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Non-Melanoma Skin Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Irene De Francesco, Sean Whittaker, Stephen L. Morris
Bexarotene is highly selective for the retinoid X receptor and was the first “rexinoid” to undergo clinical development.255,256 The drug has received EMA approval in Europe for the treatment of skin manifestations in advanced CTCL.257 Although the precise mechanisms are unknown, in vitro studies have shown that bexarotene can inhibit growth in tumor cell lines and cause in vivo tumor regression in animal models: the drug also stimulates apoptosis.258 In Phase II and III studies of 152 patients with CTCL, response rates from 20% to 67% have been reported.257,259 Bexarotene is usually administered at 300 mg/m2/day, and treatment is continued indefinitely in patients who respond.173,260 Bexarotene causes severe central hypothyroidism with high frequency, associated with marked reductions in serum concentrations of thyroid-stimulating hormone and thyroxine. During treatment, patients should be monitored for thyroid function and for hyper-triglyceridemia.172 Most patients will require concomitant treatment with a lipid-lowering agent and thyroxine.173,260 Gemfibrozil is contraindicated in this regard because it increases plasma concentrations of bexarotene, presumably due to inhibition of cytochrome P450 3A4, which in turn, results in a paradoxical elevation of triglycerides.173,260
Mechanism of Action of Alitretinoin
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
Ömer Faruk Elmas, Necmettin Akdeniz
Bexarotene has also been approved by the FDA for the treatment of cutaneous T-cell lymphoma both topically and systemically. It has been postulated that it has apoptotic effects on malignant cells via RXR receptors. Two patients with cutaneous T-cell lymphoma have had good results with alitretinoin (28). Here, the mechanism of action of alitretinoin may be related to its antiproliferative, pro-apoptotic, and immunomodulatory effects (1,28).
Drug profiles: generic names A–Z
Published in Jerome Z. Litt, Neil H. Shear, Litt's Drug Eruption & Reaction Manual, 2017
Clinically important, potentially hazardous interactions with: atazanavir, bexarotene, buspirone, carbamazepine, cisplatin, clarithromycin, delavirdine, doxorubicin, efavirenz, eletriptan, felodipine, gadobenate, gemfibrozil, indinavir, itraconazole, ketoconazole, lapatinib, lovastatin, nefazodone, nelfinavir, repaglinide, rifampin, ritonavir, rosiglitazone, saquinavir, sildenafil, simvastatin, telithromycin, teriflunomide, thalidomide, trastuzumab, triazolam
Repurposing existing drugs: identification of SARS-CoV-2 3C-like protease inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Wei-Chung Chiou, Meng-Shiuan Hsu, Yun-Ti Chen, Jinn-Moon Yang, Yeou-Guang Tsay, Hsiu-Chen Huang, Cheng Huang
A compound library of FDA-approved drugs was screened for SARS-CoV-2 3CLpro inhibitory activity using an IQF peptide substrate. A flowchart of the screening procedure is shown in Figure 1. To identify compounds as potential SARS-CoV-2 3CLpro inhibitors, 774 FDA-approved drugs were screened at 20 µM in the high-throughput, initial screening. Among these 774 FDA-approved drugs, twenty potentially active compounds were found, including seven drugs with superior inhibitory activity against SARS-CoV-2 3CLpro. The twenty most active SARS-CoV-2 3CLpro inhibitors are listed in Table 1, with their IC50 values. Briefly, ethacrynic acid, naproxen, allopurinol, butenafine hydrochloride, raloxifene hydrochloride, tranylcypromine hydrochloride, and saquinavir mesylate led to 50% inhibition on SARS-CoV-2 3CLpro activity at concentrations below 10 µM. In addition, triptorelin acetate, goserelin acetate, rocuronium bromide, bisacodyl, armodafinil, and clobetasol propionate had an IC50 value of 10–20 µM, followed sequentially by seven moderate SARS-CoV-2 3CLpro inhibitors: sirolimus (rapamycin), colistin sulphate, cetirizine, bexarotene, cefpodoxime proxetil, clindamycin palmitate hydrochloride and oxaliplatin.
Therapeutic modulation of retinoid X receptors – SAR and therapeutic potential of RXR ligands and recent patents
Published in Expert Opinion on Therapeutic Patents, 2019
NRs are attractive drug targets as their modulation tends to cause a sustained pharmacological effect. With bexarotene (2), an RXR-targeting drug is already approved for the treatment of cutaneous T-cell lymphoma. In the recent decade, 2 has been clinically studied in several other cancers such as non-small cell lung cancer, acute myeloid leukemia, breast cancer, thyroid cancer, and melanoma. All these trials have reported a therapeutic benefit by 2 at least in subpopulations. RXR activation, thus, appears to possess high therapeutic potential in various RXR expressing cancers [13–15]. Moreover, recent mechanistic studies point to an important role of RXR in the induction of cancer cell apoptosis. In vitro and in vivo data indicate that RXR modulation blocks NF-κB dependent survival signaling in cancer cells and enhances the pro-apoptotic potential of TNFα. Accordingly, an RXR modulating nitrostyrene derivative caused marked repression of tumor growth in a mouse xenograft tumor model and concomitant treatment with TNFα led to synergistic anti-tumor activity [16].
Treatment of Rosai–Dorfman disease with oral bexarotene: a case series
Published in Journal of Dermatological Treatment, 2019
Shamir Geller, Klaus Busam, Paul A. Hamlin, Alison J. Moskowitz, Steven M. Horwitz, Patricia L. Myskowski
Few RDD cases that responded to the oral retinoids isotretinoin and acitretin have been reported so far (8–11). We herein report for the first time on oral bexarotene treatment in RDD patients with cutaneous disease. Two patients had excellent response, and regression of their skin lesions was achieved with long-term therapy. In the other patient, pruritus was promptly controlled while the lesions did not seem to regress and treatment was discontinued after five months. In all three cases, response was achieved with doses of 150–300 mg/day (65–160 mg/m2/day). Retinoids are immunomodulating agents that are vitamin A analogs. While isotretinoin and acitretin target nuclear retinoic acid receptor (RAR), bexarotene selectively binds to retinoid X receptors (RXR), thereby effecting cell differentiation and apoptosis in certain hematopoietic cells and inducing tumor regression. The most common side effects of oral bexarotene are hypertriglyceridemia, hypercholesterolemia, and central hypothyroidism, requiring dose adjustments, lipid lowering, and thyroid replacement medications. Like other retinoids, bexarotene is teratogenic and is contraindicated during pregnancy.