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https://www.readbyqxmd.com/read/28944496/the-unidirectional-hypoxia-activated-prodrug-oct1002-inhibits-growth-and-vascular-development-in-castrate-resistant-prostate-tumors
#1
Heather Nesbitt, Jenny Worthington, Rachel J Errington, Laurence H Patterson, Paul J Smith, Stephanie R McKeown, Declan J McKenna
BACKGROUND: OCT1002 is a unidirectional hypoxia-activated prodrug (uHAP) OCT1002 that can target hypoxic tumor cells. Hypoxia is a common feature in prostate tumors and is known to drive disease progression and metastasis. It is, therefore, a rational therapeutic strategy to directly target hypoxic tumor cells in an attempt to improve treatment for this disease. Here we tested OCT1002 alone and in combination with standard-of-care agents in hypoxic models of castrate-resistant prostate cancer (CRPC)...
September 24, 2017: Prostate
https://www.readbyqxmd.com/read/28944416/regulating-the-alky-chain-length-of-fatty-acid-didanosine-prodrugs-and-evaluating-its-role-in-albumin-binding
#2
Hongxiang Chen, Gang Wang, Lanzhen Sun, Huicong Zhang, Mengchi Sun, Jin Sun, Lei Shang, Cong Luo
Rational design of prodrugs for efficient albumin binding shows distinct advantages in drug delivery in terms of drug availability, systemic circulation, and potential targeting effect. And fatty acids are good candidates due to their high affinity to albumin. However, how the alkyl chain length of fatty acids affects the binding dynamics between prodrugs and albumin, despite its importance, is still unclear. In the present study, three prodrugs of didanosine (DDI) and fatty acids were designed and synthesized to evaluate the effect of the alkyl chain length on prodrug-albumin binding process, including capric acid-didanosine (CA-DDI), myristic acid-didanosine (MA-DDI), and stearic acid-didanosine (SA-DDI)...
September 24, 2017: Drug Delivery and Translational Research
https://www.readbyqxmd.com/read/28943956/hbv-suppresses-thapsigargin-induced-apoptosis-via-inhibiting-chop-expression-in-hepatocellular-carcinoma-cells
#3
Danqi Zhao, Yan Liu, Xing Liu, Tao Li, Zhenhui Xin, Xilin Zhu, Xiaopan Wu, Ying Liu
Hepatocellular carcinoma (HCC) accounts for a proportion of cancer-associated mortalities worldwide. Hepatitis B virus (HBV) infection is a major cause of HCC in China. Thapsigargin (TG) is a potential antitumor prodrug, eliciting endoplasmic reticulum (ER) stress via the inhibition of the ER calcium pump, effectively inducing apoptosis. The present study therefore examined the role of HBV in TG-induced apoptosis using two HCC cell lines, HBV positive HepG2.2.15 and HBV negative HepG2. When these two cell lines were treated with TG, HepG2...
October 2017: Oncology Letters
https://www.readbyqxmd.com/read/28943195/diels-alder-mediated-release-of-gemcitabine-from-hybrid-nanoparticles-for-enhanced-pancreatic-cancer-therapy
#4
Adeolu Oluwasanmi, Wejdan Al-Shakarchi, Ayesha Manzur, Mohammed H Aldebasi, Rayan S Elsini, Malek K Albusair, Katherine J Haxton, Anthony D M Curtis, Clare Hoskins
Hybrid nanoparticles (HNPs) have shown huge potential as drug delivery vehicles for pancreatic cancer. Currently, the first line treatment, gemcitabine, is only effective in 23.8% of patients. To improve this, a thermally activated system was developed by introducing a linker between HNPs and gemcitabine. Whereby, heat generation resulting from laser irradiation of the HNPs promoted linker breakdown resulting in prodrug liberation. In vitro evaluation in pancreatic adenocarcinoma cells, showed the prodrug was 4...
September 21, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28940980/sulfocoumarin-coumarin-4-sulfamoylphenyl-bearing-indazole-3-carboxamide-hybrids-synthesis-and-selective-inhibition-of-tumor-associated-carbonic-anhydrase-isozymes-ix-and-xii
#5
Srinivas Angapelly, P V Sri Ramya, Andrea Angeli, Claudiu T Supuran, Mohammed Arifuddin
A series of sulfocoumarin-, coumarin-, and 4-sulfamoylphenyl-bearing indazole-3-carboxamide hybrids were synthesized and investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms I and II (cytosolic isozymes), as well as hCA IX and XII (transmembrane, tumor-associated enzymes). Compounds 6 a-g (amide derivatives) and 7 a-h (triazoles) act as "prodrugs", and their hydrolysis products are the de facto CA inhibitors. These compounds displayed sub-micromolar to high-nanomolar inhibitory activity against hCA isoforms IX and XII, which were recently validated as antitumor drug targets...
September 2, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28940404/a-rapid-and-simple-hptlc-assay-for-therapeutic-drug-monitoring-of-capecitabine-in-colorectal-cancer-patients
#6
Sonali G Thorat, Rupesh V Chikhale, Madhukar R Tajne
Capecitabine is a prodrug of 5-flurouracil, employed as a broad spectrum chemotherapeutic agents. It is also used as monotherapy or a combination chemotherapy agent for treatment of colorectal cancer. Capecitabine is administered in combination with oxaliplatin and hence it becomes essential to determine that co-administration does not affect its metabolism. To determine the plasma concentration of capecitabine a simple HPTLC method was developed and validated. Blood samples from 12 patients with colorectal cancer were collected and analysed by the HPTLC method with a reference internal standard...
September 22, 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/28940154/elsulfavirine-first-global-approval
#7
Zaina T Al-Salama
Elsulfavirine (Elpida(®)) is a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) being developed by Viriom for the treatment and prevention of human immunodeficiency virus (HIV) infections. It is the prodrug of the active compound VM-1500A, a small molecule selective NNRTI, which prevents HIV replication. In June 2017, elsulfavirine received its first global approval in Russia for the treatment of HIV-1 infections in combination with other antiretroviral medicines. Other formulations of this drug are also being evaluated in preclinical and phase II studies for the treatment of HIV infections and/or pre-exposure and post-exposure prophylaxis...
September 23, 2017: Drugs
https://www.readbyqxmd.com/read/28937592/spatiotemporal-control-of-doxorubicin-delivery-from-stealth-like-prodrug-micelles
#8
Li Kong, Dimitrios Poulcharidis, Gregory F Schneider, Frederick Campbell, Alexander Kros
In the treatment of cancer, targeting of anticancer drugs to the tumor microenvironment is highly desirable. Not only does this imply accurate tumor targeting but also minimal drug release en route to the tumor and maximal drug release once there. Here we describe high-loading, "stealth-like" doxorubicin micelles as a pro-drug delivery system, which upon light activation, leads to burst-like doxorbicin release. Through this approach, we show precise spatiotemporal control of doxorubicin delivery to cells in vitro...
September 22, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28936175/pharmacokinetics-and-pharmacodynamics-of-lisdexamfetamine-compared-with-d-amphetamine-in-healthy-subjects
#9
Patrick C Dolder, Petra Strajhar, Patrick Vizeli, Felix Hammann, Alex Odermatt, Matthias E Liechti
Rationale: Lisdexamfetamine is a prodrug of D-amphetamine used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Lisdexamfetamine is thought to have a prolonged pharmacokinetic profile compared with oral D-amphetamine, possibly associated with lower drug liking and a lower risk of oral misuse. However, differences in the pharmacokinetics and pharmacodynamics of lisdexamfetamine and D-amphetamine have not been directly compared. Methods: Equimolar doses of D-amphetamine (40 mg) and lisdexamfetamine (100 mg), and placebo were administered in 24 healthy subjects in a randomized, double-blind, placebo-controlled, cross-over study...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28935141/antioxidative-peptide-from-milk-exhibits-antiosteopenic-effects-through-inhibition-of-oxidative-damage-and-bone-resorbing-cytokines-in-ovariectomized-rats
#10
Sanusi Bello Mada, Srinu Reddi, Naveen Kumar, Rohit Kumar, Suman Kapila, Rajeev Kapila, Ritu Trivedi, Anirudha Karvande, Naseer Ahmad
OBJECTIVES: Oxidative stress has been implicated as a crucial pathogenic factor in the development of postmenopausal osteoporosis. Milk-derived antioxidative peptides are gaining much attention toward the development of prodrugs for alleviating several human diseases, including osteoporosis. The aim of the present study was to determine whether antioxidant peptides are good candidates for alleviating postmenopausal osteoporosis. METHODS: In the present study, an ovariectomized (OVX) osteoporotic rat model was used to investigate the protective effects of buffalo milk casein-derived novel peptide VLPVPQK (PEP) against OVX-induced bone loss and the related mechanisms...
November 2017: Nutrition
https://www.readbyqxmd.com/read/28933502/synthesis-and-evaluation-of-new-5-aminolevulinic-acid-derivatives-as-prodrugs-of-protoporphyrin-for-photodynamic-therapy
#11
Wei Zhu, Ying-Hua Gao, Chun-Hong Song, Zhi-Bin Lu, Tabbisa Namulinda, Yi-Ping Han, Yi-Jia Yan, Lai-Xing Wang, Zhi-Long Chen
Protoporphyrin IX (PpIX) is used as a photosensitizer in the photodynamic diagnosis (PDD) and photodynamic therapy (PDT) of cancer and is synthesized intracellularly from 5-aminolevulinic acid (5-ALA) precursors. Thirteen novel 5-ALA derivatives were designed and synthesized appropriately with tailored hydrophilicity and lipophilicity. The generation of PpIX was detected and their antitumor activity in vitro and in vivo was also investigated. It was shown that compounds 9b-c, 11b-c and 13a displayed a characteristic long wavelength absorption peak at 593 nm after 5 h incubation in mice fibrosarcoma S180 cells...
September 21, 2017: Photochemical & Photobiological Sciences
https://www.readbyqxmd.com/read/28927276/alkoxycarbonate-ester-prodrugs-of-preclinical-drug-candidate-elq-300-for-prophylaxis-and-treatment-of-malaria
#12
Lisa Frueh, Yuexin Li, Michael Mather, Qigui Li, Sovitj Pou, Aaron Nilsen, Rolf W Winter, Isaac Forquer, April Pershing, Lisa H Xie, Martin J Smilkstein, Diana Caridha, Robert F Campbell, Richard J Sciotti, Mara Kreishman-Deitrick, Jane X Kelly, Brian Andrew Vesely, Akhil Vaidya, Michael K Riscoe
ELQ-300 is a preclinical antimalarial drug candidate that is active against liver, blood, and transmission stages of Plasmodium falciparum. While ELQ-300 is highly effective when administered in a low multi-dose regimen, poor aqueous solubility and high crystallinity have hindered its clinical development. To overcome its challenging physiochemical properties, a number of bioreversible alkoxycarbonate ester prodrugs of ELQ-300 were synthesized. These bioreversible prodrugs are converted to ELQ-300 by host and parasite esterase action in the liver and bloodstream of the host...
September 19, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28923872/exposure-response-relationships-for-isavuconazole-in-patients-with-invasive-aspergillosis-and-other-filamentous-fungi
#13
Amit V Desai, Laura L Kovanda, William W Hope, David Andes, Johan W Mouton, Donna L Kowalski, Robert W Townsend, Salim Mujais, Peter L Bonate
Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and other filamentous fungi from the SECURE trial. Two hundred and thirty one patients who received the clinical dosing regimen and had exposure parameters were included in this analysis...
September 18, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28922598/proteolytic-unlocking-of-ultrastable-twin-acylhydrazone-linkers-for-lysosomal-acid-triggered-release-of-anticancer-drugs
#14
Yiwu Zheng, Jing Ren, Yaqi Wu, Xiaoting Meng, Yibing Zhao, Chuanliu Wu
Targeted prodrugs exploiting cleavable linkers capable of responding to endogenous stimuli have increasingly been explored for cancer therapy. Successful application of these prodrug designs relies on the manipulation of both stability and responsiveness of the cleavable linkers, which, however, are difficult to be finely regulated, particularly for acid-responsive acylhydrazone bonds. Here we developed a new class of peptide-bridged twin-acylhydrazone linkers (PTA linkers) displaying both an ultrahigh stability and a rapid responsiveness-highly stable in neutral and acidic conditions due to the effect of cooperativity between the two acylhydrazone bonds, easily cleavable in acidic conditions after enzymatically triggered unlocking of the two bonds...
September 22, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28922021/pharmacokinetic-drug-evaluation-of-ezetimibe-simvastatin-for-the-treatment-of-hypercholesterolemia
#15
Marilisa Bove, Federica Fogacci, Arrigo Cicero
-Introduction: Cholesterol lowering treatment is mainly based on statins eventually associated to adjunctive drugs of different class such as ezetimibe. In the present review, we analysed the pharmacokinetics, efficacy and safety of ezetimibe+simvastatin drug association. -Areas covered: The bio-equivalence of ezetimibe and simvastatin when co-administrated in separate tablets or combined in a single pill is well documented. Ezetimibe is absorbed in small intestine, reaching peak plasma concentrations in 4-12 hours, with a plasma half-life of 22 hours...
September 18, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28921911/update-of-antitubercular-prodrugs-in-a-molecular-perspective-mechanisms-of-action-bioactivation-pathways-and-associated-resistances
#16
Vania Bernardes Genisson, Julie Laborde, Céline Deraeve
The place of prodrugs in the current antitubercular therapeutic arsenal is preponderant, since two of the four first-line antitubercular agents, isoniazid (INH) and pyrazinamide (PZA), need to be activated by Mycobacterium tuberculosis before exerting their activity. In addition, six other prodrugs can be found in the second- and third-line therapeutic regimens, namely ethionamide (ETH), prothionamide (PTH), p-aminosalicylic acid (PAS), thiacetazone (TAC), isoxyl (ISO) and the recently approved delamanid. The emergence of mycobacterial strains resistant to one or several antitubercular agents is one of the main issues of the antitubercular therapy...
September 16, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28920426/methotrexate-camptothecin-prodrug-nanoassemblies-as-a-versatile-nanoplatform-for-biomodal-imaging-guided-self-active-targeted-and-synergistic-chemotherapy
#17
Yang Li, Jinyan Lin, Jinyuan Ma, Liang Song, Huirong Lin, Bowen Tang, Dengyue Chen, Guanghao Su, Shefang Ye, Xuan Zhu, Fang-Hong Luo, Zhenqing Hou
"All-in-one" carrier-free-based nano-multi-drug self-delivery system could combine triple advantages of small molecules, nanoscale characteristics, and synergistic combination therapy together. Researches have showed that dual-acting small molecular methotrexate (MTX) could target and kill the folate receptors-overexpressing cancer cells. Inspired by this mechanism, a novel collaborative "early-phase tumor-selective targeting and late-phase synergistic anticancer" approach was developed for the self-assembly of chemotherapeutic drug-drug conjugate, which showed various advantages of more simplicity, efficiency, and flexibility over the conventional approach that was only based on single or combination cancer chemotherapy...
September 18, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28919713/layer-by-layer-nanoparticles-co-loading-gemcitabine-and-platinum-iv-prodrugs-for-synergistic-combination-therapy-of-lung-cancer
#18
Rongrong Zhang, Yun Ru, Yiping Gao, Jinyin Li, Shilong Mao
PURPOSE: Cisplatin plus gemcitabine (GEM) is a standard regimen for the first-line treatment of advanced non-small cell lung cancer. The aim of this study was to prepare biocompatible and biodegradable polymeric prodrugs and construct nanoparticles (NPs) with layer-by-layer (LbL) technique. METHODS: Platinum (Pt) (IV) complex with a carboxyl group was conjugated to the amino group of chitosan (CH), resulting in a CH-Pt conjugation with positive charge. GEM with amino group was conjugated to the carboxyl group of hyaluronic acid (HA), resulting in a HA-GEM conjugation with negative charge...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28919026/a-novel-fap%C3%AE-based-z-gly-pro-epirubicin-prodrug-for-improving-tumor-targeting-chemotherapy
#19
Jun Wang, Qiuwen Li, Xiaojuan Li, Weiqi Yuan, Sichao Huang, Shaohui Cai, Jun Xu
Fibroblast activation protein-α (FAPα) is a serine protease of the post-prolyl peptidase family that is specifically expressed in the majority of human epithelial tumors, but not in normal tissues. In this study, we demonstrated the anti-tumor activity of a novel targeting drug formed by conjugating epirubicin (EPI) with an FAPα-specific dipeptide (Z-Gly-Pro) and named it Z-GP-EPI. Consistent with this tumor-targeting delivery strategy, the results illustrated that Z-GP-EPI could release EPI efficiently after incubating with FAPα and could exhibit similar antitumor effects as EPI in vitro in FAPα over-expressed tumor cells (4T1/FAPα(+))...
September 14, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28916498/antibody-directed-enzyme-prodrug-therapy-adept-trials-and-tribulations
#20
Surinder K Sharma, Kenneth D Bagshawe
Antibody directed enzyme prodrug therapy has the potential to be an effective therapy for most common solid cancers. Clinical studies with CPG2 system have shown the feasibility of this approach. The key limitation has been immunogenicity of the enzyme. Technologies now exist to eliminate this problem. Non-immunogenic enzymes in combination with prodrugs that generate potent cytotoxic drugs can provide a powerful approach to cancer therapy. ADEPT has the potential to be non -toxic to normal tissue and can therefore be combined with other modalities including immunotherapy for greater clinical benefit...
September 12, 2017: Advanced Drug Delivery Reviews
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