase of gastric mucosa: correlation with endoscopic lesions and adverse reactions.

The aim of this study was to evaluate the effect of ibuprofen on gastric mucosa and enzymes involved in gastroprotection in healthy volunteers. Twenty-four Helicobacter pylori-negative subjects were randomized to treatment with ibuprofen or ibuprofen-arginate (each 600 mg/6 hr during 3 days). Endoscopies were performed 1 week before and after treatment. Biopsies were taken from the gastric antrum and corpus for determination of prostaglandin E2 (PGE2) by ELISA and cyclooxygenase (COX-1 and COX-2) and nitric oxide synthase (eNOS and iNOS) by western blot. All subjects had at least one gastric lesion except for two individuals taking ibuprofen-arginate. Ibuprofen-arginate caused a lower rate of clinical adverse reactions than ibuprofen. Subjects with gastric lesions or adverse reactions had lower PGE2 levels. COX-1, COX-2, eNOS, and iNOS were detectable in all subjects. The constitutive enzymes (COX-1 and eNOS) did not change after treatment. COX-2 was higher in corpus than antrum and it increased after ibuprofen treatment. iNOS tended to increase mildly in the corpus in subjects with adverse reactions or endoscopic lesions. There were no significant differences between ibuprofen and ibuprofen-arginate in PGE2, or enzymes.

Stool antigen test for the diagnosis of Helicobacter pylori infection: a systematic review.

Our aim was to review systematically the diagnostic accuracy of the Helicobacter pylori stool antigen test. Bibliographical searches were performed in several electronic databases and abstracts from congresses up to May 2003. Eighty-nine studies (10,858 patients) evaluated the stool antigen test in untreated patients. Mean sensitivity, specificity, positive predictive value and negative predictive value were 91%, 93%, 92% and 87%, respectively. Analysis of the eight studies (1399 patients) in which pretreatment evaluation of the monoclonal stool antigen test was performed showed better (p < .001) results (96%, 97%, 96% and 97%, respectively), with a clearer distinction between positive and negative results. Thirty-nine studies (3147 patients) evaluated the stool antigen test for the confirmation of H. pylori eradication 4-8 weeks after therapy, with accuracies of 86%, 92%, 76% and 93% for mean sensitivity, specificity, positive predictive value and negative predictive value, respectively. Results were similar when a gold standard based on at least two methods was used. Relatively low accuracy was reported in some posttreatment studies with the polyclonal stool antigen test. However, excellent results (p < .001) were achieved in all the six studies evaluating the monoclonal stool antigen test 4-8 weeks posttreatment. Results evaluating the stool antigen test < 4 weeks posttreatment are contradictory. Proton-pump inhibitors seem to affect the accuracy of the stool antigen test. Sensitivity and/or specificity in patients with gastrointestinal bleeding may be suboptimal. The stool antigen test performs well in children. Finally, the stool antigen test seems to be a cost-effective method.

The TETRA study: a prospective evaluation of Helicobacter pylori 'test-and-treat' strategy on 736 patients in clinical practice.

AIMS: To prospectively evaluate the effectiveness of the test-and-treat strategy in a large group of dyspeptic patients in clinical practice. METHODS: Patients with ulcer-like dyspepsia, < 45 years, without alarm symptoms, were prospectively studied. Helicobacter pylori infection was diagnosed with the 13C-urea-breath-test, and eradication or symptomatic treatment was prescribed accordingly. 'Symptomatic improvement' was defined as the percentage of patients with a decrease of > or = 2 levels in the dyspepsia-severity-score or with no symptoms after treatment. Health status and use of health resources were also assessed. Endoscopy was performed in therapeutic failures. RESULTS: Out of 736 patients initially included, 422 received eradication, and 314 symptomatic therapy; 87% returned at 6 weeks and 67% at 6 months. At 6 months, 'symptomatic improvement' was achieved in 73% and 54% of the patients, in eradication and symptomatic groups, respectively (p < .001), and overall in 66%. A reduction of 78% in mean self-assessment visual analogical score was observed at 6 months. More than 50% of patients were 'much better' at control visits. Endoscopy (18%) and physician's visits (13%) were the main health resources used. No gastric or oesophageal cancer was diagnosed. CONCLUSION: This large prospective study shows that the test-and-treat strategy is effective and safe for management of dyspeptic patients in clinical practice.

Pantoprazole based therapies in Helicobacter pylori eradication: a systematic review and meta-analysis.

AIM: To perform a systematic review on the efficacy of pantoprazole based therapies in Helicobacter pylori eradication, and to conduct a meta-analysis comparing the efficacy of pantoprazole and other proton pump inhibitors (PPIs) when co-prescribed with antibiotics. METHODS: Studies evaluating pantoprazole combined with antibiotics were considered. Only randomized clinical trials comparing pantoprazole and other PPIs when co-prescribed with antibiotics, and differing only in the PPI (pantoprazole vs other), were eligible for inclusion in the meta-analysis. Bibliographical searches in several electronic databases, and manual search of abstracts from congresses, were conducted. The percentage (weighted mean) of patients with eradication success was calculated. Meta-analysis was performed combining the odds ratios (ORs) of the individual studies in a global OR. RESULTS: The mean eradication rate with pantoprazole plus clarithromycin for 14 days was 60%. Cure rates with 7 day pantoprazole based triple regimens were higher: pantoprazole, amoxicillin and clarithromycin (78%); pantoprazole, clarithromycin and nitroimidazole (84%); and pantoprazole, amoxicillin and nitroimidazole (74%). Twelve studies comparing pantoprazole and other PPIs were selected for the meta-analysis, including 534 and 603 patients, respectively. The mean eradication rate for H. pylori using pantoprazole plus antibiotics was 83%, and 81% when other PPIs were used (OR = 1; 95% confidence interval (CI) from 0.61 to 1.64). When sub-analysis was performed, including only studies comparing pantoprazole with omeprazole, or pantoprazole with lansoprazole, differences were also statistically non-significant. The meta-analysis of the six studies prescribing equivalent doses of all PPIs demonstrated similar results with pantoprazole and with other PPIs (OR = 1.07; 95% CI from 0.71 to 1.62), the results being statistically homogeneous. CONCLUSIONS: Pantoprazole achieves similar cure rates to those of omeprazole and lansoprazole when co-prescribed with antibiotics for the eradication of H. pylori infection.

Lack of benefit of treating Helicobacter pylori infection in patients with functional dyspepsia. Randomized one-year follow-up study.

BACKGROUND/AIMS: To assess whether H. pylori therapy is significantly better than control therapy in patients with functional dyspepsia, and to assess whether curing the infection relieves symptoms of dyspepsia. METHODOLOGY: We prospectively included consecutive H. pylori-positive patients in whom a gastroscopy was carried out and who were diagnosed of functional dyspepsia. At endoscopy, biopsies were obtained (histology and rapid urease test), and a 13C-urea breath test was carried out. Patients were randomly assigned to 10 days of treatment with either eradication therapy (omeprazole, amoxicillin and clarithromycin) or with ranitidine. No antisecretory therapy was prescribed thereafter. Breath test was repeated four weeks after completing eradication treatment. A validated five-point Likert scale was used to measure severity of symptoms, both at the beginning of the study and 6 and 12 months after treatment. RESULTS: Fifty patients were included in the study. Sixteen patients were randomized to ranitidine and 34 to eradication treatment. The two groups were well balanced for base-line characteristics. One patient in each treatment arm was lost to follow-up at 12 months. Differences between ranitidine and eradication groups were not demonstrated in any of the symptom comparisons, either initially or at 12 months. The rates of treatment success for each symptom were similar in both groups. H. pylori was eradicated in 76% of the patients receiving antibiotics. Differences between groups of patients with eradication success and failure were not demonstrated in any of the symptom comparisons, either initially or at 12 months. Among the groups given eradication regimen, the rates of treatment success for each symptom were similar in the group with H. pylori eradication success and failure. CONCLUSIONS: H. pylori eradication is not likely to play a major role in the treatment of symptoms in patients with functional dyspepsia.