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Nanocarrier Technologies for Enhancing the Solubility and Dissolution Rate of Api
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Ashwini Deshpande, Tulshidas S. Patil
Epichlorohydrin β-cyclodextrin is used to make inclusion complex with drug altretamine (ALT-Epi-βCD) to treat ovarian cancer. Complex made with kneading method showed maximum solubility as compared to other methods. SLNs were prepared with ALT-Epi-βCD complex and with the drug alone by using modified emulsification-ultrasonication method. 2.47 fold enhanced peak plasma concentration and enhanced area under the curve of altretamine showed its increased bioavailability after oral administration [23]. Similar kind of enhancement in the oral bioavailability was noticed for the drug acyclovir [228].
Pharmacotherapeutic treatment options for recurrent epithelial ovarian cancer
Published in Expert Opinion on Pharmacotherapy, 2023
Nilanchali Singh, Aarthi S Jayraj, Avir Sarkar, Trishala Mohan, Amlin Shukla, Prafull Ghatage
Effective chemotherapy regimens for platinum-resistant ovarian cancer with tolerable side effect profile are still being evaluated. The role of chemotherapy and targeted agents in this setting is mainly palliative for symptom control and improvement of quality of life. The response rates are around 20–40% for single agent chemotherapeutic agents such as paclitaxel, topotecan, pegylated liposomal doxorubicin, gemcitabine, trabectedin, etc. In the 2000s, the GOG started a series of single arm phase II studies for evaluating chemotherapeutic regimens in platinum-resistant ovarian cancers in patients who had received 1 prior therapy [79,80]. Docetaxel (126 J), Nab-paclitaxel (126 R), weekly paclitaxel (126 N), pemetrexed (126Q) were all tested, showing a response rate of 20–25%. Other agents such as oxaliplatin (126 K), ixabepilone (126 M), and altretamine (126C) showed response rates of 5–15%. The 186 series was started in 2002 to evaluate response in women who had undergone 1–3 previous therapies [80]. The other trials that evaluated various chemotherapeutic agents in platinum resistant ovarian cancer are summarized in Table 2.
The mechanisms and therapeutic targets of ferroptosis in cancer
Published in Expert Opinion on Therapeutic Targets, 2021
Long Ye, Fengyan Jin, Shaji K. Kumar, Yun Dai
Ferroptosis is involved in the mechanisms underlying the cytotoxicity of various chemotherapeutic agents, including cisplatin, decitabine, altretamine, and TMZ. In addition to apoptosis induction, cisplatin results in GSH depletion and inactivates GPX4, which triggers ferroptosis in NSCLC and colon cancer. The combination of erastin and cisplatin displays a synergistic effect[80]. Decitabine also decreases GSH and inhibits GPX4 activity to increase ROS levels in myelodysplastic syndromes (MDS)/AML cells, while FINs enhance the anti-leukemia effect of decitabine. Altretamine, an alkylator with anti-tumor activity against ovarian cancer, inhibits GPX4 and effectively kills DLBCL cells. TMZ, the first-line therapeutic agent for the treatment of GBM, inhibits the growth of glioblastoma stem cell-like cells (GSCs) via autophagy, while pharmacological inhibition of autophagy leads to the accumulation of lipid peroxide and facilitates the cytotoxicity of TMZ against GSCs[81].
Improving the efficacy-safety balance of polypharmacology in multi-target drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Balaguru Ravikumar, Tero Aittokallio
A systematic study that evaluated the performance of NBI algorithms against standard target-based inference and compound-based inference algorithms was carried out by Cheng et al. [43]. Their implementation of the NBI algorithm outperformed both the target and compound-centric based methods, and was successful in repositioning drugs for human estrogen receptor (ER). Another network polypharmacology approach, Target Inhibition using Maximization and Minimization Averaging (TIMMA), uses only monotherapy responses in a given cell sample to identify selective target combination through target inhibition networks. TIMMA model makes use of the target space of promiscuous kinase inhibitors to predict efficacies for novel drug-target combinations [89]. As a case study, TIMMA was used to identify selective target combinations for breast cancer and pancreatic cell-lines, and the prediction was later experimentally validated using siRNA-mediated silencing. Recently, a gene regulatory network-based approach was developed to elucidate compounds MoA using algorithm called Detecting Mechanism of Action by Network Dysregulation (DeMAND) [44]. DeMAND interrogates tissue-specific gene regulatory network changes following compound perturbation, and identifies novel proteins that are accompanied with the established MoA of the given compound. This method identified glutathione peroxidase 4 (GPX4) as a novel MoA effector for altretamine, which was later experimentally validated using liquid chromatography-mass spectrometry (LC-MS)-based GPX4 assay.