Current Pharmaceutical Design - Volume 21, Issue 35, 2015

Low-dose aspirin, commonly defined as 75-325 mg daily, is widely used for cardiovascular (CV) protection. It reduced the risk of CV events and death in patients with coronary and cerebrovascular diseases and has the advantages of both low cost and long duration of antiplatelet action. However, low-dose aspirin therapy is associated with upper gastrointestinal (GI) side effects, which range from dyspepsia (point prevalence: 31%), gastroduodenal erosions (point prevalence: 60%), endoscopic peptic ulcer (3-month incidence: 7%) to symptomatic or complicated ulcers (annual incidence of upper GI bleeding: 0.6%; relative risk of upper GI bleeding: 2.6). The important factors that increase the risk of low-dose aspirin-related ulcer complications include a history of bleeding peptic ulcer, prior peptic ulcer, age > 70 years, H pylori infection, and concomitant drug therapy with non-steroidal anti-inflammatory drugs, other antiplatelet agents (e.g., clopidogrel) or anticoagulants. The use of enteric-coated or buffered preparations do not reduce the risk of upper GI complications. Assessment of GI risk for patients is a crucial step in preventing complications of antiplatelet agents. Patients with a high GI risk should prevent peptic ulcer or ulcer complications by co-therapy with an antisecretory agent, especially proton pump inhibitors. H pylori eradication is recommended for patients requiring long-term low-dose aspirin therapy who have a prior history of peptic ulcer or GI bleeding.

Nowadays, low-dose aspirin is widely administered at low dose as an antithrombotic drug for the prevention of cerebrovascular and cardiovascular diseases. However, aspirin, even at a low dose, can induce varying degrees of gastroduodenal mucosal injury (erosion, ulcer, ulcer bleeding). Hence, co-prescription of proton pump inhibitors with low-dose aspirin is recommended for those at high risk for adverse gastroduodenal events. At present, a history of peptic ulcer, especially that of complicated ulcer, is the most important risk factor for low-dose aspirin-associated gastroduodenal adverse events. Additionally, concomitant use of non-steroidal anti-inflammatory drugs including COX-2 selective inhibitors, anti-platelet agents, anti-coagulants, and oral corticosteroid is recognized to increase the risk for adverse gastroduodenal events in low-dose aspirin users. H. pylori infection could also be associated with the increased risk for adverse gastroduodenal events in low-dose aspirin users, especially in patients with histories of peptic ulcers. Therefore, eradication therapy for such patients can prevent ulcer recurrence. However, the efficacy of eradication therapy on low-dose aspirin-related gastroduodenal lesions in unselected H. pylori-positive lowdose aspirin users without histories of peptic ulcers remains to be clarified.

The risk of gastrointestinal (GI) bleeding is increased in association with the use of low-dose aspirin (LDA). There are few studies of the association between genetic polymorphisms and the risks of aspirin-induced ulcer or its complications. Individuals with two single nucleotide polymorphisms (SNPs) of cyclooxygenase-1 (COX-1), A-842G and C50T, exhibit increased sensitivity to aspirin and lower prostaglandin synthesis capacity but the polymorphism lacked statistical significance in relation to an association with bleeding peptic ulcer. In our previous Japanese study, SLCO1B1 521TT genotype and the SLCO1B1 *1b haplotype were significantly associated with the risk of peptic ulcer and ulcer bleeding in patients taking LDA, especially in the patients with angiotensin converting enzyme inhibitor (ACEI), angiotensin type 1 receptor blocker (ARB), or statin co-treatment. Protonpump inhibitors (PPIs) are recommended for patients who require antiplatelet therapy and have a history of upper GI bleeding. The interaction between PPIs and consequent impaired effectiveness of clopidogrel has caused concern regarding the effect of genetic polymorphisms of the CYP2C19 which mediates conversion of clopidogrel to its active metabolite. The later recent genome-wide analysis of SNPs indicated the association of several SNPs with small bowel bleeding in Japanese patients taking LDA. The data are still lacking and further prospective studies are needed to identify the specific gene polymorphisms as risk or protective factors for GI bleeding associated with LDA.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed group of drugs in the world. They are used primarily for pain relief in chronic inflammatory joint disease and act by inhibiting enzymes COX1 and COX2 and ultimately preventing the production of active prostanoids which are required for the innate inflammatory pathway. The use of NSAIDs have been associated with the development of gastrointestinal (GI) symptoms ranging from simple dyspepsia to life threatening GI bleeds and perforations. The definition of dyspepsia has evolved over the years and this has hampered accurate studies on the prevalence of dyspepsia as different studies used varying criteria to define dyspepsia. It is now known that NSAIDs significantly increase the risk of dyspepsia.The risk of developing peptic ulcer disease vary with specific NSAIDs and dosages but there is no correlation between the symptoms of dyspepsia and underlying peptic ulcers. The pathogenesis of dyspepsia with NSAIDs is not completely understood. Peptic ulceration alone is not able to account for the majority of dyspepsia symptoms encountered by NSAIDs users. Erosive oesophagitis secondary to NSAIDs may be contributing factor to the prevalence of dyspepsia in NSAIDs users. Altered gut permeability and changes in gastric mechanosensory function due to NSAIDs may also be a contributory factor. Management of NSAID induced dyspepsia is involves a multipronged approach. Drug avoidance if possible would be ideal. Other options include using the lowest effective dose, changing to an NSAIDs with a safer GI risk profile, avoiding concurrent use with other NSAIDs or if the patient has a previous history of peptic ulcer disease, and co-prescribing with anti-secretory medications such as proton pump inhibitors. Eradication of Helicobacter pylori has a protective role against developing peptic ulcers and may also improve symptoms of NSAIDs induced dyspepsia.

Low-dose aspirin (LDA) has been increasingly used worldwide to prevent atherothrombotic events. At the same time, the adverse events, most frequent of which are gastrointestinal (GI) ulcers and complications have been raising a big concern with its wider use. These adverse events including reflux and dyspeptic symptoms not only jeopardize adherence of LDA, but my cause more serious outcomes. To reduce GI events by informing best evidence for physicians prescribing LDA, guidelines were published some years ago. Since then, more clinical evidence concerning preventive strategies for upper GI events has been accumulated. Notable differences between East and West are also recognized in terms of primary prevention strategy. Among several options to provide cardiovascular protection with LDA while reducing GI risk, PPI co-therapy is considered to be preferred approach for wider populations according to recent cost-effectiveness analyses based on increasing awareness of importance on adherence of LDA together with declining cost of PPI. This review will focus on these new developments on the prevention of upper gastrointestinal ulcer and complications in LDA users.

Aspirin is in many ways a non- steroidal anti-inflammatory drug (NSAID) prototype. Similar to conventional NSAIDs the gastric side effects of aspirin are well studied. However its potential adverse effects on the small and large intestine are less well known and under- researched. Experimental studies support a pathogenic pathway leading to NSAID enteropathy involving the topical effects on the intestinal barrier (mucous layer, enterocytes) that lead to dysfunction and increased intestinal permeability followed by increased exposure to luminal triggers and acute inflammation. Although aspirin has a toxic effect in vitro, enteral or parenteral administration in vivo, in animal models, did not result to intestinal injury. In man, experimental studies have revealed changes in intestinal permeability similar to conventional NSAIDs but of lesser magnitude. The clinical implication of these changes though is not known. Population studies have associated aspirin use with occult gastrointestinal bleeding from the small or large bowel although the magnitude of this risk is difficult to estimate but certainly small. Associations to colitis flare-ups have been made in case reports and retrospective cohort studies but low dose aspirin appears safe. Complications of diverticular disease may also be more frequent with aspirin use.

Low dose aspirin (ASA), commonly defined as the cardiovascular (CV) dose of 75 to 325 mg daily, is one of the most widely prescribed drugs in the world and the cornerstone of therapy and prophylaxis for CV disease. However, the use of low dose ASA is well known to be associated with an increased risk of different upper and lower gastrointestinal (GI) complications, such as peptic ulceration and bleeding. In the recent past, clinical research was mainly focused on ASA-related injury of the upper GI tract. However, the introduction of new endoscopic techniques, such as capsule endoscopy and balloon-assisted endoscopy for the evaluation of small bowel lesions have resulted in an increasing interest among gastroenterologists about the side effects of ASA on the large and small bowel. Furthermore, it has been demonstrated that chronic use of low dose ASA results in a variety of lesions in the lower GI tract, including multiple petechiae, erosions, ulcers, diverticular bleeding and even circumferential ulcers with stricture. The ideal treatment for small bowel injury in low dose ASA users would be withdrawal of ASA, however, this withdrawal could increase the risk of CV/cerebrovascular morbidity and mortality in high percentage of patients. Therefore, several drugs have been evaluated to identify the best choice to prevent or treat ASA-induced small bowel injury with different results. Nevertheless, further specifically designed studies with more sample size are needed to determine the best treatment for low dose ASA related GI injury.

This review highlights practical aspects related to aspirin therapy in cardiovascular diseases, specifically, the benefits and hazards in different clinical settings. Aspirin reduces one fourth of all major cardiovascular events but also increases major gastrointestinal bleeds by about half. As with other cardiovascular prevention strategies, the absolute benefit of aspirin is linearly related to the cardiovascular risk of the patient. The risk-benefit of aspirin can vary substantially in different settings: in secondary prevention, the benefits usually outweigh the excess of major bleeding complications. In primary prevention, it is not unusual that the number of vascular events avoided equals the number of major bleeds induced by aspirin. Finally, there is a growing body of evidence suggesting that aspirin may interfere with the early stages of cancer, metastasis and mortality. For all these reasons, in this article new developments in the field directed towards individualized risk assessment strategies are also discussed.

Aspirin has been one of the most widely used medications since its first synthesis more than 100 years ago. In addition to short-term use for pain and fever relief, regular use of aspirin has been shown to reduce the risk of cardiovascular diseases and strokes. The issue of regular aspirin use in cancer prevention is definitely promising, which has been supported by growing evidence from a number of observational studies and post-trial follow-up data. Among all cancers, aspirin is showing to be the most effective in reducing the risk of colorectal cancer, and even at lower doses demonstrates a 30-40% effectiveness in preventing colorectal cancer. Esophagus and stomach cancers are two cancers getting increased attention from emerging evidence of meta-analyses. Given the common side effects of aspirin, such as gastrointestinal complications, whether it is ready to take aspirin regularly for general population remains controversial since more studies are needed to clarify the net balance between harm and benefit. The decision might become more complicated since recently one molecular epidemiology study showed that different genetic traits may impact the effect of aspirin on colorectal cancer. Here we summarize recent evidence from meta-analyses related to gastrointestinal cancers. We reviewed updated observational studies and post-trial follow up data from randomized controlled trials focusing on the role of aspirin in the incidence and mortality of gastrointestinal cancers.

The results of clinical studies have shown that the chronic administration of aspirin, even at the lowdoses (75-100 mg daily) recommended for the prevention of cardiovascular disease, is associated with a reduction of cancer incidence and mortality, in particular colorectal cancer (CRC). The mechanism of action of aspirin as an antineoplastic agent remains controversial. However, data of clinical pharmacology and several features of the chemopreventive effect of aspirin, emerged from clinical trials, suggest that the antiplatelet effect of aspirin plays a central role in its anticancer effects. In addition to their contribution to tumor metastasis, platelets may play a role in the early phases of tumorigenesis. In response to lifestyle and environment factors, intestinal epithelial damage/ dysfunction may be associated with platelet activation, initially as a mechanism to repair the damage. However, if the platelet response is unconstrained, it may contribute to the development of chronic inflammation. Altogether these events lead to alter the normal functions of intestinal epithelial cells and may translate into cellular transformation through several mechanisms, including the overexpression of cyclooxygenase(COX)-2 and epidermal growth factor receptor (EGFR), which are considered early events in colorectal tumorigenesis. Thus, antiplatelet agents may play a role in the prevention of CRC by modifying epigenetic events involved in early phases of colorectal tumorigenesis. Finally, we carried out a critical review of the literature on off-target mechanisms of aspirin action as anticancer drug.

Aspirin has been extensively investigated in the context of the prevention of cardiovascular disease. It has one of the strongest cumulative evidence supporting its use in colorectal cancer (CRC) chemoprevention. Epidemiological, clinical, and observational studies have demonstrated that aspirin and non-steroidal antiinflammatory drugs (NSAIDs), including COX-2 inhibitors, can protect against CRC and significantly reduce its incidence. Moreover, prospective randomized controlled trials of colorectal polyp recurrence and in patients with hereditary CRC syndromes have shown that aspirin can produce regression of existing colorectal adenomas and prevent the formation of new polyps. However, the lowest effective doses, treatment duration, target populations, and the effects on survival are not entirely clear. Although not common serious side effects and in particular gastrointestinal and intracerebral hemorrhage do occur, better selection of individuals who might benefit the most from aspirin use must be carefully performed in order to maximize their risk/benefit ratio. In the era of precision medicine, genetic information, blood and/or urinary biomarkers, could potentially help in tailoring chemopreventive therapeutic strategies, based on aspirin use, while limiting adverse toxic effects. The current review will cover the use of aspirin for the prevention of colorectal adenomas and CRC, potential markers for chemoprevention, and patient stratification.

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a ubiquitous molecule generated in all mammalian tissues from the N-terminal sequence of thymosin β4 (Tβ4) by the action of propyl oligopeptidase. Ac-SDKP is an alternative substrate for angiotensin converting enzyme (ACE). There are several indications that Ac-SDKP may be protective in the cardiovascular system. First, the level of Ac- SDKP in plasma and tissues is reduced in some cardiovascular pathologies such as hypertension. Second, an administration of Ac-SDKP to rodents attenuates inflammation, cell differentiation, proliferation, and migration resulting in a reduction of fibrosis in the heart, vessels and kidneys in conditions of their disorders. Third, the treatment with ACE-inhibitors is associated with a reduced degradation and hence increased levels of Ac-SDKP, while a simultaneous treatment with monoclonal antibodies against Ac- SDKP partly counteracts the benefit of ACE-inhibition. Since Ac-SDKP fails to reduce blood pressure and left ventricular hypertrophy (LVH), its potential structural benefit is obviously mediated by direct action on tissue in preventing or reversing excessive fibrosis. The protection by ACE-inhibition seems to be partly mediated by increased availability of Ac-SDKP. Thus, it is to suppose that harvesting the knowledge on the role of Ac-SDKP in cardiovascular physiology and pathology could deepen our insight into the mechanisms of action of the renin-angiotensin system (RAS) as well as agents interfering with this system. The exciting protective potential of Ac-SDKP suggests that this compound could be a focused drug target not only in animal experiments but also in the clinical cardio-pharmacologic research in the near future.

Nonalcoholic fatty liver disease (NAFLD) is defined as the accumulation of triglycerides (TGs) within hepatocytes exceeding 5 % of liver weight. NAFLD is a spectrum of pathological processes from nonalcoholic fatty liver or simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. As NAFLD induces metabolic syndrome (MS), then, NAFLD is associated with insulin resistance (IR), type 2 diabetes mellitus (T2DM), hypertension and even Polycystic Ovary Syndrome (PCOS). Because it is well established that patients carrying gene mutations also develop NAFLD in the absence of IR, the genetic predisposition to NAFLD is also discussed. Little is known about the diagnosis and treatment of NAFLD in children and adolescents and the lack of non-invasive diagnostic tools in these populations is a major problem faced by physicians. The present review aims to discuss recent findings of NAFLD in children and adolescents and, considering the features in common with PCOS, we also discuss their relationship.

Atherosclerosis has been widely recognized as a slow progressing inflammatory disease of the arterial walls involving both inflammation and autoimmune processes with a complex etiology in which the immune system plays a key role. A hallmark of atherosclerosis is that the macrophages pick up the lipids to form the foam cells which build up the plaque in the arterial wall. Consequently, the arteries become narrowed. Plaque rupture can trigger thrombosis which is superimposed on atherosclerotic lesion. The activation of macrophages and T cells plays key roles in these lesions. Cells involved in the atherosclerotic process secrete soluble factors, known as cytokines. These cytokines can be further divided into two classes namely proinflammatory and anti-inflammatory cytokines based on their roles in inflammation. Among the cytokines, interleukin (IL)-35 is the one most recently discovered that suppresses inflammatory responses of immune cells. Accumulating evidence suggests that IL-35 represents an attractive target for antiatherosclerotic therapy based on its several atheroprotective features. In this review, we will provide a brief overview of IL-35 biology and the role of IL-35 in the development, or the progression of atherosclerosis.

MicroRNAs (miRNA), small noncoding RNA molecules, are endogenous regulators of gene expression that have been implicated in the pathogenesis of various diseases such as cancer and arthritis. The aim of this study was to explore the biological function of microRNA-16-5p (miR-16-5p) and the molecular mechanism in osteoarthritis (OA). MiRNA targets were identified using bioinformatics. Using real-time PCR, the expression of miR-16-5p and SMAD3 in cartilage specimens was determined in 10 patients with knee OA and in 10 traumatic amputees (control). Functional analysis of miR-16-5p in chondrocytes was performed at both mRNA and protein levels after miRNA transfection. A luciferase reporter assay was used to verify interaction between miRNA and target mRNA. Expression of miR-16-5p was significantly higher in OA cartilages than in healthy cartilages. The data from the reporter assay and western blots indicated that miR-16- 5p regulated SMAD3 expression. Functional analysis showed that miR-16-5p could reduce expression of type IIcollagen and aggrecan while inducing expression of matrix metalloproteinases and ADAMTS; however, miR-16-5p inhibition could reverse these effects. Our results indicate that miR-16-5p is an important regulator of SMAD3 expression in human chondrocytes and may contribute to the development of OA.