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drug substitution

Mohamed A Jalloh, Eric J Ip, Shadi Doroudgar
In 2017, Schmidt et al. conducted a Cochrane systematic review and meta-analysis to evaluate the effect of using proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to reduce low-density-lipoprotein- cholesterol (LDL-C) and cardiovascular disease (CVD). The Cochrane review was a systematic review and meta-analysis of 20 randomized, double-blinded trials that compared the use of PCSK9 inhibitors with statins/ezetimibe, ezetimibe, or placebo for a treatment duration of at least 24 weeks. The use of PCSK9 inhibitors lowered the risk for CVD (OR 0...
April 18, 2018: Expert Opinion on Pharmacotherapy
Tamer Nasr, Samir Bondock, Hassan M Rashed, Walid Fayad, Mahmoud Youns, Tamer M Sakr
The current work presents the synthesis and biological evaluation of new series of coumarin hydrazide-hydrazone derivatives that showed in vitro broad spectrum antitumor activities against resistant pancreatic carcinoma (Panc-1), hepatocellular carcinoma (HepG2) and leukemia (CCRF) cell lines using doxorubicin as reference standard. Bromocoumarin hydrazide-hydrazone derivative (BCHHD) 11b showed excellent anticancer activity against all tested cancer cell lines. Enzyme assays showed that BCHHD 11b induced apoptosis due to activation of caspases 3/7...
April 9, 2018: European Journal of Medicinal Chemistry
Minhua Peng, Crystall Marie Dawn Swarbrick, Kitti Wing-Ki Chan, Dahai Luo, Wei Zhang, Xiaoping Lai, Geng Li, Subhash G Vasudevan
We previously showed that luteolin, a well-known plant-derived component found in the "heat clearing" class of Traditional Chinese Medicine (TCM) herbs, is an uncompetitive inhibitor (Ki 58.6 μM) of the host proprotein convertase furin, an endoprotease that is required for maturation of flaviviruses in the trans-Golgi compartment. Luteolin also weakly inhibited recombinant dengue virus NS2B/NS3 protease (Ki 140.36 μM) non-competitively. In order to further explore the mechanism of inhibition we isolated resistant mutants by continuous passaging of DENV2 in the presence of increasing concentrations of luteolin...
April 14, 2018: Antiviral Research
Hui Zhang, Xujun Qiu, Liqiong Lv, Wenyu Sun, Chaoyue Wang, Jizhong Yan, Shengqiang Tong
Recycling countercurrent chromatography was successfully applied to resolution of 2-(4-bromomethylphenyl)propionic acid, a key synthetic intermediate for synthesis of nonsteroidal anti-inflammatory drug loxoprofen, using hydroxypropyl-β-cyclodextrin as chiral selector. The two-phase solvent system composed of n-hexane/n-butyl acetate/0.1 mol L-1 citrate buffer solution with pH = 2.4 (8:2:10, v/v/v) was selected. Influence factors for the enantioseparation were optimized, including type of substituted β-cyclodextrin, concentration of hydroxypropyl-β-cyclodextrin, separation temperature and pH of aqueous phase...
April 17, 2018: Journal of Separation Science
Prayasee Baruah, Grace Basumatary, Semen O Yesylevskyy, Kripamoy Aguan, Ghanashyam Bez, Sivaprasad Mitra
The inhibitory efficacy of two substituted coumarin derivatives on the activity of neurodegenerative enzyme acetylcholinesterase (AChE) was assessed in aqueous buffer as well as in the presence of human serum albumin (HSA) and compared against standard cholinergic AD drug, Donepezil (DON). The experimental data revealed the inhibition to be of non-competitive type with both the systems showing substantial inhibitory activity on AChE. In fact, one of the tested compounds Chromenyl Coumarate (CC) was found to be better inhibitor (IC50 = 48...
April 17, 2018: Journal of Biomolecular Structure & Dynamics
Prateek Pathak, Parjanya Kumar Shukla, Vikas Kumar, Ankit Kumar, Amita Verma
A series of quinazoline clubbed 1,3,5-triazine derivatives (QCT) were synthesized and evaluated for their in vitro anticancer activity against HeLa (human cervical cancer), MCF-7 (human breast cancer cell), HL-60 (human promyelocytic leukemia cell), HepG2 (human Hepatocellular carcinoma cell), and one normal cell line HFF (human foreskin fibroblasts). In vitro assay result encouraged to further move towards in ovo anticancer evaluation using chick embryo. The series of QCT derivatives showed higher anticancer and antiangiogenic activity against HeLa and MCF-7 cell lines...
April 16, 2018: Inflammopharmacology
Yingjun Liu, Henry Pertinez, Geraint R Davies, Stephen H Gillespie, Anthony R Coates, Yanmin Hu
Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a leading killer worldwide, and disease control is hampered by ineffective control of persistent infections. Substitution of moxifloxacin for isoniazid or ethambutol in standard TB regimens reduces treatment duration and relapse rates in animal studies and four-month regimens were not non-inferior in clinical trials. Resuscitation promoting factor (RPF) dependent bacilli have recently been implicated in M. tuberculosis persistence. We aimed to investigate the therapeutic effects of moxifloxacin substitution in the standard drug regimen for eradicating colony forming count (CFU) positive and RPF-dependent persistent M...
April 16, 2018: Antimicrobial Agents and Chemotherapy
Elibeth Mirasol-Meléndez, Luis G Brieba-de Castro, Corina Díaz-Quezada, Marisol López-Hidalgo, Elisa E Figueroa-Angulo, Leticia Ávila-González, Rossana Arroyo-Verástegui, Claudia G Benítez-Cardoza
Trichomonas vaginalis is the protist parasite that causes the most common, non-viral sexually transmitted infection called trichomonosis. Enolase is a moonlighting protein that apart from its canonical function as a glycolytic enzyme, serves as a plasminogen receptor on the cell surface of T. vaginalis and, in consequence, it has been stablished as a virulence factor in this parasite. In the Trichomonas vaginalis sequence database there are nine genes annotated as enolase. In this work, we analyzed these genes as well as their products...
April 13, 2018: Parasitology International
Anthony Cousien, Viet Chi Tran, Sylvie Deuffic-Burban, Marie Jauffret-Roustide, Guillaume Mabileau, Jean-Stéphane Dhersin, Yazdan Yazdanpanah
Direct-acting antivirals (DAAs) represent an opportunity to improve hepatitis C virus (HCV) care cascade. This, combined with improved harm reduction interventions may lead to HCV elimination especially in people who inject drugs (PWID). We assessed the effectiveness/cost-effectiveness of improvements in harm reduction and chronic hepatitis C (CHC) care cascade in PWID in France. We used a dynamic model of HCV transmission and CHC natural history and evaluated: improved needle/syringe programs-opioid substitution therapies, faster diagnosis/linkage to care, earlier treatment initiation, alone and in combination among active PWID (mean age=36)...
April 16, 2018: Journal of Viral Hepatitis
Dorleta Gonzalez, Raquel L Arribas, Lucia Viejo, Rocio Lajarin-Cuesta, Cristobal de Los Rios
Following the premises of the multitarget-directed ligands approach for the drug R&D against neurodegenerative diseases, where Alzheimer's disease (AD) outstands, we have synthesized and evaluated analogues of the gramine derivative ITH12657 (1-benzyl-5-methyl-3-(piperidin-1-ylmethyl-1H-indole, 2), which had shown important neuroprotective properties, such as blocking effect of voltage-gated Ca2+ channels (VGCC), and prevention of phosphoprotein phosphatase 2A (PP2A) inhibition. The new analogues present different substitutions at the pending phenyl ring, what slightly modified their pharmacological characteristics...
April 9, 2018: Bioorganic & Medicinal Chemistry
Gagandeep Singh, Gurjit Singh, Rajbir Bhatti, Mehak Gupta, Ajay Kumar, Ankita Sharma, Mohan Paul Singh Ishar
A library of indolyl-isoxazolidines (6-9) has been synthesized by regio- and stereoselective microwave irradiated 1,3-dipolar cycloadditions of C-(3-indolyl)-N-phenylnitrone (2') with variedly substituted dipolarophiles (3'-5') and screened for their anti-inflammatory activities through inhibition of pro-inflammatory cytokines such as TNF-α and IL-6. Amongst the evaluated compounds (6-9), bicyclic isoxazolidine (9a) was found to exhibit significant inhibitory potential against LPS induced human IL-6 and TNF-α in THP-1 cells...
April 3, 2018: European Journal of Medicinal Chemistry
Christopher John Moody, Steven Wales, Elena Merisor, Holly Adcock, Christopher Pearce, Ian Strutt, William Lewis, Daniel Hamza
A series of highly substituted tetrahydrofurans (THFs), decorated with modifiable 2-aryl, 3-carboxy and 4-amino substituents, has been prepared for biological evaluation within the European Lead Factory. Diastereoselective reductive amination of pre-functionalised 4-oxofurans, readily prepared from cinnamate esters via oxa-Michael/Dieckmann annulation, provided the requisite THF cores on gram scale with three contiguous stereocentres, including full substitution at C-3. In a second series, a pyrrolidine ring was fused to the same oxofuran scaffold via an intramolecular reductive amination, inverting the configuration at C-4 relative to the other ring substituents...
April 14, 2018: Chemistry: a European Journal
Rachael Bonawitz, Alana T Brennan, Lawrence Long, Timothy Heeren, Mhairi Maskew, Ian Sanne, Matthew P Fox
INTRODUCTION: In April 2010 tenofovir and abacavir replaced stavudine in public-sector first-line antiretroviral therapy (ART) for children under 20 years old in South Africa. The association of both abacavir and tenofovir with fewer side-effects and toxicities compared to stavudine could translate to increased durability of tenofovir or abacavir-based regimens. We evaluated changes over time in regimen durability for pediatric patients 3 to 19 years of age at 8 public sector clinics in Johannesburg, South Africa...
April 15, 2018: Tropical Medicine & International Health: TM & IH
Saravanan Parthasarathy, Kenneth Henry, Huaxing Pei, Josh Clayton, Mark Rempala, Deidre Johns, Oscar De Frutos, Pablo Garcia, Carlos Mateos, Sehila Pleite, Yong Wang, Stephanie Stout, Bradley Condon, Sheela Ashok, Zhohai Lu, William Ehlhardt, Tom Raub, Mei Lai, Sandaruwan Geeganage, Timothy P Burkholder
During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK2 . A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties...
April 2, 2018: Bioorganic & Medicinal Chemistry Letters
Bryan Williams, Thomas M MacDonald, Steve V Morant, David J Webb, Peter Sever, Gordon T McInnes, Ian Ford, J Kennedy Cruickshank, Mark J Caulfield, Sandosh Padmanabhan, Isla S Mackenzie, Jackie Salsbury, Morris J Brown
BACKGROUND: In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension. METHODS: PATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25-50 mg, bisoprolol 5-10 mg, and doxazosin 4-8 mg and the change in home systolic blood pressure was assessed as the primary outcome...
April 11, 2018: Lancet Diabetes & Endocrinology
Sujeet Kumar Gupta, Pratik Khanal, Arun Kumar, Arun Kumar, Neha Srivastava, Bhumika Yogi, Anshuman Sinha
BACKGROUND: Recently, pyrazole derivatives have shown significant anti-inflammatory activity. Non-steroidal anti-inflammatory drugs have the drawbacks of such as gastric irritation and gastric ulceration in treatment of inflammation. So the current study deals with the synthesis and pharmacological evaluation of a series of novel pyrazole derivatives as anti-inflammatory agents. METHODS: A series of novel ethyl 5-(substituted)-1H-pyrazole-3-carboxylate (2a-j) were synthesized and evaluated for anti-inflammatory activity using carrageenan-induced inflammation in rat paw edema model...
April 11, 2018: Anti-inflammatory & Anti-allergy Agents in Medicinal Chemistry
Khaled El-Adl, Abdel-Ghany A El-Helby, Rezk R A Ayyad, Helmy Sakr, Mamdouh M Ali, Fathalla Khedr
In view of their expected anticancer activity, novel triazolo[3,4-a]phthalazine derivatives 5-6a-o and 3-substituted-bis([1,2,4]triazolo)[3,4-a:4',3'-c]phthalazines 9a-b were designed, synthesized and evaluated for their anti-proliferative activity against two human tumor cell lines HCT-116 human colon adenocarcinoma and MCF-7 breast cancer. It was found that, compound 6o the most potent derivative against both HCT116 and MCF-7 cancer cell lines. Compounds 6o, 6m, 6d and 9b showed the highest anticancer activities against HCT116 human colon adenocarcinoma with IC50 of 7±0...
April 12, 2018: Anti-cancer Agents in Medicinal Chemistry
Feng Chen, Joan J Soldevila-Barreda, Isolda Romero-Canelón, James P C Coverdale, Ji-Inn Song, Guy J Clarkson, Jana Kasparkova, Abraha Habtemariam, Viktor Brabec, Juliusz A Wolny, Volker Schünemann, Peter J Sadler
A series of neutral pseudo-octahedral RuII sulfonamidoethylenediamine complexes [(η6-p-cym)Ru(N,N')Cl] where N,N' is N-(2-(R1,R2-amino)ethyl)-4-toluenesulfonamide (TsEn(R1,R2)) R1,R2 = Me,H (1); Me,Me (2); Et,H (3); benzyl,H (Bz, 4); 4-fluorobenzyl,H (4-F-Bz, 5) or naphthalen-2-ylmethyl,H (Naph, 6), were synthesised and characterised including the X-ray crystal structure of 3. These complexes catalyse the reduction of NAD+ regioselectively to 1,4-NADH by using formate as the hydride source. The catalytic efficiency depends markedly on the steric and electronic effects of the N-substitutent, with turnover frequencies (TOFs) increasing in the order: 1 < 2 < 3, 6 < 4, 5, achieving a TOF of 7...
April 13, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
Amine Ourahmane, Anne Sauer, Daniel E Nixon, Christine Murphy, Melissa Mondello, Erin Douglass, Stephanie Siegmund, Jian Ben Wang, Michael A McVoy
Herpesvirus DNA packaging is an essential step in virion morphogenesis and an important target for antiviral development. The halogenated benzimidazole 2-bromo-5,6-dichloro-1-β-d-ribofuranosyl-1H-benzimidazole (BDCRB) was the first compound found to selectively disrupt DNA packaging. It has activity against human cytomegalovirus as well as guinea pig cytomegalovirus. The latter provides a useful small animal model for congenital cytomegalovirus infection. To better understand the mechanism by which BDCRB acts, a guinea pig cytomegalovirus resistant to BDCRB was derived and characterized...
April 9, 2018: Antiviral Research
Douglas Sheridan, Zhao-Xue Yu, Yuchun Zhang, Rekha Patel, Fang Sun, Melissa A Lasaro, Keith Bouchard, Bruce Andrien, Andre Marozsan, Yi Wang, Paul Tamburini
Eculizumab, a monoclonal antibody (mAb) directed against complement protein C5, is considered to be the current standard of care for patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome. This study describes the generation and preclinical attributes of ALXN1210, a new long-acting anti-C5 mAb, obtained through select modifications to eculizumab to both largely abolish target-mediated drug disposition (TMDD) and increase recycling efficiency via the neonatal Fc receptor (FcRn)...
2018: PloS One
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