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https://www.readbyqxmd.com/read/29343945/the-impact-of-pharmaceutical-interventions-on-the-rational-use-of-proton-pump-inhibitors-in-a-chinese-hospital
#1
Chuanwei Xin, Zhu Dong, Mengmeng Lin, Gong-Hua Li
Background: The prescriptions of proton pump inhibitors (PPIs) have raised concern due to both huge increase in medical expenditure and the possible long-term adverse events caused by them; therefore, an approach to taper off the irrational use of PPIs by patients is clinically warranted. The aim of this study was to evaluate the impact of pharmaceutical interventions on the rational use of PPIs. Patients and methods: A single-center, pre- to post-intervention study (pharmaceutical interventions group and control group) was performed in a Chinese hospital...
2018: Patient Preference and Adherence
https://www.readbyqxmd.com/read/29343185/exploring-protein-protein-intermolecular-recognition-between-meprin-%C3%AE-and-endogenous-protease-regulator-cystatinc-coupled-with-pharmacophore-elucidation
#2
Ankur Chaudhuri, Sampa Biswas, Sibani Chakraborty
Meprins are a group of zinc metalloproteases of the astacin family which play pivotal role in several physiological and pathologocal diseases. The inhibition of the meprins by various inhibitors; macromolecular and small molecules are crucial in the control of several diseases. Human cystatinC, an amyloidogenic protein is reported to be an endogenous inhibitor of meprin-α. In this computational study, we elucidate a rational model for meprinα-cystatinC complex by using protein-protein docking. The complex model as well as the unbound form was evaluated by molecular dynamics simulation...
January 17, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29343012/-the-effectiveness-of-individualized-treatment-regimen-on-smear-positive-retreatment-pulmonary-tuberculosis-with-mono-and-poly-drug-resistance
#3
Y H Liu, W W Gao, L Li, J Du, Y Ma, W Shu, X Y Lyu, S H Xie, H H Wang, T Chen
Objective: To analyze and evaluate the effectiveness of individualized treatment regimen in the therapy of smear-positive retreatment pulmonary tuberculosis with mono-and poly-drug resistance, and therefor to provide information on how to develop rational individualized regimen for retreatment tuberculosis cases with drug resistance. Methods: This was a multi-centered, prospective cohort study. Totally 254 cases of sputum positive tuberculosis with previous treatment history during the period from July 1, 2009 to August 30, 2016 were included in the analysis...
January 12, 2018: Chinese Journal of Tuberculosis and Respiratory Diseases
https://www.readbyqxmd.com/read/29341608/molecular-dynamics-pinpoint-the-global-fluorine-effect-in-balanoids-binding-to-pkc%C3%AE%C2%B5-and-pka
#4
Ari Hardianto, Fei Liu, Shoba Ranganathan
(-)-Balanol is an ATP mimic that inhibits protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA) with little selectivity. While PKA is known as a tumour promoter, PKC isozymes can be tumour promoters or suppressors. In particular, PKCε is frequently involved in tumorigenesis and a potential target for anticancer drugs. We recently reported that stereospecific fluorination of balanol yielded a balanoid with enhanced selectivity for PKCε over other PKC isozymes and PKA, although the global fluorine effect behind the selectivity enhancement is not fully understood...
January 17, 2018: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29341435/bifunctional-fluorescent-probe-for-sequential-sensing-thiols-and-primary-aliphatic-amines-in-distinct-fluorescence-channels
#5
Lingliang Long, Meiyu Huang, Ning Wang, Xiangqi Yuan, Siyu Cao, Aihua Gong, Kun Wang
Thiols and primary aliphatic amines (PAA) are ubiquitous and extremely important species in biological system. They have performed significant interplaying roles in complex biological events. A single fluorescent probe differentiating both thiol and PAA can contribute to understanding the intrinsic inter-relationship of thiols and PAA in biological processes. Herein, we rationally constructed the first fluorescent probe that can respond to thiols and PAA in different fluorescence channels. The probe exhibited high selectivity and sensitivity to thiols and PAA...
January 17, 2018: Chemistry, An Asian Journal
https://www.readbyqxmd.com/read/29340039/integrative-molecular-network-analysis-identifies-emergent-enzalutamide-resistance-mechanisms-in-prostate-cancer
#6
Carly J King, Josha Woodward, Jacob Schwartzman, Daniel J Coleman, Robert Lisac, Nicholas J Wang, Kathryn Van Hook, Lina Gao, Joshua Urrutia, Mark A Dane, Laura M Heiser, Joshi J Alumkal
Recent work demonstrates that castration-resistant prostate cancer (CRPC) tumors harbor countless genomic aberrations that control many hallmarks of cancer. While some specific mutations in CRPC may be actionable, many others are not. We hypothesized that genomic aberrations in cancer may operate in concert to promote drug resistance and tumor progression, and that organization of these genomic aberrations into therapeutically targetable pathways may improve our ability to treat CRPC. To identify the molecular underpinnings of enzalutamide-resistant CRPC, we performed transcriptional and copy number profiling studies using paired enzalutamide-sensitive and resistant LNCaP prostate cancer cell lines...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29339792/assemble-and-match-a-novel-hybrid-tool-for-enhancing-education-and-research-in-rational-structure-based-drug-design
#7
Pouya Tavousi, Reza Amin, Sina Shahbazmohamadi
Rational drug design is the process of finding new medication that can activate or inhibit the biofunction of a target molecule by binding to it and forming a molecular complex. Here, shape and charge complementarities between drug and target are key. To help find effective drug molecules out of a huge pool of possibilities, physical and computer aided tools have been developed. Former offers a tangible experience of the molecular interactions yet lacks measurement and evaluation capabilities. Latter enables accurate and fast evaluations, but does not deliver the interactive tangible experience of physical models...
January 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29339082/water-mediated-interactions-enable-smooth-substrate-transport-in-a-bacterial-efflux-pump
#8
Attilio Vittorio Vargiu, Venkata Krishnan Ramaswamy, Ivana Malvacio, Giuliano Malloci, Ulrich Kleinekathöfer, Paolo Ruggerone
BACKGROUND: Efflux pumps of the Resistance-Nodulation-cell Division superfamily confer multi-drug resistance to Gram-negative bacteria. The most-studied polyspecific transporter belonging to this class is the inner-membrane trimeric antiporter AcrB of Escherichia coli. In previous studies, a functional rotation mechanism was proposed for its functioning, according to which the three monomers undergo concerted conformational changes facilitating the extrusion of substrates. However, the molecular determinants and the energetics of this mechanism still remain unknown, so its feasibility must be proven mechanistically...
January 12, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29338693/in-vitro-antimicrobial-susceptibility-testing-of-human-brucella-melitensis-isolates-from-ulanqab-of-inner-mongolia-china
#9
Zhi-Guo Liu, Dong-Dong Di, Miao Wang, Ri-Hong Liu, Hong-Yan Zhao, Dong-Ri Piao, Zhong-Zhi Zhao, Yong-Qing Hao, Ya-Nan Du, Hai Jiang, Bu-Yun Cui, Xian-Zhu Xia
BACKGROUND: Brucellosis is an endemic disease in the Inner Mongolia Autonomous Region of China and Ulanqab exhibits the highest prevalence of brucellosis in this region. Due to the complex nature of Brucellosis, a cure for this disease has proven to be elusive. Furthermore, the reduced susceptibility of Brucella spp. to antimicrobial agents has been reported as a potential cause of therapeutic failure. However, detailed in vitro antimicrobial susceptibility patterns pertaining to Brucella isolates from this region have not yet been published...
January 16, 2018: BMC Infectious Diseases
https://www.readbyqxmd.com/read/29337562/physiologically-based-pharmacokinetic-modeling-in-lead-optimization-ii-rational-bioavailability-design-by-global-sensitivity-analysis-to-identify-properties-affecting-bioavailability
#10
Pankaj R Daga, Michael B Bolger, Ian Haworth, Robert Daniel Clark, Eric J Martin
When medicinal chemists need to improve oral bioavailability (%F) during lead optimization, they systematically modify compound properties mainly based on their own experience and general rules of thumb. However, at least a dozen properties can influence %F, and the difficulty of multi-parameter optimization for such complex non-linear processes grows combinatorially with the number of variables. Furthermore, strategies can be in conflict. For example, adding a polar or charged group will generally increase solubility but decrease permeability...
January 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29335213/jietacins-azoxy-antibiotics-with-potent-nematocidal-activity-design-synthesis-and-biological-evaluation-against-parasitic-nematodes
#11
Akihiro Sugawara, Masahiko Kubo, Tomoyasu Hirose, Kyoichi Yahagi, Noriaki Tsunoda, Yoshihiko Noguchi, Takuji Nakashima, Yoko Takahashi, Claudia Welz, Dennis Mueller, Christina Mertens, Johannes Koebberling, Satoshi Ōmura, Toshiaki Sunazuka
Jietacins, an azoxy antibiotic class of chemicals, were isolated from the culture broth of Streptomyces sp. KP-197. They have a unique structural motif, including a vinyl azoxy group and a long acyclic aliphatic chain, which is usually branched but non-branched in the case of jietacin C. During a drug discovery program, we found that jietacins display potent anthelmintic activity against parasitic nematodes and that jietacin A has a moderate or low acute toxicity (LD50 > 300 mg/kg) and no mutagenic potential in a mini Ames screen...
December 28, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29333777/-retrospective-analysis-of-adverse-drug-reactions-in-stomatology-hospital-from-2014-to-2016
#12
Li Jia, Wang Jianli, Zhao Ke, Zhao Shaofeng
OBJECTIVE: This study aims to investigate the characteristics and general rules of adverse drug reactions (ADR) in a 3A-grade stomatology hospital for safe and rational drug use in clinical stomatology. METHODS: We retrospectively analyzed 52 ADR cases (1∶1.36, males∶females) reported in the West China Hospital of Stomatology of Sichuan University from 2014 to 2016 in terms of gender and age distributions, drug categories, and clinical manifestations. RESULTS: Eight kinds of drugs and antibiotics were predominately used [24 cases, 46...
December 1, 2017: Hua Xi Kou Qiang Yi Xue za Zhi, Huaxi Kouqiang Yixue Zazhi, West China Journal of Stomatology
https://www.readbyqxmd.com/read/29332842/ligand-cascading-nano-delivery-devices-to-enable-multiscale-targeting-of-anti-neurodegenerative-therapeutics
#13
Adam Mullis, Benjamin William Schlichtmann, Balaji Narasimhan, Rebecca Cademartiri, Surya K Mallapragada
Neurodegenerative diseases are a debilitating set of conditions that affect a significant fraction of the world's population, and this fraction is expected to increase as the population ages. Many therapeutic strategies have been explored to treat the pathological mechanisms of neurodegenerative disease, but multiple sequential hurdles to central nervous system delivery, including the blood-brain barrier, diseased neuronal membranes, and the organelle barrier, make drug delivery challenging and necessitate the use of innovative strategies to target and cross each barrier...
January 15, 2018: Biomedical Materials
https://www.readbyqxmd.com/read/29332563/multi-target-directed-drugs-as-a-modern-approach-for-drug-design-towards-alzheimer-s-disease-an-update
#14
Matheus de Freitas Silva, Kris Simone Tranches Dias, Vanessa Silva Gontijo, Cindy Juliet Cristancho Ortiz, Claudio Viega
Alzheimer's disease (AD) is a progressive multifactorial neurodegenerative disorder. Currently, no effective treatment is available and this is due to multiple factors involved in pathophysiology and severity of AD. A recent approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDL) strategy, has been used to develop a variety of hybrid compounds capable to act simultaneously in diverse biological targets. The discovery of drug molecules capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies...
January 10, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29330855/getting-innovative-therapies-faster-to-patients-at-the-right-dose-impact-of-quantitative-pharmacology-towards-first-registration-and-expanding-therapeutic-use
#15
Satyaprakash Nayak, Oliver Sander, Nidal Al-Huniti, Dinesh de Alwis, Anne Chain, Marylore Chenel, Soujanya Sunkaraneni, Shruti Agrawal, Neeraj Gupta, Sandra A G Visser
Quantitative pharmacology (QP) applications in translational medicine, drug-development, and therapeutic use were crowd-sourced by the ASCPT Impact and Influence initiative. Highlighted QP case studies demonstrated faster access to innovative therapies for patients through 1) rational dose selection for pivotal trials; 2) reduced trial-burden for vulnerable populations; or 3) simplified posology. Critical success factors were proactive stakeholder engagement, alignment on the value of model-informed approaches, and utilizing foundational clinical pharmacology understanding of the therapy...
January 13, 2018: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29330437/a-computational-assay-of-estrogen-receptor-%C3%AE-antagonists-reveals-the-key-common-structural-traits-of-drugs-effectively-fighting-refractory-breast-cancers
#16
Matic Pavlin, Angelo Spinello, Marzia Pennati, Nadia Zaffaroni, Silvia Gobbi, Alessandra Bisi, Giorgio Colombo, Alessandra Magistrato
Somatic mutations of the Estrogen Receptor α (ERα) occur with an up to 40% incidence in ER sensitive breast cancer (BC) patients undergoing prolonged endocrine treatments. These polymorphisms are implicated in acquired resistance, disease relapse, and increased mortality rates, hence representing a current major clinical challenge. Here, multi-microseconds (12.5 µs) molecular dynamics simulations revealed that recurrent ERα polymorphisms (i. e. L536Q, Y537S, Y537N, D538G) (mERα) are constitutively active in their apo form and that they prompt the selection of an agonist (active)-like conformation even upon antagonists binding...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29328649/phenylthiomethyl-ketone-based-fragments-show-selective-and-irreversible-inhibition-of-enteroviral-3c-proteases
#17
Robert Schulz, Amira Atef, Daniel Becker, Franziska Gottschalk, Carolin Tauber, Stefan Wagner, Christoph Arkona, Atef A Abdel-Hafez, Hassan H Farag, Jörg Rademann, Gerhard Wolber
Lead structure discovery mainly focuses on the identification of noncovalently binding ligands. Covalent linkage, however, is an essential binding mechanism for a multitude of successfully marketed drugs although discovered by serendipity in most cases. We present a concept for the design of fragments covalently binding to proteases. Covalent linkage enables fragment binding unrelated to affinity to shallow protein binding sites and at the same time allows differentiated targeted hit verification and binding location verification through mass spectrometry...
January 12, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29326367/organic-anion-transporter-2-mediates-hepatic-uptake-of-tolbutamide-a-cytochrome-p450-2c9-probe-drug
#18
Yi-An Bi, Sumathy Mathialagan, Laurie Tylaska, Myra Fu, Julie Keefer, Anna Vildhede, Chester Costales, A David Rodrigues, Manthena Varma
Tolbutamide is primarily metabolized by cytochrome P450 (CYP)2C9, and thus, frequently applied as a clinical probe substrate for CYP2C9 activity. However, there is a marked discrepancy in the in vitro-in vivo extrapolation of its metabolic clearance implying potential for additional clearance mechanisms. The goal of this study was to evaluate the role of hepatic uptake transport in the pharmacokinetics of tolbutamide and identify the molecular mechanism thereof. Transport studies using singly-transfected cells expressing six major hepatic uptake transporters showed that tolbutamide is a substrate to organic anion transporter (OAT)2 alone -- with transporter affinity (Km) of 19...
January 11, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29322778/using-genome-sequence-to-enable-the-design-of-medicines-and-chemical-probes
#19
Alicia J Angelbello, Jonathan L Chen, Jessica L Childs-Disney, Peiyuan Zhang, Zi-Fu Wang, Matthew D Disney
Rapid progress in genome sequencing technology has put us firmly into a postgenomic era. A key challenge in biomedical research is harnessing genome sequence to fulfill the promise of personalized medicine. This Review describes how genome sequencing has enabled the identification of disease-causing biomolecules and how these data have been converted into chemical probes of function, preclinical lead modalities, and ultimately U.S. Food and Drug Administration (FDA)-approved drugs. In particular, we focus on the use of oligonucleotide-based modalities to target disease-causing RNAs; small molecules that target DNA, RNA, or protein; the rational repurposing of known therapeutic modalities; and the advantages of pharmacogenetics...
January 11, 2018: Chemical Reviews
https://www.readbyqxmd.com/read/29322474/pharmacovigilance-in-developing-countries-part-ii-a-path-forward
#20
Shaimaa Elshafie, Anne Marie Roberti, Iman Zaghloul
In recent years, attention to pharmacovigilance has gained momentum in developing countries, however awareness of, and policies or systems for pharmacovigilance in most developing countries still lags sharply behind developed countries. This article proposes different strategies to encourage the introduction and sustain the advancement of robust pharmacovigilance systems in developing countries. To this end, this article seeks to accomplish the ultimate goal of pharmacovigilance in a developing country context; ensuring patient safety and promoting safe and rational use of drugs...
January 10, 2018: International Journal of Clinical Pharmacy
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