Current Drug Targets - Volume 19, Issue 7, 2018

Background: Personalized medicine is becoming a widespread effort to provide the right treatment to the right patient at the right time. However, it lacks of consideration for nonmedical factors, such as patient preferences and psychosocial factors, which should not be avoided. Objective and Methods: The present study summarizes the psychosocial difficulties experienced by patients with inflammatory bowel disease (IBD) during different phases of the disease in order to identify methods to assess psychosocial risk factors and personalize treatment strategies. To reach this goal, the quantitative literature is matched with the patients' perspective, offering a broad overview of psychosocial risk factors that IBD patients experience. Results: Quantitative results offer strong evidences for specific psychosocial risk factors in IBD and for weak results of psychosocial interventions, but show a lack of individually tailored researches, instruments and interventions, increasing the distance between the research findings and clinical practice. At the same time, qualitative findings show important, though veiled information uncovered by the quantitative research (e.g., identity recovery, fight for control, sexual concerns), which may be used as a starting point for further explorations. Conclusion: The present study suggests a need to adopt individualized therapeutic approach and deliver psychological therapies while taking into account patients' experiences and preferences.

Background: Recurrence is a common event after surgical resections secondary to Crohn's disease (CD). Endoscopic signs of inflammation, defined as postoperative endoscopic recurrence (PER) occur in up to 90% of the patients after one year. PER precedes clinical recurrence and further need for reoperations due to consequent bowel damage. Therefore, controlling inflammation after surgery in a preventive way is essential for disease control. Objective: to review data regarding PER in CD, and demonstrate algorithms for its management after surgery. Results: There is no fixed strategy to prevent recurrence after surgery in CD. There are several risk factors that must be taken into consideration to guide physicians to choose the best therapeutic agents and strategies in this scenario. In this review, the authors describe in details the stratification based on risk factors, the therapeutic agents mostly used to prevent recurrence and discuss the several options for the postoperative management in CD. Conclusions: No fixed strategy is recommended after surgical resections in CD. Thus, the need for a personalized approach for each patient is emphasized, in accordance with several conditions and variables.

Treatment strategies and treatment options have changed considerably over the past decade for Inflammatory Bowel Disease (IBD). Alongside this shift in therapeutic options has come an opportunity to personalize treatment decisions based on individual patient profiles and preferences. One of the most important aspects of therapy in IBD is treatment related risk, and an opportunity exists to personalize therapy through optimization of drug safety profiles in individual patients. In this review we discuss the potential risks of therapy in IBD, opportunities to mitigate those risks, and a personalized approach to consider when using these agents in clinical practice.

Background: In the last decade, the introduction of the first anti-tumor necrosis factor (TNF)-α agent infliximab has revolutionized the treatment of ulcerative colitis (UC). However, this drug is not a magic bullet since up to 50% of UC patients do not respond (primary failure) or lose response to infliximab (secondary failure). Hence the demand for novel drugs to fill the unmet medical need. Objective: The aim of this review is to discuss the data from randomized controlled trials (RCTs) of available biological agents for the treatment of moderate-to-severe UC in adults, in order to support clinical decision making. Results and Conclusion: New biological agents are now available for the treatment of moderate-tosevere UC. Adalimumab and golimumab are anti-TNF-α monoclonal antibodies, as is infliximab, whereas vedolizumab blocks the integrin α4β7/mucosal addressin cell adhesion molucule-1 (MAd- CAM). Additions to the therapeutic arsenal boost the chances of successful treatment of UC, but lead to difficulty choosing the most appropriate biological drug: which biologic to use first and when and how to switch. In the absence of head-to-head trials to answer these questions, a network metaanalysis of the available RCTs can provide estimates of relative efficacy between interventions. Other factors, including convenience and satisfaction for the patient, route of administration, the cost of treatment, and the safety and efficacy profile, should all be considered.

Background: Anti-tumor necrosis factor-alpha and anti-integrin monoclonal antibodies show great benefits for inducing and maintaining remission, healing the mucosa and restoring the quality of life of patients with inflammatory bowel disease. However, the therapeutic potential of these intrinsically powerful biologicals is abated by a high variability in response. Some patients experience no benefit from these treatments, while others lose response over time. Therapeutic Drug Monitoring (TDM) is a promising tool to further improve therapeutic outcome, substantiated by the finding that highly variable clinical response is correlated with pharmacokinetic (PK) variability. Serum Trough Concentrations (TCs) of the drug are measured and dosage regimens are adapted in order to achieve target TCs that correlate with beneficial therapeutic outcomes. The TC concept is relatively simple but gives only a partial insight in PK. PK profiles should be interpreted in the light of patient specific influences (i.e., covariates) that explain variability. Objective: Therefore, the aim of TDM must be to dose the biological in such a way that a personal optimal PK profile is achieved. Furthermore, currently used “treat-to-target” algorithms have proven to increase the therapeutic potential of the drugs, but dosage regimen adaptations are still robust guesswork. Results: A clinical decision support tool for accurately forecasting drug exposure would significantly impact TDM and is suggested to promote successful implementation of individualized predictive treatment in clinical practice. Conclusion: This review provides a clinician-oriented overview of the state-of-the-art, the gaps in current knowledge and future potential of individualized predictive treatment.

Background: While predictors of disease course in inflammatory bowel diseases (IBD) are not accurate, we adapt therapies reactively, after objective demonstration of the presence of active disease, complications, or an inadequate response to a therapeutic intervention. In this context, adequate monitoring is essential to make timely management decisions. Objective: To review the role of clinical assessment, biomarkers, radiology and endoscopy in monitoring patients with IBD. Results: Assessment of clinical symptoms is the cornerstone of monitoring in IBD; in ulcerative colitis (UC) there is acceptable correspondence between mucosal lesions and presence of symptoms, but in Crohn's disease (CD) there is a considerable disconnection between these two, and monitoring requires complementary tests. Blood and stool markers such as C-reactive protein and fecal calprotectin are increasingly used. However, the operating properties of these biomarkers are different according to disease type (UC vs. CD), age (pediatric or adult), and disease location (small bowel vs. colonic disease). Cross-sectional imaging has a similar accuracy to endoscopy to detect inflammation in CD, and a higher accuracy to detect stenosing and penetrating complications. It has also been shown that magnetic resonance imaging is accurate for measuring response to therapeutic interventions. Conclusion: Cross-sectional imaging is one of the preferred monitoring options in patients with CD. Endoscopy continues to be the preferred examination for assessing UC, and should still be considered in patients with CD who have symptoms or altered biomarkers and cross-sectional imaging is negative.

Background: Crohn's disease (CD) is a chronic, disabling and destructive condition. Half of patients will develop some bowel damage (stricture, fistula and/or abscess). Current therapeutic strategies failed to alter its natural history. Objective: We explore in a review article the evolution of CD treatment over a quarter of a century from a linear sequence of treatment intensification to a complex algorithm focused on individualized patient care by looking beyond symptoms. Specifically we focus on evolving concepts in assessing disease severity, selecting rigorous treatment end-targets, initiating an effective therapeutic therapy, and managing secondary loss of response. Results: A tight monitoring of objective signs of inflammation and a treat-to-target approach are probably the only way to change patients' life and disease course. We now seek to optimize our therapeutic tools according to patient profile, disease phenotype and the unique pharmacodynamics that ensues. Conclusion: Standardizing the clinical practice of gastroenteroogists with the most current treatment algorithm may minimize disease related complications while favouring patient's quality of life.

Background: The disease phenotype at diagnosis and the disease course of Crohn's disease (CD) and ulcerative colitis (UC) show remarkable heterogeneity across patients. Objective: This review aims to summarize the currently available evidence on clinical and some environmental predictive factors, which clinicians should evaluate in the everyday practice together with other laboratory and imaging data to prevent disease progression, enable a more personalized therapy, and avoid negative disease outcomes. Results: In recent population-based epidemiological and referral cohort studies, the evolution of disease phenotype of CD and UC varied significantly. Most CD and severe UC patients still require hospitalization or surgery/colectomy during follow-up. A change in the natural history of inflammatory bowel diseases (IBD) with improved outcomes in parallel with tailored positioning of aggressive immunomodulator and biological therapy has been suspected. Conclusion: According to the currently available literature, it is of major importance to refer IBD cases at risk for adverse disease outcomes as early during the disease course as possible.

Background: In the treatment of Inflammatory Bowel Diseases (IBD) despite advances in medical therapies, surgery has maintained a leading role in the management of complications of the disease, as well as in cases of failure of medical therapy. Objective: discuss the possible role for a personalization in debated fields of surgical treatment of Crohn's disease and ulcerative colitis. Conclusions: Surgery has become more and more minimally invasive, struggling for a difficult balance between guidelines and personalized treatment tailored on the single patient's need. There is no room for fixed management for surgery in IBD. A tailored approach is key to better outcome in each specific patient.

Multiple sclerosis is a common chronic, disabling autoimmune neurological disease affecting mainly young adults. In its pathomechanism, neurodegenerative and acute inflammatory characteristics are both involved. Disease-modifying therapies aim to reduce relapse-rate and slow down the deterioration in neurological functions. The currently available therapies fail to exert neuroprotective effects and most of them are associated with potentially toxic side-effects, therefore, ongoing research aims to develop novel drug candidates to cover these therapeutic gaps. The kynurenine pathway has been implicated in both the physiological processes of the central nervous system and in the pathomechanism of several neurological disorders as well. Alterations of the kynurenine pathway metabolites have been detected in multiple sclerosis and a number of potential therapeutic targets related to this metabolic route have been already identified. Laquinimod is a quinoline carboxamide showing structural similarities with kynurenic acid, which proved to have beneficial effects on reduction of brain atrophy and disability progression. The kynurenine pathway is therefore a promising target for the development of future drugs for the treatment of autoimmune diseases such as multiple sclerosis.

Histone deacetylase inhibitors, the small molecules modulating the biological activity of histone deacetylases are emerging as potent chemotherapeutic agents. Despite their considerable therapeutic benefits in disease models, the lack of isoform specificity culminates in debilitating off target effects, raising serious concerns regarding their applicability. This emphasizes the pressing and unmet medical need of designing isoform selective inhibitors for safe and effective anticancer therapy. Keeping these grim facts in view, the current article sheds light on structural basis of off-targeting. Furthermore, the article discusses extensively the role of in silico strategies such as Molecular Docking, Molecular Dynamics Simulation and Energetically-optimized structure based pharmacophore approach in designing on-target inhibitors against classical HDACs.

Background: Nephropathy is a debilitating complication of diabetes associated with increased risk for renal failure, leading to poor quality of life of the affected patients and eventually to mortality. Early intervention is crucial to enhance the well-being of the patients with nephropathy. Albuminuria is a well-known predictor of weak renal outcomes in patients with diabetes and hypertension, unfortunately, it is not an early marker for kidney injury. Objective: Assessment of new and precise markers is necessary to predict the early onset and progression of nephropathy. It is important to find early markers which could predict kidney injury even before the clinical signs (no microalbuminuria) appear. Results: Prevention and therapy for kidney diseases using surrogate markers such as serum creatinine have not proven to be better indicators for interventions that have been shown to decrease morbidity or mortality. A number of studies have elucidated the importance of kidney injury markers. This article describes the significance of urinary markers such as nephrin, Cystatin C, Monocyte chemoattractant protein (MCP-1), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM- 1) and nestin, which are associated with early renal dysfunction. Conclusion: Although significant advances have been made in medical therapy, the degree of morbidity and mortality associated with kidney diseases remain despondently high. Besides the serum markers, urinary markers may provide a better prediction of progression of the damage to the kidneys in diabetic patients.

Background: Bacterial resistance to antibiotics is one of the most serious challenge to global public health. The introduction of new antibiotics in clinical settings, i.e. agents that belong to a new class of antibacterials, act on new targets or has a novel mechanisms of action, may not be sufficient to cope with the emergence of multidrug-resistant pathogens such as Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii and Escherichia coli, which are increasingly prevalent in healthcare settings in Europe, the USA and Asia. Hence, coordinated efforts in minimizing the risk of spread of resistant bacteria and renewing research efforts in the search for novel antibacterial agents are urgently needed to manage this global crisis. Objective: This review highlights the challenges and potential in using current technologies in the discovery and development of novel antibacterial agents to keep up with the constantly evolving resistance in bacteria. Conclusion: With the explosion of bacterial genomic data and rapid development of new sequencing technologies, the understanding of bacterial pathogenesis and identification of novel antibiotic targets have significantly improved.

Background: Isoflavones are natural compounds belonging to the class of isoflavonoids, molecules with a chemical structure based on the 3-phenyl chromen-4-one backbone. As a particular element, the isoflavones are also called phytoestrogens, due to the structural similarity with 17-β estradiol, the primary female sex hormone, presenting both estrogen-agonist and estrogen-antagonist properties. This class of secondary plant metabolites has been extensively reported in the literature for a wide range of therapeutic activities including antioxidant, chemopreventive, anti-inflammatory, antiallergic, antibacterial, and cardio preventive effects. Objective: To sum up the latest information regarding the main isoflavones found in dietary sources as natural anti-inflammatory agents. Results: The review updates with the recent research about genistein, daidzein, glycitein, biochanin A, formononetin and equol as anti-inflammatory phytocompounds. As a particular element, the implications of these isoflavones in the link between inflammation and angiogenesis are also discussed. Conclusion: The review concludes that the main isoflavones in dietary sources display in vitro and/or in vivo anti inflammatory potential by activating various biochemical and molecular mechanisms. The depicted findings translated into practical aspects strengthen the idea that the isoflavones genistein, daidzein, glycitein, biochanin A, formononetin and equol can be used in various inflammation based diseases as an alternative source for classical medication and that consummation of foods rich in isoflavones may represent prerequisite use in order to prevent the evolution of inflammation based diseases.