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A M Dhople - One of the best experts on this subject based on the ideXlab platform.
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in vitro and in vivo activity of k 130 a Dihydrofolate Reductase Inhibitor against mycobacterium leprae
Drug Research, 2011Co-Authors: A M DhopleAbstract:The antimicrobial effects of a new Dihydrofolate Reductase Inhibitor, K-130 (2,4-diaminodiphenyl sulfone substituted 2,4-diamino-5-benzylpyrimidine), alone and in combination with dapsone (CAS 80-08-0) against both dapsone-sensitive and dapsone-resistant strains of Mycobacterium leprae were evaluated in vitro, in cell-free culture system, and in vivo, in mouse foot pads. The minimal Inhibitory concentration of K-130 against dapsone-sensitive as well as dapsone resistant strains of M. leprae was 0.03 μg/ml, and the activity was bactericidal in both cases. However, when combined with dapsone, K-130 exhibited synergism in case of dapsone-sensitive M. leprae, while in case of dapsone-resistant M. leprae, the effect was merely additive. Similar synergistic effects were also observed in the mouse foot pad system for both types of M. leprae strains.
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in vivo activity of epiroprim a Dihydrofolate Reductase Inhibitor singly and in combination with dapsone against mycobacterium leprae
International Journal of Antimicrobial Agents, 2002Co-Authors: A M DhopleAbstract:The antimicrobial effects of a new Dihydrofolate Reductase Inhibitor, epiroprim, either singly or in combination with dapsone against Mycobacterium leprae, were evaluated in vivo using a mouse footpad model. When fed to mice at concentration of 0.05% in diet, epiroprim completely inhibited the growth of both dapsone-sensitive and dapsone-resistant strains of M. leprae in the footpads of mice and the effects were bactericidal. To achieve similar effects, the concentration of dapsone in the diet had to be 0.0005 and 0.01%, respectively. When used in combination, the concentrations of the drugs in the diet could be lowered by 50-80% and still achieve bactericidal effects. The data support the earlier results on in vitro studies and suggest the use of epiroprim in the multidrug regimen in the treatment of leprosy.
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Short communication In vivo activity of epiroprim, a Dihydrofolate Reductase Inhibitor, singly and in combination with dapsone, against Mycobacterium leprae
2002Co-Authors: A M DhopleAbstract:The antimicrobial effects of a new Dihydrofolate Reductase Inhibitor, epiroprim, either singly or in combination with dapsone against Mycobacterium leprae, were evaluated in vivo using a mouse footpad model. When fed to mice at concentration of 0.05% in diet, epiroprim completely inhibited the growth of both dapsone-sensitive and dapsone-resistant strains of M. leprae in the footpads of mice and the effects were bactericidal. To achieve similar effects, the concentration of dapsone in the diet had to be 0.0005 and 0.01%, respectively. When used in combination, the concentrations of the drugs in the diet could be lowered by 50–80% and still achieve bactericidal effects. The data support the earlier results on in vitro studies and suggest the use of epiroprim in the multidrug regimen in the treatment of leprosy. © 2002 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved.
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in vitro activity of epiroprim a Dihydrofolate Reductase Inhibitor singly and in combination with brodimoprim and dapsone against mycobacterium leprae
International Journal of Antimicrobial Agents, 1999Co-Authors: A M DhopleAbstract:The antimicrobial effects of a new Dihydrofolate Reductase Inhibitor, epiroprim, alone and in combination with dapsone and brodimoprim against Mycobacterium leprae were evaluated in vitro in cell-free culture system. Two biochemical parameters were used to measure metabolic activity (and growth) of the organism. The minimal Inhibitory activity of epiroprim against M. leprae was 10 mg/l and the action was bactericidal. When combined with dapsone, epiroprim exhibited a strong synergism; on the other hand, combination of epiroprim and brodimoprim provided only additive effects. The results suggest that epiroprim can be a component in multidrug therapy regimen in leprosy.
I. David Goldman - One of the best experts on this subject based on the ideXlab platform.
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The membrane transport and polyglutamation of pralatrexate: a new-generation Dihydrofolate Reductase Inhibitor
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Michele Visentin, Ersin Selcuk Unal, Rongbao Zhao, I. David GoldmanAbstract:Purpose To characterize, directly and for the first time, the membrane transport and metabolism of pralatrexate, a new-generation Dihydrofolate Reductase Inhibitor approved for the treatment for peripheral T-cell lymphoma. Experimental design [^3H]pralatrexate transport was studied in unique HeLa cell lines that express either the reduced folate carrier (RFC) or the proton-coupled folate transporter (PCFT). Metabolism to active polyglutamate derivatives was assessed by liquid chromatography. These properties were compared to those of methotrexate (MTX). Results The pralatrexate influx K _t, mediated by RFC, the major route of folate/antifolate transport at systemic pH, was 0.52 μΜ, 1/10th the MTX influx K _i. The electrochemical potential of pralatrexate within HeLa cells far exceeded the extracellular level and was greater than for MTX. In contrast, MTX transport mediated by PCFT, the mechanism of folate/antifolate absorption in the small intestine, exceeded that for pralatrexate. After a 6 h exposure of HeLa cells to 0.5 μM pralatrexate, 80 % of intracellular drug was its active polyglutamate forms, predominantly the tetraglutamate, and was suppressed when cells were loaded with natural folates. There was negligible formation of MTX polyglutamates. The difference in pralatrexate and MTX growth inhibition was far greater after transient exposures (375-fold) than continuous exposure (25-fold) to the drugs. Conclusions Pralatrexate’s enhanced activity relative to MTX is due to its much more rapid rate of transport and polyglutamation, the former less important when the carrier is saturated. The low affinity of pralatrexate for PCFT predicts a lower level of enterohepatic circulation and increased fecal excretion of the drug relative to MTX.
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The membrane transport and polyglutamation of pralatrexate: a new-generation Dihydrofolate Reductase Inhibitor.
Cancer chemotherapy and pharmacology, 2013Co-Authors: Michele Visentin, Ersin Selcuk Unal, Rongbao Zhao, I. David GoldmanAbstract:Purpose To characterize, directly and for the first time, the membrane transport and metabolism of pralatrexate, a new-generation Dihydrofolate Reductase Inhibitor approved for the treatment for peripheral T-cell lymphoma.
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Comparison of methotrexate polyglutamylation in L1210 leukemia cells when influx is mediated by the reduced folate carrier or the folate receptor. Lack of evidence for influx route-specific effects.
Biochemical Pharmacology, 1996Co-Authors: Michael J. Spinella, Kevin E. Brigle, Sarah J. Freemantle, Esteban E. Sierra, I. David GoldmanAbstract:Abstract We previously described a methotrexate-resistant L1210 cell line (MTX r A) that lacks a functional reduced folate carrier and does not appreciably express the folate receptor. In the present study, we utilized MTX r A cell lines stably transfected with cDNAs encoding either the folate receptor or the reduced folate carrier to investigate the influence of the route of folate influx on the rate and extent of methotrexate polyglutamylation. At an extracellular methotrexate concentration of 0.1 μM, influx in the folate receptor transfectant (MTX r A-TF1) and in the reduced folate carrier transfectant (MTX r A-R1) was equal and methotrexate polyglutamates accumulated at an identical rate, but the onset was delayed until Dihydrofolate Reductase was saturated with the monoglutamate (~3 hr). The onset of polyglutamate formation was immediate and identical among the lines in cells pretreated with the lipophilic Dihydrofolate Reductase Inhibitor trimetrexate to block methotrexate binding to Dihydrofolate Reductase. The spectra of individual methotrexate polyglutamates that accumulated were similar, with the tetraglutamate present as the predominant form. A 100-fold higher methotrexate concentration was required to detect methotrexate uptake and polyglutamylation in the transport defective parent MTX r A line, demonstrating that diffusion or an unidentified low affinity route also supports polyglutamylation. Since the folate receptor and the reduced folate carrier achieve nearly identical rates of polyglutamylation despite very different mechanisms of methotrexate delivery, the data suggest that transport-mediated substrate channeling to folylpolyglutamate synthetase is unlikely to play a role in tetrahydrofolate metabolism. This study supports the notion that it is the intracellular concentration of methotrexate achieved within the cell that drives polyglutamylation irrespective of its route of entry.
Dennis L Stevens - One of the best experts on this subject based on the ideXlab platform.
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Iclaprim: a novel Dihydrofolate Reductase Inhibitor for skin and soft tissue infections
Future microbiology, 2009Co-Authors: Andrew Morgan, Christine Cofer, Dennis L StevensAbstract:Antibiotic resistance is an ever-increasing concern in the treatment of severe skin and skin-structure infections, pneumonia, bacteremia and other serious infections caused by methicillin-resistant Staphylococcus aureus, vancomycin-resistant S. aureus, group A Streptococcus and vancomycin-resistant Enterococcus. In this review, we summarize the current status of both US FDA-approved and investigational agents aimed at this group of pathogens. We also describe, in detail, the chemistry, mechanism of action, pharmacokinetic properties and spectrum of microbiological activity of iclaprim, a novel Dihydrofolate Reductase Inhibitor recently awarded fast-track approval status by the FDA. Finally, we review the clinical efficacy of iclaprim compared with linezolid for skin and skin-structure infections as demonstrated in Phase III randomized, controlled trials, and comment on its potential role in the treatment of other severe infections with drug-resistant Gram-positive pathogens.
Godefridus J. Peters - One of the best experts on this subject based on the ideXlab platform.
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schedule dependent synergy between the histone deacetylase Inhibitor belinostat and the Dihydrofolate Reductase Inhibitor pralatrexate in t and b cell lymphoma cells in vitro
Frontiers in Cell and Developmental Biology, 2020Co-Authors: Godefridus J. Peters, Frank H. Van Gemert, Ietje Kathmann, Saskia A.g.m. Cillessen, Guru Reddy, Gerrit JansenAbstract:Pralatrexate (Folotyn; PLX) and belinostat (Beleodaq; BLS) are registered for the treatment of patients with peripheral T-cell lymphoma (PTCL) and are being considered for other lymphomas. In this study we investigated whether BLS had the ability to potentiate the cytotoxicity of PLX. A panel of lymphoma cell lines was used for the combination studies: the B-cell SUDHL-4, SUDHL-5, HT, Jeko-1 and T-cell Karpas-299 and Hut-78. Uptake of PLX was mediated by the reduced folate carrier (RFC). PLX showed a 6-fold better RFC substrate affinity compared to methotrexate, and 2-fold better than levoleucovorin (l-LV). Sensitivity expressed as the concentration that resulted in 50% growth inhibition (IC50) after 72 hr exposure to PLX varied from 2.8 to 20 nM and for BLS from 72 to 233 nM, independent of the background of the cell lines. The interaction between BLS and PLX was studied using the median-drug effect analysis. At a fixed molar ratio between the drugs based on the IC50 concentration the average combination index (CI) for all cell lines showed additivity (CI: around 1.0). In three selected cell lines (SUDHL-4, SUDHL-5, and HT) sequential exposure (24 h pretreatment with BLS, followed by 48 h to PLX + BLS), did not improve interaction (CI: 0.9-1.4). As an alternative approach a non-fixed ratio was used by exposing SUDHL-4, SUDHL-5, and HT cells to IC25 concentrations of either BLS or PLX in combination with the other drug. Exposure to IC25 of PLX did not decrease the IC50 for BLS (CI from 0.6-1.2), but exposure to IC25 of BLS markedly increased PLX sensitivity (low CIs from 0.40 to 0.66). Mechanistic studies focused on induction of apoptosis, and showed cleavage of predominantly caspase-9 in HT and SUDHL-4 cells for both drugs at their IC50s, being similar in the combination setting. Moreover, at these concentrations, the drugs were shown to confer an S-phase arrest. In conclusion, the combination of PLX and BLS showed additivity in various lymphoma cell lines, with a schedule-dependent synergism in B-cell lymphoma. Based on these data, proficient inhibition of HDAC activity by BLS holds promise in sensitization of tumor cells to PLX.
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Abstract C69: Schedule-dependent synergy between the histone deacetylase Inhibitor belinostat and the Dihydrofolate Reductase Inhibitor pralatrexate in T-and B-cell lymphoma cells in vitro
Drug Resistance and Modifiers, 2015Co-Authors: Godefridus J. Peters, Frank H. Van Gemert, Ietje Kathmann, Saskia A.g.m. Cillessen, Gerrit Jansen, ReddyAbstract:Pralatrexate (Folotyn; FOL) and belinostat (Beleodaq; BEL) have recently been registered for the treatment of patients with peripheral T-cell lymphoma (PTCL) and have promising activity in other lymphoma. FOL is a folate analog and a potent Dihydrofolate Reductase (DHFR) Inhibitor, designed to accumulate in cancer cells via the reduced folate carrier (RFC) and retained via efficient polyglutamylation. DHFR inhibition leads to an imbalance of deoxynucleotides (depletion of dTTP and an increase in dUTP) resulting in DNA strand breaks and inhibition of DNA synthesis. BEL is a hydroxamic acid-based pan-histone deacetylase (HDAC) Inhibitor that inhibits all of the zinc-dependent HDAC enzymes, with high affinity for the Class I, II and IV isozymes. HDAC inhibition results in an alteration in the degree of histone and non-histone protein acetylation, which in turn affects transcription of genes essential in cellular proliferation, cell cycle and DNA repair. In this study we investigated whether folate transporters other than RFC, i.e. folate receptor α (FRα) and the proton-coupled folate transporter (PCFT) could contribute to the efficacy of FOL. Moreover, we explored whether in combination experiments BEL had the ability to potentiate the cytotoxicity of FOL. A panel of lymphoma cell lines was used for the combination studies: the B-cell SU-DHL-4, SU-DHL-5, HT, Jeko-1 and T-cell Karpas-299 and Hut-78. RFC-mediated uptake efficiency of FOL (in competition with [3H]-methotrexate), showed a 6-fold better RFC substrate affinity for FOL, and 2-fold better than levo-leucovorin (l-LV). FOL had a very poor substrate binding affinity for FRα (>100-fold lower than folic acid and > 10 lower than l-LV) and a low affinity for PCFT (>10-fold lower than folic acid and l-LV in [3H]-LV uptake competition experiments). Sensitivity (IC50 concentrations after 72 hr exposure) to FOL varied from 2.8 (Hut-78), 5.5 (SU-DHL4 and 5), 7.4 (HT) to 20 nM (Karpas-299 and Jeko-1) and for BEL from 100 (SU-DLH-4 and 5, Jeko-1 and Hut-78) to 200 nM (Karpas-299 and HT). The interaction between BEL and FOL was studied using the median-drug effect analysis. At a fixed ratio between the drugs based on the IC50 concentration the average combination index (CI) for all cell lines showed additivity (CI: ±1.0). In two selected cell lines (SU-DHL-4 and HT) sequential exposure (24 hr pretreatment with either BEL or FOL, followed by 48 hr to FOL + BEL), did not improve interaction (CI: 0.9-1.4). As an alternative approach a non-fixed ratio was used by exposing SU-DHL-4 and HT cells to IC25 concentrations of either BEL or FOL in combination with the other drug. Exposure to IC25 of FOL did not decrease the IC50 for BEL (CI around 1.2), but exposure to IC25 of BEL markedly increased FOL sensitivity (low CIs from 0.40-0.66). Mechanistic studies focused on induction of apoptosis, showed cleavage of caspase 8 and 9 in HT and SU-DHL-4 cells for both drugs at their IC50s, being similar in the combination setting. Moreover, at these concentrations, the drugs were shown to confer an S-phase arrest. In conclusion, the combination of FOL and BEL showed additivity in various lymphoma cell lines, with a schedule-dependent synergism. Based on these data, proficient inhibition of HDAC activity by BEL holds promise in sensitization of tumor cells to FOL. Citation Format: Godefridus J. Peters, Frank H. Van Gemert, I. Kathmann, Saskia A. Cillessen, Gerrit Jansen, Guru Reddy. Schedule-dependent synergy between the histone deacetylase Inhibitor belinostat and the Dihydrofolate Reductase Inhibitor pralatrexate in T-and B-cell lymphoma cells in vitro. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C69.
Joseph A Kovacs - One of the best experts on this subject based on the ideXlab platform.
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efficacy of epiroprim ro11 8958 a new Dihydrofolate Reductase Inhibitor in the treatment of acute toxoplasma infection in mice
American Journal of Tropical Medicine and Hygiene, 1996Co-Authors: Anthony Martinez, Carmen J Allegra, Joseph A KovacsAbstract:Abstract Toxoplasma gondii is a major cause of focal encephalitis in patients with acquired immunodeficiency syndrome. Epiroprim, an Inhibitor of Dihydrofolate Reductase, was evaluated in vitro and in a mouse model of acute infection for activity against T. gondii. The 50% Inhibitory concentration (IC50) of epiroprim for T. gondii Dihydrofolate Reductase was 0.9 µM, similar to that of pyrimethamine, but epiroprim was 650-fold more selective than pyrimethamine for T. gondii compared with human Dihydrofolate Reductase. While intraperitoneally administered epiroprim (300 mg/kg/day for 14 days) alone was ineffective in mice acutely infected with the RH strain of T. gondii, 100% survival was seen when it was combined with orally administered sulfadiazine (375 mg/kg/day), which alone was also ineffective. Increases in survival were seen in combination with doses of sulfadiazine as low as 0.375 mg/kg/day. Orally administered epiroprim combined with dapsone also prolonged survival. Thus, epiroprim is an active and potentially less toxic alternative to pyrimethamine for the treatment of toxoplasmosis.
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salvage trial of trimetrexate leucovorin for the treatment of cerebral toxoplasmosis in patients with aids
The Journal of Infectious Diseases, 1993Co-Authors: Henry Masur, Michael A Polis, Carmelita U Tuazon, Debbie Ogata Arakaki, Joseph A Kovacs, David F Katz, Dana Hilt, Thayer Simmons, Irwin M Feuerstein, Bettina LundgrenAbstract:The clinical efficacy of trimetrexate, a Dihydrofolate Reductase Inhibitor with potent in vitro antitoxoplasma activity, was assessed in 9 sulfonamide-intolerant patients with AIDS and biopsy-proven cerebral toxoplasmosis. The 9 patients were treated for 28-149 days with trimetrexate (30-280 mg/m2/day) plus leucovorin (20-90 mg/m2 every 6 h). Radiographic responses were documented in 8 patients, and clinical responses in 5 patients. Despite continued therapy, all patients deteriorated clinically and radiographically within 13-109 days of their initial improvement. Trimetrexate at very high doses for extended periods was not associated with serious toxicity. Trimetrexate alone had dramatic but transient activity in sulfonamide-intolerant patients and thus is not adequate as single-agent therapy for AIDS-associated toxoplasmosis.