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1.
Prediction of drug-target interaction based on protein features using undersampling and feature selection techniques with boosting.
Mahmud, SMH, Chen, W, Meng, H, Jahan, H, Liu, Y, Hasan, SMM
Analytical biochemistry. 2020;:113507
Abstract
Accurate identification of drug-target interaction (DTI) is a crucial and challenging task in the drug discovery process, having enormous benefit to the patients and pharmaceutical company. The traditional wet-lab experiments of DTI is expensive, time-consuming, and labor-intensive. Therefore, many computational techniques have been established for this purpose; although a huge number of interactions are still undiscovered. Here, we present pdti-EssB, a new computational model for identification of DTI using protein sequence and drug molecular structure. More specifically, each drug molecule is transformed as the molecular substructure fingerprint. For a protein sequence, different descriptors are utilized to represent its evolutionary, sequence, and structural information. Besides, our proposed method uses data balancing techniques to handle the imbalance problem and applies a novel feature eliminator to extract the best optimal features for accurate prediction. In this paper, four classes of DTI benchmark datasets are used to construct a predictive model with XGBoost. Here, the auROC is utilized as an evaluation metric to compare the performance of pdti-EssB method with recent methods, applying five-fold cross-validation. Finally, the experimental results indicate that our proposed method is able to outperform other approaches in predicting DTI, and introduces new drug-target interaction samples based on prediction probability scores. pdti-EssB webserver is available online at http://pdtiessb-uestc.com/.
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The Effects of Cruciferous Vegetable-Enriched Diets on Drug Metabolism: A Systematic Review and Meta-Analysis of Dietary Intervention Trials in Humans.
Eagles, SK, Gross, AS, McLachlan, AJ
Clinical pharmacology and therapeutics. 2020;(2):212-227
Abstract
Relatively few studies exist in the literature that discuss the effects of diet on drug metabolism and how this can affect interindividual differences in systemic drug exposure. Several studies have investigated the effects of cruciferous vegetables (Cruciferae) or their constituents on drug-metabolizing activity, as these vegetables form an important part of many peoples' diets. In general, the ingestion of cruciferous vegetables is associated with induction of cytochrome P450 (CYP) 1A2 activity in vivo; however, there is contention between reports, and the clinical significance of potential diet-drug interactions remains unclear. This study reports a systematic review, critical appraisal, and meta-analysis of the published literature in this area, and discusses the clinical significance of Cruciferae-enriched diets in the context of diet-drug interactions. Twenty-three dietary intervention trials with drug metabolism end points were identified across Embase, Medline, and the Cochrane Controlled Register of Trials (CENTRAL). Cruciferous vegetables represented in the literature included broccoli, Brussels sprout, cabbage, cauliflower, radish, and watercress. A range of phase I and II drug-metabolizing enzymes and phenotyping metrics were represented in the literature. The meta-analyses performed demonstrated a significant effect on CYP1A2 and glutathione S-transferase-alpha (GST-α), with consumption of Cruciferae increasing the activities of these enzymes by 20-40% and 15-35%, respectively. The results herein suggest that patients undergoing pharmacotherapy with CYP1A2 or GST-α substrates could have altered drug exposure profiles if they regularly eat large or variable amounts of cruciferous vegetables. Recommendations regarding the design of future randomized, controlled trials to test hypotheses in this area are included.
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Safety of the Geneva Cocktail, a Cytochrome P450 and P-Glycoprotein Phenotyping Cocktail, in Healthy Volunteers from Three Different Geographic Origins.
Rollason, V, Mouterde, M, Daali, Y, Čížková, M, Priehodová, E, Kulichová, I, Posová, H, Petanová, J, Mulugeta, A, Makonnen, E, et al
Drug safety. 2020;(11):1181-1189
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Abstract
UNLABELLED INTRODUCTION AND OBJECTIVE Cytochrome P450 enzymes are the major drug-metabolizing enzymes in humans and the importance of drug transport proteins, in particular P-glycoprotein, in the variability of drug response has also been highlighted. Activity of cytochrome P450 enzymes and P-glycoprotein can vary widely between individuals and genotyping and/or phenotyping can help assess their activity. Several phenotyping cocktails have been developed. The Geneva cocktail is composed of a specific probe for six different cytochrome P450 enzymes and one for P-glycoprotein and was used in the context of a research aiming at exploring genotypes and phenotypes in distinct human populations (NCT02789527). The aim of the present study is to solely report the safety results of the Geneva cocktail in the healthy volunteers of these populations. MATERIALS AND METHODS The Geneva cocktail is composed of caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam, and fexofenadine. The volunteers fasted and avoided drinking caffeine-containing beverages or food and grapefruit juice overnight before receiving the cocktail orally. They provided blood spots for the probes' concentrations at 2, 3, and 6 h after ingestion and were asked about adverse events. RESULTS A total of 265 healthy adult volunteers were included from Ethiopia, Oman, and the Czech Republic. The mean plasma concentrations at the 2-h sampling time of each probe drug in the total sample were: 1663 ng/mL for caffeine, 8 ng/mL for bupropion, 789 ng/mL for flurbiprofen, 6 ng/mL for dextromethorphan, 2 ng/mL for midazolam, 35 ng/mL for fexofenadine, and 103 ng/mL for omeprazole. Four adverse events were observed representing an occurrence of 1.5%. All these events were categorized as mild to moderate, non-serious, and resolved spontaneously. A causal link with the cocktail cannot be excluded because of the temporal relationship but is at most evaluated as possible according to the World Health Organization-Uppsala Monitoring Centre causal assessment system. CONCLUSIONS In this research, healthy volunteers from three different human populations were phenotyped with the Geneva cocktail. Four adverse events were observed, confirming the safety of this cocktail that is given at lower than clinically relevant doses and therefore results in concentrations lower than those reported to cause adverse events.
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[Computer-aided drug design: from discovery of novel pharmaceutical agents to systems pharmacology].
Poroikov, VV
Biomeditsinskaia khimiia. 2020;(1):30-41
Abstract
New drug discovery is based on the analysis of public information about the mechanisms of the disease, molecular targets, and ligands, which interaction with the target could lead to the normalization of the pathological process. The available data on diseases, drugs, pharmacological effects, molecular targets, and drug-like substances, taking into account the combinatorics of the associative relations between them, correspond to the Big Data. To analyze such data, the application of computer-aided drug design methods is necessary. An overview of the studies in this area performed by the Laboratory for Structure-Function Based Drug Design of IBMC is presented. We have developed the approaches to identifying promising pharmacological targets, predicting several thousand types of biological activity based on the structural formula of the compound, analyzing protein-ligand interactions based on assessing local similarity of amino acid sequences, identifying likely molecular mechanisms of side effects of drugs, calculating the integral toxicity of drugs taking into account their metabolism, have been developed in the human body, predicting sustainable and sensitive options strains and evaluating the effectiveness of combinations of antiretroviral drugs in patients, taking into account the molecular genetic characteristics of the clinical isolates of HIV-1. Our computer programs are implemented as the web-services freely available on the Internet, which are used by thousands of researchers from many countries of the world to select the most promising substances for the synthesis and determine the priority areas for experimental testing of their biological activity.
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Gut microbiota as an "invisible organ" that modulates the function of drugs.
Li, X, Liu, L, Cao, Z, Li, W, Li, H, Lu, C, Yang, X, Liu, Y
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2020;:109653
Abstract
Gut microbiota plays an important role in the gut and have become a hotspot of recent research interests. Commensal microbiota in gut exert a variety of effects on the host, from shaping the structure and function of the gut and the immune system to the modulation of nutrient status of the host and the treatment outcomes of some drugs. Gut microbiota and its enzyme product and subsequent products, such as short-chain fatty acid and bile acid, play important roles in the biotransformation of drugs via directly or indirectly affecting drug absorption, toxicity, metabolism and bioavailability. Drugs, especially antibiotics, also affect the homeostasis of probiotics and the integrity and function of the intestinal mucosa. These interplaying processes produce a variety of important metabolites of the host and drugs and affect the balance of microbiota and the mucosal barrier then modulate the function of drugs. Gut microbiota imbalance is associated with a broad range of disease mechanisms, and this association denotes a new drug-therapeutic avenue. The present review summarizes how gut microbiota acts as an "invisible organ" to directly or indirectly modulate the function of drugs, on the aspects of probiotic homeostasis, drugs and host nutritional metabolism, AJC, mucus layer and microfold cells.
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Analysis of Scientific Research Driving Microalgae Market Opportunities in Europe.
Rumin, J, Nicolau, E, Junior, RGO, Fuentes-Grünewald, C, Picot, L
Marine drugs. 2020;(5)
Abstract
A bibliographic database of scientific papers published by authors affiliated to research institutions worldwide, especially focused in Europe and in the European Atlantic Area, and containing the keywords "microalga(e)" or "phytoplankton" was built. A corpus of 79,020 publications was obtained and analyzed using the Orbit Intellixir software to characterize the research trends related to microalgae markets, markets opportunities and technologies that could have important impacts on markets evolution. Six major markets opportunities, the production of biofuels, bioplastics, biofertilizers, nutraceuticals, pharmaceuticals and cosmetics, and two fast-evolving technological domains driving markets evolution, microalgae harvesting and extraction technologies and production of genetically modified (GM-)microalgae, were highlighted. We here present an advanced analysis of these research domains to give an updated overview of scientific concepts driving microalgae markets.
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Detection of Beta-Glucan Contamination in Nanotechnology-Based Formulations.
Neun, BW, Cedrone, E, Potter, TM, Crist, RM, Dobrovolskaia, MA
Molecules (Basel, Switzerland). 2020;(15)
Abstract
Understanding the potential contamination of pharmaceutical products with innate immunity modulating impurities (IIMIs) is essential for establishing their safety profiles. IIMIs are a large family of molecules with diverse compositions and structures that contribute to the immune-mediated adverse effects (IMAE) of drug products. Pyrogenicity (the ability to induce fever) and activation of innate immune responses underlying both acute toxicities (e.g., anaphylactoid reactions or pseudoallergy, cytokine storm) and long-term effects (e.g., immunogenicity) are among the IMAE commonly related to IIMI contamination. Endotoxins of gram-negative bacteria are the best-studied IIMIs in that both methodologies for and pitfalls in their detection and quantification are well established. Additionally, regulatory guidance documents and research papers from laboratories worldwide are available on endotoxins. However, less information is currently known about other IIMIs. Herein, we focus on one such IIMI, namely, beta-glucans, and review literature and discuss the experience of the Nanotechnology Characterization Lab (NCL) with the detection of beta-glucans in nanotechnology-based drug products.
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Drug-Induced Hypophosphatemia: Current Insights.
Megapanou, E, Florentin, M, Milionis, H, Elisaf, M, Liamis, G
Drug safety. 2020;(3):197-210
Abstract
Phosphate is actively involved in many important biochemical pathways, such as energy and nucleic acid metabolism, cellular signaling, and bone formation. Hypophosphatemia, defined as serum phosphate levels below 2.5 mg/dL (0.81 mmol/L), is frequently observed in the course of treatment with commonly used drugs, such as diuretics, bisphosphonates, antibiotics, insulin, and antacids. Furthermore, this undesired effect may complicate the use of several novel medications, including teriparatide, denosumab, parenteral iron, and antiviral and antineoplastic agents. This review addresses drug-associated hypophosphatemia, focusing on underlying mechanisms and the most recent knowledge on this topic, in order to increase the insight of clinicians, with reference to early diagnosis and appropriate management.
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Symptomatic Efficacy of Pharmacological Treatments for Knee Osteoarthritis: A Systematic Review and a Network Meta-Analysis with a 6-Month Time Horizon.
Beaudart, C, Lengelé, L, Leclercq, V, Geerinck, A, Sanchez-Rodriguez, D, Bruyère, O, Reginster, JY
Drugs. 2020;(18):1947-1959
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Abstract
INTRODUCTION Several pharmacological treatments aiming at a better symptomatic control of osteoarthritis (OA) are used in daily practice but their efficacy is often disputed. The purpose of this network meta-analysis (NMA) is to assess the efficacy on pain and function of the drugs that are most widely prescribed against knee OA. METHODS Medline, Scopus, and Cochrane database of systematic reviews were searched for randomized controlled trials published up to August 2019 and assessing the efficacy of knee OA treatments using a 6-month time horizon. Pain and function changes from baseline were the primary outcomes. A Bayesian network meta-analysis was run and standardized mean differences (SMDs) with 95% credibility intervals (95% CrIs) were calculated. RESULTS 9697 references were identified and 80 RCTs were concordant with our inclusion criteria (79 studies involving 15,609 individuals reported pain outcomes and 55 studies involving 13,655 individuals reported function outcomes). A significant decrease in pain was observed for the intra-articular (IA) combination of hyaluronic acid (HA) and triamcinolone (SMD - 0.49, 95% CrI - 0.78; - 0.19), vitamin D (SMD - 0.31, 95% CrI - 0.56; - 0.06), IA HA (SMD - 0.29, 95% CrI - 0.40; - 0.17), prescription-grade crystalline glucosamine sulfate (pCGS) (SMD - 0.29, 95% CrI - 0.58; - 0.004), and prescription-grade chondroitin sulfate (pCS) (SMD - 0.26, 95% CrI - 0.44; - 0.08). Significant improvements in physical function were found with pCGS (SMD - 0.44, 95% CrI - 0.66; - 0.21), vitamin D (SMD - 0.30, 95% CrIs - 0.49; - 0.11) and IA HA (SMD - 0.21, 95% CrIs - 0.31; - 0.11). CONCLUSION Six months of treatment with IA HA, pCGS, pCS, vitamin D and the combination of IA HA and triamcinolone improve pain and/or physical function in patients suffering from knee OA.
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Distribution and Removal of Pharmaceuticals in Liquid and Solid Phases in the Unit Processes of Sewage Treatment Plants.
Park, J, Kim, C, Hong, Y, Lee, W, Chung, H, Jeong, DH, Kim, H
International journal of environmental research and public health. 2020;(3)
Abstract
In this study, we analyzed 27 pharmaceuticals in liquid and solid phase samples collected from the unit processes of four different sewage treatment plants (STPs) to evaluate their distribution and behavior of the pharmaceuticals. The examination of the relative distributions of various categories of pharmaceuticals in the influent showed that non-steroidal anti-inflammatory drugs (NSAIDs) were the most dominant. While the relative distribution of antibiotics in the influent was not high (i.e., 3%-5%), it increased to 14%-30% in the effluent. In the four STPs, the mass load of the target pharmaceuticals was reduced by 88%-95% mainly in the biological treatment process, whereas the ratio of pharmaceuticals in waste sludge to those in the influent (w/w) was only 2%. In all the STPs, the removal efficiencies for the stimulant caffeine, NSAIDs (acetaminophen, naproxen, and acetylsalicylic acid), and the antibiotic cefradine were high; they were removed mainly by biological processes. Certain compounds, such as the NSAID ketoprofen, contrast agent iopromide, lipid regulator gemfibrozil, and antibiotic sulfamethoxazole, showed varying removal efficiencies depending on the contribution of biodegradation and sludge sorption. In addition, a quantitative meta-analysis was performed to compare the pharmaceutical removal efficiencies of the biological treatment processes in the four STPs, which were a membrane bioreactor (MBR) process, sequencing batch reactor (SBR) process, anaerobic-anoxic-oxic (A2O) process, and moving-bed biofilm reactor (MBBR) process. Among the biological processes, the removal efficiency was in the order of MBR > SBR > A2O > MBBR. Among the tertiary treatment processes investigated, powdered activated carbon showed the highest removal efficiency of 18%-63% for gemfibrozil, ibuprofen, ketoprofen, atenolol, cimetidine, and trimethoprim.