Mini Reviews in Medicinal Chemistry - Volume 16, Issue 3, 2016

The gastrointestinal tract is a complex and dynamic network where an intricate and mutualistic symbiosis modulates the relationship between the host and the microbiota in order to establish and ensure gut homeostasis. Every day, thousands of compounds derived from food and microorganisms come in contact with the intestinal mucosa. This interaction requires a complex defense system that separates intestinal contents from the host tissues, regulates nutrient absorption, and allows tolerance between the resident bacterial flora and the mucosal immune system, while inhibiting translocation of infectious agents to the inner tissues. Unfavorable alteration of microbiota composition has been implicated in hepatic, gastrointestinal, and perhaps also systemic disorders. In this scenario, gut microbiota modulation represents an intriguing field and can be obtained by several approaches, including antibiotics, proand pre-biotics supplementation. Among antibiotics, Rifaximin seems to be a promising antibiotic to treat conditions related to gut microbiota imbalance and to potentially modulate intestinal homeostasis. This review focuses on what is currently known regarding the possible role of Rifaximin in restoring normal gut immune physiology and a healthy gutliver axis. Detailed mechanistic studies will improve the development of targeted therapies that may shape gut microflora composition with the end goal of promoting gut health.

A large number of clinical studies using breath testing and a smaller number of studies using quantitative cultures of the upper small intestine established a link between irritable bowel syndrome (IBS) and small intestinal bacterial overgrowth (SIBO). A series of 12 studies both prospective and retrospective in design in a population of patients with SIBO without IBS showed that the non-absorbable antibiotic rifaximin can eradicate SIBO as proved through decrease of the exhaled hydrogen and methane in breath tests. The efficacy of rifaximin was superior over the comparator treatment in most of these studies. Based on these findings, short course rifaximin was tested in various concentrations in eight open-label trials in patients with IBS and proven SIBO by breath test. Similar efficacy of rifaximin was shown in SIBO eradication; this was accompanied by improvement of the global score for IBS symptoms. Finally, five doubleblind randomized clinical trials were conducted in patients with IBS; four were placebo-controlled. The larger trials were TARGET 1 and TARGET 2 studies testing rifaximin at a regimen of 550mg tid for 14 days. All trials showed a significant superiority of rifaximin over comparator for the improvement of global symptoms of IBS and bloating. Although the aforementioned results render rifaximin a revolutionary therapeutic approach for IBS, several concerns on induction of antimicrobial resistant flora remain.

Graft versus host disease (GVHD) remains a major life threatening complication and one of the primary barriers to successful allogeneic hematopoietic stem cell transplantation, limiting its application in nonmalignant conditions. Immunosuppression is used for prevention and treatment of GVHD, dampening the graft versus leukemia effect. Intestinal bacteria play a major role in inflammation and augmenting the GVHD cytokine response. Early studies in murine models showed that manipulating the presence of intestinal flora or counteracting its byproducts could limit GVHD. Thus multiple clinical trials targeting gut decontamination were conducted, with the aims of modulating inflammation and protecting against GVHD, with mixed results. More recent work has improved our understanding of the role of intestinal microbiota in the maintenance of innate immunity, mucosal integrity and limiting inflammation. This review offers a summary of this data, with a discussion of potential therapeutic interventions manipulating the intestinal microbiota.

Rifaximin is a poorly absorbed rifamycin drug with unique pharmacokinetic properties: bile solubility making it highly active against pathogenic and non-pathogenic bacterial flora in the bile-rich small bowel and low water solubility making it active only against highly susceptible bacteria, primarily anaerobes, in the aqueous colon. The drug has anti-inflammatory gut mucosal stabilization properties that are important to its sustained effects in non-infectious diseases. Rifaximin is used chronically or recurrently for hepatic encephalopathy and diarrhea-predominant irritable bowel syndrome. Monitoring of long-term use of rifaximin for development of resistance and then determining whether developed resistance is associated with reduced efficacy are needed. Studies of changes of intestinal flora during therapy and the health implications of these changes are also needed.

Rifaximin is a broad-spectrum oral antibiotic, exhibiting limited systemic absorption, that is used clinically to treat a variety of gastrointestinal disorders, including traveller’s diarrhea, hepatic encephalopathy, irritable bowel syndrome, and the inflammatory bowel diseases. Rifaximin’s antimicrobial properties, in the context of enteric infections, and its effects on the host’s intestinal microbiota have been well characterized. More recently, it has been reported that rifaximin can modulate host tissue function through the activation of distinct molecular events. Within the gastrointestinal tract, rifaximin is a selective agonist of the pregnane X receptor (PXR), a nuclear receptor that regulates the expression of genes related to xenobiotic metabolism and drug detoxification. The PXR can also elicit immunomodulatory effects through its interaction with a variety of intracellular signaling cascades, including the nuclear factor kappa B and c-jun N-terminal kinase pathways. In this review, we will summarize the clinical uses of rifaximin and discuss its mechanism of action in relation to the modulation of the intestinal microbiota and the regulation of gastrointestinal host cell function, with a specific focus on PXR-dependent pathways.

We review our experience on Rifaximin in uncomplicated diverticular disease. Our data show that a 2 week treatment induces modifications in the immune system: local mucosal lymphocytes with TLR-4 were increased. In the peripheral blood CD103 cells, which increased before treatment, returned to normal values after Rifaximin.

The evolution of human microbiome research has lead to a systems biology approach that encompasses multidisciplinary investigations. The implementation of next generation sequencing technologies has allowed researchers to study unculturable organisms, discover novel ones, and provide insights into the role of the human microbiome in health and disease. When these approaches are applied to large-scale longitudinal studies designed to interrogate the association of the microbiome with specific clinical outcomes, the development of new therapeutics and diagnostics intended to modulate or detect changes in microbiome composition to improve human health are born. We are just starting to unravel the role of the microbiome in a wide-variety of diseases, and while some of it appears to be related to causation and provide opportunities for intervention, a good dose of pragmatism is warranted as the field is still in its infancy.

Inflammatory bowel diseases are characterised by an altered composition of the intestinal microbiota, which may contribute to their development and maintenance in susceptible hosts. The involvement of bacteria in the inflammation has provided the rationale for a therapeutic manipulation of the gut flora through the use of antibiotics. However, the role of antibiotics has not been clearly demonstrated and their long-term employment is often restricted by an elevated number of adverse events. The use of rifaximin, which is characterised by an excellent safety profile thanks to its negligible intestinal absorption, appears to have some promise. Study results suggest that rifaximin could be useful in Crohn’s disease, and a new gastroresistant formulation (rifaximin-extended intestinal release) has recently shown its efficacy in patients with moderate Crohn’s disease. Less consistent data support the use of rifaximin in ulcerative colitis and in pouchitis, although the results of some studies have been encouraging. Further large controlled trials are warranted to confirm the role of rifaximin in inflammatory bowel disease treatment.

Brain presents very complex advanced protective mechanisms. However, these mechanisms occasionally fail due to risk factors represented by genetic, environmental or social stress and consequently, severe psychiatric disorders such as depression, schizophrenia or psychotic depression are induced. Under such circumstances, latest strategies in experimental and in silico neuroscience consider essential to identify new applications of already clinically-approved drugs for the treatment of psychiatric disorders but also as promoters of neurogenesis and neurites outgrowth. Results of recent studies suggested that antidepressants are able to induce neurogenesis and neurites outgrowth by their agonistic effects on 5-hydroxytryptamine receptor (5-HT), especially 5-HT1A, and sigma1 receptor (σ1R), but many molecular aspects of these processes are still unclear. Here we present structural aspects of molecular complexes (5-HT1A and σ1R and their ligands) revealed by experimental and in silico studies. Here we present the chemical structures-biological activity relationship (SAR) of these molecules revealed by recent experimental and in silico studies, offering a new perspective on the antidepressants mechanism as neurogenesis and neurites outgrowth promoters.

Extensive research during the past three decades has demonstrated the mechanisms by which an imbalance in the redox status of prooxidant/antioxidant reactions in cells with advantage of prooxidant reactions (oxidative stress, OS) can cause peroxidation of nucleic acids, bases, lipids, proteins and carbohydrates, thus resulting in their damage. These actions result in stimulation of signal transduction pathways and activation of transcription factors that can lead to chronic inflammation and cause tissue dysfunction. The most important oxidants are reactive oxygen species (ROS) and reactive nitrogen species (RNS) generated by various metabolic pathways, physical, chemical and biological factors, and pathological conditions. The eye is one of the major target of the ROS/RNS attack due to exposition on several environmental factors like high pressure of oxygen, light exposure, ultraviolet rays, ionizing radiation, chemical pollutants, irritant, and pathogenic microbes, which are able to shift the redox status of a cell towards oxidizing conditions. There is increasing evidence indicating that persistent OS contributes to the development of many ocular diseases. Increases in the accumulation of hydrogen peroxide and markers of the oxidative damage to DNA, lipids, proteins observed in several eye diseases and usage of antioxidants in their treatment and prevention emphasize the involvement of OS pathways. This paper summarizes the present state of knowledge in the involvement of OS in the etiology of non-cancer ocular diseases (dry eye syndrome; corneal and conjunctive diseases; cataract; glaucoma; age-related macular degeneration; retinitis pigmentosa; diabetic retinopathy, autoimmune and inflammatory uveitis) and cancer ocular diseases (melanoma; retinoblastoma; lymphoma). The paper also discusses the potential applications of antioxidants in the prevention of eye diseases and shows a duality of physical exercise actions: protection against the ROS/RNS damage by regular-moderate physical activity and damaging effect through mediation of OS by endurance exercise without adaptable physical training.