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Khushbu Shah, Xin Lin, Sherry F Queener, Vivian Cody, Jim Pace, Aleem Gangjee
To combine the potency of trimetrexate (TMQ) or piritrexim (PTX) with the species selectivity of trimethoprim (TMP), target based design was carried out with the X-ray crystal structure of human dihydrofolate reductase (hDHFR) and the homology model of Pneumocystis jirovecii DHFR (pjDHFR). Using variation of amino acids such as Met33/Phe31 (in pjDHFR/hDHFR) that affect the binding of inhibitors due to their distinct positive or negative steric effect at the active binding site of the inhibitor, we designed a series of substituted-pyrrolo[2,3-d]pyrimidines...
April 17, 2018: Bioorganic & Medicinal Chemistry
Dong-Mei Wu, Yong-Jian Wang, Shao-Hua Fan, Juan Zhuang, Zi-Feng Zhang, Qun Shan, Xin-Rui Han, Xin Wen, Meng-Qiu Li, Bin Hu, Chun-Hui Sun, Ya-Xing Bao, Hai-Juan Xiao, Lin Yang, Jun Lu, Yuan-Lin Zheng
This network meta-analysis compared the short-term and long-term efficacies of first-line chemotherapy regimens in patients with advanced colorectal cancer (CRC). The 10 regimens included folinic acid + 5-fluorouracil + oxaliplatin (FOLFOX), folinic acid + 5-fluorouracil + irinotecan (FOLFIRI), folinic acid + 5-fluorouracil + gemcitabine (FFG), folinic acid + 5-fluorouracil + trimetrexate (FFT), folinic acid + 5-fluorouracil (FF), irinotecan + oxaliplatin (IROX), raltitrexed + oxaliplatin (TOMOX), folinic acid + tegafur-uracil (FTU), raltitrexed, and capecitabine...
November 21, 2017: Oncotarget
Yu-Shan Huang, Jen-Jia Yang, Nan-Yao Lee, Guan-Jhou Chen, Wen-Chien Ko, Hsin-Yun Sun, Chien-Ching Hung
Pneumocystis pneumonia is a potentially life-threatening pulmonary infection that occurs in immunocompromised individuals and HIV-infected patients with a low CD4 cell count. Trimethoprim-sulfamethoxazole has been used as the first-line agent for treatment, but mutations within dihydropteroate synthase gene render potential resistance to sulfamide. Despite advances of combination antiretroviral therapy (cART), Pneumocystis pneumonia continues to occur in HIV-infected patients with late presentation for cART or virological and immunological failure after receiving cART...
September 2017: Expert Review of Anti-infective Therapy
Claudia Maria Hattinger, Elisa Tavanti, Marilù Fanelli, Serena Vella, Piero Picci, Massimo Serra
Antifolates are structural analogs of folates, which have been used as antitumor drugs for more than 60 years. The antifolate drug most commonly used for treating human tumors is methotrexate (MTX), which is utilized widely in first-line treatment protocols of high-grade osteosarcoma (HGOS). In addition to MTX, two other antifolates, trimetrexate and pemetrexed, have been tested in clinical settings for second-line treatment of recurrent HGOS with patients unfortunately showing modest activity. Areas covered: There is clinical evidence which suggsest that, like other chemotherapeutic agents, not all HGOS patients are equally responsive to antifolates and do not have the same susceptibility to experience adverse drug-related toxicities...
March 2017: Expert Opinion on Drug Metabolism & Toxicology
Marc W Gibson, Simon Dewar, Han B Ong, Natasha Sienkiewicz, Alan H Fairlamb
Bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) is a chemically and genetically validated target in African trypanosomes, causative agents of sleeping sickness in humans and nagana in cattle. Here we report the kinetic properties and sensitivity of recombinant enzyme to a range of lipophilic and classical antifolate drugs. The purified recombinant enzyme, expressed as a fusion protein with elongation factor Ts (Tsf) in ThyA- Escherichia coli, retains DHFR activity, but lacks any TS activity...
May 2016: PLoS Neglected Tropical Diseases
Yu-Shan Cheng, James C Sacchettini
Mycobacterium tuberculosis (Mtb) Rv2671 is annotated as a 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione 5'-phosphate (AROPP) reductase (RibD) in the riboflavin biosynthetic pathway. Recently, a strain of Mtb with a mutation in the 5' untranslated region of Rv2671, which resulted in its overexpression, was found to be resistant to dihydrofolate reductase (DHFR) inhibitors including the anti-Mtb drug para-aminosalicylic acid (PAS). In this study, a biochemical analysis of Rv2671 showed that it was able to catalyze the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), which explained why the overexpression of Rv2671 was sufficient to confer PAS resistance...
February 23, 2016: Biochemistry
Qiong Zhang, Thao Nguyen, Megan McMichael, Sadanandan E Velu, Jing Zou, Xuedong Zhou, Hui Wu
Streptococcus mutans is a major aetiological agent of dental caries. Formation of biofilms is a key virulence factor of S. mutans. Drugs that inhibit S. mutans biofilms may have therapeutic potential. Dihydrofolate reductase (DHFR) plays a critical role in regulating the metabolism of folate. DHFR inhibitors are thus potent drugs and have been explored as anticancer and antimicrobial agents. In this study, a library of analogues based on a DHFR inhibitor, trimetrexate (TMQ), an FDA-approved drug, was screened and three new analogues that selectively inhibited S...
August 2015: International Journal of Antimicrobial Agents
J W van der Heijden, Y G Assaraf, A H Gerards, R Oerlemans, W F Lems, R J Scheper, B A C Dijkmans, G Jansen
OBJECTIVES: Although methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis (RA), patients experience clinical resistance to MTX upon prolonged treatment. We explored whether new-generation antifolates elicit superior anti-inflammatory properties when compared to MTX, based on their capacity to inhibit tumour necrosis factor (TNF)-α production. METHOD: T cells in whole blood from 18 RA patients (including MTX-naïve, MTX- responsive, and MTX non-responsive patients) and seven healthy volunteers were stimulated with αCD3/αCD28 antibodies and incubated ex vivo for 72 h with MTX and eight novel antifolate drugs with potentially favourable biochemical and pharmacological properties...
2014: Scandinavian Journal of Rheumatology
Menghang Xia, Ruili Huang, Srilatha Sakamuru, David Alcorta, Ming-Hsuang Cho, Dae-Hee Lee, Deric M Park, Michael J Kelley, Josh Sommer, Christopher P Austin
Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by radiotherapy, although postoperative complications remain significant. Recurrence of the disease occurs frequently due to the anatomy of the tumor location and violation of the tumor margins at the initial surgery. Currently, there are no effective drugs available for patients with chordoma. Due to the rarity of the disease, there is limited opportunity to test agents in clinical trials and no concerted effort to develop agents for chordoma in the pharmaceutical industry...
July 2013: Cancer Biology & Therapy
Osvaldo A Santos-Filho, Delphine Forge, Lucas V B Hoelz, Guilherme B L de Freitas, Thiago O Marinho, Jocley Q Araújo, Magaly G Albuquerque, Ricardo B de Alencastro, Nubia Boechat
Pneumocystis carinii is typically a non-pathogenic fungus found in the respiratory tract of healthy humans. However, it may cause P. carinii pneumonia (PCP) in people with immune deficiency, affecting mainly premature babies, cancer patients and transplant recipients, and people with acquired immunodeficiency syndrome (AIDS). In the latter group, PCP occurs in approximately 80% of patients, a major cause of death. Currently, there are many available therapies to treat PCP patients, including P. carinii dihydrofolate reductase (PcDHFR) inhibitors, such as trimetrexate (TMX), piritrexim (PTX), trimethoprim (TMP), and pyrimethamine (PMT)...
September 2012: Journal of Molecular Modeling
Anindya Dasgupta, Jordan E Shields, H Trent Spencer
Multimodal therapy approaches, such as combining chemotherapy agents with cellular immunotherapy, suffers from potential drug-mediated toxicity to immune effector cells. Overcoming such toxic effects of anticancer cellular products is a potential critical barrier to the development of combined therapeutic approaches. We are evaluating an anticancer strategy that focuses on overcoming such a barrier by genetically engineering drug-resistant variants of immunocompetent cells, thereby allowing for the coadministration of cellular therapy with cytotoxic chemotherapy, a method we refer to as drug-resistant immunotherapy (DRI)...
July 2012: Human Gene Therapy
J P Borde, W B Offensperger, K de With
No abstract text is available yet for this article.
July 2011: Deutsche Medizinische Wochenschrift
Rebecca Sowers, Bethanne D Wenzel, Condon Richardson, Paul A Meyers, John H Healey, Adam S Levy, Richard Gorlick
Osteosarcoma does not respond well to conventional dose methotrexate but does respond to high-dose methotrexate. Previous work has indicated that this resistance may be due to impaired transport of methotrexate across the cell membrane. In this study, the PT430 competitive displacement assay was adapted to evaluate methotrexate transport in 69 high-grade osteosarcoma tumor samples. All samples studied were shown to have relatively impaired methotrexate transport by PT430 assay. Ninety-nine percent of the samples had less than 20% PT430 displacement by methotrexate...
2011: Sarcoma
A Tomillero, M A Moral
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Thomson Reuters Integrity(SM), the drug discovery and development portal, This issue focuses on the following selection of drugs: 17-Hydroxyprogesterone caproate; Abacavir sulfate/lamivudine, Aclidinium bromide, Adalimumab, Adefovir, Alemtuzumab, Alkaline phosphatase, Amlodipine, Apilimod mesylate, Aripiprazole, Axitinib, Azacitidine; Belotecan hydrochloride, Berberine iodide, Bevacizumab, Bortezomib, Bosentan, Bryostatin 1; Calcipotriol/hydrocortisone, Carglumic acid, Certolizumab pegol, Cetuximab, Cinacalcet hydrochloride, Cixutumumab, Coumarin, Custirsen sodium; Darbepoetin alfa, Darifenacin hydrobromide, Darunavir, Dasatinib, Denibulin hydrochloride, Denosumab, Diacetylmorphine, Dulanermin, Duloxetine hydrochloride; Ecogramostim, Enfuvirtide, Entecavir, Enzastaurin hydrochloride, Eplerenone, Escitalopram oxalate, Esomeprazole sodium, Etravirine, Everolimus, Ezetimibe; Fenofibrate/pravastatin sodium, Ferric carboxymaltose, Flavangenol, Fondaparinux sodium; Glutamine, GSK-1024850A; Hepatitis B hyperimmunoglobulin, Hib-MenC, HIV-LIPO-5; Immunoglobulin intravenous (human), Indacaterol maleate, Indibulin, Indium 111 (¹¹¹In) ibritumomab tiuxetan, Influenza A (H1N1) 2009 Monovalent vaccine, Inhalable human insulin, Insulin glulisine; Lapatinib ditosylate, Leucovorin/UFT; Maraviroc, Mecasermin, MMR-V, Morphine hydrochloride, Morphine sulfate/naltrexone hydrochloride, Mycophenolic acid sodium salt; Naproxen/esomeprazole magnesium, Natalizumab; Oncolytic HSV; Paliperidone, PAN-811, Paroxetine, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b/ribavirin, Pegvisomant, Pemetrexed disodium, Pimecrolimus, Posaconazole, Pregabalin; Raltegravir potassium, Ranelic acid distrontium salt, Rasburicase, Rilpivirine hydrochloride; Sertindole, Sivelestat sodium hydrate, Sorafenib, Sumatriptan succinate/naproxen sodium, Sunitinib malate; Tafluprost, Telithromycin, Temsirolimus, Tenofovir disoproxil fumavate, Tenofovir disoproxil fumarate/emtricitabine, Teriparatide, Ticagrelor, Tigecycline, Tipranavir, Tirapazamine, Trimetrexate; Ulipristal acetate; Valganciclovir hydrochloride, Vicriviroc, Vorinostat; Yttrium 90 (90Y) ibritumomab tiuxetan...
December 2010: Methods and Findings in Experimental and Clinical Pharmacology
Alice Dawson, Lindsay B Tulloch, Keri L Barrack, William N Hunter
Pteridine reductase (PTR1) is a potential target for drug development against parasitic Trypanosoma and Leishmania species. These protozoa cause serious diseases for which current therapies are inadequate. High-resolution structures have been determined, using data between 1.6 and 1.1 Å resolution, of T. brucei PTR1 in complex with pemetrexed, trimetrexate, cyromazine and a 2,4-diaminopyrimidine derivative. The structures provide insight into the interactions formed by new molecular entities in the enzyme active site with ligands that represent lead compounds for structure-based inhibitor development and to support early-stage drug discovery...
December 2010: Acta Crystallographica. Section D, Biological Crystallography
Alexis Nzila, John Okombo, Ruy Perez Becker, Roma Chilengi, Trudie Lang, Tim Niehues
The emergence of artemisinin resistance could adversely impact the current strategy for malaria treatment; thus, new drugs are urgently needed. A possible approach to developing new antimalarials is to find new uses for old drugs. Some anticancer agents such as methotrexate and trimetrexate are active against malaria. However, they are commonly perceived to be toxic and thus not suitable for malaria treatment. In this opinion article, we examine how the toxicity of anticancer agents is just a matter of dose or 'only dose makes the poison', as coined in Paracelsus' law...
March 2010: Trends in Parasitology
John J Peterson
This article presents a case-study review of synergy concepts of nonlinear blending and dose-reduction profiles. "Strong nonlinear blending" is a novel concept that provides a flexible paradigm for the assessment of combination drug synergy that is applicable to any shaped combination-drug dose-response surface; issues of varying relative potency, partial inhibitors, potentiation, or coalism pose no problems at all. Dose-reduction profiles are overlay plots created to show how much each drug can be reduced in amount and yet achieve the same efficacy as larger amounts of each drug used individually...
2010: Frontiers in Bioscience (Scholar Edition)
J Jack Lee, Heather Y Lin, Diane D Liu, Maiying Kong
Applying the Emax model in a Lowe additivity model context, we analyze data from a combination study of trimetrexate (TMQ) and AG2034 (AG) in media of low and high concentrations of folic acid (FA). The Emax model provides a sufficient fit to the data. TMQ is more potent than AG in both low and high FA media. At low TMQ:AG ratios, when a smaller amount of the more potent drug (TMQ) is added to a larger amount of the less potent drug (AG), synergy results. When the TMQ:AG ratio reaches 0.4 or larger in low FA medium, or when the TMQ:AG ratio reaches 1 or larger in high FA medium, synergy is weakened and drug interaction becomes additive...
January 1, 2010: Frontiers in Bioscience (Elite Edition)
Maiying Kong, J Jack Lee
We review the semiparametric approach previously proposed by Kong and Lee and extend it to a case in which the dose-effect curves follow the Emax model instead of the median effect equation. When the maximum effects for the investigated drugs are different, we provide a procedure to obtain the additive effect based on the Loewe additivity model. Then, we apply a bivariate thin plate spline approach to estimate the effect beyond additivity along with its 95 per cent point-wise confidence interval as well as its 95 per cent simultaneous confidence interval for any combination dose...
January 1, 2010: Frontiers in Bioscience (Elite Edition)
Roel Straetemans, Luc Bijnens
In this paper we review the application of the Separate Ray Model to analyze drug combination experiments coming from a fixed ratio design. The idea is the joint fit of separate concentration response curves to each ray under investigation leading to an interaction index for each together with a 95 percent Confidence Interval. The approach is a simple and easy to implement parametric modeling approach and allows estimation and testing of drug interactions based on regularly sampling in the entire space of all combinations going from pure compound A to pure compound B...
2010: Frontiers in Bioscience (Elite Edition)
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