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Role of Natural Polyphenols in Oxidative Stress: Prevention of Diabetes
Published in Megh R. Goyal, Durgesh Nandini Chauhan, Assessment of Medicinal Plants for Human Health, 2020
Brahm Kumar Tiwari, Kanti Bhooshan Pandey
Several studies on intervention of diabetes and its complications have reported that polyphenols may improve insulin sensitivity through the factors like increased insulin-dependent glucose uptake via GLUT-4, translocation of cell membrane, activation of adenosine 5’-monophosphate-activated protein kinase (AMPK), and phosphoinositide 3-kinase inhibitor (PI3K).4,51
Inhibiting Low-Density Lipoproteins Intimal Deposition and Preserving Nitric Oxide Function in the Vascular System
Published in Christophe Wiart, Medicinal Plants in Asia for Metabolic Syndrome, 2017
Ligustrazine from Ligusticum wallichii Franch. given intravenously at a dose of 10 mg/kg to Sprague–Dawley rats 5 minutes before myocardial infarction (induced by ligation of the left anterior descending artery followed by reperfusion) reduced infarct size by 25% and this effect was abrogated by co-administration with either phosphoinositide 3-kinase inhibitor wortmannin or nitric oxide synthetase inhibitor Nω-nitro-l-arginine methyl ester.250 The treatment reduced the content of malondialdehyde, increased the enzymatic activity of superoxide dismutase, elevated contents of nitric oxide and lowered the apoptotic index from 25.2% to 15% in myocardial tissues.250 Further caspase 3 activity was decreased by ligustrazine pretreatment by more than half in cardiac tissues.250 In addition, this tetramethyl pyrazine induced the activation of Akt and endothelial nitric oxide synthetase in cardiac tissue.250
Surgery, wound healing, and peritoneal minimal residual disease in colorectal cancer
Published in Wim P. Ceelen, Edward A. Levine, Intraperitoneal Cancer Therapy, 2015
Since dormant cells are resistant to cytotoxic drugs, therapeutic efforts should be directed toward inhibiting angiogenesis and activation of dormant cancer populations possibly starting already before surgery. In preclinical models, maintenance drugs shown to suppress the metastatic phenotype include histone deacetylase inhibitors, NFκB inhibitors, MMP modifiers, or growth factor antagonists [120–123]. Coffey et al. showed that adjuvant administration of the phosphoinositide 3-kinase inhibitor LY294002 prolonged survival and significantly attenuated recurrent tumor growth in a murine model of cytoreduction of a flank tumor [124].
Combination therapies in clinical trials for renal cell carcinoma: how could they impact future treatments?
Published in Expert Opinion on Investigational Drugs, 2021
Novel VEGF and strategies continue to be explored. ESK981 is a pan-VEGF and TIE inhibitor, which is being explored in a phase 2 trial in both combination with nivolumab and as monotherapy in patients previously treated with VEGF blockade [NCT03562507]. Eganelisib (IPI-549) is a first in class PI3K-γ inhibitor, which is being trialed in combination with atezolizumab and bevacizumab in the first-line setting. Sapanisertib, a highly selective inhibitor of mTORC1/mTORC2, has shown preliminary antitumor activity in patients with RCC and is the current subject of both a single agent Phase 2 trial and a combination trial with MLN1117 (a phosphoinositide 3-kinase inhibitor) compared with everolimus. Famitinib (famitinib l-malate) is a novel and potent receptor TKI (rTKI) which targets c-KIT, vascular endothelial growth factor receptor-2 and −3 (VEGFR-2 and −3), platelet-derived growth factor receptor (PDGFR), FMS-like TK-3 receptor (FLT3) and RET [40]. Ningetinib (CT053PTSA) is a potent, orally bioavailable smallmolecule TKI against c-Met, VEGFR2 as well as AXL, MER, and FLT3 and is being tested in an ongoing Phase 1b trial. [NCT03758287].
Advances in cyclin-dependent kinase inhibitors for the treatment of melanoma
Published in Expert Opinion on Pharmacotherapy, 2021
Maximilian Julve, James J. Clark, Mark P. Lythgoe
Specifically, in melanoma several trials are underway which explore the use of CDK 4/6i with concomitant use of exploratory biomarkers. The LOGIC (NCT01820364) & LOGIC-2 (NCT02159066) trials utilizes an adaptive trial design which focuses on BRAFv600 mutant melanoma patients who have progressed on encorafenib and binimetinib. This drug combination is continued beyond progression with a third agent added based on tumor molecular phenotyping, including ribociclib, buparlisib (phosphoinositide-3-kinase inhibitor), infigratinib (fibroblast growth factor receptor inhibitor) or capmatinib (MET inhibitor). The LOGIC trial has been terminated due to scientific and business considerations, however LOGIC 2 is still recruiting at the date of censoring. A further clinical trial based on molecular profiling and matched targeted therapy, called MatchMel (NCT02645149) is underway for patients with melanoma and BRAF or NRAS mutations. This includes palbociclib as a potential therapy, in addition to other targeted therapies for patients with abnormalities in cyclin D1, cyclin D3 and p16INK4A.
Melflufen for relapsed and refractory multiple myeloma
Published in Expert Opinion on Investigational Drugs, 2020
Albert Oriol, Alessandra Larocca, Xavier Leleu, Roman Hajek, Hani Hassoun, Paula Rodríguez-Otero, Agne Paner, Fredrik H. Schjesvold, Joachim Gullbo, Paul G. Richardson
Idecabtagene vicleucel (bb2121; ide-cel), an investigational autologous BCMA chimeric antigen receptor (CAR) T-cell therapy [36], was evaluated in a Phase I study (CRB-401) in 33 patients with RRMM who had received at least three prior therapies, including an IMiD, a proteasome inhibitor, or both, and in the expansion phase, patients had prior daratumumab, and were refractory to their most recent therapy [36]. The ORR was 85% and, with a median follow-up of 11.3 months (range, 6.2–22.8), the median PFS was 11.8 months [36]. Common grade 3/4 AEs with ide-cel were anemia (45%/0%), leukopenia (18%/39%), thrombocytopenia (15%/30%), and neutropenia (6%/79%) [36]. Grade ≥3 cytokine release syndrome and neurotoxicity events were reported in 6% (n = 2) and 3% (n = 1) of patients treated with ide-cel, respectively, and no grade 4 cytokine release syndrome was reported [36]. One death (cardiopulmonary arrest) considered to be unrelated to treatment was reported [36]. Results from the CRB-401 study suggest ide-cel is safe and yields high response rates in patients with RRMM with at least three prior therapies [36]. KArMMA, an ongoing, multicenter Phase II study of ide-cel, examining the efficacy and safety of a 150-to-450x106 dose of ide-cel, has enrolled 128 patients with triple-exposed RRMM [37]. After a median follow up of 11.3 months, the study has met its primary endpoint, with an ORR of 73.4% [37]. The next-generation anti-BCMA CAR T–cell therapy bb21217, which adds a phosphoinositide 3-kinase inhibitor to enrich for memory-like T cells, is currently in Phase I clinical studies [38].