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Today, 12 Ιουλίου 2016, 4:19:40 μμ
Allosteric Modulation of Nicotinic Acetylcholine Receptors: The Concept and Therapeutic Trends
Today, 12 Ιουλίου 2016, 4:19:41 μμ
Expressing functional nicotinic acetylcholine receptors (nAChRs) may be beneficial to central neurons and neuronal networks because activation of nAChRs enhances neuronal resistance to injury, improves attention, cognitive performance, and produces robust anti-inflammatory and analgesic effects in mammals. Although exogenous orthosteric nAChR ligands present valuable tools in treatment of age- and trauma-related neurological deficits, therapeutic approaches that could amplify the brain’s innate ability to maintain cholinergic homeostasis and resist injury may serve as intriguing and promising alternatives and have not been fully explored. One of these novel approaches utilizes positive allosteric modulators (PAMs) of nAChRs. Because of the ubiquitous expression of nAChRs in neuronal, glial and immune tissues, highly selective PAMs could amplify multiple endogenous neuroprotective, pro-cognitive, anti-inflammatory and anti-nociceptive cholinergic pathways to offset cholinergic hypofunction and generate therapeutic efficacy by targeting only a single player: i.e., nAChRs activated by endogenous cholinergic tone. In this article, I review the concept of allosteric modulation and current trends in therapeutic applications of nicotinic PAMs.
The Effects of Statin Therapy on the Human Airway
Today, 12 Ιουλίου 2016, 4:19:41 μμ
Background: Statins have been long known for their lipid-lowering properties however there has been recent interest in their potential to positively influence clinical outcomes in pulmonary disease processes manifesting primarily as airway disorders. </p><p> Objectives: We review the potential use of statin therapy in respiratory medicine, with particular emphasis on airway disease. We also explore the possible mechanisms for the observed benefits of statins in conditions of the airway. </p><p> Method: A literary review of published articles related to defining the potential scientific basis for touted clinical efficacy, pertinent clinical data and review articles of statin therapy in airway disease. </p><p> Results: There was a vast quantity of publications available pertaining to the topic of interest. </p><p> Conclusion: Statins may have beneficial pleiotropic effects in addition to their actions as potent lipid-lowering agents particularly in patients with chronic obstructive pulmonary disease and post lung transplantation. Further human studies are required to substantiate their possible potential as many of the clinical trials performed to date have not demonstrated the translation of results of these promising scientific and observational studies into positive outcomes in well-designed, randomized, placebo-controlled human trials.
Effects of Antiplatelet Medication on Arteriovenous Fistula Patency After Surgical Thrombectomy
Today, 12 Ιουλίου 2016, 4:19:41 μμ
Objectives: To study the effect of antiplatelet agents on preventing arteriovenous (AV) fistulae thrombosis in hemodialysis (HD) patients after surgical thrombectomy (ST) for acute AV fistulae occlusion. Whether post-operative antiplatelet drugs have similar effects on the patency of AV fistula after surgical thrombectomy in patients with end-stage renal disease who undergo HD has not been investigated. </p><p> Design, Materials and Methods: We employed the Taiwan National Health Insurance Research Database (NHIRD) from 1999 to 2010 to assess the recurrent occlusion requiring ST and longevity of AV fistula after ST in 1049 patients on regular HD, with or without antiplatelet drugs. </p><p> Results: From the propensity-score (PS)-matched NHIRD, Multivariate Cox model demonstrated that concomitant antiplatelet medication in the HD patients who received the first ST significantly reduced the duration of recurrent ST (adjusted hazard ratio (HR) 1.69; 95% confidence interval (CI) 1.22-2.35, p=0.002) and the longevity of the fistula (adjusted HR 1.79; 95% CI 1.31-2.46, p<0.001). </p><p> Conclusion: Treatment with antiplatelet drugs in HD patients did not prevent recurrent thrombosis requiring further ST, but significantly jeopardized the longevity of AV fistula after ST. </p><p>
Synthesis and Anticonvulsant Effect of Novel Thiazolidinedione Containing Benzene-sulfonylurea and Sulfonylthiourea Derivatives
Today, 12 Ιουλίου 2016, 4:19:41 μμ
A newer series of 1-(4-substitutedphenyl)-3-(4-((2,4-dioxothiazolidin-5-lidene)methyl)phenyl sulfonyl)urea/thiourea (4a-l) were synthesized for their anticonvulsant activity. The activity is attributed to its potential to restrain astrocytic Na<sup>+</sup>, 2HCl, and K<sup>+</sup> co-transport similar to torasemide which has sulfonylurea in its structure. Torasemide having the similar action as the furosemide that obstructs kainic acid-induced electrical discharges observed from cortex and it has neuroprotective agents, for instance antagonizing the N-methyl-D-aspartate (NMDA) and non-NMDA receptors for evaluating antiepileptic activity. The structures of new derivatives were established by elemental analysis and spectroscopic techniques viz. FTIR, <sup>1</sup>H NMR and LC-MS. The all twelve derivatives were assessed for anticonvulsant activity at three different doses at 30, 100 and 300 mg/kg body weight into maximal electroshock (MES) and subcutaneous pentylenetetrazole (sports) models. Compounds 4c and 4e were formed to be most active among all the derivatives for both the models of anticonvulsant activity. Beside these compounds 4g, 4i and 4k also possessed the prominent anticonvulsant activity devoid of any neurotoxicity. The sulfonylurea and sulfonylthiourea both were proved to be effective anticonvulsant pharmacophore. Other structure activity relationships were established by considering the aspect of substitution in the lead.
Monofunctional Platinum (PtII) Compounds – Shifting the Paradigm in Designing New Pt-based Anticancer Agents
Today, 12 Ιουλίου 2016, 4:19:41 μμ
Platinum (Pt)-based anticancer drugs, exemplified by cisplatin, are key components in combination chemotherapy. However, their effective use is hindered by toxicity and emergence of drug resistance. They bind to DNA and mainly form the Pt-GG diadduct, subsequently leading to apoptosis to mediate cell death. On the other hand, the Pt drug –proteins and –metabolites interactions, which involve the reaction between Pt and sulfur sites located in protein side chains and important bionucleophiles (e.g., glutathione), are responsible for the toxicity and drug resistance problem. Therefore, carefully designed coordinating ligands may provide the means of fine tuning the electronic environment around the core Pt atom and allow the resulting Pt compounds to bind with the DNA in a different manner. This may produce alternative cell death mechanisms in cancer cells, thereby circumventing Pt resistance. This article reviewed the recent development in monofunctional Pt complexes and their prospects in becoming a new generation of anticancer drugs.
Arene ruthenium(II) Complexes: The Promising Chemotherapeutic Agent in Inhibiting the Proliferation, Migration and Invasion
Today, 12 Ιουλίου 2016, 4:19:41 μμ
Arene ruthenium(II) complexes have been widely investigated as one of the most promising candidates in chemotherapy because of their low toxicity and high inhibiting activity against the proliferation, invasion, migration, and angiogenesis of various tumors in vitro and in vivo. This review highlights the recent developments in different chemical types of arene Ru(II) complexes, as well as their biological activity and underlying mechanisms. The sustained efforts in this aspect of arene Ru(II) complexes would be essential in developing novel anti-tumor agents in the near future.
A Computational Analysis of Indomethacin Derivative as Tubulin Inhibitor: Insights into Development of Chemotherapeutic Agents
Today, 12 Ιουλίου 2016, 4:19:41 μμ
Tubulin is a potent molecular target for development of anticancer agents. In this report, the binding of non-steroidal anti-inflammatory drugs as tubulin inhibitors potential are investigated by extensive computational techniques, such as, molecular docking, molecular dynamics simulations and binding free energy calculations. The results suggest that a potent indomethacin derivative inhibits the tubulin polymerization by interacting on the colchicine-site binding. This potential chemotherapeutic agent showed high stability in the molecular dynamics simulations, when complexed on the same binding site of colchicine, a potent and toxic, tubulin inhibitor. Then, our results can be useful designing new compounds for cancer treatments.
Genomic Variations Affecting Biological Effects of Statins
Today, 12 Ιουλίου 2016, 4:19:41 μμ
Background: Statins are inhibitors of hydroxy-methyl-glutaryl coenzymeA (HMG-CoA) reductase, the rate-limiting enzyme involved in de novo cholesterol synthesis. The patient health profile needs to be taken in account during the interpretation of the variability in the outcome of drug therapy, as well as compliance with prescribed pharmacological treatments, and genetic profile. </p><p> Objective: Several genetic polymorphisms playing a role in the different response to lipid lowering therapy have recently been identified. Statins, today are used to reduce Low Density Lipoprotein-Cholesterol (LDL-C), represent the treatment of choice in individuals with increased risk of Cardio-Vascular Disease (CVD), both in primary and secondary prevention of cardiovascular events. Regardless of the usefulness in a wide range of patients, the common interindividual genetic variability, along with phenotypic aspects, lead to resistance and adverse responses. </p><p> Methods: we reviewed on PubMed, inserting as term search “statin and polymorphism”, “statin and pharmacogenomic”, “statin and gene”, “HMG-CoA reductase and gene”. </p><p> Results: A large number of candidate genes and many single nucleotide polymorphisms (SNPs) have been evaluated and related to pharmacokinetic and/or pharmacodynamic of statins. </p><p> Conclusion: Despite these several findings there is still not enough evidence to recommend pharmacogenomic tests before starting statin therapy. </p><p>
In silico Studies Toward the Discovery of Novel Type-II Inhibitors of TrkA: Pharmacophore-based 3D-QSAR Modeling, Database Screening and Molecular Docking
Today, 12 Ιουλίου 2016, 4:19:41 μμ
Tropomysin receptor kinase A (TrkA) is an excellent drug target for its important roles in pain sensation as well as tumour cell growth. Up to now, the discovered TrkA inhibitors belong mostly to type-I class targeting the ATP binding site, while we aim to find type-II inhibitors because they are deemed to have improved kinase selectivity and slower off-rates than their counterparts. The type-II inhibitors can induce TrkA in an inactive DFG-out form and insert in an additional hydrophobic cavity adjacent to the ATP binding pocket. The current article describes efforts to discover novel type-II scaffolds against TrkA via integrating pharmacophore-based 3D-QSAR modeling, database screening and molecular docking. The robustness of the best model, AAHRR.8, was seriously ascertained by the high R<sup>2</sup> (0.9027), Q<sup>2</sup> (0.7048), low RMSE (0.4016) and SD (0.3635). It was further used as a 3D query to screen against our in-house collection of almost 1.3 million compounds followed by molecular docking simulations using three docking protocols involving Glide SP, Surflex and Glide XP. 12 hits, which mapped well on the best pharmacophore model, displayed good docking score and rational binding mode, were selected as promising selective leads of TrkA. Finally, ADME study was carried out and the results indicated that these 12 compounds own drug-like properties. The 12 hits together with the best 3D-QSAR model will be helpful for future potent TrkA agent development.
Regulation of Gait and Balance: The Underappreciated Role of Neuronal Nicotinic Receptor Agonists
Today, 12 Ιουλίου 2016, 4:19:41 μμ
Alterations in gait and balance are manifest in numerous neurological disorders such as the ataxias and Parkinson's disease, and may occur as a consequence of stroke, traumatic brain injury and chemical insults to the brain. Although the underlying etiology of these disorders differs, disturbances in gait and balance appear to reflect deficits in cholinergic pathways within the brain. During the past 40 years, both clinical case studies and preclinical data have provided evidence that nicotinic cholinergic activation is beneficial for alleviating gait and balance deficits in many disorders. Further, studies indicate that activation of neuronal nicotinic receptors leads to neuroprotective and neurotrophic actions. And yet, despite these findings, there hsas been no concerted effort to develop neuronal nicotinic agonists for the treatment of abnormal gait and balance. The goal of this review is to shed light on the therapeutic benefit of the cholinergic nicotinic system for the treatment of ataxia, and discuss the challenges and limitations associated with developing drugs to treat disorders involving deficits in gait and balance.
Self-Organizing Map (SOM) and Support Vector Machine (SVM) Models for the Prediction of Human Epidermal Growth Factor Receptor (EGFR/ ErbB-1) Inhibitors
Today, 12 Ιουλίου 2016, 4:19:41 μμ
EGFR (ErbB-1/HER1) kinase plays an important role in cancer therapy. Two classification models were established to predict whether a compound is an inhibitor or a decoy of human EGFR (ErbR-1) by using Kohonen’s self-organizing map (SOM) and support vector machine (SVM). A dataset containing 1248 ATP binding site inhibitors and 3090 decoys was collected and randomly divided into a training set (831 inhibitors and 2064 decoys) and a test set (417 inhibitors and 1029 decoys). The descriptors that represent molecular structures were calculated by software ADRIANA.Code. Thirteen significant descriptors including five global descriptors and eight 2D property autocorrelation descriptors were selected by Pearson correlation analysis and stepwise analysis. The prediction accuracies on training set and test set are 98.5% and 96.3% for SOM model, 99.0% and 97.0% for SVM model, respectively. Both of these two classification models have good performance on distinguishing EGFR inhibitors from decoys.
Design and Synthesis of Novel Schiff Base-Benzothiazole Hybrids as Potential Epidermal Growth Factor Receptor (EGFR) Inhibitors
Today, 12 Ιουλίου 2016, 4:19:41 μμ
A series of novel Schiff bases -benzothiazole hybrids was designed, synthesized and evaluated for their anticancer activity by MTT assay and western blot method. Antiproliferative screening indicated that compound containing dihydroxy substituents had potent inhibitory activity with IC50 value 34µg/ml against SKOV3, A2780-S and A2780-CR cell lines. It showed more potent cytotoxicity in combination with cisplatin and paclitaxel than alone in the selected cell lines (SKOV3, A2780 and A2780-CR models). The in vitro cytotoxicity of the compounds on IOSE 364 cell line was evaluated to establish the selectivity. Molecular docking study exhibited good binding against epidermal growth factor receptor, which was further ascertained by immunoblot assay using specific antibody against phosphorylated EGFR, and thus unravelling the targeted anticancer mechanism.
The Recent Development of α7 Nicotinic Acetylcholine Receptor (nAChR) Ligands as Therapeutic Candidates for the Treatment of Central Nervous System (CNS) Diseases
Today, 12 Ιουλίου 2016, 4:19:41 μμ
Homomeric α<sub>7</sub> nicotinic acetylcholine receptors (nAChRs) are implicated in the regulation of cognitive processes such as memory and attention and have potential as therapeutic targets for the treatment of the cognitive deficits associated with schizophrenia. Though numerous α<sub>7</sub> nAChR agonists have been developed, and several have progressed to clinical trials, these are derived from few common chemotypes. Consequently, many of these α<sub>7</sub> nAChR clinical candidates share unfavorable side-effect profile. SEN12333 represents a novel chemotype for the development of α<sub>7</sub> nAChR agonists, and exploration of this scaffold has produced structurally diverse ligands with promising pharmacological properties. This review will summarize structure-affinity and -activity relationships surrounding analogs of SEN12333.
Oral Delivery of Antidiabetic Polypeptide-k: Journey so far and the Road Ahead
Today, 12 Ιουλίου 2016, 4:19:41 μμ
The prevalence of diabetes mellitus is growing rapidly. According to the global report of International Diabetes Fedration (IDF), about 382 million people are suffering from diabetes and among them, 90% cases were of type-II. By 2035, it is expected that this number will reach to 592 million. In the last 5 decades, various efforts have been put towards the development of synthetic medicines or synergistic combination of herbal and synthetic medicines to treat diabetes mellitus. Polypeptide-k is an antihyperglycaemic protein isolated from dried seeds collected from ripened fruits of Momordica charantia. Extensive research has been carried out in the last fifteen years on polypeptide-k to explore its potential applications for the treatment of both types of diabetes mellitus. This review highlights the available marketed formulations and research investigations conducted on humans to prove the potential of polypeptide-k as an antihyperglycaemic agent. This article also marks the reasons and need for oral delivery of polypeptide-k.
An Update on Herbal Anti-inflammatory Agents in Periodontal Therapy
Today, 12 Ιουλίου 2016, 4:19:41 μμ
Periodontal diseases are a group of disorders characterized by an inflammatory reaction of periodontium induced by bacterial challenge leading to gingival inflammation, periodontal tissue destruction and alveolar bone loss. The use of naturally derived agents is becoming more common. Many of these agents contain a mixture of active pharmaceutical ingredients combined based on their additive or synergistic properties. The aim of the present study is to review the literature about the use of herbal drugs and other natural products in the treatment of periodontal diseases and their antiinflammatory properties. A web search through Pubmed and hand search including several dental journals was performed up to December 2015, using the keywords (herbal anti-inflammatory agents OR herbal antioxidant) AND (periodontitis OR periodontal disease OR periodontosis). Three topics were investigated: 1) major herbal agents and their biological properties compared with chlorhexidine, the most used chemical agent in periodontal therapy 2) toothpaste, gel and mouthrinse formulations as principal vehicles for herbal products 3) In vitro and in vivo studies to test their ability in reducing periodontal inflammation. The search revealed numerous papers investigating herbal products in the treatment of periodontal diseases. As bacteria develop resistance to classical antibiotics, studies aim to formulate alternative options for controlling periodontal pathogens using plants with anti-inflammatory properties.
Editorial: MicroRNA-33 Inhibition: A Potential Adjunct to Statin Therapy?
Today, 12 Ιουλίου 2016, 4:19:41 μμ
PEG Assisted Manganese (II) Carbonate as an Efficient Catalyst for Regioselective Nitration of Aromatic Compounds Under Acid Free Conventional and Non-Conventional Conditions Using NaNO2
Today, 12 Ιουλίου 2016, 4:19:41 μμ
Background: Nitration of aromatic and hetero aromatic compounds has received enormous attention for the past several decades because many of these nitro products are used as chemical feed stocks and important intermediates for the synthesis of several lifesaving drugs, dyes, pharmaceuticals, perfumes, plastics and explosives. The classical nitration method demands the use of acid mixture (a potent mixture of concentrated nitric and sulfuric acids), which results in large amounts of inorganic acid waste pumped into the industrial drains. Such a large acid waste is not only hazardous but also causes environmental pollution and often leads to over nitration or by-products. Over the years, numerous useful methods have been developed for environmentally safe nitration. Poly ethylene glycol (PEG) and its derivatives have been extensively used as phase-transfer catalyst (PTC) in many commercial processes. Inspired by these procedures we report herein, a clean, economically cheap and, easy to operate, and efficient protocol for the nitration of aromatic compounds, using laboratory desktop chemicals such as nanocrystalline manganese (II) carbonate and polyethylene glycols (PEG). </p><p> Materials and Methods: Chemicals were purchased from Merck, Sigma-Aldrich. Nitration reactions were conducted under sonication and microwave irradiation in addition to the conventional method of organic synthesis. The progress of the reaction was monitored by Thin Layer Chromatography on commercial precoated TLC plates. Melting points were determined by using open capillary tubes with a Buchi 510 apparatus and corrected. UV spectra were recorded on a Shimadzu UV-2700 model UV-VIS Spectrophotometer. </p><p> Conclusion: In conclusion, a regioselective nitration of a various aromatic compounds using green, available, inexpensive and easy to handle catalyst PEG/Mn (II) has been reported. The scope and generality of this protocol was illustrated with several aromatic compounds, short reaction times with good to excellent yields. Non-conventional methods such as sonochemical and microwave affords the nitration of aromatic compounds of both ring activated and deactivated compounds. </p><p>
Natural Products as Farnesoid X Receptor (FXR) Agonists: Their Interactions with FXR Ligand Binding Region
Today, 12 Ιουλίου 2016, 4:19:41 μμ
Nuclear receptors (NRs) are ligand-activated transcription factors modulating significant biological functions including cell growth, lipid metabolism, and glucose homeostasis, so they are frequently to be utilized as important drug targets to develop therapeutic reagents. Farnesoid X receptor (FXR) with bile acids as the natural ligands, plays an essential role in regulation of bile acid and glucose metabolism, and is involved in the pathologies of human diseases including diabetes and chronic liver diseases. Thus, FXR is a promising pharmacological target for these diseases. Synthetic FXR agonists like INT-747 developed by Intercept Pharmaceutical Company is in the clinical trial phase III for non-alcoholic steatohepatitis and can be approved as the treatment of primary biliary cirrhosis in 2016. Due to the promising clinical trial results of INT-747, the naturally occurring FXR ligands may be utilized as the preventive nutraceuticals or treatments of the chronic liver diseases and diabetes. In this review, the natural FXR agonists are summarized and their possible interactions with FXR ligand binding region are discussed.
Endoplasmic Stress Inhibitors for Homocysteine Induced Cardiovascular Disease
Today, 12 Ιουλίου 2016, 4:19:41 μμ
Cardiovascular disease (CVD) remains a major cause of death and disability worldwide, thus preventing and inhibiting CVD remains a health priority. Several lines of pharmacological interventions have not met with great success, thus inhibition of novel cellular stress pathways could be a novel therapeutic avenue to treat CVD. This review will focus on homocysteine and endoplasmic reticulum stress linked to mitochondria function, and possible therapeutic avenues for treatment.
Valproic Acid Metabolism and its Consequences on Sexual Functions
Today, 12 Ιουλίου 2016, 4:19:41 μμ
Background: Valproic acid (VPA) is a broad spectrum antiepileptic drug (AED) that is generally regarded as a first-choice agent for most forms of idiopathic and symptomatic generalised epilepsies. Available data suggest that menstrual disorders and certain endocrine manifestations of reproductive system disorders may be more common in women treated with VPA than in those treated with other AEDs. </p><p> Methods: A PubMed search for MEDLINE was undertaken to look for studies using the terms “VPA metabolism”, “VPA and sexual functions in men”, “VPA and sexual functions in women” and “VPA metabolism and endocrine disorders” as key words. The period covered was approximately 20 years. </p><p> Results: In women, VPA medication is associated with hyperandrogenism, polycystic ovary/polycystic ovarian syndrome, menstrual disorders and ovulatory failure. Men on VPA therapy show abnormalities in androgens blood levels, sperm motility and erectile dysfunctions. VPA negatively affects the release of luteinizing hormone, follicle stimulating hormone and prolactin but also the drug interferes in peripheral endocrine hormones. Its broad inhibitory action on cytochrome and glucuronidation systems can lead to high serum concentration of testosterone, androstenedione and dehydroepiandrosterone sulfate. VPA-dependent obesity and hyperinsulinemia can further contribute to an increase in sexual dysfunctions. </p><p> Conclusions: VPA interferes with the endocrine system at multiples levels causing several reproductive and sexual dysfunctions in women and men with epilepsy, especially when administered in pubertal age. Since VPA is a first line AED both in children and adult with epilepsy and long-term medication with this drug is sometimes necessary, it is very important for physicians to implement strict monitoring of patients taking VPA in order to identify these kinds of side effects at an early stage. </p><p>
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