Generic placeholder image

Recent Patents on Anti-Cancer Drug Discovery

Editor-in-Chief

ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

Review Article

Feasibility of Repurposing Clioquinol for Cancer Therapy

Author(s): Raheel Khan, Harras Khan, Yassen Abdullah and Q. Ping Dou*

Volume 15, Issue 1, 2020

Page: [14 - 31] Pages: 18

DOI: 10.2174/1574892815666200227090259

Price: $65

Abstract

Background: Cancer is a prevalent disease in the world and is becoming more widespread as time goes on. Advanced and more effective chemotherapeutics need to be developed for the treatment of cancer to keep up with this prevalence. Repurposing drugs is an alternative to discover new chemotherapeutics. Clioquinol is currently being studied for reposition as an anti-cancer drug.

Objective: This study aimed to summarize the anti-cancer effects of clioquinol and its derivatives through a detailed literature and patent review and to review their potential re-uses in cancer treatment.

Methods: Research articles were collected through a PubMed database search using the keywords “Clioquinol” and “Cancer.” The keywords “Clioquinol Derivatives” and “Clioquinol Analogues” were also used on a PubMed database search to gather research articles on clioquinol derivatives. Patents were gathered through a Google Patents database search using the keywords “Clioquinol” and “Cancer.”

Results: Clioquinol acts as a copper and zinc ionophore, a proteasome inhibitor, an anti-angiogenesis agent, and is an inhibitor of key signal transduction pathways responsible for its growth-inhibitory activity and cytotoxicity in cancer cells preclinically. A clinical trial conducted by Schimmer et al., resulted in poor outcomes that prompted studies on alternative clioquinol-based applications, such as new combinations, new delivery methods, or new clioquinol-derived analogues. In addition, numerous patents claim alternative uses of clioquinol for cancer therapy.

Conclusion: Clioquinol exhibits anti-cancer activities in many cancer types, preclinically. Low therapeutic efficacy in a clinical trial has prompted new studies that aim to discover more effective clioquinol- based cancer therapies.

Keywords: Cancer, clioquinol, copper ionophore, cytotoxicity, proteasome, zinc ionophore.

[1]
Sleire L, Førde HE, Netland IA, Leiss L, Skeie BS, Enger PO. Drug repurposing in cancer. Pharmacol Res 2017; 124: 74-91.
[http://dx.doi.org/10.1016/j.phrs.2017.07.013] [PMID: 28712971]
[2]
Cha Y, Erez T, Reynolds IJ, et al. Drug repurposing from the perspective of pharmaceutical companies. Br J Pharmacol 2018; 175(2): 168-80.
[http://dx.doi.org/10.1111/bph.13798] [PMID: 28369768]
[3]
Pushpakom S, Iorio F, Eyers PA, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 2019; 18(1): 41-58.
[http://dx.doi.org/10.1038/nrd.2018.168] [PMID: 30310233]
[4]
Arbiser JL, Kraeft S-K, Leeuwen R van, et al. Clioquinol-zinc chelate: a candidate causative agent of subacute myelo-optic neuropathy. Mol Med 1998; 4(10): 665-70.
[http://dx.doi.org/10.1007/BF03401927] [PMID: 9848083]
[5]
Tateishi J. Subacute myelo-optico-neuropathy: clioquinol intoxication in humans and animals. Neuropathology 2000; 20: S20-4.
[http://dx.doi.org/10.1046/j.1440-1789.2000.00296.x] [PMID: 11037182]
[6]
Konagaya M. [SMON: toxicity of clioquinol and the status quo]. Brain Nerve 2015; 67(1): 49-62.
[PMID: 25585435]
[7]
Perez DR, Sklar LA, Chigaev A. Clioquinol: To harm or heal. Pharmacol Ther 2019; 199: 155-63.
[http://dx.doi.org/10.1016/j.pharmthera.2019.03.009] [PMID: 30898518]
[8]
Benvenisti-Zarom L, Chen J, Regan RF. The oxidative neurotoxicity of clioquinol. Neuropharmacology 2005; 49(5): 687-94.
[http://dx.doi.org/10.1016/j.neuropharm.2005.04.023] [PMID: 15992834]
[9]
Mao X, Schimmer AD. The toxicology of Clioquinol. Toxicol Lett 2008; 182(1-3): 1-6.
[http://dx.doi.org/10.1016/j.toxlet.2008.08.015] [PMID: 18812216]
[10]
Bareggi SR, Cornelli U. Clioquinol: review of its mechanisms of action and clinical uses in neurodegenerative disorders. CNS Neurosci Ther 2012; 18(1): 41-6.
[http://dx.doi.org/10.1111/j.1755-5949.2010.00231.x] [PMID: 21199452]
[11]
McInerney MP, Volitakis I, Bush AI, Banks WA, Short JL, Nicolazzo JA. Ionophore and biometal modulation of p-glycoprotein expression and function in human brain microvascular endothelial cells. Pharm Res 2018; 35(4): 83.
[http://dx.doi.org/10.1007/s11095-018-2377-6] [PMID: 29508078]
[12]
Melov S. '...and C is for Clioquinol’ - the AbetaCs of Alzheimer’s disease. Trends Neurosci 2002; 25(3): 121-3.
[http://dx.doi.org/10.1016/S0166-2236(00)02086-5] [PMID: 11852134]
[13]
Mao F, Yan J, Li J, et al. New multi-target-directed small molecules against Alzheimer’s disease: a combination of resveratrol and clioquinol. Org Biomol Chem 2014; 12(31): 5936-44.
[http://dx.doi.org/10.1039/C4OB00998C] [PMID: 24986600]
[14]
Regland B, Lehmann W, Abedini I, et al. Treatment of Alzheimer’s disease with clioquinol. Dement Geriatr Cogn Disord 2001; 12(6): 408-14.
[http://dx.doi.org/10.1159/000051288] [PMID: 11598313]
[15]
Opazo C, Luza S, Villemagne VL, et al. Radioiodinated clioquinol as a biomarker for beta-amyloid: Zn complexes in Alzheimer’s disease. Aging Cell 2006; 5(1): 69-79.
[http://dx.doi.org/10.1111/j.1474-9726.2006.00196.x] [PMID: 16441845]
[16]
Barcia E, Salama A, Fernández-Carballido A, Negro S. Protective effects of clioquinol on human neuronal-like cells: a new formulation of clioquinol-loaded PLGA microspheres for Alzheimer’s disease. J Drug Target 2011; 19(8): 637-46.
[http://dx.doi.org/10.3109/1061186X.2010.523789] [PMID: 20945972]
[17]
Wang T, Zheng W, Xu H, Zhou J-M, Wang Z-Y. Clioquinol inhibits zinc-triggered caspase activation in the hippocampal CA1 region of a global ischemic gerbil model. PLoS One 2010; 5(7) e11888
[http://dx.doi.org/10.1371/journal.pone.0011888] [PMID: 20686690]
[18]
Duncan C, White AR. Copper complexes as therapeutic agents. Metallomics 2012; 4(2): 127-38.
[http://dx.doi.org/10.1039/C2MT00174H] [PMID: 22187112]
[19]
Frezza M, Hindo S, Chen D, et al. Novel metals and metal complexes as platforms for cancer therapy. Curr Pharm Des 2010; 16(16): 1813-25.
[http://dx.doi.org/10.2174/138161210791209009] [PMID: 20337575]
[20]
Zhai S, Yang L, Cui QC, Sun Y, Dou QP, Yan B. Tumor cellular proteasome inhibition and growth suppression by 8-hydroxyquinoline and clioquinol requires their capabilities to bind copper and transport copper into cells. J Biol Inorg Chem 2010; 15(2): 259-69.
[http://dx.doi.org/10.1007/s00775-009-0594-5] [PMID: 19809836]
[21]
Franklin RB, Zou J, Costello LC. The cytotoxic role of RREB1, ZIP3 zinc transporter, and zinc in human pancreatic adenocarcinoma. Cancer Biol Ther 2014; 15(10): 1431-7.
[http://dx.doi.org/10.4161/cbt.29927] [PMID: 25050557]
[22]
Costello LC, Franklin RB. Cytotoxic/tumor suppressor role of zinc for the treatment of cancer: an enigma and an opportunity. Expert Rev Anticancer Ther 2012; 12(1): 121-8.
[http://dx.doi.org/10.1586/era.11.190] [PMID: 22149438]
[23]
Daniel KG, Chen D, Orlu S, Cui QC, Miller FR, Dou QP. Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteasome inhibitors and apoptosis inducers in human breast cancer cells. Breast Cancer Res 2005; 7(6): R897-908.
[http://dx.doi.org/10.1186/bcr1322] [PMID: 16280039]
[24]
Ding WQ, Liu B, Vaught JL, Yamauchi H, Lind SE. Anticancer activity of the antibiotic clioquinol. Cancer Res 2005; 65(8): 3389-95.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-3577] [PMID: 15833873]
[25]
Zhang H, Chen D, Ringler J, et al. Disulfiram treatment facilitates phosphoinositide 3-kinase inhibition in human breast cancer cells in vitro and in vivo. Cancer Res 2010; 70(10): 3996-4004.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-3752] [PMID: 20424113]
[26]
Zheng J, Benbrook DM, Yu H, Ding WQ. Clioquinol suppresses cyclin D1 gene expression through transcriptional and post-transcriptional mechanisms. Anticancer Res 2011; 31(9): 2739-47.
[PMID: 21868515]
[27]
Zheng J, Zhang XX, Yu H, Taggart JE, Ding WQ. Zinc at cytotoxic concentrations affects posttranscriptional events of gene expression in cancer cells. Cell Physiol Biochem 2012; 29(1-2): 181-8.
[http://dx.doi.org/10.1159/000337599] [PMID: 22415087]
[28]
Xue J, Wang S, Wu J, Hannafon BN, Ding WQ. Zinc at sub-cytotoxic concentrations induces heme oxygenase-1 expression in human cancer cells. Cell Physiol Biochem 2013; 32(1): 100-10.
[http://dx.doi.org/10.1159/000350128] [PMID: 23868099]
[29]
Lu S, Ke Y, Wu C, et al. Radiosensitization of clioquinol and zinc in human cancer cell lines. BMC Cancer 2018; 18(1): 448.
[http://dx.doi.org/10.1186/s12885-018-4264-2] [PMID: 29678153]
[30]
Kumar S, Ahmad MK, Waseem M, Pandey AK. Drug targets for cancer treatment: An overview. Med Chem (Los Angeles) 2015; 5(3): 115-23.
[http://dx.doi.org/10.4172/2161-0444.1000252]
[31]
Cao B, Li J, Zhu J, et al. The antiparasitic clioquinol induces apoptosis in leukemia and myeloma cells by inhibiting histone deacetylase activity. J Biol Chem 2013; 288(47): 34181-9.
[http://dx.doi.org/10.1074/jbc.M113.472563] [PMID: 24114842]
[32]
Cao B, Li J, Zhou X, et al. Clioquinol induces pro-death autophagy in leukemia and myeloma cells by disrupting the mTOR signaling pathway. Sci Rep 2014; 4(5749): 5749.
[PMID: 25034786]
[33]
Mao H, Wang M, Cao B, Zhou H, Zhang Z, Mao X. Interferon-stimulated gene 15 induces cancer cell death by suppressing the NF-κB signaling pathway. Oncotarget 2016; 7(43): 70143-51.
[http://dx.doi.org/10.18632/oncotarget.12160] [PMID: 27659523]
[34]
Perez D, Simons PC, Smagley Y, Sklar LA, Chigaev A. A high throughput flow cytometry assay for identification of inhibitors of 3′:5′-cyclic adenosine monophosphate efflux. Methods Mol Biol 2016; 1439: 227-44.
[http://dx.doi.org/10.1007/978-1-4939-3673-1_15] [PMID: 27316999]
[35]
Mao X, Li X, Sprangers R, et al. Clioquinol inhibits the proteasome and displays preclinical activity in leukemia and myeloma. Leukemia 2009; 23(3): 585-90.
[http://dx.doi.org/10.1038/leu.2008.232] [PMID: 18754030]
[36]
Perez DR, Smagley Y, Garcia M, et al. Cyclic AMP efflux inhibitors as potential therapeutic agents for leukemia. Oncotarget 2016; 7(23): 33960-82.
[http://dx.doi.org/10.18632/oncotarget.8986] [PMID: 27129155]
[37]
Carpentieri U, Myers J, Thorpe L, Daeschner CW III, Haggard ME. Copper, zinc, and iron in normal and leukemic lymphocytes from children. Cancer Res 1986; 46(2): 981-4.
[PMID: 3455680]
[38]
Chen D, Cui QC, Yang H, et al. Clioquinol, a therapeutic agent for Alzheimer’s disease, has proteasome-inhibitory, androgen receptor-suppressing, apoptosis-inducing, and antitumor activities in human prostate cancer cells and xenografts. Cancer Res 2007; 67(4): 1636-44.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-3546] [PMID: 17308104]
[39]
Barrea RA, Chen D, Irving TC, Dou QP. Synchrotron X-ray imaging reveals a correlation of tumor copper speciation with Clioquinol’s anticancer activity. J Cell Biochem 2009; 108(1): 96-105.
[http://dx.doi.org/10.1002/jcb.22231] [PMID: 19530227]
[40]
Cater MA, Haupt Y. Clioquinol induces cytoplasmic clearance of the X-linked inhibitor of apoptosis protein (XIAP): therapeutic indication for prostate cancer. Biochem J 2011; 436(2): 481-91.
[http://dx.doi.org/10.1042/BJ20110123] [PMID: 21426304]
[41]
Yu H, Zhou Y, Lind SE, Ding W-Q. Clioquinol targets zinc to lysosomes in human cancer cells. Biochem J 2009; 417(1): 133-9.
[http://dx.doi.org/10.1042/BJ20081421] [PMID: 18764784]
[42]
Yu H, Lou JR, Ding WQ. Clioquinol independently targets NF-kappaB and lysosome pathways in human cancer cells. Anticancer Res 2010; 30(6): 2087-92.
[PMID: 20651355]
[43]
Costello LC, Franklin RB. A proposed efficacious treatment with clioquinol (zinc ionophore) and cabergoline (prolaction dopamine agonist) for the treatment of terminal androgen-independent prostate cancer. Why and how? J Clin Oncol 2019; 2(1): 1-15.
[44]
Franklin RB, Zou J, Zheng Y, Naslund MJ, Costello LC. Zinc ionophore clioquinol inhibition of hZIP1 deficient prostate tumor growth in the mouse. Int J Cancer Clin Res 2016; 3(1): 1-11.
[http://dx.doi.org/10.23937/2378-3419/3/1/1037] [PMID: 26878064]
[45]
Huang Z, Wang L, Chen L, Zhang Y, Shi P. Induction of cell cycle arrest via the p21, p27-cyclin E,A/Cdk2 pathway in SMMC-7721 hepatoma cells by clioquinol. Acta Pharm 2015; 65(4): 463-71.
[http://dx.doi.org/10.1515/acph-2015-0034] [PMID: 26677902]
[46]
Chan-On W, Huyen NTB, Songtawee N, Suwanjang W, Prachayasittikul S, Prachayasittikul V. Quinoline-based clioquinol and nitroxoline exhibit anticancer activity inducing FoxM1 inhibition in cholangiocarcinoma cells. Drug Des Devel Ther 2015; 9: 2033-47.
[PMID: 25897210]
[47]
Du T, Filiz G, Caragounis A, Crouch PJ, White AR. Clioquinol promotes cancer cell toxicity through tumor necrosis factor alpha release from macrophages. J Pharmacol Exp Ther 2008; 324(1): 360-7.
[http://dx.doi.org/10.1124/jpet.107.130377] [PMID: 17940196]
[48]
Ding WQ, Yu HJ, Lind SE. Zinc-binding compounds induce cancer cell death via distinct modes of action. Cancer Lett 2008; 271(2): 251-9.
[http://dx.doi.org/10.1016/j.canlet.2008.06.011] [PMID: 18639975]
[49]
Katsuyama M, Iwata K, Ibi M, Matsuno K, Matsumoto M, Yabe-Nishimura C. Clioquinol induces DNA double-strand breaks, activation of ATM, and subsequent activation of p53 signaling. Toxicology 2012; 299(1): 55-9.
[http://dx.doi.org/10.1016/j.tox.2012.05.013] [PMID: 22627294]
[50]
Kawamura K, Kuroda Y, Sogo M, Fujimoto M, Inui T, Mitsui T. Superoxide dismutase as a target of clioquinol-induced neurotoxicity. Biochem Biophys Res Commun 2014; 452(1): 181-5.
[http://dx.doi.org/10.1016/j.bbrc.2014.04.067] [PMID: 24755073]
[51]
Schimmer AD, Jitkova Y, Gronda M, et al. A phase I study of the metal ionophore clioquinol in patients with advanced hematologic malignancies. Clin Lymphoma Myeloma Leuk 2012; 12(5): 330-6.
[http://dx.doi.org/10.1016/j.clml.2012.05.005] [PMID: 22683301]
[52]
Wehbe M, Malhotra AK, Anantha M, et al. Development of a copper-clioquinol formulation suitable for intravenous use. Drug Deliv Transl Res 2018; 8(1): 239-51.
[http://dx.doi.org/10.1007/s13346-017-0455-7] [PMID: 29247315]
[53]
Tsai W, Tsai H, Wong Y, Hong J, Chang S, Lee M. Preparation and characterization of gellan gum/glucosamine/clioquinol film as oral cancer treatment patch. Mater Sci Eng C 2018; 82: 317-22.
[http://dx.doi.org/10.1016/j.msec.2017.05.040] [PMID: 29025664]
[54]
Jiang H, Xing J, Wang C, et al. Discovery of novel BET inhibitors by drug repurposing of nitroxoline and its analogues. Org Biomol Chem 2017; 15(44): 9352-61.
[http://dx.doi.org/10.1039/C7OB02369C] [PMID: 29087414]
[55]
Mao H, Du Y, Zhang Z, et al. Nitroxoline shows antimyeloma activity by targeting the TRIM25/p53 axle. Anticancer Drugs 2017; 28(4): 376-83.
[http://dx.doi.org/10.1097/CAD.0000000000000466] [PMID: 28301380]
[56]
Li X, Wood TE, Sprangers R, et al. Effect of noncompetitive proteasome inhibition on bortezomib resistance. J Natl Cancer Inst 2010; 102(14): 1069-82.
[http://dx.doi.org/10.1093/jnci/djq198] [PMID: 20505154]
[57]
Yu JG, Ji CH, Shi MH. Nitroxoline induces cell apoptosis by inducing MDM2 degradation in small-cell lung cancer. Kaohsiung J Med Sci 2019; 35(4): 202-8.
[http://dx.doi.org/10.1002/kjm2.12051] [PMID: 30896891]
[58]
Veschi S, De Lellis L, Florio R, et al. Effects of repurposed drug candidates nitroxoline and nelfinavir as single agents or in combination with erlotinib in pancreatic cancer cells. J Exp Clin Cancer Res 2018; 37(1): 236.
[http://dx.doi.org/10.1186/s13046-018-0904-2] [PMID: 30241558]
[59]
Kim YH, Woo KJ, Lim JH, et al. 8-Hydroxyquinoline inhibits iNOS expression and nitric oxide production by down-regulating LPS-induced activity of NF-kappaB and C/EBPbeta in Raw 264.7 cells. Biochem Biophys Res Commun 2005; 329(2): 591-7.
[http://dx.doi.org/10.1016/j.bbrc.2005.01.159] [PMID: 15737626]
[60]
Pun IHY, Chan D, Chan SH, et al. Anti-cancer effects of a novel quinoline derivative 83b1 on human esophageal squamous cell carcinoma through down-regulation of COX-2 mRNA and PGE2. Cancer Res Treat 2017; 49(1): 219-29.
[http://dx.doi.org/10.4143/crt.2016.190] [PMID: 27456944]
[61]
Joshi PV, Sayed AA, RaviKumar A, Puranik VG, Zinjarde SS. 4-Phenyl quinoline derivatives as potential serotonin receptor ligands with antiproliferative activity. Eur J Med Chem 2017; 136: 246-58.
[http://dx.doi.org/10.1016/j.ejmech.2017.05.002] [PMID: 28499170]
[62]
Mitrović A, Sosič I, Kos Š, et al. Addition of 2-(ethylamino)acetonitrile group to nitroxoline results in significantly improved anti-tumor activity in vitro and in vivo. Oncotarget 2017; 8(35): 59136-47.
[http://dx.doi.org/10.18632/oncotarget.19296] [PMID: 28938624]
[63]
Shaw AY, Chang CY, Hsu MY, et al. Synthesis and structure-activity relationship study of 8-hydroxyquinoline-derived Mannich bases as anticancer agents. Eur J Med Chem [Internet] 2010; 45(7): 2860-7.
[http://dx.doi.org/10.1016/j.ejmech.2010.03.008] [PMID: 20359788]
[64]
Zhang YL, Qin QP, Cao QQ, et al. Synthesis, crystal structure, cytotoxicity and action mechanism of a Rh(iii) complex with 8-hydroxy-2-methylquinoline as a ligand. MedChemComm 2016; 8(1): 184-90.
[http://dx.doi.org/10.1039/C6MD00462H] [PMID: 30108704]
[65]
Xie F, Peng F. Anti-Prostate Cancer Activity of 8-Hydroxyquinoline-2-carboxaldehyde-thiosemicarbazide copper complexes by fluorescent microscopic imaging. J Fluoresc 2017; 27(6): 1937-41.
[http://dx.doi.org/10.1007/s10895-017-2133-z] [PMID: 28653241]
[66]
Chan SH, Chui CH, Chan SW, et al. Synthesis of 8-hydroxyquinoline derivatives as novel antitumor agents. ACS Med Chem Lett 2012; 4(2): 170-4.
[http://dx.doi.org/10.1021/ml300238z] [PMID: 24900641]
[67]
Ariyasu S, Sawa A, Morita A, et al. Design and synthesis of 8-hydroxyquinoline-based radioprotective agents. Bioorg Med Chem 2014; 22(15): 3891-905.
[http://dx.doi.org/10.1016/j.bmc.2014.06.017] [PMID: 25002230]
[68]
Barilli A, Atzeri C, Bassanetti I, et al. Oxidative stress induced by copper and iron complexes with 8-hydroxyquinoline derivatives causes paraptotic death of HeLa cancer cells. Mol Pharm 2014; 11(4): 1151-63.
[http://dx.doi.org/10.1021/mp400592n] [PMID: 24592930]
[69]
Jiang H, Taggart JE, Zhang X, Benbrook DM, Lind SE, Ding W-Q. Nitroxoline (8-hydroxy-5-nitroquinoline) is more a potent anti-cancer agent than clioquinol (5-chloro-7-iodo-8-quinoline). Cancer Lett 2011; 312(1): 11-7.
[http://dx.doi.org/10.1016/j.canlet.2011.06.032] [PMID: 21899946]
[70]
Shim JS, Matsui Y, Bhat S, et al. Effect of nitroxoline on angiogenesis and growth of human bladder cancer. J Natl Cancer Inst 2010; 102(24): 1855-73.
[http://dx.doi.org/10.1093/jnci/djq457] [PMID: 21088277]
[71]
Chen HL, Chang CY, Lee HT, et al. Synthesis and pharmacological exploitation of clioquinol-derived copper-binding apoptosis inducers triggering reactive oxygen species generation and MAPK pathway activation. Bioorg Med Chem 2009; 17(20): 7239-47.
[http://dx.doi.org/10.1016/j.bmc.2009.08.054] [PMID: 19748786]
[72]
Oliveri V, Viale M, Caron G, Aiello C, Gangemi R, Vecchio G. Glycosylated copper(II) ionophores as prodrugs for β-glucosidase activation in targeted cancer therapy. Dalton Trans 2013; 42(6): 2023-34.
[http://dx.doi.org/10.1039/C2DT32429F] [PMID: 23174818]
[73]
Oliveri V, Giuffrida ML, Vecchio G, Aiello C, Viale M. Gluconjugates of 8-hydroxyquinolines as potential anti-cancer prodrugs. Dalton Trans 2012; 41(15): 4530-5.
[http://dx.doi.org/10.1039/c2dt12371a] [PMID: 22354329]
[74]
Tuller ER, Brock AL, Yu H, Lou JR, Benbrook DM, Ding WQ. PPARalpha signaling mediates the synergistic cytotoxicity of clioquinol and docosahexaenoic acid in human cancer cells. Biochem Pharmacol 2009; 77(9): 1480-6.
[http://dx.doi.org/10.1016/j.bcp.2009.02.002] [PMID: 19426685]
[75]
Ding W-Q, Liu B, Vaught JL, Palmiter RD, Lind SE. Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells. Mol Cancer Ther 2006; 5(7): 1864-72.
[http://dx.doi.org/10.1158/1535-7163.MCT-06-0067] [PMID: 16891473]
[76]
Denoyer D, Pearson HB, Clatworthy SAS, et al. Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution. Oncotarget 2016; 7(24): 37064-80.
[http://dx.doi.org/10.18632/oncotarget.9245] [PMID: 27175597]
[77]
He M, Luo M, Liu Q, et al. Combination treatment with fasudil and clioquinol produces synergistic anti-tumor effects in U87 glioblastoma cells by activating apoptosis and autophagy. J Neurooncol 2016; 127(2): 261-70.
[http://dx.doi.org/10.1007/s11060-015-2044-2] [PMID: 26725099]
[78]
Bhat S, Shim JS, Zhang F, Chong CR, Liu JO. Substituted oxines inhibit endothelial cell proliferation and angiogenesis. Org Biomol Chem 2012; 10(15): 2979-92.
[http://dx.doi.org/10.1039/c2ob06978d] [PMID: 22391578]
[79]
Gobec M, Kljun J, Sosič I, et al. Structural characterization and biological evaluation of a clioquinol-ruthenium complex with copper-independent antileukaemic activity. Dalton Trans 2014; 43(24): 9045-51.
[http://dx.doi.org/10.1039/C4DT00463A] [PMID: 24781711]
[80]
Mitrović A, Kljun J, Sosič I, Gobec S, Turel I, Kos J. Clioquinol-ruthenium complex impairs tumour cell invasion by inhibiting cathepsin B activity. Dalton Trans 2016; 45(42): 16913-21.
[http://dx.doi.org/10.1039/C6DT02369J] [PMID: 27711842]
[81]
León IE, Díez P, Baran EJ, Etcheverry SB, Fuentes M. Decoding the anticancer activity of VO-clioquinol compound: the mechanism of action and cell death pathways in human osteosarcoma cells. Metallomics 2017; 9(7): 891-901.
[http://dx.doi.org/10.1039/C7MT00068E] [PMID: 28581009]
[82]
Russl-Jones GJ, Luke MR, Himes SR. Transdermal delivery of pharmaceutical agents. US20070243132. (2007).
[83]
LeMahieu E, Jones C, Stern T, et al. Methods and systems of delivering medication via inhalation. US20080066741. (2008).
[84]
Maksoud YAA, Maher MA. Pharmaceutical compositions for intranasal administration for the treatment of neurodegenerative disorders. US8987199. (2015).
[85]
Castaigne J, Demeule M, Che C, Regina A. Compositions and methods for the transport of therapeutic agents. WO2011041897. (2011).
[86]
Bezwada RS. Control release of biologically active compounds from multi-armed oligomers. US8026285. (2011).
[87]
Tsien R, Aguilera T, Olson E, Jiang T, Nguyen Q. Peptides whose uptake in cells is controllable. US9682151. (2017).
[88]
Emanuel N. Sustained-release drug carrier composition. US10105443. (2018).
[89]
Schutt EG, McGuire RW, Walter PA, Los KDA. Method for formulating large diameter synthetic membrane vesicles. US980842. (2017).
[90]
Lind SE, Ding W. Ionophores as a cancer chemotherapeutic agents. US20060040980. (2006).
[91]
Laughlin M, Anderson MB, Willardsen A, Pleiman C. Methods of treating cancer. US20100093773. (2010).
[92]
Tsai C. Hydroxylated tolans and related compounds in the treatment of a cancer. US8716355. (2014).
[93]
Xilinas M. Method for treating cancer, coronary, inflammatory, and macular disease, combining the modulation of zinc and/or copper dependent proteins. US20080207673. (2008).
[94]
Mumper RJ, Gupte A, Wadhwa S. Polymer-metal chelator conjugates and uses thereof. US20090092664. (2009).
[95]
Gomis R, Arnal A, Pavlovic M, Tarragona M. Method of designing a therapy for breast cancer metastasis. EP3091085. (2011).
[96]
Gomis R, Planet E, Pavlovic M, Arnal A, Tarragona M. Method for the prognosis and treatment of metastasizing cancer of the bone originating from breast cancer. EP3055429. (2014).
[97]
Schimmer AD, Mao X, Steward K. Clioquinol for the treatment of hematological malignancies. US20110123617. (2011).
[98]
Schimmer AD, Li X, Batey R, Wood T, Mao X. 8- Hydroxyquinolin derivatives for the treatment of hematoligcal malignancies. US20110144155. (2011).
[99]
Gajewski TF, Sivan A, Corrales L. Treatment of cancer by manipulation of commensal microflora. US98553202. (2018).
[100]
Chigaev A, Sklar LA, Perez D. Method for cancer cell reprogramming. US9314460. (2016).

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version430msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[19:59:20] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[19:59:20] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[19:59:20] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (125ms)time
  • Application (306ms)time
  • 1 x Application (71.03%)
    306ms
    1 x Booting (28.97%)
    125ms
    14 templates were rendered
    • articlearticle.blade.php#?blade
    • includes.article_top_bannerarticle_top_banner.blade.php#?blade
    • includes.article_referencearticle_reference.blade.php#?blade
    • export_citation_formexport_citation_form.blade.php#?blade
    • includes.article_bottom_bannerarticle_bottom_banner.blade.php#?blade
    • includes.inc_related_journalsinc_related_journals.blade.php#?blade
    • includes.inc_related_ebooksinc_related_ebooks.blade.php#?blade
    • includes.journal_rightmenujournal_rightmenu.blade.php#?blade
    • includes.journal_right_bannerjournal_right_banner.blade.php#?blade
    • layouts.appapp.blade.php#?blade
    • layouts._login_access_login_access.blade.php#?blade
    • layouts._header_header.blade.php#?blade
    • layouts._main_menu_main_menu.blade.php#?blade
    • layouts._footer_menu_footer_menu.blade.php#?blade
    uri
    GET article/{article_id}/{param?}
    middleware
    web, check_user_access
    controller
    App\Http\Controllers\ArticleController@GetArticleDetails
    namespace
    App\Http\Controllers
    where
    as
    article
    file
    app/Http/Controllers/ArticleController.php:1974-2510
    37 statements were executed, 4 of which were duplicates, 33 unique. Show only duplicated220ms
    • Connection Establishedalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 9. middleware::check_user_access:24
      • 10. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 11. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address (ip_address,visitor_agent,visitor_count, created_on,updated_on) VALUES ('59650778','',1,1740513560,1740513560) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740513560
      1.18msalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 11. middleware::check_user_access:24
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address_detail (ip_address,visitor_url,visitor_count, created_on,updated_on) VALUES ('59650778','/article/104871',1,1740513560,1740513560)
      150μsalphaeurekaselec_live_10_06_2022UserAccessCheck.php#27
      Backtrace
      • 11. middleware::check_user_access:27
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_trail WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_corporate WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_token WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_trail WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_corporate WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_token WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 59650778 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59650778) limit 1
      11.67msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 59650778
      • 1: 59650778
      • 2: 59650778
      • 3: 59650778
      • 4: 59650778
      • 5: 59650778
      • 6: 59650778
      • 7: 59650778
      • 8: 59650778
      • 9: 59650778
      • 10: 59650778
      • 11: 59650778
      • 12: 59650778
      • 13: 59650778
      • 14: 59650778
      • 15: 59650778
      Backtrace
      • 14. app/Models/UserAccess/UserAccess.php:784
      • 15. middleware::check_user_access:114
      • 16. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 18. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
    • SELECT at.type_name, p.copyright, p.publisher_location,m.month,y.year, a.publish_on, a.nid article_nid,a.article_id, a.pmid, a.issue_id, a.title, a.abstract,a.podcast,a.altmetric_score,a.altmetric_url,a.kudos_url, a.page_count, a.first_page, a.elocator, a.last_page, i.publication_date, a.file_name, a.file_path, a.doi, a.is_epub,a.epub_type, a.volume_id, a.is_uploaded, a.editor_choice, a.is_epub, j.image_file_name, a.article_no, a.art_type AS article_type, a.supplementary_filename,a.html_filename,a.prc_filename,a.epub_filename, a.graph_abs_lg_filename, a.graph_abs_sm_filename, a.oa_image_lg_filename, a.oa_image_sm_filename, j.journal_banner,a.animated_abstract,a.erratum_in,a.erratum_for, (CASE WHEN a.issue_id =0 THEN j.epub_price ELSE j.price END) AS sell_price, j.epub_price, j.nid AS jour_nid, j.title AS journal_title, j.issn, j.eissn,j.journal_id, j.subtitle AS jour_subtitle, v.volume_id,v.volume_name AS volume, v.year_id, i.title AS issue, i.month_id ,i.type issue_type, j.subtitle,j.formerly_title, ac.subtitle AS epub_title,a.crossmark_enabled,a.text_mining_urls,a.license_urls,a.created, a.receivedate, a.revisedate, a.acceptdate,js.js_title FROM article a LEFT JOIN article_section ac ON a.is_epub = ac.art_sec_id LEFT JOIN journal_section js ON a.js_id = js.js_id LEFT JOIN article_type at ON a.art_type = at.art_type_id LEFT JOIN issue i ON a.issue_id = i.issue_id LEFT JOIN month m ON m.id = i.month_id LEFT JOIN volume v ON v.volume_id = a.volume_id INNER JOIN year y ON y.id = v.year_id INNER JOIN journal j ON j.journal_id = a.journal_id INNER JOIN publisher p ON p.publisher_id = j.publisher_id WHERE a.article_id=104871
      620μsalphaeurekaselec_live_10_06_2022Article.php#408
      Backtrace
      • 11. app/Models/Article.php:408
      • 12. app/Http/Controllers/ArticleController.php:2515
      • 13. app/Http/Controllers/ArticleController.php:2035
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `journal` where `journal_id` = 46 limit 1
      730μsalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 46
      Backtrace
      • 14. app/Models/Journal.php:64
      • 15. app/Http/Controllers/ArticleController.php:2516
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=46) and sj.journal_id!=46 group by `j`.`nid`) as `aggregate_table`
      920μsalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 16. app/Models/Subject.php:200
      • 17. app/Http/Controllers/ArticleController.php:2517
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=46) and sj.journal_id!=46 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      750μsalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 14. app/Models/Subject.php:200
      • 15. app/Http/Controllers/ArticleController.php:2517
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=46) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      1.38msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 16. app/Models/Subject.php:220
      • 17. app/Http/Controllers/ArticleController.php:2518
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=46) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      1.24msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 14. app/Models/Subject.php:220
      • 15. app/Http/Controllers/ArticleController.php:2518
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `keywords` where `article_id` = '104871'
      940μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 104871
      Backtrace
      • 13. app/Models/Keywords.php:43
      • 14. app/Http/Controllers/ArticleController.php:2519
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `article_citation` where `article_id` = '104871'
      7.12msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 104871
      Backtrace
      • 13. app/Models/Article.php:1570
      • 14. app/Http/Controllers/ArticleController.php:2520
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT(au.last_name, IFNULL(CONCAT(' ', au.initials), ''), ' ', au.first_name) AS authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs, CONCAT_WS(' ',au.first_name, IFNULL(CONCAT(' ', au.initials), ''), IFNULL(CONCAT(' ', au.last_name), '')) as authorsmodal , `au`.*, `af`.`ror_id`, `af`.`institution`, `af`.`department`, `af`.`country`, `af`.`city`, `af`.`address`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.institution,','),''), ifnull(concat(af.department,','),''), ifnull(concat(af.address,','),''), ifnull(concat(af.city,','),''), ifnull(concat(af.country,','),''), ifnull(concat(af.postal_code,','),''), ifnull(concat(af.phone,','),''), ifnull(concat(af.fax,','),''))) SEPARATOR '|')) as `author_affiliation`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.web_view,','),''))) SEPARATOR '|')) as `web_view` from `author` as `au` left join `author_affiliation` as `af` on `au`.`author_id` = `af`.`author_id` where `au`.`article_id` = '104871' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      1.17msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 104871
      Backtrace
      • 13. app/Models/Author.php:86
      • 14. app/Http/Controllers/ArticleController.php:2533
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      250μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2535
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `subtitle` from `journal` where `continues_publication_journal` = 1
      430μsalphaeurekaselec_live_10_06_2022Article.php#1960
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/Article.php:1960
      • 14. app/Http/Controllers/ArticleController.php:2062
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • Select j.subtitle, v.volume_id as volume_id,v.year_id,y.year as year,v.volume_name, v.total_no_of_issues, i.issue_id as issue_id,i.title as issue, i.publication_date as issue_pub_date from journal j join volume v on j.journal_id = v.journal_id join issue i on v.volume_id = i.volume_id join article a on a.issue_id = i.issue_id join year y on v.year_id = y.id where j.journal_id = 46 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      26.59msalphaeurekaselec_live_10_06_2022Issue.php#298
      Backtrace
      • 11. app/Models/Issue.php:298
      • 12. app/Http/Controllers/ArticleController.php:2068
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 1 and a.journal_id = 46 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      4.17msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2070
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 4 and a.journal_id = 46 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      2.8msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2071
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select pdf, html, epub, prc from `article_metrics` where `article_id` = 104871 limit 1
      650μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 104871
      Backtrace
      • 14. app/Models/Article.php:744
      • 15. app/Http/Controllers/ArticleController.php:2091
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from content_by_diseases where content_id = 104871 and content_type = 'article' order by status desc limit 1
      280μsalphaeurekaselec_live_10_06_2022Article.php#751
      Backtrace
      • 11. app/Models/Article.php:751
      • 12. app/Http/Controllers/ArticleController.php:2094
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid article_nid,a.title article_title,j.title journal_title from content_by_diseases cd inner join article a on a.article_id=cd.content_id inner join journal j on j.journal_id=a.journal_id where cd.pid = 16 and cd.sub_disease_id = 298 and content_id!=104871 and cd.content_type = 'article' order by rand() limit 20
      132msalphaeurekaselec_live_10_06_2022Article.php#769
      Backtrace
      • 11. app/Models/Article.php:769
      • 12. app/Http/Controllers/ArticleController.php:2098
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `node_meta` where `nid` = 179781 limit 1
      270μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 179781
      Backtrace
      • 14. app/Models/Meta.php:30
      • 15. app/Http/Controllers/ArticleController.php:2101
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      250μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2108
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `tbl_ht_submission` as `h` where `h`.`subtitle` = 'PRA' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      270μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: PRA
      Backtrace
      • 13. app/Models/Article.php:2025
      • 14. app/Http/Controllers/ArticleController.php:2112
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '104871' and content_type = 'a' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      470μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2186
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '9770' and content_type = 'i' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      330μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2207
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '2740' and content_type = 'v' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      290μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2231
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59650778 and j.to_ip >=59650778 )) and ((j.from_date <= 1740513560 and j.to_date >= 1740513560 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2740) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59650778 and j.to_ip >=59650778 )) and ((j.from_date <= 1740513560 and j.to_date >= 1740513560 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2740) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59650778 and j.to_ip >=59650778 )) and ((j.from_date <= 1740513560 and j.to_date >= 1740513560 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2740)
      9.06msalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2272
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59650778 and j.to_ip >=59650778 )) and ((j.from_date <= 1740513560 and j.to_date >= 1740513560 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9770) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59650778 and j.to_ip >=59650778 )) and ((j.from_date <= 1740513560 and j.to_date >= 1740513560 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9770) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59650778 and j.to_ip >=59650778 )) and ((j.from_date <= 1740513560 and j.to_date >= 1740513560 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9770)
      780μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2297
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59650778 and j.to_ip >=59650778 )) and ((j.from_date <= 1740513560 and j.to_date >= 1740513560 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 104871) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59650778 and j.to_ip >=59650778 )) and ((j.from_date <= 1740513560 and j.to_date >= 1740513560 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 104871) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59650778 and j.to_ip >=59650778 )) and ((j.from_date <= 1740513560 and j.to_date >= 1740513560 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 104871)
      780μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2329
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `first_page` < '14' and is_uploaded = 1 and issue_id = 9770 order by cast(first_page as SIGNED) desc limit 1
      670μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 14
      Backtrace
      • 14. app/Models/Article.php:1819
      • 15. app/Http/Controllers/ArticleController.php:2470
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `last_page` > '31' and is_uploaded = 1 and issue_id = 9770 order by cast(first_page as SIGNED) asc limit 1
      520μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 31
      Backtrace
      • 14. app/Models/Article.php:1831
      • 15. app/Http/Controllers/ArticleController.php:2472
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `language_id` from `multilanguage` where `short_code` = 'en'
      250μsalphaeurekaselec_live_10_06_2022ArticleController.php#2497
      Bindings
      • 0: en
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2497
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 1
      290μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2498
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `id` from `multilanguage_article` where `article_id` = 104871 limit 1
      3.81msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 104871
      Backtrace
      • 16. app/Http/Controllers/ArticleController.php:2506
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 46 and `b`.`banner_from_date` <= 1740513560 and `b`.`banner_to_date` >= 1740513560 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.55msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 46
      • 3: 1740513560
      • 4: 1740513560
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 46 and `b`.`banner_from_date` <= 1740513560 and `b`.`banner_to_date` >= 1740513560 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.46msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 46
      • 3: 1740513560
      • 4: 1740513560
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='096e8f774b8aa9aca7ca287d0cc01909'
      4.41msalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
        _token
        1nH8Qf3Vq3LKo0Wym1POeE1XUwz53qlM0OWEutBe
        uc_cart_id
        096e8f774b8aa9aca7ca287d0cc01909
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/104871" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/104871
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:8 [ "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        request_cookies
        []
        
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 19:59:20 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IkF5YWY5WnRJclVtTEVWTmc1MXlYb1E9PSIsInZhbHVlIjoiU2tUTjd0bjNlY3VnOE9wd1I5Q0lyUXM5QnMyWGgwZHN2bjljaWJabjFESWlWdzZITFVGRlFyZmxrNmdHM2xsNnM0TlRNV2xKWWhtVG1TRk9HYU1lMERMVEVaV1JQS0dVSU1KK3YrQUFVeDkyYlRRWTBkZmVGMHp3K3ZWWmJZaFIiLCJtYWMiOiI2ZTU2YmM0NzEyNzE0MzE5YmJjMzUxMTVhZjI1OGQ0ODNhMWIzZGE5YzdiYjNhOGZmNjMyMWQ2MTUxMWJmYTM3IiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 07:59:20 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IkF5YWY5WnRJclVtTEVWTmc1MXlYb1E9PSIsInZhbHVlIjoiU2tUTjd0bjNlY3VnOE9wd1I5Q0lyUXM5QnMyWGgwZHN2bjljaWJabjFESWlWdzZITFVGRlFyZmxrNmdHM2xsNnM0TlRNV" 1 => "alphaeurekaselectnet_session=eyJpdiI6InhhdDEyWmQ3NWdDek14NXZXOG9scWc9PSIsInZhbHVlIjoicU9pZXhTUllSS0JVUVpUYWN0RkVSNHZXZ1FZYkNPM1JKYnVnZU8xUHg2VU1nRU5EcmJoU0YvTEsrODIySmQ4Qk43TDFUbm9hN3BMRmkwVlV5Q05iQlJyaUVMbXd1OWhIdzQ0cHBlalMwczhwWjJvS09Zak8xOXJTOHIxWGF0TDEiLCJtYWMiOiJmM2M1ODE4MDg5NjM0NjEwOWRiYzVhZjAxZjYzZWY0Y2UxOTc5NGY5YWQwZGI1ZTEwODA5YTU1ODZlMGNjZDM2IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6InhhdDEyWmQ3NWdDek14NXZXOG9scWc9PSIsInZhbHVlIjoicU9pZXhTUllSS0JVUVpUYWN0RkVSNHZXZ1FZYkNPM1JKYnVnZU8xUHg2VU1nRU5EcmJoU0YvTEs" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IkF5YWY5WnRJclVtTEVWTmc1MXlYb1E9PSIsInZhbHVlIjoiU2tUTjd0bjNlY3VnOE9wd1I5Q0lyUXM5QnMyWGgwZHN2bjljaWJabjFESWlWdzZITFVGRlFyZmxrNmdHM2xsNnM0TlRNV2xKWWhtVG1TRk9HYU1lMERMVEVaV1JQS0dVSU1KK3YrQUFVeDkyYlRRWTBkZmVGMHp3K3ZWWmJZaFIiLCJtYWMiOiI2ZTU2YmM0NzEyNzE0MzE5YmJjMzUxMTVhZjI1OGQ0ODNhMWIzZGE5YzdiYjNhOGZmNjMyMWQ2MTUxMWJmYTM3IiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 07:59:20 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IkF5YWY5WnRJclVtTEVWTmc1MXlYb1E9PSIsInZhbHVlIjoiU2tUTjd0bjNlY3VnOE9wd1I5Q0lyUXM5QnMyWGgwZHN2bjljaWJabjFESWlWdzZITFVGRlFyZmxrNmdHM2xsNnM0TlRNV" 1 => "alphaeurekaselectnet_session=eyJpdiI6InhhdDEyWmQ3NWdDek14NXZXOG9scWc9PSIsInZhbHVlIjoicU9pZXhTUllSS0JVUVpUYWN0RkVSNHZXZ1FZYkNPM1JKYnVnZU8xUHg2VU1nRU5EcmJoU0YvTEsrODIySmQ4Qk43TDFUbm9hN3BMRmkwVlV5Q05iQlJyaUVMbXd1OWhIdzQ0cHBlalMwczhwWjJvS09Zak8xOXJTOHIxWGF0TDEiLCJtYWMiOiJmM2M1ODE4MDg5NjM0NjEwOWRiYzVhZjAxZjYzZWY0Y2UxOTc5NGY5YWQwZGI1ZTEwODA5YTU1ODZlMGNjZDM2IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6InhhdDEyWmQ3NWdDek14NXZXOG9scWc9PSIsInZhbHVlIjoicU9pZXhTUllSS0JVUVpUYWN0RkVSNHZXZ1FZYkNPM1JKYnVnZU8xUHg2VU1nRU5EcmJoU0YvTEs" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "1nH8Qf3Vq3LKo0Wym1POeE1XUwz53qlM0OWEutBe" "uc_cart_id" => "096e8f774b8aa9aca7ca287d0cc01909" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/104871" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 19:59:20GET/article/104871314371