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Maraviroc
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Michael Roche, Sharon R. Lewin, Paul R. Gorry
A concern regarding the use of CCR5 antagonists and the potential for an increased risk of malignancies was raised as a result of the ACTG 5211 trial conducted with vicriviroc. In this trial, after only 14 days of vicriviroc, there were six malignancies in the treatment arm and two with placebo (Gulick et al., 2007). However, the MOTIVATE trials did not show an increase in malignancy in patients receiving maraviroc. A total of 11 malignancies were reported including Kaposi’s sarcoma (three in the two maraviroc arms and three in the single placebo arm) and lymphoma (three in the two maraviroc arms and two in the placebo arm) (Gulick et al., 2008; Soriano et al., 2008).
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
S-Flurbiprofen (4′-hydroxylation) (Yamazaki et al. 1998a), S-warfarin (7-hydroxylation) (Yamazaki et al. 1998a), tolbutamide (methylhydroxylation), phenytoin (4′-hydroxylation) (Giancarlo et al. 2001), losartan (oxidation) (C.R. Lee et al. 2003), and diclofenac (4′-hydroxylation) (Yamazaki et al. 1998a) have been commonly used as probe substrates for CYP2C9 (Kumar et al. 2006). The substrates of CYP2C9 include oral sulfonylurea hypoglycemics (e.g., tolbutamide, glyburide, glimepiride, gliclazide, and glipizide), NSAIDs (e.g., diclofenac, ibuprofen, ketoprofen, suprofen, naproxen, flurbiprofen, indomethacin, meloxicam, piroxicam, tenoxicam, and lornoxicam), selective cyclooxygenase 2 inhibitors (e.g., celecoxib, lumiracoxib, etoricoxib, and valdecoxib), diuretics (e.g., torasemide and sulfinpyrazone), antiepileptics (e.g., phenytoin and phenobarbital), angiotensin II receptor inhibitors (e.g., losartan, irbesartan, and candesartan), anticancer drugs (e.g., cyclophosphamide and tamoxifen), and anticoagulants (e.g., S-acenocoumarol, phenprocoumon, and S-warfarin) (He et al. 2011; Miners and Birkett 1998; Rettie and Jones 2005). Vicriviroc (SCH 417690), a CCR5 receptor antagonist, is metabolized by CYP3A4/5 and 2C9 (Ghosal et al. 2007). CYP2C9 is also involved in the metabolism of the procarcinogen BaP, although CYP1A1/1A2 are the major enzymes responsible for its bioactivation (Ma and Lu 2007). Typical substrates of CYP2C9 such as celecoxib, ibuprofen, flurbiprofen, and diclofenac are relatively small, are lipophilic, and contain acidic groupings with pKa values in the range 3.8–8.1, which will be ionized at physiological pH, forming anions in vivo (He et al. 2011). The carboxylate groups of tienilic acid and diclofenac have been shown to be responsible for substrate preference and orientation in the active site of CYP2C9. Therefore, a typical CYP2C9 substrate should contain an anionic site and a hydrophobic site. However, neutral or positively charged compounds may also be substrates of CYP2C9.
CCR5 is a potential therapeutic target for cancer
Published in Expert Opinion on Therapeutic Targets, 2021
Hossein Hemmatazad, Martin D. Berger
Interestingly, anti-CCR5 treatment led to the reduction of lung metastases, but had no impact on tumor cell proliferation in severe combined immunodeficiency (SCID) mice. This observation suggests that the CCL5/CCR5 axis plays an intriguing role in homing of cancer cells to the metastatic sites. Therefore, targeting CCR5 might be a promising approach to prevent metastases in basal subtype breast cancer [51]. Using a breast cancer mouse model, Halvorsen et al. could demonstrate that treatment with maraviroc inhibited the growth of metastatic tumor cells in the lungs [53]. Jiao et al. could demonstrate that treatment with the CCR5 antagonist maraviroc decreased breast cancer metastases in a mouse model. Interestingly, both CCR5 inhibitors, maraviroc and vicriviroc reduced DNA repair and increased tumor cell death caused by doxorubicin in breast cancer cell lines [49]. Furthermore, anti-CCR5 treatment with vicriviroc and leronlimab inhibited metastatic dissemination of human breast cancer xenografts in SCID mice through increasing cancer cell death by DNA damaging chemotherapeutics [23,106]. Another group found that CCR5 inhibition prevented bone metastasis in nude rats after inoculation of metastatic breast cancer-derived cell lines [99].
The increasing importance of the novel Coronavirus
Published in Hospital Practice, 2021
Mohammad Ridwane Mungroo, Naveed Ahmed Khan, Ruqaiyyah Siddiqui
New treatment options can be discovered faster using drug repurposing rather than searching for novel drugs as the safety profiles for approved drugs are readily accessible. Bioinformatics can be used to effectively identify appropriate drugs for repurposing purposes by analyzing the interactions between dugs with proteins of SARS-CoV-2, the target organism. The use of bioinformatics recently led to the identification of 78 drugs as possible repurposed drugs that could target SARS-CoV-2 [71]. After being refined by eliminating drugs deemed unsuitable for repurposing, based on their side effects and influence on symptoms of SARS-CoV-2, the list was updated to 30 drugs [71]. Pseudoephedrine, Atiprimod, Adalimumab, Tapinarof, Epinephrine, Thalidomide, YSIL6, Infliximab, Andrographolide, Pranlukast, Afelimomab, Siltuximab, Ibalizumab, Abacavir, Etanercept, Golimumab, Cefazolin, Proline, Chloroquine, N-Formylmethionine, Framycetin, Olsalazine, Vicriviroc, Ruplizumab, Artenimol, Clenbuterol, Quercetin, Myricetin, Ketoprofen and Maraviroc are the 30 compounds recognized as potential compounds for repurposing versus SARS-CoV-2 [71]. Bioinformatic tools were also used in another study to elucidate existing compounds that may be appropriate candidates for repurposing against SARS-CoV-2. 15 approved compounds, 4 compounds being tested in phase 1 clinical trials and 18 compounds currently in the pre-clinical stage were elucidated using chemoinformatics while 12 approved compounds, 10 being tested in phase 1 clinical trials and 10 compounds currently in the pre-clinical stage were discovered via specialist knowledge [72]. 3 C-like protease, a 33.8kDa protease, identified as the main protease of SARS-CoV has been described as essential for the transcription and replication of the virus owing to its pivotal role in the processing of pp1a and pp1ab, 2 replicase polyproteins [73]. By using computer-aided drug design, the crystal structure of SARS-CoV-2 main protease was determined and using virtual and high-throughput screening based on the crystalline structure, 6 compounds that can inhibit the activity of the SARS-CoV-2 main protease with IC50 values between 0.67 μM and 21.4 μM were identified [74]. 2 of the compounds, namely disulfiram and carmofur are drugs that are approved by the Food and Drug Administration, and Ebselen, PX-12, Shikonin and Tideglusib are currently undergoing preclinical or clinical trials [74]. It was also demonstrated in vitro that Ebselen displayed activity against SARS-CoV-2 with EC50 value of 4.67 μM, suggesting that it might serve as a potential anti-SARS-CoV-2 drug [74].