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Pixantrone

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https://www.readbyqxmd.com/read/27757832/pixantrone-a-review-in-relapsed-or-refractory-aggressive-non-hodgkin-s-lymphoma
#1
Gillian M Keating
Pixantrone (Pixuvri(®)) is an aza-anthracenedione with a novel mode of action that is conditionally approved in the EU for use as monotherapy in adult patients with multiply relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma (NHL). In the randomized, open-label, multinational, phase 3 PIX301 trial in patients with multiply relapsed or refractory aggressive NHL, the complete response (CR) plus unconfirmed CR (uCR) rate at the end of treatment (primary endpoint) was significantly higher with intravenous pixantrone monotherapy than with a single-agent comparator (vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone or gemcitabine)...
October 18, 2016: Drugs
https://www.readbyqxmd.com/read/27420111/rethinking-drugs-from-chemistry-to-therapeutic-opportunities-pixantrone-beyond-anthracyclines
#2
Pierantonio Menna, Emanuela Salvatorelli, Giorgio Minotti
Pixantrone (6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione) has been approved by the European Medicines Agency for the treatment of refractory or relapsed non-Hodgkin's lymphoma (NHL). It is popularly referred to as a novel aza-anthracenedione, and as such it is grouped with anthracycline-like drugs. Preclinical development of pixantrone was in fact tailored to retain the same antitumor activity as that of anthracyclines or other anthracenediones while also avoiding cardiotoxicity that dose-limits clinical use of anthracycline-like drugs...
August 15, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27142235/reversible-and-formaldehyde-mediated-covalent-binding-of-a-bis-amino-mitoxantrone-analogue-to-dna
#3
Shyam K Konda, Celine Kelso, Paul P Pumuye, Jelena Medan, Brad E Sleebs, Suzanne M Cutts, Don R Phillips, J Grant Collins
The ability of a bis-amino mitoxantrone anticancer drug (named WEHI-150) to form covalent adducts with DNA, after activation by formaldehyde, has been studied by electrospray ionisation mass spectrometry and HPLC. Mass spectrometry results showed that WEHI-150 could form covalent adducts with d(ACGCGCGT)2 that contained one, two or three covalent links to the octanucleotide, whereas the control drugs (daunorubicin and the anthracenediones mitoxantrone and pixantrone) only formed adducts with one covalent link to the octanucleotide...
May 18, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27124765/critical-concepts-practice-recommendations-and-research-perspectives-of-pixantrone-therapy-in-non-hodgkin-lymphoma-a-sie-sies-and-gitmo-consensus-paper
#4
Pier Luigi Zinzani, Paolo Corradini, Maurizio Martelli, Giorgio Minotti, Stefano Oliva, Michele Spina, Giovanni Barosi, Sante Tura
OBJECTIVES: In this paper, we present a review of critical concepts and research perspectives and produce recommendations on the optimal use of pixantrone in non-Hodgkin lymphoma (NHL) by group discussion from an expert panel appointed by the Italian Society of Hematology and the affiliate societies, Società Italiana di Ematologia Sperimentale and Gruppo Italiano Trapianto di Midollo Osseo. METHODS: Recommendations were produced using the Delphi process. Scientific evidence on pixantrone efficacy was analyzed using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology in the areas where at least one randomized trial was published...
December 2016: European Journal of Haematology
https://www.readbyqxmd.com/read/27118109/monotherapy-with-pixantrone-in-histologically-confirmed-relapsed-or-refractory-aggressive-b-cell-non-hodgkin-lymphoma-post-hoc-analyses-from-a-phase-iii-trial
#5
Ruth Pettengell, Catherine Sebban, Pier Luigi Zinzani, Hans Gunter Derigs, Sergey Kravchenko, Jack W Singer, Panteli Theocharous, Lixia Wang, Mariya Pavlyuk, Kahina M Makhloufi, Bertrand Coiffier
This post hoc analysis of a phase 3 trial explored the effect of pixantrone in patients (50 pixantrone, 47 comparator) with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) confirmed by centralized histological review. Patients received 28-d cycles of 85 mg/m(2) pixantrone dimaleate (equivalent to 50 mg/m(2) in the approved formulation) on days 1, 8 and 15, or comparator. The population was subdivided according to previous rituximab use and whether they received the study treatment as 3rd or 4th line...
September 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/27093976/pixantrone-rituximab-versus-gemcitabine-rituximab-in-relapsed-refractory-aggressive-non-hodgkin-lymphoma
#6
David Belada, Pencho Georgiev, Shaker Dakhil, Lowell F Inhorn, David Andorsky, J Thaddeus Beck, Donald Quick, Ruth Pettengell, Robert Daly, James P Dean, Mariya Pavlyuk, Nelly Failloux, Kai Hübel
UNLABELLED: We describe the rationale and design of the ongoing randomized, active-controlled, multicenter, Phase III study evaluating the efficacy of pixantrone and rituximab versus gemcitabine and rituximab in patients with diffuse large B-cell lymphoma or follicular grade 3 lymphoma, who are ineligible for high-dose chemotherapy and stem cell transplantation, and who failed front-line regimens containing rituximab. The administration schedule is pixantrone 50 mg/m(2) intravenously (iv...
August 2016: Future Oncology
https://www.readbyqxmd.com/read/26966886/something-old-new-borrowed-blue-anthracenedione-agents-for-treatment-of-multiple-sclerosis
#7
Boyd M Koffman, Miles Hacker, William T Gunning, Anthony Quinn
OBJECTIVE: This study aimed to present anthracenedione agents that have been used to treat multiple sclerosis (MS), problems related to their use, and knowledge gained from our experiences using these agents to develop more efficacious drugs with fewer adverse effects. METHODS: We review preclinical and clinical data during the development mitoxantrone, an anthracycline, for the treatment of MS; benefits and potential risks; and strategies to reduce complications of anthracyclines...
March 2016: Clinical Neuropharmacology
https://www.readbyqxmd.com/read/26956150/results-of-a-multicentre-uk-wide-retrospective-study-evaluating-the-efficacy-of-pixantrone-in-relapsed-refractory-diffuse-large-b-cell-lymphoma
#8
Toby A Eyre, Kim M Linton, Phillipa Rohman, Jaimal Kothari, Kate Cwynarski, Kirit Ardeshna, Chris Bailey, Wendy L Osborne, Clare Rowntree, Dewi Eden, Paneesha Shankara, David W Eyre, Parag Jasani, Aristeidis Chaidos, Graham P Collins, Chris S Hatton
Relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in those unfit or ineligible for autologous stem cell transplantation is associated with a poor outcome and new treatment approaches are needed. Pixantrone is a novel aza-anthracenedione which is structurally similar to anthracyclines and is licenced in R/R DLBCL and National Institute for Health and Care Excellence (NICE)-approved following the PIX301 trial. No data exist post-NICE approval. We performed a UK-wide retrospective multi-centre study of 92 R/R DLBCL who received pixantrone...
June 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/26856929/the-cost-effectiveness-of-pixantrone-for-third-fourth-line-treatment-of-aggressive-non-hodgkin-s-lymphoma
#9
RANDOMIZED CONTROLLED TRIAL
Noemi Muszbek, Ananth Kadambi, Tereza Lanitis, Anthony J Hatswell, Dilip Patel, Lixia Wang, Jack W Singer, Ruth Pettengell
PURPOSE: Aggressive non-Hodgkin's lymphoma (aNHL) is associated with poor long-term survival after relapse, and treatment is limited by a lack of consensus regarding standard of care. Pixantrone was studied in a randomized trial in patients with relapsed or refractory aNHL who had failed ≥ 2 lines of therapy, demonstrating a significant improvement in complete or unconfirmed complete response and progression-free survival (PFS) compared with investigators' choice of single-agent therapy...
March 2016: Clinical Therapeutics
https://www.readbyqxmd.com/read/26660439/mechanisms-of-action-and-reduced-cardiotoxicity-of-pixantrone-a-topoisomerase-ii-targeting-agent-with-cellular-selectivity-for-the-topoisomerase-ii%C3%AE-isoform
#10
Brian B Hasinoff, Xing Wu, Daywin Patel, Ragu Kanagasabai, Soumendrakrishna Karmahapatra, Jack C Yalowich
Pixantrone is a new noncardiotoxic aza-anthracenedione anticancer drug structurally related to anthracyclines and anthracenediones, such as doxorubicin and mitoxantrone. Pixantrone is approved in the European Union for the treatment of relapsed or refractory aggressive B cell non-Hodgkin lymphoma. This study was undertaken to investigate both the mechanism(s) of its anticancer activity and its relative lack of cardiotoxicity. Pixantrone targeted DNA topoisomerase IIα as evidenced by its ability to inhibit kinetoplast DNA decatenation; to produce linear double-strand DNA in a pBR322 DNA cleavage assay; to produce DNA double-strand breaks in a cellular phospho-histone γH2AX assay; to form covalent topoisomerase II-DNA complexes in a cellular immunodetection of complex of enzyme-to-DNA assay; and to display cross-resistance in etoposide-resistant K562 cells...
February 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/26369630/nuclear-trapping-through-inhibition-of-exosomal-export-by-indomethacin-increases-cytostatic-efficacy-of-doxorubicin-and-pixantrone
#11
Raphael Koch, Thiha Aung, Daniel Vogel, Bjoern Chapuy, Dirk Wenzel, Sabrina Becker, Ursula Sinzig, Vivek Venkataramani, Tobias von Mach, Ralf Jacob, Lorenz Truemper, Gerald G Wulf
PURPOSE: Although R-CHOP-based immunochemotherapy cures significant proportions of patients with aggressive B-cell lymphoma, tumor cell susceptibility to chemotherapy varies, with mostly fatal outcome in cases of resistant disease. We and others have shown before that export of cytostatic drugs contributes to drug resistance. Now we provide a novel approach to overcome exosome-mediated drug resistance in aggressive B-cell lymphomas. EXPERIMENTAL DESIGN: We used well-established centrifugation protocols to purify exosomes from DLBCL cell lines and detected anthracyclines using FACS and HPLC...
January 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26286699/pixantrone-a-b-cell-depleting-immunosuppressant-for-multiple-sclerosis-patients-with-active-disease
#12
Richard Gonsette, Marc Debouverie, Christian Sindic, Jean-Christophe Ferré, Gilles Edan
BACKGROUND: Mitoxantrone has been approved for patients with worsening relapsing-remitting (RR) or secondary progressive multiple sclerosis (SPMS), but its long-term use is limited by its cardiotoxicity. Pixantrone (PIX) is an analog of mitoxantrone. OBJECTIVES: The aim of this open-label, multicenter, noncomparative Phase I/II trial was to explore the immunosuppressive effect of PIX, its impact on clinical disease activity and cerebral gadolinium-enhanced (Gd(+)) lesions, and its safety...
May 2016: Multiple Sclerosis: Clinical and Laboratory Research
https://www.readbyqxmd.com/read/26177126/pixantrone-induces-cell-death-through-mitotic-perturbations-and-subsequent-aberrant-cell-divisions
#13
Neil Beeharry, Andrea Ghelli Luserna Di Rora, Mitchell R Smith, Timothy J Yen
Pixantrone is a novel aza-anthracenedione active against aggressive lymphoma and is being evaluated for use against various hematologic and solid tumors. The drug is an analog of mitoxantrone, but displays less cardiotoxicity than mitoxantrone or the more commonly used doxorubicin. Although pixantrone is purported to inhibit topoisomerase II activity and intercalate with DNA, exact mechanisms of how it induces cell death remain obscure. Here we evaluated the effect of pixantrone on a panel of solid tumor cell lines to understand its mechanism of cell killing...
2015: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/25929194/binding-of-pixantrone-to-dna-at-cpa-dinucleotide-sequences-and-bulge-structures
#14
Shyam K Konda, Haiqiang Wang, Suzanne M Cutts, Don R Phillips, J Grant Collins
The binding of the anti-cancer drug pixantrone to three oligonucleotide sequences, d(TCATATGA)2, d(CCGAGAATTCCGG)2 {double bulge = DB} and the non-self complementary d(TACGATGAGTA) : d(TACCATCGTA) {single bulge = SB}, has been studied by NMR spectroscopy and molecular modelling. The upfield shifts observed for the aromatic resonances of pixantrone upon addition of the drug to each oligonucleotide confirmed the drug bound by intercalation. For the duplex sequence d(TCATATGA)2, NOEs were observed from the pixantrone aromatic H7/8 and aliphatic Ha/Hb protons to the H6/H8 and H1' protons of the C2, A3, T6 and G7 nucleotides, demonstrating that pixantrone preferentially binds at the symmetric CpA sites...
June 7, 2015: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/25716061/pixantrone-a-novel-anthracycline-like-drug-for-the-treatment-of-non-hodgkin-lymphoma
#15
Eileen Mary Boyle, Franck Morschhauser
INTRODUCTION: The current treatment approach of high-grade non-Hodgkin lymphoma (NHL) relies to a large extent on anthracycline-based regimens yielding cure rates in ∼ 65 - 75% of patients. Despite being highly effective, these regimens are associated with significant long-term toxicity with a cumulative 10-year incidence of cardiovascular disease of 22%. Moreover, for the 25 - 35% of patients who fail first-line therapy there has been very little progress in terms of salvage regimens over the past 15 years...
April 2015: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/25453806/design-synthesis-and-dna-sequence-selectivity-of-formaldehyde-mediated-dna-adducts-of-the-novel-n-4-aminobutyl-acridine-4-carboxamide
#16
Elizabeth A Ankers, Benny J Evison, Don R Phillips, Robert T C Brownlee, Suzanne M Cutts
A novel derivative of the anti-tumor agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) was prepared by reduction of 9-oxoacridan-4-carboxylic acid to acridine-4-carboxylic acid with subsequent conversion to N-(4-aminobutyl)acridine-4-carboxamide (C4-DACA). Molecular modeling studies suggested that a DACA analogue comprising a side chain length of four carbons was optimal to form formaldehyde-mediated drug-DNA adducts via the minor groove. An in vitro transcription assay revealed that formaldehyde-mediated C4-DACA-DNA adducts selectively formed at CpG and CpA dinucleotide sequences, which is strikingly similar to that of formaldehyde-activated anthracenediones such as pixantrone...
December 15, 2014: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/24926199/pixantrone-for-the-treatment-of-adult-patients-with-relapsed-or-refractory-aggressive-non-hodgkin-b-cell-lymphomas
#17
REVIEW
Stefano Volpetti, Francesco Zaja, Renato Fanin
Treatment of patients with relapsed or refractory aggressive non-Hodgkin B-cell lymphoma remains an unmet clinical need, and the progressive myocardial toxicity related to cumulative, dose-dependent damage induced by anthracyclines represents a tricky issue in the planning of therapy. Pixantrone is a promising aza-anthracenedione with reduced cardiotoxicity and significant antineoplastic activity, and has been investigated in solid and hematologic tumors in several Phase I, II, and III trials. The aim of this review is to summarize the data reported so far on pixantrone as a salvage therapy in relapsed/refractory non-Hodgkin B-cell lymphoma...
2014: OncoTargets and Therapy
https://www.readbyqxmd.com/read/24818252/nice-guidance-on-pixantrone-monotherapy-for-multiply-relapsed-or-refractory-aggressive-non-hodgkin-lymphoma
#18
Linda J Landells, Carl Prescott, Nicola Hay, Frances Sutcliffe, Andrew Stevens
No abstract text is available yet for this article.
April 2014: Lancet Oncology
https://www.readbyqxmd.com/read/24703714/the-anticancer-efficacy-of-pixantrone-loaded-liposomes-decorated-with-sialic-acid-octadecylamine-conjugate
#19
Zhennan She, Ting Zhang, Xuling Wang, Xuan Li, Yanzhi Song, Xiaobo Cheng, Zhenjun Huang, Yihui Deng
Based on the knowledge that sialic acid is a critical element for tumor development and its receptors are highly expressed on the tumor-associated macrophages (TAMs) which play important roles in the growth and metastasis of tumors, we synthesized a sialic acid-octadecylamine conjugate (SA-ODA) and anchored it on the surface of pixantrone (Pix)-loaded liposomes, to achieve an improved anticancer effect. Four Pix formulations (Pix-S, Pix-CL, Pix-PL and Pix-SAL represent solution, conventional liposome, stealth liposome, and SA-ODA modified liposome, respectively) were developed, and various parameters, including drug loading, stability, in vitro release, cytotoxicity and pharmacokinetics, were evaluated...
June 2014: Biomaterials
https://www.readbyqxmd.com/read/24602559/tolerability-and-toxicological-profile-of-pixantrone-pixuvri%C3%A2-in-juvenile-mice-comparative-study-with-doxorubicin
#20
COMPARATIVE STUDY
Monica Longo, Paola Della Torre, Cecilia Allievi, Alberto Morisetti, Suliman Al-Fayoumi, Jack W Singer
The tolerability of pixantrone dimaleate (Pixuvri(®)), an aza-anthracenedione for non-Hodgkin lymphoma, was assessed in juvenile mice after intraperitoneal injection. Twenty animals/sex/dose received pixantrone 15 or 27 mg/kg/day on Post-Natal-Days (PND) 10, 13, 17, 20, 35, 39 and 42 in comparison with doxorubicin, 3 mg/kg/day. Animals were sacrificed on PND 42, 73 and 96. All pixantrone animals survived, while doxorubicin induced 52.5% mortality and the surviving animals were sacrificed early due to severe toxicity...
July 2014: Reproductive Toxicology
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