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https://www.readbyqxmd.com/read/28335600/redox-potential-sensitive-n-acetyl-cysteine-prodrug-nanoparticles-inhibit-the-activation-of-microglia-and-improve-neuronal-survival
#1
Eleni Markoutsa, Peisheng Xu
One hallmark of neuroinflammation is the activation of microglia, which triggers the production and release of reactive oxygen species (ROS), nitrate, nitrite, and cytokines. N-acetyl cysteine (NAC) is a free radical scavenger that is involved in the intracellular and extracellular detoxification of ROS in the brain. However, the clinical application of NAC is limited by its low bioavailability and short half-life. Herein, NAC was conjugated to a polymer through disulfide bond to form a NAC-prodrug nanoparticle (NAC-NP)...
March 23, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28335548/study-of-different-variants-of-mo-enzyme-crarc-and-the-interaction-with-its-partners-crcytb5-r-and-crcytb5-1
#2
Alejandro Chamizo-Ampudia, Aurora Galvan, Emilio Fernandez, Angel Llamas
The mARC (mitochondrial Amidoxime Reducing Component) proteins are recently discovered molybdenum (Mo) Cofactor containing enzymes. They are involved in the reduction of several N-hydroxylated compounds (NHC) and nitrite. Some NHC are prodrugs containing an amidoxime structure or mutagens such as 6-hydroxylaminopurine (HAP). We have studied this protein in the green alga Chlamydomonas reinhardtii (crARC). Interestingly, all the ARC proteins need the reducing power supplied by other proteins. It is known that crARC requires a cytochrome b₅ (crCytb5-1) and a cytochrome b₅ reductase (crCytb5-R) that form an electron transport chain from NADH to the substrates...
March 21, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28334528/why-prodrugs-and-propesticides-succeed
#3
John E Casida
What are the advantages of bioactivation in optimizing drugs and pesticides? Why are there so many prodrugs and propesticides? These questions are examined here by considering compounds selected on the basis of economic value or market success. The 100 major drugs and 90 major pesticides are divided into ones acting directly and those definitely or possibly requiring bioactivation. Established or candidate prodrugs accounted for 19% of the total drug sales with corresponding values of 20, 37 and 17% for proinsecticides, proherbicides and profungicides...
March 23, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28331290/effects-of-dexamethasone-coadministered-with-oseltamivir-on-the-pharmacokinetics-of-oseltamivir-in-healthy-volunteers
#4
Kyungho Jang, Min-Kyoung Kim, Jaeseong Oh, SeungHwan Lee, Joo-Youn Cho, Kyung-Sang Yu, Tai Kiu Choi, Sang-Hyuk Lee, Kyoung Soo Lim
PURPOSE: Oseltamivir is widely used in the treatment and prophylaxis of influenza A and B viral infections. It is ingested as an oral prodrug that is rapidly metabolized by carboxylesterase 1 (CES1) to its active form, oseltamivir carboxylate. Dexamethasone is also used in the treatment of acute respiratory distress syndrome, a severe complication of influenza; however, its influence on the pharmacokinetics (PK) of oseltamivir is controversial. The aim of this study was to investigate the effects of coadministering oseltamivir and dexamethasone on the PK of oseltamivir in healthy volunteers...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28329729/prodrugs-of-triterpenoids-and-their-derivatives
#5
REVIEW
Meng Zhou, Rong-Hong Zhang, Min Wang, Guo-Bo Xu, Shang-Gao Liao
Triterpenoids are structurally diverse organic compounds that exist widely as natural products. Triterpenoids and their derivatives possess a wide range of biological effects including hepatoprotective, hypoglycemic, immunomodulatory, anti-inflammatory, anti-oxidant, and antitumor activities. In particular, the lupane-, oleanane-, and ursane-type triterpenes have been reported to exhibit pharmacological effects without prominent toxicity even at higher concentrations. Whereas, the poor drug-like properties (e...
March 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28327633/cardiac-drug-drug-interaction-between-hcv-ns5b-pronucleotide-inhibitors-and-amiodarone-is-determined-by-their-specific-diastereochemistry
#6
Armando Lagrutta, Christopher P Regan, Haoyu Zeng, John P Imredy, Kenneth Koeplinger, Pierre Morissette, Liping Liu, Gordon Wollenberg, Christopher Brynczka, José Lebrón, Joseph DeGeorge, Frederick Sannajust
Severe bradycardia/bradyarrhythmia following coadministration of the HCV-NS5B prodrug sofosbuvir with amiodarone was recently reported. Our previous preclinical in vivo experiments demonstrated that only certain HCV-NS5B prodrugs elicit bradycardia when combined with amiodarone. In this study, we evaluate the impact of HCV-NS5B prodrug phosphoramidate diastereochemistry (D-/L-alanine, R-/S-phosphoryl) in vitro and in vivo. Co-applied with amiodarone, L-ala,SP prodrugs increased beating rate and decreased beat amplitude in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), but D-ala,RP produgs, including MK-3682, did not...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28323427/kinetin-riboside-and-its-protides-activate-the-parkinson-s-disease-associated-pten-induced-putative-kinase-1-pink1-independent-of-mitochondrial-depolarisation
#7
Laura Osgerby, Yu-Chiang Lai, Peter J Thornton, Joseph Amalfitano, Cécile S Le Duff, Iqra Jabeen, Hachemi Kadri, Ageo Miccoli, James H R Tucker, Miratul M K Muqit, Youcef Mehellou
Since loss of function mutations of PINK1 lead to early-onset Parkinson's disease, there has been growing interest in the discovery of small molecules that amplify the kinase activity of PINK1. We herein report the design, synthesis, serum stability and hydrolysis of four kinetin riboside ProTides. These ProTides, along with kinetin riboside, activated PINK1 in cells independent of mitochondrial depolarization. This highlights the potential of modified nucleosides and their phosphate prodrugs as treatments for neurodegenerative diseases...
March 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28323403/discovery-of-potent-antiallodynic-agents-for-neuropathic-pain-targeting-p2x3-receptors
#8
Young-Hwan Jung, Yong-Chul Kim, Yeo Ok Kim, Hai Lin, Joong-Heui Cho, Jin-Hee Park, So-Deok Lee, Jinsu Bae, Koon Mook Kang, Yoon Gyoon Kim, Ae Nim Pae, Hyojin Ko, Chul-Seung Park, Myung Ha Yoon
Antagonism of the P2X3 receptor is one of the potential therapeutic strategies for the management of neuropathic pain because P2X3 receptors are predominantly localized on small to medium diameter C- and Aδ-fiber primary afferent neurons, which are related to the pain-sensing system. In this study, 5-hydroxy pyridine derivatives were designed, synthesized, and evaluated for their in vitro biological activities by two-electrode voltage clamp assay at hP2X3 receptors. Among the novel hP2X3 receptor antagonists, intrathecal treatment of compound 29 showed parallel efficacy with pregabalin (calcium channel modulator) and higher efficacy than AF353 (P2X3 receptor antagonist) in the evaluation of its antiallodynic effects in spinal nerve ligation rats...
March 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28320998/design-synthesis-and-biological-evaluation-of-potent-human-glyoxalase-i-inhibitors
#9
Tian Jin, Jing Zhai, Xiao Liu, Yan Yue, Maolin Huang, Zonghe Li, Caixia Ni, Qishan Deng, Yankui Sang, Zhongwei Yao, Hong Zhang, Xiaopeng Hu, Zhe-Bin Zheng
Several glutathione derivatives bearing the S-(N-aryl-N-hydroxycarbamoyl) or S-(C-aryl-N-hydroxycarbamoyl) moieties [10, 10' and 13-15] were synthesized, characterized, and their human glyoxalase I (hGLO1) inhibitory activity was evaluated. Compound 10 was proved to be the effective hGLO1 inhibitor with a Ki value of 1 nM and the inhibition effect of compound 10 on hGLO1 was nearly ten-fold higher than that of the strongest inhibitor 2 (Ki = 10 nM) which has been reported in the field of glutathione-type hGLO1 inhibitors...
March 17, 2017: Chemical & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28319647/cancer-specific-intracellular-reductive-activation-of-anticancer-pt-iv-prodrugs
#10
Andriy Mokhir, Viktor Reshetnikov, Steffen Daum
Since cellular uptake of anticancer Pt(II)- and Pt(IV)-drugs occurs via different mechanisms, the latter ones can exhibit substantial activity towards cells, which have either intrinsic or acquired resistance towards Pt(II)-drugs. However, this positive effect is diminished due to reductive activation of Pt(IV)-drugs in extracellular space that can be one of the reasons why they were not yet approved for clinical use despite over 60 clinical trials conducted worldwide. Herein we suggest a solution to this problem by achieving highly specific intracellular versus extracellular prodrug reduction...
March 20, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28317871/insights-into-molecular-therapy-of-glioma-current-challenges-and-next-generation-blueprint
#11
REVIEW
Y Rajesh, Ipsita Pal, Payel Banik, Sandipan Chakraborty, Sachin A Borkar, Goutam Dey, Ahona Mukherjee, Mahitosh Mandal
Glioma accounts for the majority of human brain tumors. With prevailing treatment regimens, the patients have poor survival rates. In spite of current development in mainstream glioma therapy, a cure for glioma appears to be out of reach. The infiltrative nature of glioma and acquired resistance substancially restrict the therapeutic options. Better elucidation of the complicated pathobiology of glioma and proteogenomic characterization might eventually open novel avenues for the design of more sophisticated and effective combination regimens...
March 20, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28317022/water-dispersible-silica-coated-upconverting-liposomes-can-a-thin-silica-layer-protect-tta-uc-against-oxygen-quenching
#12
Sven H C Askes, Vincent C Leeuwenburgh, Wim Pomp, Hadi Arjmandi-Tash, Stefania Tanase, Thomas Schmidt, Sylvestre Bonnet
Light upconversion by triplet-triplet annihilation (TTA-UC) in nanoparticles has received considerable attention for bioimaging and light activation of prodrugs. However, the mechanism of TTA-UC is inherently sensitive for quenching by molecular oxygen. A potential oxygen protection strategy is the coating of TTA-UC nanoparticles with a layer of oxygen-impermeable material. In this work, we explore if (organo)silica can fulfill this protecting role. Three synthesis routes are described for preparing water-dispersible (organo)silica-coated red-to-blue upconverting liposomes...
March 13, 2017: ACS Biomaterials Science & Engineering
https://www.readbyqxmd.com/read/28315153/effects-of-histone-deacetylase-inhibitory-prodrugs-on-epigenetic-changes-and-dna-damage-response-in-tumor-and-heart-of-glioblastoma-xenograft
#13
Nataly Tarasenko, Abraham Nudelman, Gabriela Rozic, Suzanne M Cutts, Ada Rephaeli
The histone deacetylase (HDAC) inhibitory prodrugs of butyric (AN7) and valproic (AN446) acids, which release the active acids upon metabolic degradation, were studied examining their differential effects on the viability, HDAC inhibitory activity and the DNA damage response (DDR), in glioblastoma cell and normal human astrocytes (NHAs). In xenografts of glioblastoma, AN7 or AN446 given or the combination of each of them with Dox augmented the anticancer activity of Dox and protected the heart from its toxicity...
March 17, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28314511/novel-platinum-iv-complexes-conjugated-with-a-wogonin-derivative-as-multi-targeted-anticancer-agents
#14
Xiaodong Qin, Gang Xu, Feihong Chen, Lei Fang, Shaohua Gou
Platinum-based complexes like cisplatin and oxaliplatin are well known the mainstay of chemotherapy regimens on clinic. Wogonin, a natural product that possesses wide biological activities, is now in phase I clinical test as an anticancer agent in China. Herein reported are a series of novel Pt(IV) complexes that conjugated a wogonin derivative (compound 3) to the axial position via a linker group. After being tethered to the platinum(IV) complexes, the wogonin derivative provided multiple anticancer effects, especially in compound 10, a fusion containing wogonin and cisplatin units...
March 7, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28303266/novel-hypoxia-targeting-pt-iv-prodrugs
#15
Zichen Xu, Jian Zhao, Shaohua Gou, Gang Xu
Novel Pt(iv) prodrugs targeting hypoxia inducible factor HIF-1α were prepared for evaluating their antitumor activity on hypoxic cancer cells for the first time. The resulting Pt(iv) prodrug exhibited effective inhibition on tumor growth in the HCT-116 xenograft mouse model with low toxicity in vivo.
March 17, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28302858/reversion-of-antibiotic-resistance-in-mycobacterium-tuberculosis-by-spiroisoxazoline-smart-420
#16
Nicolas Blondiaux, Martin Moune, Matthieu Desroses, Rosangela Frita, Marion Flipo, Vanessa Mathys, Karine Soetaert, Mehdi Kiass, Vincent Delorme, Kamel Djaout, Vincent Trebosc, Christian Kemmer, René Wintjens, Alexandre Wohlkönig, Rudy Antoine, Ludovic Huot, David Hot, Mireia Coscolla, Julia Feldmann, Sebastien Gagneux, Camille Locht, Priscille Brodin, Marc Gitzinger, Benoit Déprez, Nicolas Willand, Alain R Baulard
Antibiotic resistance is one of the biggest threats to human health globally. Alarmingly, multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis have now spread worldwide. Some key antituberculosis antibiotics are prodrugs, for which resistance mechanisms are mainly driven by mutations in the bacterial enzymatic pathway required for their bioactivation. We have developed drug-like molecules that activate a cryptic alternative bioactivation pathway of ethionamide in M. tuberculosis, circumventing the classic activation pathway in which resistance mutations have now been observed...
March 17, 2017: Science
https://www.readbyqxmd.com/read/28302831/countering-tb-prodrug-resistance
#17
EDITORIAL
Caroline Ash
No abstract text is available yet for this article.
March 17, 2017: Science
https://www.readbyqxmd.com/read/28302582/characterization-of-pegylated-and-non-pegylated-liposomal-formulation-for-the-delivery-of-hypoxia-activated-vinblastine-n-oxide-for-the-treatment-of-solid-tumors
#18
Vidhi M Shah, Duc X Nguyen, Adel Alfatease, Shay Bracha, Adam Wg Alani
Solid tumors often contain hypoxic regions which are resistant to standard chemotherapy and radiotherapy. We have developed a liposomal delivery system for a prodrug of vinblastine (CPD100) which converts to the parent compound only in the presence of lower oxygen levels. As a part of this work we have developed and optimized two formulations of CPD100: one composed of sphingomyelin/cholesterol (55/45; mol/mol) (CPD100Li) and the other composed of sphingomyelin/cholesterol/PEG (55/40/5; mol/mol) (CPD100 PEGLi)...
March 14, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28290486/creation-of-nano-eye-drops-and-effective-drug-delivery-to-the-interior-of-the-eye
#19
Yoshikazu Ikuta, Shigenobu Aoyagi, Yuji Tanaka, Kota Sato, Satoshi Inada, Yoshitaka Koseki, Tsunenobu Onodera, Hidetoshi Oikawa, Hitoshi Kasai
Nano eye-drops are a new type of ophthalmic treatment with increased potency and reduced side effects. Compounds in conventional eye-drops barely penetrate into the eye because the cornea, located at the surface of eye, has a strong barrier function for preventing invasion of hydrophilic or large-sized materials from the outside. In this work, we describe the utility of nano eye-drops utilising brinzolamide, a commercially available glaucoma treatment drug, as a target compound. Fabrication of the nanoparticles of brinzolamide prodrug increases the eye penetration rate and results in high drug efficacy, compared with that of commercially available brinzolamide eye-drops formulated as micro-sized structures...
March 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28289034/the-impact-of-mucositis-on-absorption-and-systemic-drug-exposure-of-isavuconazole
#20
Laura L Kovanda, Francisco M Marty, Johan Maertens, Amit V Desai, Christopher Lademacher, Marc Engelhardt, Qiaoyang Lu, William W Hope
Isavuconazonium sulfate is the water-soluble prodrug of isavuconazole. Population analyses have demonstrated relatively predictable pharmacokinetic (PK) behavior in diverse patient populations. We evaluated the impact of mucositis on the oral isavuconazole exposure using population PK modeling. METHODS: We evaluated patients treated in two phase 3 trials of isavuconazole, SECURE for treatment of invasive aspergillosis (IA) and other filamentous fungi and VITAL for patients with mucormycosis, invasive fungal disease (IFD) caused by other rare fungi, or IA and renal impairment...
March 13, 2017: Antimicrobial Agents and Chemotherapy
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