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Lifestyle Medicine in Menopause and Bone Health
Published in Michelle Tollefson, Nancy Eriksen, Neha Pathak, Improving Women's Health Across the Lifespan, 2021
The two primary types of estrogen receptors are alpha and beta receptors. Endogenous and synthetic estrogens act as nonselective agonists at both receptor types. Drugs that are considered “anti-estrogen” such as fulvestrant, used to treat metastatic breast cancer, are nonselective antagonists at all estrogen receptors. Mixed agonist-antagonists such as synthetic selective estrogen receptor modifiers (SERMs), like tamoxifen, and phytoestrogens act selectively and primarily on beta-receptors.14
Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Early preclinical studies showed that fulvestrant has an antiproliferative effect in both human breast cancer cells in vitro and also in human tumor xenografts with or without acquired resistance to tamoxifen or letrozole. A good toxicity profile in animal studies was also established, and together these data provided the rationale for clinical development in breast cancer patients whose disease has recurred or progressed following endocrine treatment. In early clinical trials in locally advanced or metastatic breast cancer, it was shown to have similar efficacy to the other hormonal agents (i.e., tamoxifen and the aromatase inhibitors) and with a good tolerability profile. In particular, it produced a lower incidence of joint disorders. It was approved by the FDA and EMA in 2002 and 2004, respectively. The original patents protecting fulvestrant are dated to 1985 and were filed by (the then) ICI before it was acquired by AstraZeneca. These patents expired in 2004, although AstraZeneca received a patent extension to December 2011. However, due to other patents filed by AstraZeneca, the latest of which expires in January 2021, there is presently no generic fulvestrant available.
Hormone Receptors and Endocrine Therapy in Breast Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Sherry X. Yang, Nancy E. Davidson
The pure anti-estrogen agent fulvestrant downregulates ER and has no agonist effects [36, 37] It is approved for postmenopausal patients with disease progression following anti-estrogen therapy. Fulvestrant is an active agent in patients who are refractory to tamoxifen or an AI [68–70]. Fulvestrant given at 500 mg every 14 days for the first month followed by every 28 days thereafter, significantly increased progression-free survival as compared with 250 mg every 28 days [71]. In 2017, FDA approved fulvestrant as upfront monotherapy for postmenopausal women with HR+, HER2-advanced breast cancer. One advantage of fulvestrant is its monthly intramuscular injection instead of daily oral intake.
Solubilization of a novel antitumor drug ribociclib in water and ten different organic solvents at different temperatures
Published in Drug Development and Industrial Pharmacy, 2022
Ramadan Al-Shdefat, Mohammad Hailat, Osama Y. Alshogran
Ribociclib (RCB) (chemical structure: Figure 1; IUPAC name: 7-cyclopentyl-N,N-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide) occurs as a light yellow to yellowish-brown crystalline powder [1,2]. In March 2017, the United States Food and Drug Administration (FDA) approved RCB for the treatment of advanced or metastatic breast cancer [2]. It is marketed as a film-coated tablet containing 200 mg RCB (as RCB succinate) for the treatment of advanced or metastatic breast cancer [2,3]. This drug could also be combined with fulvestrant for postmenopausal women for the treatment of advanced or metastatic breast cancer, as the first endocrine-based therapy. RCB is an orally administered small-molecule kinase inhibitor highly selective for CDK4 and CDK6 [4]. The drug starting dose is 600 mg/day for a starting period of 21 out of a 28-day cycle regimen [5]. This dose is under further study since this dosing regimen resulted in a lower rate of corrected QT (QTc) prolongation [6].
An update on first line therapies for metastatic breast cancer
Published in Expert Opinion on Pharmacotherapy, 2018
Palma Fedele, Mariangela Ciccarese, Giammarco Surico, Saverio Cinieri
The open label FACT trial [29] included 514 postmenopausal MBC patients and evaluated the clinical advantage of the combination versus anastrozole alone. The study failed to demonstrate a significant clinical advantage of the combination arm. Time to progression, the primary end point of the study, was not significantly improved from the combination versus anastrozole alone (10.8 versus 10.2 months; HR: 1.0; 95% CI: 0.76–1.32; p = 1.00). Conversely, the SWOG S0226 trial [15] that compared the same combination to anastrozole alone in 707 postmenopausal MBC patients showed a significant benefit in PFS from the combination compared to anastrozole (median PFS: 15 months in the combination arm and 13.5 months in the anastrozole arm; HR: 0.80; 95% CI: 0.68–0.94; p = 0.007). In both the studies, fulvestrant was administered intramuscularly, using a 500-mg loading dose on day 1 followed by 250 mg on days 14 and 28, and 250-mg monthly thereafter.
Deficiency of PSRC1 accelerates atherosclerosis by increasing TMAO production via manipulating gut microbiota and flavin monooxygenase 3
Published in Gut Microbes, 2022
Tiantian Luo, Zhigang Guo, Dan Liu, Zhongzhou Guo, Qiao Wu, Qinxian Li, Rongzhan Lin, Peier Chen, Caiwen Ou, Minsheng Chen
The bile acid receptor nuclear farnesoid X receptor (FXR) induces FMO3 expression.24 Therefore, we assessed the expression of FXR and the target gene bile salt export pump (BSEP), but no corresponding upregulation was found (Figure S4). Further analysis of the differentially expressed genes revealed that the transcriptional levels of estrogen receptor alpha (ERα) were significantly decreased following PSRC1 knockout (p = .027, log2FC = −0.824) (Figure 4a), which verified direct binding to the promoter region of mouse FMO3.25 As expected, a reduction in ERα levels after PSRC1 knockout was observed, which exhibited negative correlations with FMO3 levels in both male and female mice (Figures 4e,4f). We confirmed these results in murine hepatocytes. AML12 cells were transfected with a recombinant adenovirus encoding PSRC1 (PSRC1 OE) and the best transfection efficiency was observed at an MOI at 200 (Figure S5a). Compared with the PBS- or negative control (NC)-treated cells, the AML12 cells treated with PSRC1 OE showed a significant upregulation of PSRC1 mRNA levels (Figure S5b). In contrast, overexpression of PSRC1 strongly inhibited the levels of FMO3 (Figure 4g). Fulvestrant, a selective estrogen receptor inhibitor, has been approved for the treatment of breast cancer by inhibiting ERα signaling and suppressing the immune response.26 To explain the underlying mechanism by which PSRC1 OE inhibited FMO3, we used Fulvestrant to treat the transfected cells. We found that blocking ERα reversed the inhibited effect of PSRC1 OE on FMO3 (Figure 4g). These data demonstrated that PSRC1 inhibited FMO3 expression via the ERα-mediated signaling.