A strategy for second-line anti-Helicobacter pylori therapy in patients with previously failed treatment

Highly effective H. pylori eradication therapies are currently used in Japan. However, eradication failures still appear in a considerable proportion of cases. In such refractory cases, several second-line eradication therapies and therapeutic efficacies have been only exceptionally studied. Our aims were to analyze the reasons and evaluate the second-line therapies when first-line eradication therapies fail. We make a strategy for second-line anti-H. pylori therapy in patients with previously failed treatment.     

Treatment of refractory Wegener's granulomatosis with humanized monoclonal antibodies

Conventional immunosuppression for systemic vasculitides is limited by substantial side-effects, cumulative drug toxicity and refractoriness in some patients. Six Wegener's granulomatosis patients who had been refractory to conventional therapy for at least 6 months, were treated with humanized monoclonal antibodies specific to lymphocyte CD52 or CD4 antigens. Diagnosis was on clinicopathological grounds, supported by the presence of autoantibodies to Proteinase 3. Histological evidence of persistent disease activity was obtained for each patient. Humanized monoclonal anti-CD52, with or without anti-CD4, was given intravenously up to 40 mg/day for up to 10 days. Remission, (programmed withdrawal of drug therapy without return of refractory disease) was achieved in all patients. Cytotoxic drugs were discontinued at the time of monoclonal antibody treatment and not used again; steroids were withdrawn gradually. Four patients relapsed at 1.5, 5, 10 and 18 months, and were treated successfully with further monoclonal antibody therapy alone. Three years after the study began, five patients are well; one patient died at surgery whilst in remission. Humanized monoclonal antilymphocyte antibodies may provide an effective treatment in patients with systemic vasculitis which is refractory to steroids or cytotoxic agents, or who are intolerant of these drugs.      

免疫性血小板减少性紫癜分型施治的基础与临床研究进展

免疫性血小板减少性紫癜(ITP)的发病涉及血小板免疫性破坏增多和骨髓巨核细胞产生血小板过少两个方面。经典的ITP治疗只涉及抑制血小板免疫破坏的一个方面,即采用免疫抑制剂如糖皮质激素、免疫球蛋白和抗-D抗体(针对Rh系统D抗原的抗体),也有采用长春新碱或抗人CD20单克隆抗体清除B淋巴细胞,以及环孢菌素等免疫抑制剂等。对难治性病例还要进行脾脏切除手术。虽然免疫抑制治疗方案对大多数患者治疗有效,但30%以上的ITP患者会复发,且这类治疗不良反应较多,脾脏切除还会导致机体免疫力下降,容易出现感染等并发症。临床需要更加安全有效的治疗方法。重组人血小板生成素(TPO)由于自身抗体而继发严重的血小板,目前已退出ITP的治疗。最近,欧洲批准了2个血小板受体激活剂AMG 531和Eltrombopag,通过促进巨核细胞分化和血小板生成来治疗ITP。国内采用泛细胞保护剂为主的联合方案治疗难治/复发性ITP也取得了良好的效果。总之,根据ITP患者不同的发病机理进行个体化治疗是未来ITP基础与临床的研究方向。本文就ITP的发病机理和临床治疗作一综述,并对ITP分型施治的可能性进行了初步的探讨。     

A strategy for second-line anti-Helicobacter pylori therapy in eradication-failure patients

Although available H. pylori eradication regimens in Japan fail to cure 10-20% of patients, an optimal re-treatment therapy for eradication-failure patients has still not been established. Since patient compliance, bacterial resistance and genotypic differences in CYP2C19 influence the eradication rate, re-eradication therapy should be selected, taking them into consideration. In the West, meta-analysis of the second-line treatment of H. pylori infection showed therapies comprising ranitidine bismuth and two antimicrobials are very effective re-treatment therapies irrespective of factors influencing H. pylori eradication. However ranitidine bismuth is not available in Japan and re-eradication therapy consisting of PPI, amoxicillin and metronidazole have been often undertaken and have achieved high eradication rate, even including patients with metronidazole resistant H. pylori.     

Significance of H. pylori eradication in treatment and prevention for low-dose aspirin induced gastric ulcer of elderly

Although treatment and prevention for low-dose aspirin (LDA) induced gastrointestinal mucosal injury is important problem, significance of H. pylori eradication has not been clarified. NSAIDs including LDA and H. pylori infection are independent causal factors for gastroduodenal ulcer. However, the interaction between these factors is complicated. H. pylori eradication can reduce the risk of NSAIDs induced ulcer in NSAIDs naive patients. However, H. pylori eradication is not recommended in NSAIDs user because of no ulcer suppression and ulcer healing delay. In prevention of LDA induced ulcer recurrence, H. pylori eradication plus PPI treatment are necessary.     

The significance of H. pylori eradication in NSAIDs ulcer

The significance of H. pylori eradication for NSAIDs induced gastroduodenal ulcer has not been clarified. NSAIDs and H. pylori infection are independent causal factors for gastroduodenal mucosal injuries. However, the interaction between these two factors is complicated. H. pylori eradication can reduce the risk of NSAIDs induced ulcer in NSAIDs naive patients. However, H. pylori eradication is not recommended in NSAIDs user because of no ulcer suppression and ulcer healing delay. In prevention of NSAIDs induced ulcer recurrence, H. pylori eradication plus PPI treatment is necessary.     

Selection of antibiotics and planning of eradication for H. pylori infection

There is general agreement that H. pylori should be eradicated in patients with peptic ulcers. But the optimal therapeutical regimen to be used still remains a matter for many investigations. An increase in the prevalence of antibiotic-resistant H. pylori strains has been reported recently. The recommended drugs for the eradication in Japan are clarithromycin (CAM) and amoxicillin (AMPC) because metronidazole (MNZ) is anti-parasites drug in Japan. A total of 392 H. pylori strains in the last twelve years were tested for sensitivity to CAM, MNZ, and AMPC. The Primary resistance of H. pylori to CAM, MNZ, and AMPC were found in 10.2%, 26.5%, and 0.3% strains, respectively. The resistant strains to CAM were gradually increasing in the last few years. The eradication therapies which do not increase antibiotics resistant strains after eradication failure were reported. The recommendation for eradication in patients with peptic ulcer disease includes those with bleeding ulcers. The pretreatment with proton pump inhibitors (PPI) does not influence the success of PPI-based triple therapy in eradicating H. pylori.     

Optimizing the treatment of patients with rituximab-pretreated recurrent indolent non-Hodgkin lymphoma

Indolent non-Hodgkin lymphomas (NHLs) are among the most prevalent hematologic malignancies; their incidence has been increasing over the last several decades. Because advanced-stage indolent lymphoma is generally incurable, therapy for this group of patients is geared toward chronic management over years. Recently, numerous trials have demonstrated that the combination of chemotherapy and the anti-CD20 monoclonal antibody rituximab can provide superior efficacy to chemotherapy alone. Thus, rituximab-containing regimens are the standard approach for primary therapy in patients with symptomatic advanced disease. As these patients progress and receive multiple rituximab-based regimens over time, new treatment options are needed for this new group of rituximab-pretreated patients. This review focuses on the development of novel therapies for rituximab-pretreated, relapsed or refractory indolent NHL.     

Radioimmunotherapy for B-cell non-Hodgkin lymphoma

Radioimmunotherapy is an established and effective treatment in B-cell non-Hodgkin lymphoma (NHL). Currently, two radioimmunoconjugates (RICs) are approved for clinical use in the United States, ibritumomab tiuxetan and tositumomab. Both agents target the CD20 antigen on B-cell lymphoma cells. Although there are differences between these two agents, such as different murine monoclonal antibodies, radioisotopes, and dosimetry techniques, they share similar toxicity and efficacy profiles. These anti-CD20 RICs are active in patients who are refractory to single-agent rituximab, documenting the added value of the conjugated radioisotope. This review focuses on the current use of these agents in the treatment of previously untreated indolent NHL and relapsed/refractory and transformed NHL.     

免疫性血小板减少性紫癜分型施治的基础与临床研究进展

免疫性血小板减少性紫癜（ITP）的发病涉及血小板免疫性破坏增多和骨髓巨核细胞产生血小板过少两个方面。经典的ITP治疗只涉及抑制血小板免疫破坏的一个方面，即采用免疫抑制剂如糖皮质激素、免疫球蛋白和抗-D抗体（针对Rh系统D抗原的抗体），也有采用长春新碱或抗人CD20单克隆抗体清除B淋巴细胞，以及环孢菌素等免疫抑制剂等。对难治性病例还要进行脾脏切除手术。虽然免疫抑制治疗方案对大多数患者治疗有效，但30％以上的ITP患者会复发，且这类治疗不良反应较多，脾脏切除还会导致机体免疫力下降，容易出现感染等并发症。临床需要更加安全有效的治疗方法。重组人血小板生成素（TPO）由于自身抗体而继发严重的血小板，目前已退出ITP的治疗。最近。欧洲批准了2个血小板受体激活剂AMG531和Eltrombopag，通过促进巨核细胞分化和血小板生成来治疗ITP。国内采用泛细胞保护剂为主的联合方案治疗难治／复发性ITP也取得了良好的效果。总之，根据ITP患者不同的发病机理进行个体化治疗是未来ITP基础与临床的研究方向。本文就ITP的发病机理和临床治疗作一综述．并对ITP分型施治的可能性进行了初步的探讨。     

Guidelines in the management of Helicobacter pylori infection in Japan--in comparison with the guidelines published in other countries

Helicobacter pylori(H. pylori) is a causative agent for chronic gastritis and is an important risk factor for peptic ulcers, gastric carcinomas, and gastric MALT lymphomas. In 2000, the Japanese Society for Helicobacter Research published a guideline on the diagnosis and treatment of H. pylori infection for physicians in routine medical practice. In this guideline, H. pylori eradication therapy is recommended in gastric or duodenal ulcer patients. H. pylori eradication is also recommended in gastric MALT lymphoma patients but the guideline says it should be done at specialist institutions. Considering the high prevalence of gastric carcinomas in Japan. H. pylori eradication for the prevention of gastric carcinomas should be discussed urgently.     

Guidelines for the management of Helicobacter pylori--Maastricht III-2005 and Japanese guidelines

The guidelines on the management of Helicobacter pylori were updated at the European Helicobacter study group third Maastricht consensus conference in March 2005. Especially, this conference emphasis on the management of non ulcer dyspepsia, GERD, and the patients who use non steroidal anti-inflammatory drug. Eradication of H. pylori is recommended in patients with peptic ulcer, low grade MALT lymphoma, atrophic gastritis, unexplained iron deficiency anemia, chronic idiopathic thrombocytopenic purpura and first degree relatives of patients with gastric cancer. H. pylori eradication is less effective than proton pomp inhibitor(PPI) treatment in preventing ulcer recurrence in long term NSAIDs users. This meeting also emphasized on the relationship between H. pylori and gastric cancer. The guideline concluded that H. pylori eradication has the potential to reduce the risk of gastric cancer development. Japanese guideline in 2003 does not mention the effect of eradication for prevention of gastric cancer. The H. pylori eradication and new strategy should be desirable for global strategy of gastric cancer prevention.     

Practical advice on eradicating Helicobacter pylori infection

Peptic ulcer disease associated with H pylori infection is curable. The important factors in selecting therapy are efficacy of eradication, prevention of resistance, avoidance or minimization of adverse effects, patient compliance, and cost. The most effective regimens include a bismuth preparation or antisecretory drug (proton pump inhibitor or H2 receptor antagonist) plus two antibiotics administered for 14 days. Dual-drug therapies are not recommended. Triple-drug regimens are more likely to eradicate H pylori and less likely to generate resistant strains among surviving organisms. In general, cure of the infection should be confirmed 4 weeks after completion of the treatment. Antibiotic resistance is an important consideration in choosing therapy, and patients should be taught the importance of compliance. When treatment fails, antibiotic combinations should not be repeated. Considerations for anti-H pylori treatment in a managed care environment mirror those for good medical practice in general, with special attention to stringent cost-control or outcomes-driven measures.     

Current state and measures of NSAIDs induced ulcer

In recent years, the incidence of Helicobacter pylori (H. pylori) infection has been decreasing and the incidence of peptic ulcer and bleeding ulcer induced by NSAIDs, especially low-dose aspirin (LDA), have been increasing. PPI and PG are useful for treatment and prevention of ulcers in patients receiving continuous administration of NSAIDs and/or LDA. H. pylori eradication is effective if performed before the start of NSAIDs administration, but a beneficial effect of H. pylori eradication performed during NSAIDs treatment cannot be expected. The incidence of ulcers is lower when administering COX-2-selective inhibitor than when administering non-selective NSAIDs, but attention must be given to cardiovascular events as side effects when administering COX-2-selective inhibitor.     

Helicobacter pylori therapy in children: a focus on proton pump inhibitors

Over the last two decades, there have been many studies on children who have sought an effective and safe treatment to eradicate Helicobacter pylori infection, but as yet, no therapy regimen has been found which is always effective and safe. Differences in drug response among pediatric patients are common. Such individual variability in drug response is multifactorial, including environmental, genetic, development and disease determinants that affect the disposition of a given drug. In pediatric efficacy studies for the management of H. pylori eradication in children, the most commonly tested regimen has contained a combination of proton pump inhibitor (PPI), clarithromycin and amoxicillin, followed by triple therapies containing PPI, clarithromycin and nitroimidazoles. Thus, PPIs are an integral part of triple therapy for H. pylori eradication in children with gastroduodenal disease. In this article, we comprehensively review, from a pediatric point of view, the literature on the clinical, pharmacologic and microbiologic properties of PPIs. We also discuss genetic, developmental and other host-related factors that may affect the efficacy of these drugs. Finally, we provide some guidance regarding their potential role and limitations for H. pylori eradication in children.     

Update on Helicobacter pylori treatment

One half of the world's population has Helicobacter pylori infection, with an estimated prevalence of 30 percent in North America. Although it is unclear whether eradication of H. pylori improves symptoms in patients with nonulcer dyspepsia, there is strong evidence that eradication of this bacteria improves healing and reduces the risk of recurrence or rebleeding in patients with duodenal or gastric ulcer. A "test-and-treat" strategy is recommended for most patients with undifferentiated dyspepsia. With this approach, patients undergo a noninvasive test for H. pylori infection and, if positive, are treated with eradication therapy. This strategy reduces the need for antisecretory medications as well as the number of endoscopies. The urea breath test or stool antigen test is recommended. Until recently, the recommended duration of therapy for H. pylori eradication was 10 to 14 days. Shorter courses of treatment (i.e., one to five days) have demonstrated eradication rates of 89 to 95 percent with the potential for greater patient compliance. A one-day treatment course consists of bismuth subsalicylate, amoxicillin, and metronidazole, all given four times with a one-time dose of lansoprazole. In children with documented H. pylori infection, however, all regimens should continue to be prescribed for seven to 14 days until short-course treatment is studied and its effectiveness has been established in this population.     

Helicobacter pylori eradication therapy for gastric ulcer in elderly

Sixty-five-years or older person accounts for 23% of the population in Japan. Hence, Helicobacter pylori (H. pylori) eradication therapy is performed in many elderly patients. Urea breath test and H. pylori stool antigen test for diagnosis of H. pylori infection before and after eradication therapy are recommended from the point of being a noninvasive test and providing accurate diagnosis. H. pylori eradication therapy in Japan consists of the PPI/AMPC/CAM as the first therapy, and PPI/AMPC/MNZ as the second therapy. Eradication therapy rate and adverse effect rate of H. pylori eradication therapy for elderly patients are the same as for young people. It is not necessary to avoid H. pylori eradication therapy merely because of high age in elderly patients. However, it is necessary to be careful regarding drug interactions in patients who are taking multiple drugs.     

Monoclonal antibody therapy for disorders of hemostasis and coagulation

Monoclonal antibody therapies have conducted to not only hematologic malignancies but also disorders of hemostasis and coagulation. This article describes the recent advances of monoclonal antibody therapy for bleeding disorders such as idiopathic thrombocytopenic purpura(ITP), hemophilia A, disseminated intravascular coagulation(DIC), and thrombosis. Rituximab, chimeric anti-CD20 monoclonal antibody treatment has a valuable effect in the patients with ITP, and clinical trials using anti-CD40 ligand monoclonal antibody for ITP are underway. Anti-CD40 ligand monoclonal antibody can be an alternative therapy for hemophilia A patients with inhibitors to factor VIII. In thrombosis, anti-tissue factor monoclonal antibody and anti-factor IX(a) monoclonal antibody were established as novel anticoagulant regents. Plasminogen activator inhibitor-1(PAI-1) increases in endotoxin-induced DIC and many thrombotic diseases such as myocardial infarction, type 2 diabetes mellitus, and hyperlipidemia. Anti-PAI-1 monoclonal antibody reduced fibrin deposition in DIC mouse model. Treatment of these monoclonal antibodies for the molecules regulating coagulation-fibrinolysis system may be utilized for acute coronary syndrome and venous thrombosis.     

Treatment of severe asthma: entering the era of targeted therapy

Introduction: It is estimated that 5 – 10% of asthma patients suffer from severe asthma. Severe asthma is associated with increased morbidity and mortality. These patients are not controlled with currently available treatments and therefore additional treatment options are needed. Asthma is a heterogeneous disease, and different asthma patient groups probably have different underlying pathophysiology. Novel therapies with, for example, monoclonal antibodies that target certain immunological pathways have become available. These novel treatments are not effective in all patients but only in certain phenotypes.

Areas covered: This review covers the current evidence and novel developments in treatment with monoclonal antibodies in different asthma phenotypes. This includes monoclonal antibodies against IgE, against interleukin (IL)-5 and antibodies targeting IL-13 pathways. Although there is a certain overlap between patient groups benefiting from these treatments, a more detailed identification of responder profiles for these therapies is needed for personalized therapy.

Expert opinion: In recent years, novel monoclonal antibodies have been developed, which are a promising addition to existing therapy in the treatment of severe asthma with eosinophilic inflammation and Th2-driven disease. We expect that several of the new antibodies will become available for clinical practice. In addition, it must be acknowledged that so far no effective strategies are available for patients with non-eosinophilic asthma and further research and development is necessary for this patient group.     

The effect of helicobacter pylori eradication on NSAID-induced gastrointestinal toxicity

OBJECTIVE: To review the data to determine whether Helicobacter pylori eradication alters nonsteroidal antiinflammatory drug (NSAID)-induced gastrointestinal toxicity. DATA SOURCE: Literature accessed through MEDLINE from 1966 to May2000 and abstracts of recently presented data at scientific meetings. DATA SYNTHESIS: NSAID use and H. pylon infection are independent risk factors for the development of gastrointestinal ulcers. An evaluation of the relationship between these two risk factors and the impact of H. pylori eradication on NSAID-induced gastrointestinal toxicity was conducted. CONCLUSIONS: H. pylori colonization and NSAID use are independent risk factors for the development of gastrointestinal ulcers. The data regarding the interaction between these two risk factors in the development of gastrointestinal ulcers are conflicting. Eradication of H. pylori does not appear to decrease the risk of NSAID-induced gastrointestinal toxicity in the majority of patients. As there is little evidence to support a clear benefit of eradicating H. pylori in patients requiring NSAID therapy, routine screening for and eradication of H. pylori in these patients is not recommended.