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Niraparib

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https://www.readbyqxmd.com/read/29043410/determination-of-the-absolute-oral-bioavailability-of-niraparib-by-simultaneous-administration-of-a-14-c-microtracer-and-therapeutic-dose-in-cancer-patients
#1
L van Andel, H Rosing, Z Zhang, L Hughes, V Kansra, M Sanghvi, M M Tibben, A Gebretensae, J H M Schellens, J H Beijnen
INTRODUCTION: Niraparib (Zejula™) is a poly(ADP-ribose) polymerase inhibitor recently approved by the US Food and Drug Administration for the maintenance treatment of patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. The pivotal phase III clinical trial has shown improved progression-free survival in patients receiving niraparib compared with those receiving placebo...
October 17, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28994564/targeted-therapy-for-ovarian-cancer-the-rapidly-evolving-landscape-of-parp-inhibitor-use
#2
Christine Walsh
INTRODUCTION: PARP (poly(ADP-ribose) polymerase) inhibitors are a targeted therapy option for ovarian cancer. The goal of this review was to organize and summarize the clinical trials evaluating PARP inhibitor therapy in ovarian cancer as monotherapy, maintenance therapy after partial or complete remission to therapy or as a part of a combination regimen. EVIDENCE ACQUISITION: PubMed, ClinicalTrials.gov, data from the United States Food and Drug Administration (US FDA) and proceedings from scientific conferences were searched for published and unpublished data pertaining to clinical trials and approvals of PARP inhibitor use in ovarian cancer...
October 9, 2017: Minerva Ginecologica
https://www.readbyqxmd.com/read/28981112/berberine-induces-oxidative-dna-damage-and-impairs-homologous-recombination-repair-in-ovarian-cancer-cells-to-confer-increased-sensitivity-to-parp-inhibition
#3
Dong Hou, Guangwei Xu, Caibo Zhang, Boxuan Li, Junchao Qin, Xiaohe Hao, Qiao Liu, Xiyu Zhang, Jinsong Liu, Jianjun Wei, Yaoqin Gong, Zhaojian Liu, Changshun Shao
Many cancer drugs exert their therapeutic effect by inducing oxidative stress in the cancer cells. Oxidative stress compromises cell survival by inflicting lesions in macromolecules like DNA. Cancer cells rely on enhanced antioxidant metabolism and increased DNA repair function to survive oxidative assault. PARP1, a protein that senses DNA-strand breaks and orchestrates their repair, has an important role in the repair of oxidative DNA damage. Berberine, an alkaloid compound present in many herbal plants, is capable of inducing oxidative DNA damage and downregulating homologous recombination repair (HRR) in cancer cells...
October 5, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28806493/olaparib-a-clinically-used-poly-adp-ribose-polymerase-inhibitor-protects-against-oxidant-induced-cardiac-myocyte-death-in-vitro-and-improves-cardiac-contractility-during-early-phase-after-heart-transplantation-in-a-rat-model-in-vivo
#4
Sevil Korkmaz-Icöz, Bartosz Szczesny, Michela Marcatti, Shiliang Li, Mihály Ruppert, Felix Lasitschka, Sivakkanan Loganathan, Csaba Szabo, Gábor Szabó
BACKGROUND AND PURPOSE: Olaparib, rucaparib and niraparib, potent inhibitors of poly(ADP-ribose) polymerase (PARP) have recently been approved for human use for oncological indications. Considering the previously demonstrated role of PARP in various forms of acute and chronic myocardial injury, we tested the effect of olaparib in in-vitro models of oxidative stress in cardiomyocytes, and in an in-vivo model of cardiac transplantation. EXPERIMENTAL APPROACH: H9c2-embryonic rat heart-derived myoblasts pretreated with vehicle or olaparib (10μM) were challenged with either hydrogen-peroxide (H2 O2 ) or with glucose-oxidase (GOx, which generates H2 O2 in the tissue culture medium)...
August 14, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28756516/synthetic-lethality-in-malignant-pleural-mesothelioma-with-parp1-inhibition
#5
Gayathri Srinivasan, Gurjit Singh Sidhu, Elizabeth A Williamson, Aruna S Jaiswal, Nasreen Najmunnisa, Keith Wilcoxen, Dennie Jones, Thomas J George, Robert Hromas
Malignant pleural mesotheliomas (MPM) are most often surgically unresectable, and they respond poorly to current chemotherapy and radiation therapy. Between 23 and 64% of malignant pleural mesothelioma have somatic inactivating mutations in the BAP1 gene. BAP1 is a homologous recombination (HR) DNA repair component found in the BRCA1/BARD1 complex. Similar to BRCA1/2 deficient cancers, mutation in the BAP1 gene leads to a deficient HR pathway and increases the reliance on other DNA repair pathways. We hypothesized that BAP1-mutant MPM would require PARP1 for survival, similar to the BRCA1/2 mutant breast and ovarian cancers...
October 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28674469/pharmaceutical-approval-update
#6
Mary Choy
Niraparib (Zejula) for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer; ocrelizumab (Ocrevus) for relapsing or primary progressive multiple sclerosis; and dupilumab (Dupixent) for moderate-to-severe atopic dermatitis.
July 2017: P & T: a Peer-reviewed Journal for Formulary Management
https://www.readbyqxmd.com/read/28631775/-innovations-in-the-treatment-of-ovarian-cancer-analysis-of-the-therapeutic-development-from-platinum-to-immunotherapy
#7
Gesuino Angius, Pierangela Sepe, Anselmo Papa, Silverio Tomao, Federica Tomao
Ovarian cancer is the seventh most common cancer in women. The therapeutic approach provides for an appropriate integration between surgery and chemotherapy. Surgery is an important step for diagnosis, staging and therapy, aiming at the complete cytoreduction of all macroscopic visible disease. At the moment, adjuvant and first-line chemotherapy has as a standard the carboplatin-paclitaxel combination. Further, the addition of bevacizumab in the advanced stage (IIIB-IV) is strongly recommended. Despite the initial effectiveness, however, 70-80% of patients develop relapsed disease within the first two years and require subsequent treatment lines that have palliative, rather than curative purposes and that seek to reach a chronic state for the disease...
June 2017: Recenti Progressi in Medicina
https://www.readbyqxmd.com/read/28631774/-il-ruolo-di-niraparib-nel-trattamento-del-carcinoma-ovarico-attualit%C3%A3-e-prospettive
#8
Ilaria Sabatucci, Domenica Lorusso
Riassunto. I PARP inibitori interferiscono con la riparazione del danno nella singola elica del DNA determinando una progressione del difetto nella doppia elica. In circa il 50% delle pazienti con carcinoma dell'ovaio sieroso di alto grado sono presenti difetti nei meccanismi di ricombinazione omologa, deputati alla riparazione del danno della doppia elica del DNA. L'incapacità di riparare il danno si traduce nella morte cellulare, un processo definito "letalità sintetica". Nella famiglia dei PARP inibitori il niraparib è stato il primo a essere approvato dalla FDA nel trattamento delle pazienti con carcinoma ovarico ricorrente indipendentemente dalla presenza o assenza di mutazioni BRCA...
June 2017: Recenti Progressi in Medicina
https://www.readbyqxmd.com/read/28607510/asymmetric-suzuki-miyaura-coupling-of-heterocycles-via-rhodium-catalysed-allylic-arylation-of-racemates
#9
Philipp Schäfer, Thomas Palacin, Mireia Sidera, Stephen P Fletcher
Using asymmetric catalysis to simultaneously form carbon-carbon bonds and generate single isomer products is strategically important. Suzuki-Miyaura cross-coupling is widely used in the academic and industrial sectors to synthesize drugs, agrochemicals and biologically active and advanced materials. However, widely applicable enantioselective Suzuki-Miyaura variations to provide 3D molecules remain elusive. Here we report a rhodium-catalysed asymmetric Suzuki-Miyaura reaction with important partners including aryls, vinyls, heteroaromatics and heterocycles...
June 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28474297/niraparib-first-global-approval
#10
Lesley J Scott
Oral niraparib, a highly-selective, potent poly(ADP-ribose) polymerase (PARP)-1 and PARP-2 inhibitor, is approved in the USA for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. It is also under regulatory review in the EU for use in maintenance treatment in patients with platinum-sensitive, recurrent epithelial ovarian cancer who are in response to platinum-based chemotherapy...
June 2017: Drugs
https://www.readbyqxmd.com/read/28382802/major-clinical-research-advances-in-gynecologic-cancer-in-2016-10-year-special-edition
#11
REVIEW
Dong Hoon Suh, Miseon Kim, Kidong Kim, Hak Jae Kim, Kyung Hun Lee, Jae Weon Kim
In 2016, 13 topics were selected as major research advances in gynecologic oncology. For ovarian cancer, study results supporting previous ones regarding surgical preventive strategies were reported. There were several targeted agents that showed comparable responses in phase III trials, including niraparib, cediranib, and nintedanib. On the contrary to our expectations, dose-dense weekly chemotherapy regimen failed to prove superior survival outcomes compared with conventional triweekly regimen. Single-agent non-platinum treatment to prolong platinum-free-interval in patients with recurrent, partially platinum-sensitive ovarian cancer did not improve and even worsened overall survival (OS)...
May 2017: Journal of Gynecologic Oncology
https://www.readbyqxmd.com/read/28303528/human-mass-balance-study-and-metabolite-profiling-of-14-c-niraparib-a-novel-poly-adp-ribose-polymerase-parp-1-and-parp-2-inhibitor-in-patients-with-advanced-cancer
#12
Lotte van Andel, Z Zhang, S Lu, V Kansra, S Agarwal, L Hughes, M M Tibben, A Gebretensae, L Lucas, M J X Hillebrand, H Rosing, J H M Schellens, J H Beijnen
Niraparib is an investigational oral, once daily, selective poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor. In the pivotal Phase 3 NOVA/ENGOT/OV16 study, niraparib met its primary endpoint of improving progression-free survival (PFS) for adult patients with recurrent, platinum sensitive, ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to platinum-based chemotherapy. Significant improvements in PFS were seen in all patient cohorts regardless of biomarker status...
March 16, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28299955/niraparib-for-the-treatment-of-ovarian-cancer
#13
REVIEW
Yada Kanjanapan, Stephanie Lheureux, Amit M Oza
Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are being developed in maintenance and recurrence treatment settings in ovarian cancer. They inhibit single-stranded DNA repair, inducing synthetic lethality in cells with underlying homologous recombination deficiency (HRD). Marked responses are seen in ovarian cancers with breast cancer gene 1 (BRCA1) or 2 (BRCA2) mutation, although up to 50% of high-grade serous ovarian cancers (HGSOC) have HRD may also benefit. Areas covered: This review focuses on niraparib (oral PARP I and II inhibitor), its clinical testing in ovarian cancer, including the Myriad MyChoice HRD test as a potential companion diagnostic...
April 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28225676/niraparib-in-recurrent-ovarian-cancer
#14
LETTER
Mansoor R Mirza, Ursula A Matulonis
No abstract text is available yet for this article.
February 23, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28001384/structural-basis-for-potency-and-promiscuity-in-poly-adp-ribose-polymerase-parp-and-tankyrase-inhibitors
#15
Ann-Gerd Thorsell, Torun Ekblad, Tobias Karlberg, Mirjam Löw, Ana Filipa Pinto, Lionel Trésaugues, Martin Moche, Michael S Cohen, Herwig Schüler
Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective...
February 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27898364/liquid-chromatography-tandem-mass-spectrometry-assay-for-the-quantification-of-niraparib-and-its-metabolite-m1-in-human-plasma-and-urine
#16
L van Andel, Z Zhang, S Lu, V Kansra, S Agarwal, L Hughes, M M Tibben, A Gebretensae, H Rosing, J H M Schellens, J H Beijnen
Niraparib (MK-4827) is a novel poly(ADP-Ribose) polymerase (PARP) inhibitor currently investigated in phase III clinical trials to treat cancers. The development of a new drug includes the characterisation of absorption, metabolism and excretion (AME) of the compound. AME studies are a requirement of regulatory agencies and for this purpose bioanalytical assays are essential. This article describes the development and validation of a bioanalytical assay for niraparib and its carboxylic acid metabolite M1 in human plasma and urine using liquid chromatography-tandem mass spectrometry (LC-MS/MS)...
January 1, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/27866910/proteome-wide-profiling-of-clinical-parp-inhibitors-reveals-compound-specific-secondary-targets
#17
Claire E Knezevic, Gabriela Wright, Lily L Remsing Rix, Woosuk Kim, Brent M Kuenzi, Yunting Luo, January M Watters, John M Koomen, Eric B Haura, Alvaro N Monteiro, Caius Radu, Harshani R Lawrence, Uwe Rix
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a promising class of targeted cancer drugs, but their individual target profiles beyond the PARP family, which could result in differential clinical use or toxicity, are unknown. Using an unbiased, mass spectrometry-based chemical proteomics approach, we generated a comparative proteome-wide target map of the four clinical PARPi, olaparib, veliparib, niraparib, and rucaparib. PARPi as a class displayed high target selectivity. However, in addition to the canonical targets PARP1, PARP2, and several of their binding partners, we also identified hexose-6-phosphate dehydrogenase (H6PD) and deoxycytidine kinase (DCK) as previously unrecognized targets of rucaparib and niraparib, respectively...
December 22, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27810860/niraparib-slows-ovarian-cancer-progression
#18
(no author information available yet)
Results from a phase III trial indicate that maintenance therapy with the PARP inhibitor niraparib is more effective than placebo in slowing the progression of recurrent platinum-sensitive ovarian cancer. Improved progression-free survival was seen regardless of the presence or absence of germline BRCA mutations, or of homologous recombination deficiency; however, patients who had these mutations or defective DNA repair did better.
December 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27717299/niraparib-maintenance-therapy-in-platinum-sensitive-recurrent-ovarian-cancer
#19
RANDOMIZED CONTROLLED TRIAL
Mansoor R Mirza, Bradley J Monk, Jørn Herrstedt, Amit M Oza, Sven Mahner, Andrés Redondo, Michel Fabbro, Jonathan A Ledermann, Domenica Lorusso, Ignace Vergote, Noa E Ben-Baruch, Christian Marth, Radosław Mądry, René D Christensen, Jonathan S Berek, Anne Dørum, Anna V Tinker, Andreas du Bois, Antonio González-Martín, Philippe Follana, Benedict Benigno, Per Rosenberg, Lucy Gilbert, Bobbie J Rimel, Joseph Buscema, John P Balser, Shefali Agarwal, Ursula A Matulonis
BACKGROUND: Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. METHODS: In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily...
December 1, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27716873/the-current-status-of-parp-inhibitors-in-ovarian-cancer
#20
REVIEW
Jennifer McLachlan, Angela George, Susana Banerjee
Recent advances in our understanding of the molecular biology of epithelial ovarian cancer have led to the development of a number of targeted therapies, including poly-ADP-ribose polymerase (PARP) inhibitors. PARP inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Early studies have shown significant efficacy for PARP inhibitors in patients with germline BRCA1/2 mutations. It has become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this therapeutic approach...
October 13, 2016: Tumori
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