Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Systematic Review Article

Nanomedicine: A Promising Avenue for the Development of Effective Therapy for Breast Cancer

Author(s): Ali Sartaj, Sanjula Baboota and Javed Ali*

Volume 20, Issue 8, 2020

Page: [603 - 615] Pages: 13

DOI: 10.2174/1568009620666200331124113

Price: $65

Abstract

Purpose: Breast cancer is the most probable cancer among women. However, the available treatment is based on targeting different stages of breast cancer viz., radiation therapy, hormonal therapy, chemotherapy, and surgical interventions, which have some limitations. The available chemotherapeutics are associated with problems like low solubility, low permeability, high first-pass metabolism, and P-glycoprotein efflux. Hence, the aforementioned restrictions lead to ineffective treatment. Multiple chemotherapeutics can also cause resistance in tumors. So, the purpose is to develop an effective therapeutic regimen for the treatment of breast cancer by applying a nanomedicinal approach.

Methods: This review has been conducted on a systematic search strategy, based on relevant literature available on Pub Med, MedlinePlus, Google Scholar, and Sciencedirect up to November 2019 using keywords present in abstract and title of the review. As per our inclusion and exclusion criteria, 226 articles were screened. Among 226, a total of 40 articles were selected for this review.

Results: The significant findings with the currently available treatment is that the drug, besides its distribution to the target-specific site, also distributes to healthy cells, which results in severe side effects. Moreover, the drug is less bioavailable at the site of action; therefore, to overcome this, a high dose is required, which again causes side effects and lower the benefits. Nanomedicinal approaches give an alternative approach to avoid the associated problems of available chemotherapeutics treatment of breast cancer.

Conclusion: The nanomedicinal strategies are useful over the conventional treatment of breast cancer and deliver a target-specific drug-using different novel drug delivery approaches.

Keywords: Breast cancer, chemotherapeutics, bioavailability, side effects, receptor targets, nanomedicine.

Graphical Abstract

[1]
DeSantis, C.E.; Ma, J.; Gaudet, M.M.; Newman, L.A.; Miller, K.D.; Goding Sauer, A.; Jemal, A.; Siegel, R.L. Breast cancer statistics. Cancer J. Clin., 2019, 69(6), 438-451.
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin., 2019, 69(1), 7-34.
[http://dx.doi.org/10.3322/caac.21551] [PMID: 30620402]
[3]
Millis, S.Z.; Gatalica, Z.; Winkler, J.; Vranic, S.; Kimbrough, J.; Reddy, S.; O’Shaughnessy, J.A. Predictive biomarker profiling of > 6000 breast cancer patients shows heterogeneity in TNBC, with treatment implications. Clin. Breast Cancer, 2015, 15(6), 473-48.
[http://dx.doi.org/10.1016/j.clbc.2015.04.008] [PMID: 26051240]
[4]
Dai, X.; Xiang, L.; Li, T.; Bai, Z. Cancer hallmarks, biomarkers and breast cancer molecular subtypes. J. Cancer, 2016, 7(10), 1281-1294.
[http://dx.doi.org/10.7150/jca.13141] [PMID: 27390604]
[5]
Weigel, M.T.; Dowsett, M. Current and emerging biomarkers in breast cancer: prognosis and prediction. Endocr. Relat. Cancer, 2010, 17(4), R245-R262.
[http://dx.doi.org/10.1677/ERC-10-0136] [PMID: 20647302]
[6]
Iqbal, N.; Iqbal, N. Human epidermal growth factor receptor 2 (HER2) in cancers: Overexpression and therapeutic implications. Mol. Biol. Int., 2014, 2014, 852748.
[http://dx.doi.org/10.1155/2014/852748] [PMID: 25276427]
[7]
Nounou, M.I.; ElAmrawy, F.; Ahmed, N.; Abdelraouf, K.; Goda, S.; Syed-Sha-Qhattal, H. Breast cancer: conventional diagnosis and treatment modalities and recent patents and technologies; Breast Cancer Basic Clin. Res, 2015.
[8]
Wu, D.; Si, M.; Xue, H.Y.; Wong, H.L. Nanomedicine applications in the treatment of breast cancer: current state of the art. Int. J. Nanomedicine, 2017, 12, 5879-5892.
[http://dx.doi.org/10.2147/IJN.S123437] [PMID: 28860754]
[9]
Cucinotto, I.; Fiorillo, L.; Gualtieri, S.; Arbitrio, M.; Ciliberto, D.; Staropoli, N.; Grimaldi, A.; Luce, A.; Tassone, P.; Caraglia, M.; Tagliaferri, P. Nanoparticle albumin bound Paclitaxel in the treatment of human cancer: nanodelivery reaches prime-time? J. Drug Deliv., 2013, 2013, 905091.
[http://dx.doi.org/10.1155/2013/905091] [PMID: 23738077]
[10]
Matsen, C.B.; Neumayer, L.A. Breast cancer: A review for the general surgeon. JAMA Surg., 2013, 148(10), 971-979.
[http://dx.doi.org/10.1001/jamasurg.2013.3393] [PMID: 23986370]
[11]
Dhankhar, R.; Vyas, S.P.; Jain, A.K.; Arora, S.; Rath, G.; Goyal, A.K. Advances in novel drug delivery strategies for breast cancer therapy; Artificial Cells, Blood Substitutes, Biotechnol, 2010.
[http://dx.doi.org/10.3109/10731199.2010.494578]
[12]
König, J.; van Ewijk, R.; Kuhr, K.; Schmidberger, H.; Wöckel, A.; Kreienberg, R.; Blettner, M. Radiotherapy effects on early breast cancer survival in observational and randomized studies: A systematic analysis of advantages, disadvantages and differences between the two study types. Breast Cancer, 2016, 23(3), 415-424.
[http://dx.doi.org/10.1007/s12282-014-0579-2] [PMID: 25585654]
[13]
Talluri, S.V.; Kuppusamy, G.; Karri, V.V.S.R.; Tummala, S.; Madhunapantula, S.V. Lipid-based nanocarriers for breast cancer treatment - comprehensive review. Drug Deliv., 2016, 23(4), 1291-1305.
[http://dx.doi.org/10.3109/10717544.2015.1092183] [PMID: 26430913]
[14]
McDonnell, D.P.; Wardell, S.E.; Norris, J.D. oral selective estrogen receptor downregulators (SERDs), a breakthrough endocrine therapy for breast cancer. J. Med. Chem., 2015, 58(12), 4883-4887.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00760] [PMID: 26039356]
[15]
Abdulkareem, I.H.; Zurmi, I.B. Review of hormonal treatment of breast cancer. Niger. J. Clin. Pract., 2012, 15(1), 9-14.
[http://dx.doi.org/10.4103/1119-3077.94088] [PMID: 22437080]
[16]
Anampa, J.; Makower, D.; Sparano, J.A. Progress in adjuvant chemotherapy for breast cancer: An overview. BMC Med., 2015, 13, 195.
[http://dx.doi.org/10.1186/s12916-015-0439-8] [PMID: 26278220]
[17]
Tao, J.J.; Visvanathan, K.; Wolff, A.C. Long term side effects of adjuvant chemotherapy in patients with early breast cancer. Breast, 2015, 24(Suppl. 2), S149-S153.
[http://dx.doi.org/10.1016/j.breast.2015.07.035] [PMID: 26299406]
[18]
Brasó-Maristany, F.; Filosto, S.; Catchpole, S.; Marlow, R.; Quist, J.; Francesch-Domenech, E.; Plumb, D.A.; Zakka, L.; Gazinska, P.; Liccardi, G.; Meier, P.; Gris-Oliver, A.; Cheang, M.C.; Perdrix-Rosell, A.; Shafat, M.; Noël, E.; Patel, N.; McEachern, K.; Scaltriti, M.; Castel, P.; Noor, F.; Buus, R.; Mathew, S.; Watkins, J.; Serra, V.; Marra, P.; Grigoriadis, A.; Tutt, A.N. PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer. Nat. Med., 2016, 22(11), 1303-1313.
[http://dx.doi.org/10.1038/nm.4198] [PMID: 27775704]
[19]
Daniel, A.R.; Gaviglio, A.L.; Knutson, T.P.; Ostrander, J.H.; D’Assoro, A.B.; Ravindranathan, P.; Peng, Y.; Raj, G.V.; Yee, D.; Lange, C.A. Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes. Oncogene, 2015, 34(4), 506-515.
[http://dx.doi.org/10.1038/onc.2013.579] [PMID: 24469035]
[20]
Ness, R.A.; Miller, D.D.; Li, W. The role of vitamin D in cancer prevention. Chin. J. Nat. Med., 2015, 13(7), 481-497.
[http://dx.doi.org/10.1016/S1875-5364(15)30043-1] [PMID: 26233839]
[21]
Hahne, C. J.B; Engel, J.; Honig, A.; R Meyer, S.; Zito, D.; Lampis, A.; Valeri, N. The PI3K/AKT/MTOR-signal transduction pathway as drug target in triple-negative breast cancer. Clin. Cancer Drugs, 2017, 4(1), 47-58.
[http://dx.doi.org/10.2174/2212697X04666170321112629]
[22]
Finn, R.S.; Aleshin, A.; Slamon, D.J. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res., 2016, 18(1), 17.
[http://dx.doi.org/10.1186/s13058-015-0661-5] [PMID: 26857361]
[23]
Liu, D.; Wang, X.; Chen, Z. Tumor necrosis factor-α, a regulator and therapeutic agent on breast cancer. Curr. Pharm. Biotechnol., 2016, 17(6), 486-494.
[http://dx.doi.org/10.2174/1389201017666160301102713] [PMID: 26927216]
[24]
Suman, S.; Sharma, P.K.; Rai, G.; Mishra, S.; Arora, D.; Gupta, P.; Shukla, Y. Current perspectives of molecular pathways involved in chronic inflammation-mediated breast cancer. Biochem. Biophys. Res. Commun., 2016, 472(3), 401-409.
[http://dx.doi.org/10.1016/j.bbrc.2015.10.133] [PMID: 26522220]
[25]
Selli, C.; Dixon, J.M.; Sims, A.H. Accurate prediction of response to endocrine therapy in breast cancer patients: current and future biomarkers. Breast Cancer Res., 2016, 18(1), 118.
[http://dx.doi.org/10.1186/s13058-016-0779-0] [PMID: 27903276]
[26]
Maughan, K.L.; Lutterbie, M.A.; Ham, P.S. Treatment of breast cancer. Am. Fam. Physician, 2010, 81(11), 1339-1346.
[PMID: 20521754]
[27]
Chiavenna, S.M.; Jaworski, J.P.; Vendrell, A. State of the art in anti-cancer mAbs. J. Biomed. Sci., 2017, 24(1), 15.
[http://dx.doi.org/10.1186/s12929-016-0311-y] [PMID: 28219375]
[28]
Bernard-Marty, C.; Lebrun, F.; Awada, A.; Piccart, M.J. Monoclonal antibody-based targeted therapy in breast cancer: Current status and future directions. Drugs, 2006, 66(12), 1577-1591.
[http://dx.doi.org/10.2165/00003495-200666120-00004] [PMID: 16956305]
[29]
Ahmed, A.R.; Hombal, S.M. Cyclophosphamide (Cytoxan). A review on relevant pharmacology and clinical uses. J. Am. Acad. Dermatol., 1984, 11(6), 1115-1126.
[http://dx.doi.org/10.1016/S0190-9622(84)80193-0] [PMID: 6392368]
[30]
Kaklamani, V.G.; Gradishar, W.J. Role of capecitabine (Xeloda) in breast cancer. Expert Rev. Anticancer Ther., 2003, 3(2), 137-144.
[http://dx.doi.org/10.1586/14737140.3.2.137] [PMID: 12722873]
[31]
Decatris, M.P.; Sundar, S.; O’Byrne, K.J. Platinum-based chemotherapy in metastatic breast cancer: Current status. Cancer Treat. Rev., 2004, 30(1), 53-81.
[http://dx.doi.org/10.1016/S0305-7372(03)00139-7] [PMID: 14766126]
[32]
Toschi, L.; Finocchiaro, G.; Bartolini, S.; Gioia, V.; Cappuzzo, F. Role of gemcitabine in cancer therapy; Futur. Oncol, 2005.
[http://dx.doi.org/10.1517/14796694.1.1.7]
[33]
Marupudi, N.I.; Han, J.E.; Li, K.W.; Renard, V.M.; Tyler, B.M.; Brem, H. Paclitaxel: A review of adverse toxicities and novel delivery strategies. Expert Opin. Drug Saf., 2007, 6(5), 609-621.
[http://dx.doi.org/10.1517/14740338.6.5.609] [PMID: 17877447]
[34]
Wigmore, P.M.; Mustafa, S.; El-Beltagy, M.; Lyons, L.; Umka, J.; Bennett, G. Effects of 5-FU. Adv. Exp. Med. Biol., 2010, 678, 157-164.
[http://dx.doi.org/10.1007/978-1-4419-6306-2_20] [PMID: 20738018]
[35]
Thorn, C.F.; Oshiro, C.; Marsh, S.; Hernandez-Boussard, T.; McLeod, H.; Klein, T.E.; Altman, R.B. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet. Genomics, 2011, 21(7), 440-446.
[http://dx.doi.org/10.1097/FPC.0b013e32833ffb56] [PMID: 21048526]
[36]
Yang, M.; Kim, J.S.; Kim, J.; Jang, S.; Kim, S.H.; Kim, J.C.; Shin, T.; Wang, H.; Moon, C. Acute treatment with methotrexate induces hippocampal dysfunction in a mouse model of breast cancer. Brain Res. Bull., 2012, 89(1-2), 50-56.
[http://dx.doi.org/10.1016/j.brainresbull.2012.07.003] [PMID: 22796103]
[37]
Xu, Y.C.; Wang, H.X.; Tang, L.; Ma, Y.; Zhang, F.C. A systematic review of vinorelbine for the treatment of breast cancer. Breast J., 2013, 19(2), 180-188.
[http://dx.doi.org/10.1111/tbj.12071] [PMID: 23320984]
[38]
Ho, M.Y.; Mackey, J.R. Presentation and management of docetaxel-related adverse effects in patients with breast cancer. Cancer Manag. Res., 2014, 6, 253-259.
[http://dx.doi.org/10.2147/CMAR.S40601] [PMID: 24904223]
[39]
Shetty, N.; Gupta, S. Eribulin drug review. South Asian J. Cancer, 2014, 3(1), 57-59.
[http://dx.doi.org/10.4103/2278-330X.126527] [PMID: 24665449]
[40]
Dong, M.; Luo, L.; Ying, X.; Lu, X.; Shen, J.; Jiang, Z.; Wang, L. Comparable efficacy and less toxicity of pegylated liposomal doxorubicin versus epirubicin for neoadjuvant chemotherapy of breast cancer: a case-control study. OncoTargets Ther., 2018, 11, 4247-4252.
[http://dx.doi.org/10.2147/OTT.S162003] [PMID: 30087568]
[41]
Rosvig, L.H.; Langkjer, S.T.; Knoop, A.; Jensen, A.B. Palliative treatment with carboplatin as late line therapy to patients with metastatic breast cancer. Acta Oncol., 2018, 57(1), 156-159.
[http://dx.doi.org/10.1080/0284186X.2017.1407495] [PMID: 29202627]
[42]
Mohit, E.; Hashemi, A.; Allahyari, M. Breast cancer immunotherapy: monoclonal antibodies and peptide-based vaccines. Expert Rev. Clin. Immunol., 2014, 10(7), 927-961.
[http://dx.doi.org/10.1586/1744666X.2014.916211] [PMID: 24867051]
[43]
Gao, J.; Swain, S.M. Pertuzumab for the treatment of breast cancer: a safety review. Expert Opin. Drug Saf., 2016, 15(6), 853-863.
[http://dx.doi.org/10.1517/14740338.2016.1167185] [PMID: 26982349]
[44]
Yang, S.X. Bevacizumab and breast cancer: Current therapeutic progress and future perspectives. Expert Rev. Anticancer Ther., 2009, 9(12), 1715-1725.
[http://dx.doi.org/10.1586/era.09.153] [PMID: 19954282]
[45]
Chomoucka, J.; Drbohlavova, J.; Huska, D.; Adam, V.; Kizek, R.; Hubalek, J. Magnetic nanoparticles and targeted drug delivering. Pharmacol. Res., 2010, 62(2), 144-149.
[http://dx.doi.org/10.1016/j.phrs.2010.01.014] [PMID: 20149874]
[46]
Chidambaram, M.; Manavalan, R.; Kathiresan, K. Nanotherapeutics to overcome conventional cancer chemotherapy limitations. J. Pharm. Pharm. Sci., 2011, 14(1), 67-77.
[http://dx.doi.org/10.18433/J30C7D] [PMID: 21501554]
[47]
Bikiaris, D.; Papageorgiou, G.Z.; Stergiou, A.; Pavlidou, E.; Karavas, E.; Kanaze, F.; Georgarakis, M. Physicochemical studies on solid dispersions of poorly water-soluble drugs: evaluation of capabilities and limitations of thermal analysis techniques. Thermochim. Acta, 2005.
[http://dx.doi.org/10.1016/j.tca.2005.09.011]
[48]
Liu, Y.; Solomon, M.; Achilefu, S. Perspectives and potential applications of nanomedicine in breast and prostate cancer. Med. Res. Rev., 2013, 33(1), 3-32.
[http://dx.doi.org/10.1002/med.20233] [PMID: 23239045]
[49]
Hare, J.I.; Lammers, T.; Ashford, M.B.; Puri, S.; Storm, G.; Barry, S.T. Challenges and strategies in anti-cancer nanomedicine development: An industry perspective. Adv. Drug Deliv. Rev., 2017, 108, 25-38.
[http://dx.doi.org/10.1016/j.addr.2016.04.025] [PMID: 27137110]
[50]
Zhang, R.X.; Wong, H.L.; Xue, H.Y.; Eoh, J.Y.; Wu, X.Y. Nanomedicine of synergistic drug combinations for cancer therapy - Strategies and perspectives. J. Control. Release, 2016, 240, 489-503.
[http://dx.doi.org/10.1016/j.jconrel.2016.06.012] [PMID: 27287891]
[51]
Lee, J.J.; Saiful Yazan, L.; Che Abdullah, C.A. A review on current nanomaterials and their drug conjugate for targeted breast cancer treatment. Int. J. Nanomedicine, 2017, 12, 2373-2384.
[http://dx.doi.org/10.2147/IJN.S127329] [PMID: 28392694]
[52]
Suk, J.S.; Xu, Q.; Kim, N.; Hanes, J.; Ensign, L.M. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv. Drug Deliv. Rev.,, 2016, 99(pt a), 28-51.
[http://dx.doi.org/10.1016/j.addr.2015.09.012] [PMID: 26456916]
[53]
Wolinsky, J.B.; Colson, Y.L.; Grinstaff, M.W. Local drug delivery strategies for cancer treatment: gels, nanoparticles, polymeric films, rods, and wafers. J. Control. Release, 2012, 159(1), 14-26.
[http://dx.doi.org/10.1016/j.jconrel.2011.11.031] [PMID: 22154931]
[54]
Contreras-Cáceres, R.; Cabeza, L.; Perazzoli, G.; Díaz, A.; López-Romero, J.M.; Melguizo, C.; Prados, J. Electrospun nanofibers: Recent applications in drug delivery and cancer therapy. Nanomaterials (Basel), 2019, 9(4), E656.
[http://dx.doi.org/10.3390/nano9040656] [PMID: 31022935]
[55]
Marty, M.; Cognetti, F.; Maraninchi, D.; Snyder, R.; Mauriac, L.; Tubiana-Hulin, M.; Chan, S.; Grimes, D.; Antón, A.; Lluch, A.; Kennedy, J.; O’Byrne, K.; Conte, P.; Green, M.; Ward, C.; Mayne, K.; Extra, J.M. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J. Clin. Oncol., 2005, 23(19), 4265-4274.
[http://dx.doi.org/10.1200/JCO.2005.04.173] [PMID: 15911866]
[56]
Narayanaswamy, R.; Torchilin, V.P. hydrogels and their applications in targeted drug delivery. Molecules, 2019, 24(3), 603.
[http://dx.doi.org/10.3390/molecules24030603] [PMID: 30744011]
[57]
Han, H.D.; Mora, E.M.; Roh, J.W.; Nishimura, M.; Lee, S.J.; Stone, R.L.; Bar-Eli, M.; Lopez-Berestein, G.; Sood, A.K. Chitosan hydrogel for localized gene silencing. Cancer Biol. Ther., 2011, 11(9), 839-845.
[http://dx.doi.org/10.4161/cbt.11.9.15185] [PMID: 21358280]
[58]
Segovia, N.; Pont, M.; Oliva, N.; Ramos, V.; Borrós, S.; Artzi, N. Hydrogel doped with nanoparticles for local sustained release of siRNA in breast cancer. Adv. Healthc. Mater., 2015, 4(2), 271-280.
[http://dx.doi.org/10.1002/adhm.201400235] [PMID: 25113263]
[59]
Chen, X.; Li, Q.W.; Wang, X.M. Gold nanostructures for bioimaging, drug delivery and therapeutics. InPrecious Metals for Biomedical Applications; , 2014.
[60]
Jain, S.; Hirst, D.G.; O’Sullivan, J.M. Gold nanoparticles as novel agents for cancer therapy. Br. J. Radiol., 2012, 85(1010), 101-113.
[http://dx.doi.org/10.1259/bjr/59448833] [PMID: 22010024]
[61]
Li, J.L.; Wang, L.; Liu, X.Y.; Zhang, Z.P.; Guo, H.C.; Liu, W.M.; Tang, S.H. In vitro cancer cell imaging and therapy using transferrin-conjugated gold nanoparticles. Cancer Lett., 2009, 274(2), 319-326.
[http://dx.doi.org/10.1016/j.canlet.2008.09.024] [PMID: 18977071]
[62]
Eissa, S.; Azzazy, H.M.E.; Matboli, M.; Shawky, S.M.; Said, H.; Anous, F.A. The prognostic value of histidine-rich glycoprotein RNA in breast tissue using unmodified gold nanoparticles assay. Appl. Biochem. Biotechnol., 2014, 174(2), 751-761.
[http://dx.doi.org/10.1007/s12010-014-1085-x] [PMID: 25091325]
[63]
Bae, P.K.; Chung, B.H. Multiplexed detection of various breast cancer cells by perfluorocarbon/quantum dot nanoemulsions conjugated with antibodies. Nano Converg., 2014, 1(1), 23.
[http://dx.doi.org/10.1186/s40580-014-0023-5] [PMID: 28191403]
[64]
Nagavarma, B. V. N.; Yadav, H. K. S.; Ayaz, A.; Vasudha, L. S.; Shivakumar, H. G. Different techniques for preparation of polymericnanoparticles- A Review Asian J. Pharmaceut. Clin. Res.,, 2012.
[65]
Dhar, S.; Kolishetti, N.; Lippard, S.J.; Farokhzad, O.C. Targeted delivery of a cisplatin prodrug for safer and more effective prostate cancer therapy in vivo. Proc. Natl. Acad. Sci. USA, 2011, 108(5), 1850-1855.
[http://dx.doi.org/10.1073/pnas.1011379108] [PMID: 21233423]
[66]
Lee, J.H.; Nan, A. Combination drug delivery approaches in metastatic breast cancer. J. Drug Deliv., 2012.2012915375
[http://dx.doi.org/10.1155/2012/915375] [PMID: 22619725]
[67]
Katiyar, S.S.; Muntimadugu, E.; Rafeeqi, T.A.; Domb, A.J.; Khan, W. Co-delivery of rapamycin- and piperine-loaded polymeric nanoparticles for breast cancer treatment. Drug Deliv., 2016, 23(7), 2608-2616.
[http://dx.doi.org/10.3109/10717544.2015.1039667] [PMID: 26036652]
[68]
Abou-El-Naga, A.M.; Mutawa, G.; El-Sherbiny, I.M.; Mousa, S.A. Activation of polymeric nanoparticle intracellular targeting overcomes chemodrug resistance in human primary patient breast cancer cells. Int. J. Nanomedicine, 2018, 13, 8153-8164.
[http://dx.doi.org/10.2147/IJN.S182184] [PMID: 30555232]
[69]
Suri, S.; Mirza, M. A.; Anwer, M. K.; Alshetaili, A. S.; Alshahrani, S. M.; Ahmed, F. J.; Iqbal, Z. Development of NIPAAm-PEG acrylate polymeric nanoparticles for co-delivery of paclitaxel with ellagic acid for the treatment of breast cancer J. Polym. Eng, 2019.
[70]
Mishra, P.; Nayak, B.; Dey, R.K. PEGylation in anti-cancer therapy: An Overview. Asian J. Pharmaceut. Sci., 2016, 11(3), 337-348.
[71]
Kalepu, S.; Nekkanti, V. Insoluble drug delivery strategies: Review of recent advances and business prospects. Acta Pharm. Sin. B, 2015, 5(5), 442-453.
[http://dx.doi.org/10.1016/j.apsb.2015.07.003] [PMID: 26579474]
[72]
Kang, D.I.; Kang, H.K.; Gwak, H.S.; Han, H.K.; Lim, S.J. Liposome composition is important for retention of liposomal rhodamine in P-glycoprotein-overexpressing cancer cells. Drug Deliv., 2009, 16(5), 261-267.
[http://dx.doi.org/10.1080/10717540902937562] [PMID: 19538007]
[73]
Kullberg, M.; Owens, J.L.; Mann, K.; Listeriolysin, O. Listeriolysin O enhances cytoplasmic delivery by Her-2 targeting liposomes. J. Drug Target., 2010, 18(4), 313-320.
[http://dx.doi.org/10.3109/10611861003663549] [PMID: 20201742]
[74]
Wong, M.Y.; Chiu, G.N.C. Simultaneous liposomal delivery of quercetin and vincristine for enhanced estrogen-receptor-negative breast cancer treatment. Anticancer Drugs, 2010, 21(4), 401-410.
[http://dx.doi.org/10.1097/CAD.0b013e328336e940] [PMID: 20110806]
[75]
Cosco, D.; Paolino, D.; Cilurzo, F.; Casale, F.; Fresta, M. Gemcitabine and tamoxifen-loaded liposomes as multidrug carriers for the treatment of breast cancer diseases. Int. J. Pharm., 2012, 422(1-2), 229-237.
[http://dx.doi.org/10.1016/j.ijpharm.2011.10.056] [PMID: 22093954]
[76]
Eloy, J.O.; Petrilli, R.; Topan, J.F.; Antonio, H.M.R.; Barcellos, J.P.A.; Chesca, D.L.; Serafini, L.N.; Tiezzi, D.G.; Lee, R.J.; Marchetti, J.M. Co-loaded paclitaxel/rapamycin liposomes: Development, characterization and in vitro and in vivo evaluation for breast cancer therapy. Colloids Surf. B Biointerfaces, 2016, 141, 74-82.
[http://dx.doi.org/10.1016/j.colsurfb.2016.01.032] [PMID: 26836480]
[77]
Bai, F.; Yin, Y.; Chen, T.; Chen, J.; Ge, M.; Lu, Y.; Xie, F.; Zhang, J.; Wu, K.; Liu, Y. Development of liposomal pemetrexed for enhanced therapy against multidrug resistance mediated by ABCC5 in breast cancer. Int. J. Nanomedicine, 2018, 13, 1327-1339.
[http://dx.doi.org/10.2147/IJN.S150237] [PMID: 29563790]
[78]
Zhang, Y.; Huang, Y.; Li, S. Polymeric micelles: Nanocarriers for cancer-targeted drug delivery. AAPS PharmSciTech, 2014, 15(4), 862-871.
[http://dx.doi.org/10.1208/s12249-014-0113-z] [PMID: 24700296]
[79]
Yuan, Y.; Cai, T.; Xia, X.; Zhang, R.; Chiba, P.; Cai, Y. Nanoparticle delivery of anticancer drugs overcomes multidrug resistance in breast cancer. Drug Deliv., 2016, 23(9), 3350-3357.
[http://dx.doi.org/10.1080/10717544.2016.1178825] [PMID: 27098896]
[80]
Lee, A.L.Z.; Wang, Y.; Cheng, H.Y.; Pervaiz, S.; Yang, Y.Y. The co-delivery of paclitaxel and Herceptin using cationic micellar nanoparticles. Biomaterials, 2009, 30(5), 919-927.
[http://dx.doi.org/10.1016/j.biomaterials.2008.10.062] [PMID: 19042015]
[81]
Xiang, J.; Wu, B.; Zhou, Z.; Hu, S.; Piao, Y.; Zhou, Q.; Wang, G.; Tang, J.; Liu, X.; Shen, Y. Synthesis and evaluation of a paclitaxel-binding polymeric micelle for efficient breast cancer therapy. Sci. China Life Sci., 2018, 61(4), 436-447.
[http://dx.doi.org/10.1007/s11427-017-9274-9] [PMID: 29572777]
[82]
Zajdel, A.; Wilczok, A.; Jelonek, K.; Musiał-Kulik, M.; Foryś, A.; Li, S.; Kasperczyk, J. Cytotoxic effect of paclitaxel and lapatinib Co-Delivered in polylactide-co-poly(ethylene glycol) micelles on HER-2-negative breast cancer cells. Pharmaceutics, 2019, 11(4), 169.
[http://dx.doi.org/10.3390/pharmaceutics11040169] [PMID: 30959904]
[83]
Wan, X.; Beaudoin, J.J.; Vinod, N.; Min, Y.; Makita, N.; Bludau, H.; Jordan, R.; Wang, A.; Sokolsky, M.; Kabanov, A.V. Co-delivery of paclitaxel and cisplatin in poly(2-oxazoline) polymeric micelles: Implications for drug loading, release, pharmacokinetics and outcome of ovarian and breast cancer treatments. Biomaterials, 2019, 192, 1-14.
[http://dx.doi.org/10.1016/j.biomaterials.2018.10.032] [PMID: 30415101]
[84]
Madaan, K.; Kumar, S.; Poonia, N.; Lather, V.; Pandita, D. Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues. J. Pharm. Bioallied Sci., 2014, 6(3), 139-150.
[http://dx.doi.org/10.4103/0975-7406.130965] [PMID: 25035633]
[85]
Wolinsky, J.B.; Grinstaff, M.W. Therapeutic and diagnostic applications of dendrimers for cancer treatment. Adv. Drug Deliv. Rev., 2008, 60(9), 1037-1055.
[http://dx.doi.org/10.1016/j.addr.2008.02.012] [PMID: 18448187]
[86]
Kulhari, H.; Pooja, D.; Shrivastava, S.; Kuncha, M.; Naidu, V.G.M.; Bansal, V.; Sistla, R.; Adams, D.J. Trastuzumab-grafted PAMAM dendrimers for the selective delivery of anticancer drugs to HER2-positive breast cancer. Sci. Rep., 2016, 6, 23179.
[http://dx.doi.org/10.1038/srep23179] [PMID: 27052896]
[87]
Gu, Y.; Guo, Y.; Wang, C.; Xu, J.; Wu, J.; Kirk, T.B.; Ma, D.; Xue, W. A polyamidoamne dendrimer functionalized graphene oxide for DOX and MMP-9 shRNA plasmid co-delivery. Mater. Sci. Eng. C, 2017, 70(Pt 1), 572-585.
[http://dx.doi.org/10.1016/j.msec.2016.09.035] [PMID: 27770930]
[88]
Torres-Pérez, S.A.; Ramos-Godínez, M.D.P.; Ramón-Gallegos, E. Effect of methotrexate conjugated PAMAM dendrimers on the viability of breast cancer cells. InAIP Conference Proceedings; , 2019.
[http://dx.doi.org/10.1063/1.5095929]
[89]
Mydin, R.B.S.M.N.; Moshawih, S. Nanoparticles in nanomedicine application: Lipid-based nanoparticles and their safety concerns. Nanotechnology: Applications in Energy, Drug and Food; Springer, 2019, pp. 227-232.
[http://dx.doi.org/10.1007/978-3-319-99602-8_10]
[90]
Rajabi, M.; Mousa, S.A. lipid nanoparticles and their application in nanomedicine. Curr. Pharm. Biotechnol., 2016, 17(8), 662-672.
[http://dx.doi.org/10.2174/1389201017666160415155457] [PMID: 27087491]
[91]
Wang, W.; Zhang, L.; Chen, T.; Guo, W.; Bao, X.; Wang, D.; Ren, B.; Wang, H.; Li, Y.; Wang, Y.; Chen, S.; Tang, B.; Yang, Q.; Chen, C. anticancer effects of resveratrol-loaded solid lipid nanoparticles on human breast cancer cells. Molecules, 2017, 22(11), 1814.
[http://dx.doi.org/10.3390/molecules22111814] [PMID: 29068422]
[92]
Naguib, Y.W.; Rodriguez, B.L.; Li, X.; Hursting, S.D.; Williams, R.O.; Cui, Z. Solid lipid nanoparticle formulations of docetaxel prepared with high melting point triglycerides: In Vitro and in Vivo evaluation; Mol. Pharm, 2014.
[93]
Guney Eskiler, G.; Cecener, G.; Dikmen, G.; Egeli, U.; Tunca, B. Solid lipid nanoparticles: Reversal of tamoxifen resistance in breast cancer. Eur. J. Pharm. Sci., 2018, 120, 73-88.
[http://dx.doi.org/10.1016/j.ejps.2018.04.040] [PMID: 29719240]
[94]
Zheng, G.; Zheng, M.; Yang, B.; Fu, H.; Li, Y. Improving breast cancer therapy using doxorubicin loaded solid lipid nanoparticles: Synthesis of a novel arginine-glycine-aspartic tripeptide conjugated, pH sensitive lipid and evaluation of the nanomedicine in vitro and in vivo. Biomed. Pharmacother., 2019.116109006
[http://dx.doi.org/10.1016/j.biopha.2019.109006] [PMID: 31152925]
[95]
García-Pinel, B.; Porras-Alcalá, C.; Ortega-Rodríguez, A.; Sarabia, F.; Prados, J.; Melguizo, C.; López-Romero, J.M. lipid-based nanoparticles: application and recent advances in cancer treatment. Nanomaterials (Basel), 2019, 9(4), 638.
[http://dx.doi.org/10.3390/nano9040638] [PMID: 31010180]
[96]
Sabzichi, M.; Mohammadian, J.; Yari Khosroushahi, A.; Bazzaz, R.; Hamishehkar, H. Folate-targeted nanostructured lipid carriers (NLCs) enhance (Letrozol) efficacy in MCF-7 breast cancer cells. Asian Pac. J. Cancer Prev., 2016, 17(12), 5185-5188.
[PMID: 28124885]
[97]
Li, X.; Jia, X.; Niu, H. Nanostructured lipid carriers co-delivering lapachone and doxorubicin for overcoming multidrug resistance in breast cancer therapy. Int. J. Nanomedicine, 2018, 13, 4107-4119.
[http://dx.doi.org/10.2147/IJN.S163929] [PMID: 30034236]
[98]
Rezazadeh, M.; Emami, J.; Hassanzadeh, F.; Sadeghi, H.; Rostami, M.; Mohammadkhani, H. Targeted nanostructured lipid carriers for delivery of paclitaxel to cancer cells: preparation, characterization, and cell toxicity. Curr. Drug Deliv., 2017, 14(8), 1189-1200.
[http://dx.doi.org/10.2174/1567201814666170503143646] [PMID: 28472908]
[99]
Beh, C.Y.; Rasedee, A.; Selvarajah, G.T.; Yazan, L.S.; Omar, A.R.; Foong, J.N.; How, C.W.; Foo, J.B. Enhanced anti-mammary gland cancer activities of tamoxifen-loaded erythropoietin-coated drug delivery system. PLoS One, 2019, 14(7), e0219285.
[http://dx.doi.org/10.1371/journal.pone.0219285] [PMID: 31291309]
[100]
Swenson, C.E.; Perkins, W.R.; Roberts, P.; Janoff, A.S. Liposome technology and the development of myocetTM (Liposomal Doxorubicin Citrate). Breast, 2001.
[http://dx.doi.org/10.1016/S0960-9776(01)80001-1]
[101]
O’Brien, M.E.R.; Wigler, N.; Inbar, M.; Rosso, R.; Grischke, E.; Santoro, A.; Catane, R.; Kieback, D.G.; Tomczak, P.; Ackland, S.P.; Orlandi, F.; Mellars, L.; Alland, L.; Tendler, C. CAELYX Breast Cancer Study Group Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann. Oncol., 2004, 15(3), 440-449.
[http://dx.doi.org/10.1093/annonc/mdh097] [PMID: 14998846]
[102]
Hamaguchi, T.; Matsumura, Y.; Suzuki, M.; Shimizu, K.; Goda, R.; Nakamura, I.; Nakatomi, I.; Yokoyama, M.; Kataoka, K.; Kakizoe, T. NK105, a paclitaxel-incorporating micellar nanoparticle formulation, can extend in vivo antitumour activity and reduce the neurotoxicity of paclitaxel. Br. J. Cancer, 2005, 92(7), 1240-1246.
[http://dx.doi.org/10.1038/sj.bjc.6602479] [PMID: 15785749]
[103]
Singer, J.W.; Shaffer, S.; Baker, B.; Bernareggi, A.; Stromatt, S.; Nienstedt, D.; Besman, M. Paclitaxel poliglumex (XYOTAX; CT-2103): An intracellularly targeted taxane. Anticancer Drugs, 2005, 16(3), 243-254.
[http://dx.doi.org/10.1097/00001813-200503000-00003] [PMID: 15711176]
[104]
Boulikas, T. Clinical overview on Lipoplatin: A successful liposomal formulation of cisplatin. Expert Opin. Investig. Drugs, 2009, 18(8), 1197-1218.
[http://dx.doi.org/10.1517/13543780903114168] [PMID: 19604121]
[105]
Zhao, M.; Lei, C.; Yang, Y.; Bu, X.; Ma, H.; Gong, H.; Liu, J.; Fang, X.; Hu, Z.; Fang, Q. Abraxane, the nanoparticle formulation of paclitaxel can induce drug resistance by up-regulation of P-gp. PLoS One, 2015, 10(7), e0131429.
[http://dx.doi.org/10.1371/journal.pone.0131429] [PMID: 26182353]
[106]
Adkins, C.E.; Nounou, M.I.; Hye, T.; Mohammad, A.S.; Terrell-Hall, T.; Mohan, N.K.; Eldon, M.A.; Hoch, U.; Lockman, P.R. NKTR-102 Efficacy versus irinotecan in a mouse model of brain metastases of breast cancer. BMC Cancer, 2015, 15, 685.
[http://dx.doi.org/10.1186/s12885-015-1672-4] [PMID: 26463521]
[107]
Swenson, C.E.; Haemmerich, D.; Maul, D.H.; Knox, B.; Ehrhart, N.; Reed, R.A. increased duration of heating boosts local drug deposition during radiofrequency ablation in combination with thermally sensitive liposomes (ThermoDox) in a porcine model. PLoS One, 2015, 10(10), e0139752.
[http://dx.doi.org/10.1371/journal.pone.0139752] [PMID: 26431204]
[108]
He, Z.; Wan, X.; Schulz, A.; Bludau, H.; Dobrovolskaia, M.A.; Stern, S.T.; Montgomery, S.A.; Yuan, H.; Li, Z.; Alakhova, D.; Sokolsky, M.; Darr, D.B.; Perou, C.M.; Jordan, R.; Luxenhofer, R.; Kabanov, A.V. A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity. Biomaterials, 2016, 101, 296-309.
[http://dx.doi.org/10.1016/j.biomaterials.2016.06.002] [PMID: 27315213]
[109]
Bulbake, U.; Doppalapudi, S.; Kommineni, N.; Khan, W. Liposomal formulations in clinical use: An updated review. Pharmaceutics, 2017, 9(2), E12.
[http://dx.doi.org/10.3390/pharmaceutics9020012] [PMID: 28346375]
[110]
Burade, V.; Bhowmick, S.; Maiti, K.; Zalawadia, R.; Ruan, H.; Thennati, R. Lipodox® (generic doxorubicin hydrochloride liposome injection): in vivo efficacy and bioequivalence versus Caelyx® (doxorubicin hydrochloride liposome injection) in human mammary carcinoma (MX-1) xenograft and syngeneic fibrosarcoma (WEHI 164) mouse models. BMC Cancer, 2017, 17(1), 405.
[http://dx.doi.org/10.1186/s12885-017-3377-3] [PMID: 28587612]
[111]
Huang, S.T.; Wang, Y.P.; Chen, Y.H.; Lin, C.T.; Li, W.S.; Wu, H.C. Liposomal paclitaxel induces fewer hematopoietic and cardiovascular complications than bioequivalent doses of Taxol. Int. J. Oncol., 2018, 53(3), 1105-1117.
[http://dx.doi.org/10.3892/ijo.2018.4449] [PMID: 29956746]
[112]
Do, V.Q.; Park, K.H.; Park, J.M.; Lee, M.Y. Comparative in vitro toxicity study of docetaxel and nanoxel, a docetaxel-loaded micellar formulation using cultured and blood cells. Toxicol. Res., 2019, 35(2), 201-207.
[http://dx.doi.org/10.5487/TR.2019.35.2.201] [PMID: 31015902]
[113]
Lee, E.; Moon, A. Identification of biomarkers for breast cancer using databases. J. Cancer Prev., 2016, 21(4), 235-242.
[http://dx.doi.org/10.15430/JCP.2016.21.4.235] [PMID: 28053957]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version402msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[23:25:01] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[23:25:02] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[23:25:02] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (88.73ms)time
  • Application (313ms)time
  • 1 x Application (77.92%)
    313ms
    1 x Booting (22.08%)
    88.73ms
    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 duplicated240ms
    • 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 ('316440840','',1,1739834701,1739834701) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1739834701
      990μsalphaeurekaselec_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 ('316440840','/article/105562',1,1739834701,1739834701)
      140μsalphaeurekaselec_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 >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) 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 >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) 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 >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) 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 >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) 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 >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) 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 >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 316440840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316440840) limit 1
      14.35msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 316440840
      • 1: 316440840
      • 2: 316440840
      • 3: 316440840
      • 4: 316440840
      • 5: 316440840
      • 6: 316440840
      • 7: 316440840
      • 8: 316440840
      • 9: 316440840
      • 10: 316440840
      • 11: 316440840
      • 12: 316440840
      • 13: 316440840
      • 14: 316440840
      • 15: 316440840
      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=105562
      1.04msalphaeurekaselec_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` = 7 limit 1
      1.13msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 7
      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=7) and sj.journal_id!=7 group by `j`.`nid`) as `aggregate_table`
      1.57msalphaeurekaselec_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=7) and sj.journal_id!=7 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.22msalphaeurekaselec_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=7) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      2.32msalphaeurekaselec_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=7) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      1.97msalphaeurekaselec_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` = '105562'
      1.16msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 105562
      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` = '105562'
      5.54msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 105562
      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` = '105562' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      1.62msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 105562
      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
      300μsalphaeurekaselec_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
      690μsalphaeurekaselec_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 = 7 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      37.83msalphaeurekaselec_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 = 7 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      12.85msalphaeurekaselec_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 = 7 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      8.61msalphaeurekaselec_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` = 105562 limit 1
      490μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 105562
      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 = 105562 and content_type = 'article' order by status desc limit 1
      770μsalphaeurekaselec_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 = 436 and content_id!=105562 and cd.content_type = 'article' order by rand() limit 20
      107msalphaeurekaselec_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` = 180609 limit 1
      270μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 180609
      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
      260μsalphaeurekaselec_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` = 'CCDT' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      360μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CCDT
      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 = '105562' 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) )
      380μsalphaeurekaselec_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 = '9995' 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) )
      310μsalphaeurekaselec_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 = '2791' 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 <= 316440840 and j.to_ip >=316440840 )) and ((j.from_date <= 1739834702 and j.to_date >= 1739834702 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2791) 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 <= 316440840 and j.to_ip >=316440840 )) and ((j.from_date <= 1739834702 and j.to_date >= 1739834702 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2791) 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 <= 316440840 and j.to_ip >=316440840 )) and ((j.from_date <= 1739834702 and j.to_date >= 1739834702 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2791)
      29.86msalphaeurekaselec_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 <= 316440840 and j.to_ip >=316440840 )) and ((j.from_date <= 1739834702 and j.to_date >= 1739834702 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9995) 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 <= 316440840 and j.to_ip >=316440840 )) and ((j.from_date <= 1739834702 and j.to_date >= 1739834702 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9995) 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 <= 316440840 and j.to_ip >=316440840 )) and ((j.from_date <= 1739834702 and j.to_date >= 1739834702 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9995)
      720μsalphaeurekaselec_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 <= 316440840 and j.to_ip >=316440840 )) and ((j.from_date <= 1739834702 and j.to_date >= 1739834702 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 105562) 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 <= 316440840 and j.to_ip >=316440840 )) and ((j.from_date <= 1739834702 and j.to_date >= 1739834702 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 105562) 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 <= 316440840 and j.to_ip >=316440840 )) and ((j.from_date <= 1739834702 and j.to_date >= 1739834702 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 105562)
      600μsalphaeurekaselec_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` < '603' and is_uploaded = 1 and issue_id = 9995 order by cast(first_page as SIGNED) desc limit 1
      500μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 603
      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` > '615' and is_uploaded = 1 and issue_id = 9995 order by cast(first_page as SIGNED) asc limit 1
      400μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 615
      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'
      160μsalphaeurekaselec_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
      180μsalphaeurekaselec_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` = 105562 limit 1
      1.97msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 105562
      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` = 7 and `b`.`banner_from_date` <= 1739834702 and `b`.`banner_to_date` >= 1739834702 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.11msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 7
      • 3: 1739834702
      • 4: 1739834702
      • 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` = 7 and `b`.`banner_from_date` <= 1739834702 and `b`.`banner_to_date` >= 1739834702 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.06msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 7
      • 3: 1739834702
      • 4: 1739834702
      • 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='02c8af6bd6ad5e65f9c5093be4f70f88'
      200μsalphaeurekaselec_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#?
    App\Models\MultiLangArticle
    1MultiLangArticle.php#?
        _token
        zReGh1K9mgeXOIrTqlFDy7sBLh3YddEWxQNYKSir
        uc_cart_id
        02c8af6bd6ad5e65f9c5093be4f70f88
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/105562" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/105562
        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:9 [ "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6ImVuMVRLZVp5WC9hTktrZVJRRDZwSGc9PSIsInZhbHVlIjoiOEc3K2JTKzFHSFIrU3J1TUJYSEZMK2tPZDNXVDlxS0lKTXBSUUFOMlhoaz0iLCJtYWMiOiIzNTEwMTU1YjhkZWYzNDkxMzViNDM5NjJlYmU2ZGNlMTYzNThhYjZjMjc5YjlhZmJmYjk3M2NiZDVlMWMwYWZlIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6ImVuMVRLZVp5WC9hTktrZVJRRDZwSGc9PSIsInZhbHVlIjoiOEc3K2JTKzFHSFIrU3J1TUJYSEZMK2tPZDNXVDlxS0lKTXBSUUFOMlhoaz0iLCJtYWMiOiIzNTEwMTU1YjhkZWYz" ] "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
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        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 => "Mon, 17 Feb 2025 23:25:02 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImpieDBwMkJIUFNRTG1vYjRQaWRoVmc9PSIsInZhbHVlIjoiTVpOcldOZFFBSG1VclliaWg0TCtjaklaK0ExYUZtVFFzQVVVaFN4UlJWQVlMUmtWbGVQeVdTTEpvdVVxNG9iRE1kOEwwNURqRzd2V1Q0Q0R4SGZxK1R2RFhDa2RUSFZnMlQ0WlVFenV0aGZ1SGIrRXNXZmNMcWU2RnJTblByVWciLCJtYWMiOiJhZGUxZmM5NmM2OTU5MDVmMjllNTdlYzllMzBmY2MyOWU4MmFlNjNlNTIxYjE1MjA4YWRlMzBhYzgwMGVkYTQzIiwidGFnIjoiIn0%3D; expires=Thu, 20 Feb 2025 11:25:02 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6ImpieDBwMkJIUFNRTG1vYjRQaWRoVmc9PSIsInZhbHVlIjoiTVpOcldOZFFBSG1VclliaWg0TCtjaklaK0ExYUZtVFFzQVVVaFN4UlJWQVlMUmtWbGVQeVdTTEpvdVVxNG9iRE1kOEwwN" 1 => "alphaeurekaselectnet_session=eyJpdiI6IitJZ1ZOblQrcVE3Z3lnUHd2ZjFqcmc9PSIsInZhbHVlIjoiU2JCL2NEK1FPaGFub2dhc1JKSE05M1hweGZoMnpkdDhTNFFaeGRZc2Y5K3E0RXBPZ0w1RXQwMTVDTHZ5bVJxVm43M00zLytoT0NkYkhVRGxHT3UwWUpHZ2tCYzU0SDYzUk1lcVhnM1ZERW43T091UTVSSGlPWTU4d29IUlQ1QmwiLCJtYWMiOiJiZmY0OGNhYTcxYWY1OTFmZDBjNDRiZGVmZmMyYTQ5OWQ5MjJlYzRjZTU2MzJiZGNkYjUyNzc0ZDU1MzZhZDYxIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IitJZ1ZOblQrcVE3Z3lnUHd2ZjFqcmc9PSIsInZhbHVlIjoiU2JCL2NEK1FPaGFub2dhc1JKSE05M1hweGZoMnpkdDhTNFFaeGRZc2Y5K3E0RXBPZ0w1RXQwMTV" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImpieDBwMkJIUFNRTG1vYjRQaWRoVmc9PSIsInZhbHVlIjoiTVpOcldOZFFBSG1VclliaWg0TCtjaklaK0ExYUZtVFFzQVVVaFN4UlJWQVlMUmtWbGVQeVdTTEpvdVVxNG9iRE1kOEwwNURqRzd2V1Q0Q0R4SGZxK1R2RFhDa2RUSFZnMlQ0WlVFenV0aGZ1SGIrRXNXZmNMcWU2RnJTblByVWciLCJtYWMiOiJhZGUxZmM5NmM2OTU5MDVmMjllNTdlYzllMzBmY2MyOWU4MmFlNjNlNTIxYjE1MjA4YWRlMzBhYzgwMGVkYTQzIiwidGFnIjoiIn0%3D; expires=Thu, 20-Feb-2025 11:25:02 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6ImpieDBwMkJIUFNRTG1vYjRQaWRoVmc9PSIsInZhbHVlIjoiTVpOcldOZFFBSG1VclliaWg0TCtjaklaK0ExYUZtVFFzQVVVaFN4UlJWQVlMUmtWbGVQeVdTTEpvdVVxNG9iRE1kOEwwN" 1 => "alphaeurekaselectnet_session=eyJpdiI6IitJZ1ZOblQrcVE3Z3lnUHd2ZjFqcmc9PSIsInZhbHVlIjoiU2JCL2NEK1FPaGFub2dhc1JKSE05M1hweGZoMnpkdDhTNFFaeGRZc2Y5K3E0RXBPZ0w1RXQwMTVDTHZ5bVJxVm43M00zLytoT0NkYkhVRGxHT3UwWUpHZ2tCYzU0SDYzUk1lcVhnM1ZERW43T091UTVSSGlPWTU4d29IUlQ1QmwiLCJtYWMiOiJiZmY0OGNhYTcxYWY1OTFmZDBjNDRiZGVmZmMyYTQ5OWQ5MjJlYzRjZTU2MzJiZGNkYjUyNzc0ZDU1MzZhZDYxIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IitJZ1ZOblQrcVE3Z3lnUHd2ZjFqcmc9PSIsInZhbHVlIjoiU2JCL2NEK1FPaGFub2dhc1JKSE05M1hweGZoMnpkdDhTNFFaeGRZc2Y5K3E0RXBPZ0w1RXQwMTV" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "zReGh1K9mgeXOIrTqlFDy7sBLh3YddEWxQNYKSir" "uc_cart_id" => "02c8af6bd6ad5e65f9c5093be4f70f88" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/105562" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-17 23:25:02GET/article/105562314372