Current Pharmaceutical Design - Volume 20, Issue 28, 2014

The eradication of Helicobacter pylori not only heals peptic ulcers but also prevents their recurrence and reduces the risk of development of gastric cancer and other H. pylori-associated disorders. H. pylori eradication heals gastritis and may prevent the spread of infection, reducing the future costs required for the treatment of subsequent H. pylori-associated diseases. There are various guidelines for the management of H. pylori infection worldwide, such as the guidelines of the American College of Gastroenterology, Maastricht IV, the Second Asia-Pacific Consensus Conference, and Japan. The Japanese health insurance system approved H. pylori eradication therapy for H. pylori-related chronic gastritis in 2013. Triple therapy regimens comprising 1 proton pump inhibitor and 2 antimicrobial agents such as amoxicillin, clarithromycin, metronidazole, levofloxacin, or tetracycline have been widely used to eradicate this bacterium. The rate of successful eradication has declined owing to the increased rate of drug resistance stemming from the wide usage of antibiotics. This issue is of particular relevance with regard to clarithromycin. In worldwide, clarithromycin-based triple therapy should be abandoned, as it is no longer effective. Quadruple therapy and sequential therapy are reasonable alternatives for initial therapy. First-line treatment should be recommended on the basis of an understanding of the local prevalence of H. pylori antimicrobial resistance.

Gastric cancer is the fourth most common cancer in the world and second most common reason for cancer related death. Projections for the future predict that gastric cancer incidence will continue to rise. Risk factors for gastric cancer are Helicobacter pylori (H pylori) infection, host genetic factors and environmental factors. H pylori is a class I carcinogen and responsible for 60 % - 80 % of all gastric cancers of intestinal and diffuse type, as well as gastric MALT lymphoma. From animal and intervention studies we know that premalignant gastric lesions development and gastric cancer can be prevented with early H pylori eradication. In countries with gastric cancer incidence higher than 20 / 100 000 per year national screening for H pylori infection and eradication of all H pylori infections should be performed. Type of eradication therapy depends on local antimicrobial resistance rates. Quadruple bismuth or non- bismuth therapies can achive more than 90 % eradication rate. The success of eradication therapy must be controlled with noninvasive test. Patients with extensive preneoplastic changes (atrophy, intestinal metaplasia) should have endoscopic and histologic controls. Endoscopic screening should be performed in intervals according to the risk stratification by OLGA / OLGIM staging system or A-D staging system. In countries with high gastric cancer incidence national screening with serological tests for pepsinogen I (PGI), PGI/PGII ratio and H pylori antibodies can select patients at higher risk for gastric cancer.

Helicobacter pylori is a gram-negative, microaerophilic spiral bacillus that is associated with life-threatening diseases such as gastric cancer, gastric MALT lymphoma, and peptic ulcer disease. The definition of an effective therapy is one that achieves at least a 90% eradication rate on a per-protocol basis with the first attempt. Eradication rates of H. pylori have declined to unacceptable levels worldwide, mostly due to antibiotic resistance and standard triple therapy gradually has lost its efficacy in most counties. However, bismuth quadruple therapy, when prescribed properly, has maintained its effectiveness. Alternative first-line regimens such as sequential and concomitant therapy were developed to substitute for standard triple therapy and were highly effective in the countries where they were developed, but proved susceptible to failure in regions with high rates of antibiotic resistance. Antibiotic resistance rates in Russia are high, however there is lack of data regarding comparative efficacy of first-line eradication options. The authors of this review extrapolate the knowledge of H. pylori first-line eradication options in Russia based on data from other countries, as well as from domestic studies. The available data support use of 14-day regimens with concomitant therapy, bismuth quadruple therapy, or furazolidone quadruple therapy for empiric use in adults. In addition, 14-day levofloxacin-containing therapies could be used if resistance is relatively low or lacking as triple therapy or possibly as a 5-day concomitant levofloxacin therapy.

Various clinical presentations have been ascribed to Helicobacter (H.) pylori. Most importantly, H. pylori is considered the leading cause of gastric cancer worldwide and because of that, in adult population, it is listed as a number one carcinogen. However, children are less prone to develop H. pylori related serious diseases such as peptic ulcer disease (PUD) and cases of malignancy are only sporadically reported. On the other hand, there is an increasing level of evidence suggesting that H. pylori in children could also have a beneficial effect. Recently, several data confirmed previously described inverse relationship of H. pylori infection and gastroesophageal reflux disease. Furthermore, it has been hypothesized that an increased prevalence of allergic diseases could be, at least partially, explained by the decreased incidence of H. pylori infection. H. pylori can, to some degree, influence immunological response. It has an ability to promote high proinflammatory cytokine expression in the gastric mucosa shifting immunity towards Th1 response, which could be a plausible explanation for the down-regulated clinical expression of allergies (including asthma) in patients with H. pylori gastritis. Based on these findings the aim of this review is to present “pros and cons” for H. pylori eradication in children.

Treatment of Helicobacter pylori (H. pylori) infection is crucial for the management of prevalent digestive and more recently also extra-digestive disorders. Rising prevalence of clarithromycin resistance worldwide has accounted for a dramatic decline in the efficacy of standard triple therapies, which should not be prescribed, unless local clarithromycin-resistance is low (<20%) or culture confirms susceptibility to this antibiotic (i,e,; as tailored treatments). Bismuth-quadruple, sequential, non-bismuth quadruple (concomitant), dual-concomitant (hybrid), and levofloxacin-based regimens have been shown to overcome clarithromycin resistance and are now preferred empirical treatments achieving improved eradication rates (>90% in per protocol analysis). In the future, empiric use of both clarithromycin and levofloxacin is likely to become steadily more challenging as even these novel eradication therapies may be prone to the effect of increasing antibiotic resistance. Tailored treatment based on the individual characterization of H. pylori therapeutic susceptibility appears to be a reasonable future alternative, currently limited by the shortcomings of systematically performing H. pylori culture (invasive, expensive, time-consuming). However, recent advances in the genotypic detection of H. pylori susceptibility to antibiotics, and in pharmacogenomics, may represent a breakthrough in our future approach to tailored therapy. Until then, efforts to optimize empirical treatments should continue.

This review evaluates the current literature based on the impact of antibiotics on the intestinal microbiota and the critical role of intestinal bacteria in controlling infection and subsequent clinical disease caused by STEC and Salmonella, and the transmissibility of these important pathogens.A number of studies have indicated that antibiotic therapy could result in unexpected changes in the clinical picture of disease. This is observed, for example, in the case of infections associated with Shiga-toxin-producing Escherichia coli (STEC), when antibiotics used in treatment of the disease may increase the risk of hemolytic uremic syndrome (HUS) and thus fatal outcomes. In the case of such infections, treatment with antibiotics is usually discouraged. The use of antibiotics could cause also undesirable changes in the intestinal microbial flora and prolonged pathogen shedding, which is observed in the case of Salmonella infections. Inappropriate antibiotic therapy can result in Salmonella remaining in the host’s cells (intracellular) and thus resulting in further asymptomatic carriage and a further complication is the development of resistance.

Inflammatory bowel disease (IBD) is a chronic, immune-mediated disease of the gastrointestinal tract that develops in genetically susceptible individuals. Questions about the role of infections in the development and exacerbations of inflammatory bowel disease remain unanswered. Among numerous bacteria that have been linked to IBD, the most frequently associated is Clostridium difficile. Clinical symptoms of C. difficile infection and an exacerbation of inflammatory bowel disease are often indistinguishable. In cases of diarrhea in patients with IBD and C. difficile infection, antibiotic treatment is recommended. This review attempts to summarize C. difficile infection’s epidemiology and clinical features and describes current evidence on treatment of C. difficile infection in children with IBD.

Probiotics are nowadays frequently used by patients with inflammatory bowel disease, however literature data are conflicting related to their importance. In mild to moderate ulcerative colitis probiotics can be used effectively in induction and maintaining remission, and prevention of pouchitis. As the other side of the shield, there is not sufficient evidence to support the use of probiotics in daily clinical practice in Crohn’s disease. The aim of the present review is to provide help for clinicians about the probiotic use in patients with inflammatory bowel disease. The comparison of literature data is limited by the large number of probiotic strains, various combined preparations, and different doses applied in the clinical studies. Small number of comparable protocols and lack of standardization encumber the analysis of study results.

The concept that the gut microbiota plays a major role in the development of pouchitis in ulcerative colitis patients after restorative proctocolectomy with ileal pouch-anal anastomosis, is widely accepted and supported by a widespread use of some antibiotics (metronidazole and/or ciprofloxacin, rifaximin) to treat this condition. A possible, safer therapeutic alternative is represented by probiotics. To date the controlled studies addressing the possible efficacy of probiotic agents in the treatment of active pouchitis are few and inconclusive. By contrast the prophylactic use of a probiotic mixture (VSL #3) appears to be able to prevent development of pouchitis. The most convincing results have been observed in the maintenance of remission, where the probiotic mixture has been found, in most of the performed controlled trials, significantly effective in preventing pouchitis recurrence.

Although several studies have been published on the gut microbiota composition, they are mainly focused on bacteria. Therefore, the world of gut yeasts, the “gut mycome”, is still unclear. Over the last years, brand new gut microbiota analysis techniques have been applied to the study of yeasts, with exciting results both in health and in disease. A therapeutic potential for many gastrointestinal and extra-intestinal diseases has been recognized for selected yeast strains, such as Saccharomyces boulardii. This narrative review represents an overview of the new evidences regarding the “gut mycome”.

Mitochondrial dysfunction has been implicated in the development of a wide spectrum of major human diseases, including diabetes mellitus, heart disorders, neurodegeneration and cancer. Several therapeutic approaches targeting mitochondrial function have been applied in most cases without however the desired outcome. The limited effectiveness of these therapeutic schemes is due to the fact that several important aspects of mitochondrial function have not been elucidated as yet, including the detailed mechanism of ATP production. Although it is known that electron transport chain (ETC) is the central machinery responsible for mitochondrial oxidative ATP production, major important functions attributed to ETC are still unresolved while other activities which are in fact carried out by the ETC have been overlooked. This review revisits ATP synthesis providing a detailed account of the experimentally-verified ETC functions focused on the ability of ETC to act as an electro-electric converter, able to accept different electrons from any given energy source (light, food or metals) in order to produce the correct voltage and store it in the form of electrostatic potentials (mitochondrial membrane potential). This stored electric energy, in the order of 3x107 V/m, can then be used by F1F0 ATP synthase for ATP production. The present review provides supportive evidence that this ETC function suffices to fully explain the missing parts of ATP production, thus redirecting the current therapeutic schemes for the management of mitochondrial diseases to a more complete and effective avenue.

Monocyte chemotactic protein-1 (MCP-1) (also referred to as chemokine (C-C motif) ligand 2 (CCL2) is expressed by mainly inflammatory cells and endothelial cells. The expression level is upregulated after proinflammatory stimuli and tissue injury which are associated with atherosclerotic lesion. Atherosclerosis is a progressive disease starting with accumulation of lipids, lipoproteins, and immune cells in the arterial wall. MCP-1 has been reported to play an important role in the pathogenesis of atherosclerosis and considerable evidence supports that the monocyte containing MCPs and macrophage influences the growth of other cell types within the atherosclerotic lesion. This review will focus on the general structure features of MCP-1 and its role in atherosclerosis.

Randomized trials comparing multi-vessel percutaneous coronary intervention to coronary artery bypass grafting (CABG) have demonstrated the long-term superiority of CABG in diabetic patients. Benefits include improved survival, fewer recurrent myocardial infarctions and a lower risk of the need for repeat intervention. The focus of this review article is to review the contemporary management of diabetic patients with multi-vessel coronary artery disease.

P2Y12 inhibitors constitute an essential part of the antithrombotic treatment, with proven clinical benefit in acute coronary syndromes and after percutaneous coronary interventions. Substantial evidence has emerged that, apart from their primary antiplatelet action, P2Y12 receptor inhibitors exhibit several off-target effects. In this review, we present the supporting evidence of P2Y12 inhibitors’ pleiotropic actions, discuss their clinical implications and underscore the necessity for further research on this issue.