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Drug Development Research

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https://www.readbyqxmd.com/read/30422335/drug-sales-confirm-clinical-advantage-of-multi-target-inhibition-of-drug-escapes-by-anticancer-kinase-inhibitors
#1
Shangying Chen, Sheng Yong Yang, Zhe Chen, Ying Tan, Yu Yang Jiang, Yu Zong Chen
Hit, Lead & Candidate Discovery The clinical advantage of co-targeting cancer drug escape has been indicated by the percentage of these co-targeting drugs among all multi-target drugs in clinics and clinical trials. This clinical advantage needs to be further interrogated from such perspectives as the clinical impact of multi-target inhibition of drug-escape mediators. This impact may be reflected by drug sales data, that is, multi-target inhibition of higher number of drug-escape mediators favors the expanded coverage of drug-resistant patients leading to higher sales...
November 13, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30414214/preparation-optimization-and-pharmacokinetic-study-of-nanoliposomes-loaded-with-triacylglycerol-bound-punicic-acid-for-increased-antihepatotoxic-activity
#2
Michael Adu-Frimpong, Caleb Kesse Firempong, Emmanuel Omari-Siaw, Qilong Wang, Yusif Mohammed Mukhtar, Wenwen Deng, Qingtong Yu, Ximing Xu, Jiangnan Yu
Hit, Lead & Candidate Discovery Punicic acid of pomegranate oil (PAP) has gained heightened interest due to several health benefits, such as anticarcinogenic, antidiabetic, and antiatherosclerotic properties. However, these bioactivities have been hampered by chemical instability, poor water solubility, rapid metabolism, and low bioavailability of PAP. Therefore, this study was aimed at optimizing the liposomal formulation of Triacylglycerol-bound punicic acid with its regioisomers (TPAR) for improved oral bioavailability and increased hepatoprotection through antioxidation and anti-inflammation...
November 10, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30394554/functional-mechanism-of-tracheal-relaxation-antiasthmatic-and-toxicological-studies-of-6-hydroxyflavone
#3
Angélica Flores-Flores, Samuel Estrada-Soto, César Millán-Pacheco, Blanca Bazán-Perkins, Rafael Villalobos-Molina, Leticia Moreno-Fierros, Rogelio Hernández-Pando, Sara García-Jiménez, Julio César Rivera-Leyva
Preclinical Research & Development Previously, we described tracheal rat rings relaxation by several flavonoids, being 6-hydroxyflavone (6-HOF) the most active derivative of the series. Thus, its mechanism of action was determined in an ex vivo tracheal rat ring bioassay. The anti-asthmatic effect was assayed in in vivo OVAlbumin (OVA)-sensitized guinea pigs. Finally, the toxicological profile of 6-HOF was studied based on Organization of Economic Cooperation and Development guidelines with modifications...
November 5, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30387164/silver-carbene-complexes-an-emerging-class-of-anticancer-agents
#4
Shravankumar Kankala, Niranjan Thota, Fredrik Björkling, Myles K Taylor, Ravinder Vadde, Ramesh Balusu
Hit, Lead & Candidate Discovery Cancer is a major global health problem with large therapeutic challenges. Although substantial progress has been made in cancer therapy, there still remains a need to develop novel and effective treatment strategies to treat several relapsed and refractory cancers. Recently, there has been growing demand for considering organometallics as antineoplastic agents. This review is focused on a group of organometallics, silver N-heterocyclic carbene complexes (SCCs) and their anticancer efficacy in targeting multiple pathways in various in vitro cancer model systems...
November 1, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30381846/design-synthesis-and-biological-evaluation-of-helicobacter-pylori-inosine-5-monophosphate-dehydrogenase-hpimpdh-inhibitors
#5
Niteshkumar U Sahu, Gayathri Purushothaman, Vijay Thiruvenkatam, Prashant S Kharkar
Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes a crucial step in the biosynthesis of guanine nucleotides. Being a validated target for immunosuppressive, antiviral, and anticancer drug development, lately it has been exploited as a promising target for antimicrobial therapy. Extending our previous work on Mycobacterium tuberculosis IMPDH, GuaB2, inhibitor development, we screened a set of 23 new chemical entities (NCEs) with substituted flavone (Series 1) and 1,2,3-triazole (Series 2) core structures for their in vitro Helicobacter pylori IMPDH (HpIMPDH) and human IMPDH2 (hIMPDH2) inhibitory activities...
November 1, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30379338/protective-role-of-fucoxanthin-in-diethylnitrosamine-induced-hepatocarcinogenesis-in-experimental-adult-rats
#6
Xin Jin, TingTing Zhao, Dan Shi, Ming Bao Ye, Qiying Yi
Hit, Lead & Candidate Discovery Hepatocellular carcinoma (HCC) accounts for majority of cancer related deaths. Two major risk factors in induction of HCC are chemical and virus, however, the possible mechanisms of their differences remain indefinable. The current study focused on protective role of Fucoxanthin (Fx) in liver affected by diethylnitrosamine (DEN)-induced HCC. In this study, levels of liver enzymes, oxidative stressors, antioxidant status, and lipoproteins were compared both in tissue and blood...
October 31, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30375672/selective-cytotoxic-activity-and-dna-damage-by-an-epoxyalkyl-galactopyranoside
#7
Estefanía Burgos-Morón, Nuria Pastor, Manuel Luis Orta, Julio José Jiménez-Alonso, Margarita Vega-Holm, José Manuel Vega-Pérez, Fernando Iglesias-Guerra, Santiago Mateos, Miguel López-Lázaro, José Manuel Calderón-Montaño
Preclinical Research & Development Several clinically useful anticancer drugs selectively kill cancer cells by inducing DNA damage; the genomic instability and DNA repair defects of cancer cells make them more vulnerable than normal cells to the cytotoxicity of DNA-damaging agents. Because epoxide-containing compounds can induce DNA damage, we have used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to evaluate the selective cytotoxicity of three epoxyalkyl galactopyranosides against A549 lung cancer cells and MRC-5 lung normal cells...
October 30, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30370682/antibiotics-as-both-friends-and-foes-of-the-human-gut-microbiome-the-microbial-community-approach
#8
Teresa Nogueira, Pedro H C David, Joël Pothier
The exposure of the human gut to antibiotics can have a great impact on human health. Antibiotics pertain to the preservation of human health and are useful tools for fighting bacterial infections. They can be used for curing infections and can play a critical role in immunocompromised or chronic patients, or in fighting childhood severe malnutrition. Yet, the genomic and phylogenetic diversity of the human gut changes under antibiotic exposure. Antibiotics can also have severe side effects on human gut health, due to the spreading of potential antibiotic resistance genetic traits and to their correlation with virulence of some bacterial pathogens...
October 28, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30370576/marine-bacteria-and-fungi-as-promising-source-for-new-antibiotics
#9
Jutta Wiese, Johannes F Imhoff
Natural products and derivatives thereof are of considerable importance in the discovery of new pharmaceuticals, for example, for the treatment of cancer, diabetes, inflammation diseases, and infection diseases caused by bacteria, fungi, viruses, or parasites. The great biodiversity of marine microorganisms is reflected in their huge chemical diversity, which provides a rich source of biologically active compounds. An increasing interest in marine microorganisms as promising producers of new compounds with potential medical applications has raised increasing interest in the sustainable exploration of marine microbial resources for the discovery of new antibiotics, which is highlighted...
October 28, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30362140/participation-of-atp-sensitive-k-channels-and-%C3%AE-opioid-receptors-in-the-antinociceptive-synergism-of-the-paracetamol-tapentadol-co-administration-in-the-formalin-induced-pain-assay-in-mice
#10
Juan R Zapata-Morales, Ángel J Alonso-Castro, Salud Pérez-Gutiérrez, Edgar Isaac Rojas-Bedolla, Sergio Sánchez-Enriquez, Jorge David Rivas-Carrillo, Nicolás A Serafín-Higuera, Mario A Isiordia-Espinoza
Preclinical Research & Development The purpose of this study was to assess the interaction and mechanisms of action of the paracetamol-tapentadol combination in the formalin-induced pain model in mice. Paracetamol (56.23-562.3 mg/kg, i.p.) or tapentadol (1-10 mg/kg, i.p.) were administered 15 min prior the intraplantar injection of formalin. The ED50 value of each drug was determined through the dose-response curves. The ED50 values were used to calculate the combinations in three fixed proportions (1:1, 1:3, and 3:1)...
October 26, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30343525/a-brief-appraisal-of-computational-modeling-of-antimicrobial-peptides-activity
#11
Jagannath Mondal
We present a brief overview of computer simulations over the span of last two decades that have made some serious attempts in providing key insights toward the mechanistic aspects of antimicrobial peptides and biomimetic peptides. We review some of the success stories of computational modeling of antimicrobial activity and also point toward the present shortcomings of the current approaches. Finally, we shed light upon the future potential directions that computational approach can adopt toward direct and closer comparisons with experiments on antimicrobial activity...
October 21, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30343499/thiazole-substituted-benzoylpiperazine-derivatives-as-acetylcholinesterase-inhibitors
#12
Zafer Sahin, Merve Ertas, Ceysu Bender, Emre F Bülbül, Barkin Berk, Sevde N Biltekin, Leyla Yurttaş, Şeref Demirayak
Hit, Lead & Candidate Discovery After acetylcholine is released into the synaptic cleft, it is reabsorbed or deactivated by acetylcholinesterase (AChE). Studies on Alzheimer's disease (AD) in the mid-20th century proved that cognitive dysfunctions are associated with cholinergic neurotransmission. Drugs, such as tacrine, rivastigmine, donepezil, and galantamine are known as acetylcholinesterase inhibitors. However, these drugs have limited use in advanced AD and dementia. Recently, the anticholinesterase activity of various heterocyclic-framed compounds, including piperazine derivatives, has been investigated, and compounds with similar effects to known drugs have been identified...
October 21, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30343496/dose-translation-between-laboratory-animals-and-human-in-preclinical-and-clinical-phases-of-drug-development
#13
Anroop Nair, Mohamed Aly Morsy, Shery Jacob
Preclinical Research & Development Appropriate translation and determination of the maximum recommended starting dose in human is a vital task in new drug development and research. Allometric scaling is the most frequently used approach for dose extrapolation based on normalization of dose-to-body surface area. Misinterpretation of allometric dose conversion and safety factor application can lead to major problems in calculating maximum recommended safe starting dose in first-in-human clinical trials. Therefore, dose translation always necessitates careful consideration of body surface area, pharmacological, physiological and anatomical factors, pharmacokinetic parameters, metabolic function, receptor, and life span...
October 21, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30343487/inhibiting-conjugation-as-a-tool-in-the-fight-against-antibiotic-resistance
#14
Fabrice E Graf, Martin Palm, Jonas Warringer, Anne Farewell
Hit, Lead & Candidate Discovery Antibiotic resistance, especially in gram-negative bacteria, is spreading globally and rapidly. Development of new antibiotics lags behind; therefore, novel approaches to the problem of antibiotic resistance are sorely needed and this commentary highlights one relatively unexplored target for drug development: conjugation. Conjugation is a common mechanism of horizontal gene transfer in bacteria that is instrumental in the spread of antibiotic resistance among bacteria. Most resistance genes are found on mobile genetic elements and primarily spread by conjugation...
October 21, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30329161/drug-development-and-bioanalytical-method-validation-for-a-novel-anticancer-molecule-4-dimethylamino-2-p-tolylamino-thiazole-5-carbonitrile
#15
Nripendra Madhab Biswas, Amit Shard, Sagarkumar Patel, Pinaki Sengupta
Preclinical Research & Development The thiazole ring system represents a significant building block that exists in many biologically active natural products and clinically successful anticancer drugs. Modifications of the thiazole core have been a proven and highly effective method in improving anticancer potency. We designed a novel thiazole-based molecule, 4-(dimethylamino)-2-(p-tolylamino) thiazole-5-carbonitrile, which showed potent in vitro anticancer effect against targeted Bcl-2 Jurkat cell-line quantified using 3-(4, 5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay...
October 17, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30312991/reaching-toward-underexplored-targets-in-antibacterial-drug-design
#16
Marko Jukič, Stanislav Gobec, Matej Sova
The increase of antimicrobial resistance necessitates the renewal and strong research involvement in antibacterial drug design. In the following work, we comment on the key approaches used in development of new antibacterials, focusing on intracellular therapeutic targets that have been so far mostly underexplored: the enzymes of the Mur pathway MurA to MurF. We identify common obstacles observed during research on MurA, MurB, and Mur ligases inhibitors and their development into potential antibacterial compounds, and discern several approaches and solutions to tackle the whole-cell activity of designed compounds...
October 12, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30312987/drug-resistance-in-mycobacterium-tuberculosis-and-targeting-the-l-d-transpeptidase-enzyme
#17
Kuppan Gokulan, Kottayil I Varughese
Hit, Lead & Candidate Discovery Tuberculosis (TB) is a disease that has afflicted mankind for thousands of years, but in the last seven decades, much progress has been made in anti-TB therapy. Early drugs, such as para-aminosalicylic acid, streptomycin, isoniazid, and rifamycins were very effective in combatting the disease, giving rise to the hope that TB would be eradicated from the face of the earth by 2010. Despite that optimism, TB continues to kill more than a million people annually worldwide. A major reason for our inability to contain TB is the emergence drug resistance in Mycobacterium tuberculosis...
October 12, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30302779/microbial-esterases-and-ester-prodrugs-an-unlikely-marriage-for-combating-antibiotic-resistance
#18
Erik M Larsen, R Jeremy Johnson
The rise of antibiotic resistance necessitates the search for new platforms for drug development. Prodrugs are common tools for overcoming drawbacks typically associated with drug formulation and delivery, with ester prodrugs providing a classic strategy for masking polar alcohol and carboxylic acid functionalities and improving cell permeability. Ester prodrugs are normally designed to have simple ester groups, as they are expected to be cleaved and reactivated by a wide spectrum of cellular esterases. However, a number of pathogenic and commensal microbial esterases have been found to possess significant substrate specificity and can play an unexpected role in drug metabolism...
October 10, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30302774/synthesis-carbonic-anhydrase-inhibitory-activity-and-antioxidant-activity-of-some-1-3-oxazine-derivatives
#19
Rabia Qamar, Aamer Saeed, Maria Saeed, Zaman Ashraf, Qamar Abbas, Mubashir Hassan, Fernando Albericio
Hit, Lead & Candidate Discovery A series of 1-(6-methyl-2-substituted phenyl-4-thioxo-4H-1,3-oxazin-5-yl)ethanones (3a-n) were synthesized by the reaction of benzoyl isothiocyanates with active methylene compound acetylacetone in the presence of triethyl amine in a one-pot process. The structures of the products were elucidated by elemental analyses, FT-IR, 1 H NMR, 13 C NMR, and mass spectroscopy. These new 1,3-oxazine derivatives were evaluated for their inhibitory activity against carbonic anhydrase II...
October 10, 2018: Drug Development Research
https://www.readbyqxmd.com/read/30291767/in-house-chemical-library-repurposing-a-case-example-for-pseudomonas-aeruginosa-antibiofilm-activity-and-quorum-sensing-inhibition
#20
L Ravithej Singh, Vikash C Tripathi, Sneha Raj, Anoop Kumar, Sampa Gupta, Soyar Horam, Akanksha Upadhyay, Pragati Kushwaha, Jesu Arockiaraj, Koneni V Sashidhara, Mukesh Pasupuleti
Drug repurposing has become a recent trend in drug development programs, where previously developed drugs are explored for hit and redeveloped into potential therapeutic agents for new diseases. Globally, in any drug development program, a series of molecules are synthesized and evaluated for the hypothesized activity. Hits are developed into lead molecules or drugs, whereas the negative ones are shelved in the lab with no immediate use. We in this project took the previously sidelined small chemical molecules to the next level of utility, where previously developed in-house small molecules library are tested for the unexplored biological relevant activity...
October 6, 2018: Drug Development Research
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