Current Drug Targets - Volume 19, Issue 6, 2018

Background: The traditional treatment of venous thromboembolism (VTE) with heparin and warfarin has numerous limitations. New oral anticoagulants represent the promising alternative with the potential to overcome the limitations of traditional treatment. Objective: Apixaban is an oral factor Xa inhibitor with a rapid onset of action and predictable pharmacokinetics that allows a fixed dose regimen. With this characteristic apixaban overcomes many limitations and simplifies treatment of VTE eliminating the need for initial parenteral anticoagulant therapy and laboratory monitoring. Results: Fixed-dose regimen of oral apixaban alone is as effective as conventional treatment regimen and is associated with a clinically relevant reduction of major bleeding. Extended anticoagulation with apixaban with either a treatment dose (5 mg twice daily) or thromboprophylactic dose (2.5 mg twice daily) reduces the risk of recurrent venous thromboembolism without increase in the rate of major bleeding. Conclusion: Therefore, apixaban provides a simple, effective and safe alternative to conventional acute or long-term treatment of VTE.

Apixaban is a new oral anticoagulant (NOACs: Novel Oral Anticoagulant), like dabigatran, rivaroxaban, and edoxaban. All of them are prescribed to patients with non valvular atrial fibrillation or venous thromboembolism, to replace warfarin, because of the lower probability of bleeding, however they can cause bleeding by themselves. Bleeding is an adverse event in patients taking anticoagulants. It is associated with a significant increase of morbidity and risk of death. However, these drugs should be used only for the time when anticoagulation is strictly required, especially when used for preventing deep vein thrombosis. Prolonged use increases the risk of bleeding. In the ARISTOTLE Trial Apixaban, compared with warfarin, was associated with a lower rate of intracranial hemorrhages and less adverse consequences following extracranial hemorrhage. Many physicians still have limited experience with new oral anticoagulants and about bleeding risk managment. We reviewed the available literature on extracranial and intracranial bleeding concerning apixaban.

Background: Prevention of stroke is a pivotal intervention in the management of patients with atrial fibrillation (AF). Because of the difficulties of safely implementing Vitamin K Antagonists in all patients, there has been a growing interest in improving the pharmacological management of AF with newer antithrombotic agents. The new oral anticoagulants (NOACs) have been developed to overcome the limitations and improve the efficacy of the conventional oral anticoagulant drugs. Among the NOACs, apixaban - a very specific antagonist of activated factor Xa – has pharmacokinetic and pharmacodynamic properties that allow significant efficacy in AF management. Objective: The aim of this review is to summarise the available data on the efficacy of apixaban in patients with AF, with a particular focus on the implications for its clinical management. Results and Conclusion: Clinical application of apixaban in subgroups of patients with AF is still under investigation and some contraindications should be taken into account. Despite these limitations, apixaban is an effective alternative to warfarin and aspirin for stroke prevention in AF, with encouraging evidence also in terms of adherence to treatment.

Histone deacetylases (HDACs) play a crucial role in regulating the expression and activity of myriad of proteins involved in tumour onset and progression. HDAC activity results in a nonpermissive chromatin conformation by erasing acetyl moiety from histone substrates culminating in transcriptional repression of those genes having significant role in tumourigenesis. Apart from histones, HDACs deacetylate a variety of non-histone proteins including transcription factors involved in controlling cell growth, differentiation and apoptosis. Histone deacetylase inhibitors (HDACi) are small-molecules restraining HDACs and hence modulating their biological activity. Emerging evidences suggest that acetylation of non-histone proteins plays a critical role in various cellular processes including mRNA stability, protein localization and degradation. Abnormal turnover or expression of non-histone proteins like nuclear factor- kappaB (NF-ΚB), heat shock protein 90 (HSP90) and frataxin fuels various diseases including cancer. The present article explores the therapeutic role of HDACi with special emphasis on modulation of clinically relevant non-histone molecular targets. Extensive details regarding the non-histone proteins and their deregulation in disease states have also been provided. Moreover, the underlying molecular mechanism triggered by HDACi to overcome disease states by modulating the predefined targets has also been illuminated. The article strongly suggests the promising use of HDACi in therapeutic intervention against complications arising due to non-histone protein deregulation.

The sympathetic nervous system is one component of the nervous regulatory system of the physiological function of the lower genitourinary tract. Our knowledge on the role of this sympathetic system has advanced during the last decade due to the characterization of β3-adrenoceptors (β3-ARs) in the urogenital system. This review focuses on the pharmacological and molecular evidence supporting the functional roles of β3-AR in male genitourinary tissues of various species. An electronic search in two different databases was performed including MEDLINE (PubMed) and EMBASE from 2010 to 2016. β3-agonists may be a promising alternative to antimuscarinics in the treatment of overactive bladder (OAB) based on available evidence. Although more recent studies have evaluated the involvement of β3-ARs in the physiological control and regulation of various tissues of the lower genitourinary tract mainly urinary bladder, penis, urethra, ureter, there are few innovations in the pipe-line. Among the β3-agonists, mirabegron is a unique drug licensed for the treatment of patients with OAB. Many drugs classified as β3-agonists are still under investigations for the treatment of OAB, lower urinary tract symptoms, ureteral stones, benign prostate hyperplasia, prostate cancer and erectile dysfunction. This review discusses the potential roles of β3-AR as new therapeutic targets by evaluating the results of preclinical and clinical studies related to male lower genitourinary tract function. Looking into the future, the potential benefits of β3- AR agonists from experimental and clinical investigations may provide an attractive therapeutic option.

Understanding and targeting the mechanisms of resistance to enzalutamide in castration resistant prostate cancer. Background: Enzalutamide (MDV3100, XTANDI) is a second generation androgen receptor inhibitor that is designed for the treatment of castration-resistant prostate cancer (CRPC) and has prolonged survival time. The mechanisms of mdv3100 resistance have not yet been clearly clarified and the majority of treated patients, innate or acquiring resistance invariably arises. Objective: The purpose of this review is to summarize the main data available on the mechanisms of resistance to mdv3100. Understanding how the resistance aroused may have clinical implications in underlying the usefulness of prognostic and predictive biomarkers in daily practice and improving the strategies. Results: Resistance to MDV3100 could be basically divided into two distinct pathways, either dependent or independent of the androgen receptor activity. Androgen receptor (AR) axis is sitll the most important pathway for prostate cancer cells and it is still currently regarded as a critical resistant mechanism. Conclusion: Targeting these newly identified signals, especially AR axis, could be potentially overcome through novel therapeutic agents, synergically improve the ADT in CRPC.

Background: High bone mass (HBM) disorders are a group of clinically and genetically heterogeneous bone diseases characterized by increased bone density on radiographs, due to progressive bone overgrowth or impaired bone resorption, or both. Some HBM cases are secondary to other diseases, such as chronic hepatitis C virus infection. Despite the great advance in gene diagnostic technology, the majority of HBM individuals remain undiagnosed. Objective: In this review, we will summarize the clinical, radiological and biochemical characteristics of HBM cases due to varying etiologies, since these features are helpful in the differential diagnosis of HBM. Results: Each subgroup of HBM cases shows distinctive clinical, radiological and biochemical characteristics. HBM, due to bone overgrowth, was designated as sclerosteosis, as a result of mutations located in genes critically involved in the Wnt/beta-catenin signal pathway. Mutations in genes encoding factors relevant to the differentiation and maturation of osteoclasts, or critical for the acidification and resorption of osteoclasts may lead to osteopetrosis. Hepatitis C associated osteosclerosis is characterized by a generalized increase in bone mass and markedly elevated serum levels of bone specific alkaline phosphatase. Conclusion: The clarification of the etiologies of HBM may have a breakthrough role in understanding the molecular mechanisms involved in bone metabolism and may provide new pathways for the intervention of osteoporosis.

Background: It is known that an increased oxidative stress is present in a wide range of diseases and, given the vulnerability of the central nervous system, its involvement has been in particular investigated in neurological and psychiatric diseases, including anxiety disorders. Objective: In this review, we analyse the studies that have been conducted on the effects of oxidative stress modulators in anxiety, focusing on their possible clinical use. Discussion and Conclusion: While preclinical studies have shown a clear anxiolytic-like effect of different oxidative stress modulators, less significant results have been obtained from clinical studies. After having reviewed the possible reasons for the discrepancy between preclinical and clinical data, we encourage further studies aimed at better investigating the utility of the modulation of oxidative stress in humans, as an adjunctive therapy of the traditional integrated psychotherapeutic and pharmacological approach.

Background: Myocardial infarction is characterized by the interruption of blood flow through the heart, directly causing mortality and disability worldwide. Cardiac macrophages exhibit distinct phenotypes (e.g., M1 or M2) and functions (e.g., proinflammatory or anti-inflammatory) in response to the alterations of myocardial microenvironment, and subsequently exacerbate or resolve inflammation in the infarcted hearts. Regulation of macrophage polarization was implicated in myocardial infarction for the quality and outcome of cardiac healing. Objective: The purpose of this review was to summarise the current understanding on the regulation of macrophage polarization in myocardial infarction and highlight the therapeutic potential of pharmacological regulators in the treatment of myocardial injury via modulating macrophage polarization. Results: Timely control of M2/M1 ratio by endogenous mediators and pharmacological regulators should help the resolution of inflammation, promote wound healing and prevent cardiac fibrosis after myocardial infarction. Conclusion: Macrophage polarization deserves better investigations as the therapeutic target for the development of novel drugs against myocardial injury.

Background: Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear receptor superfamily that functions as a ligand-inducible transcription factor. It regulates glucose and lipid metabolism, immunity, and cellular growth and differentiation. Thiazolidinediones (TZDs) are potent insulin sensitizers that function by activating PPARs, with a high specificity for PPARγ. Due to their ability to preserve pancreatic beta cell function and reduce insulin resistance, TZDs have become one of the most prescribed classes of medications for type 2 diabetes (T2D) since their approval by the US Food and Drug Administration (FDA) and initial use in 1997. Objective: However, adverse effects, including weight gain, bone loss, fluid retention, congestive heart failure, and risk to bladder cancer, have weakened the benefits of TZDs in T2D therapies. Therefore, there is an urgent need to have a deeper understanding of regulatory mechanisms of PPARγ expression and activity so that novel classes of PPARγ-modulating therapeutics with fewer or weaker side effects can be developed. Conclusion: This article systematically reviews PPARγ's mechanisms of action and multilayer regulations. In addition, novel classes of therapeutics modulating PPARγ and new direction of research on genetic variants that affect PPARγ function and antidiabetic drug response are highlighted, which sheds light on PPARγ as a promising target for developing safer and precision medicine based therapeutic strategies.

Background: Phytomedicines have been well-accepted alternative complementary therapies for the treatment of a wide range of acute and chronic skin inflammatory diseases including chronic herpes, prurigo, psoriasis, and atopic dermatitis (AD). A plethora of in vitro and in vivo studies have evidenced the therapeutic viability of phytomedicines, polyherbal formulations, plant-based materials and their decoctions for the treatment of mild-to-severe AD. Objective: This review was aimed to summarize and critically discuss the convincing evidence for the therapeutic effectiveness of phytomedicines for the treatment of AD and explore their anti-AD efficacy. Results: The critical analysis of a wide algorithm of herbal medicines revealed that their remarkable anti-AD efficacy is attributed to their potential of reducing erythema intensity, oedema, inflammation, transepidermal water loss (TEWL) and a remarkable suppression of mRNA expression of ADassociated inflammatory biomarkers including histamine, immunoglobulin (Ig)-E, prostaglandins, mast cells infiltration and production of cytokines and chemokines in the serum and skin biopsies. Conclusion: In conclusion, herbal medicines hold great promise as complementary and alternative therapies for the treatment of mild-to-moderate AD when used as monotherapy and for the treatment of moderate-to-severe AD when used in conjunction with other pharmacological agents.

Background: Resistance to therapy is a major hindrance to patient survival in cancer, underscoring a critical need to elucidate the underlying mechanisms responsible for chemoresistance. Research has demonstrated that endoplasmic reticulum (ER) stress plays a significant role in allowing cells to survive conditions that would normally elicit cell death. Specifically, elevated expression of GRP78, the master regulator of the unfolded protein response (UPR), has been shown to induce chemoresistance and serves as a indictor of poor prognosis in patients. Objective: Evaluating the expression of GRP78 and its downstream targets in a wide range of cancers may allow clinicians to predict resistance to a number of commonly used therapies. Moreover, understanding the mechanism(s) of action GRP78 uses to regulate chemoresistance will accelerate the development of more efficacious treatment strategies that target GRP78 to abrogate chemoresistance. Results: This mini-review highlighted the roles of targets downstream of GRP78 and explored their mechanisms related to cellular survival. Furthermore, a summary of the connection between GRP78 expression and patient prognosis was provided. Lastly, strategies for targeting GRP78, in order to improve treatment efficacy, was explored. Conclusions: GRP78 maintains an important role in regulating signaling pathways that control cell survival and this review draws attention to its value as a prognostic marker and therapeutic target.

Background: Chronic kidney disease (CKD) is a condition increasingly affecting millions of individuals worldwide and is ranked as the ninth leading cause of death in the United States. AMPactivated protein kinase (AMPK) is an energy sensor that plays a pivotal role in cellular homoeostasis. Deficiency in AMPK activity and autophagic signaling, and sustained activation of mammalian target of rapamycin (mTOR) signaling and endoplasmic reticulum (ER) stress have been shown to promote epithelial-to-mesenchymal transition (EMT) and renal cell apoptosis and contribute to CKD. Emerging evidences demonstrate that AMPK acts as a modulator of the aforementioned pathways that underpin the pathophysiology of CKD. Furthermore, pharmacological activators of AMPK such as metformin have been shown to exert renoprotective effects in experimental studies and improve clinical outcomes in patients with CKD. Objective: The current review focuses on the nephroprotective effects of AMPK and its utility as a therapeutic target for the prevention and treatment of CKD.