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Current Radiopharmaceuticals

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ISSN (Print): 1874-4710
ISSN (Online): 1874-4729

Research Article

[18F]Amylovis as a Potential PET Probe for β-Amyloid Plaque: Synthesis, In Silico, In vitro and In vivo Evaluations

Author(s): Suchitil Rivera-Marrero, Laura Fernández-Maza, Samila León-Chaviano, Marquiza Sablón-Carrazana, Alberto Bencomo-Martínez, Alejandro Perera-Pintado, Anais Prats-Capote, Florencia Zoppolo, Ingrid Kreimerman, Tania Pardo, Laura Reyes, Marcin Balcerzyk, Geyla Dubed-Bandomo, Daymara Mercerón-Martínez, Luis A. Espinosa-Rodríguez, Henry Engler, Eduardo Savio* and Chryslaine Rodríguez-Tanty*

Volume 12, Issue 1, 2019

Page: [58 - 71] Pages: 14

DOI: 10.2174/1874471012666190102165053

open access plus

Abstract

Background: Alzheimer’s disease (AD) is the most common form of dementia. Neuroimaging methods have widened the horizons for AD diagnosis and therapy. The goals of this work are the synthesis of 2-(3-fluoropropyl)-6-methoxynaphthalene (5) and its [18F]-radiolabeled counterpart ([18F]Amylovis), the in silico and in vitro comparative evaluations of [18F]Amylovis and [11C]Pittsburg compound B (PIB) and the in vivo preclinical evaluation of [18F]Amylovis in transgenic and wild mice.

Methods: Iron-catalysis cross coupling reaction, followed by fluorination and radiofluorination steps were carried out to obtain 5 and 18F-Amylovis. Protein/Aß plaques binding, biodistribution, PET/CT Imaging and immunohistochemical studies were conducted in healthy/transgenic mice.

Results: The synthesis of 5 was successful obtained. Comparative in silico studies predicting that 5 should have affinity to the Aβ-peptide, mainly through π-π interactions. According to a dynamic simulation study the ligand-Aβ peptide complexes are stable in simulation-time (ΔG = -5.31 kcal/mol). [18F]Amylovis was obtained with satisfactory yield, high radiochemical purity and specific activity. The [18F]Amylovis log Poct/PBS value suggests its potential ability for crossing the blood brain barrier (BBB). According to in vitro assays, [18F]Amylovis has an adequate stability in time. Higher affinity to Aβ plaques were found for [18F]Amylovis (Kd 0.16 nmol/L) than PIB (Kd 8.86 nmol/L) in brain serial sections of 3xTg-AD mice. Biodistribution in healthy mice showed that [18F]Amylovis crosses the BBB with rapid uptake (7 %ID/g at 5 min) and good washout (0.11±0.03 %ID/g at 60 min). Comparative PET dynamic studies of [18F]Amylovis in healthy and transgenic APPSwe/PS1dE9 mice, revealed a significant high uptake in the mice model.

Conclusion: The in silico, in vitro and in vivo results justify that [18F]Amylovis should be studied as a promissory PET imaging agent to detect the presence of Aβ senile plaques.

Keywords: Alzheimer's disease diagnosis, positron emission tomography, β-amyloid probe, fluorine-18, iron cross-couplingreaction, docking and dynamic simulations.

Graphical Abstract

[1]
Selkoe, D.J.; Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med., 2016, 8(6), 595-608.
[2]
Sperling, R.A.; Aisen, P.S.; Beckett, L.A.; Bennett, D.A.; Craft, S.; Fagan, A.M.; Iwatsubo, T.; Jack, C.R.; Kaye, J.; Montine, T.J. Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement., 2011, 7(3), 280-292.
[3]
Scheuner, D.; Eckman, C.; Jensen, M.; Song, X.; Citron, M.; Suzuki, N.; Bird, T.; Hardy, J.; Hutton, M.; Kukull, W. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat. Med., 1996, 2(8), 864-870.
[4]
Monsonego, A.; Weiner, H.L. Immunotherapeutic approaches to Alzheimer’s disease. Science, 2003, 302(5646), 834-838.
[5]
DeKosky, S.T.; Marek, K. Looking backward to move forward: Early detection of neurodegenerative disorders. Science, 2003, 302(5646), 830-834.
[6]
Prince, M.; Wimo, A.; Guerchet, M.; Ali, G.; Wu, Y.; Prina, M. World Alzheimer Report 2015. The global impact of dementia. An analysis of prevalence, incidence, cost and trendsAlzheimer's Disease International; London, 2015.
[7]
Salerno, M.; Porqueras, D.S.D. Alzheimer’s disease: The use of contrast agents for magnetic resonance imaging to detect amyloid beta peptide inside the brain. Coord. Chem. Rev., 2016, 327, 27-34.
[8]
Anthony, M.; Lin, F. A systematic review for functional neuroimaging studies of cognitive reserve across the cognitive aging spectrum. Arch. Clin. Neuropsychol., 2018, 33(8), 937-948.
[9]
Yang, Y.; Zhang, X.; Cui, M.; Zhang, J.; Guo, Z.; Li, Y.; Zhang, X.; Dai, J.; Liu, B. Preliminary characterization and in vivo studies of structurally identical 18 f-and 125 i-labeled benzyloxybenzenes for PET/SPECT imaging of β-amyloid plaques. Sci. Rep., 2015, 5, 12084.
[10]
Morris, E.; Chalkidou, A.; Hammers, A.; Peacock, J.; Summers, J.; Keevil, S. Diagnostic accuracy of 18 F amyloid PET tracers for the diagnosis of Alzheimer’s disease: A systematic review and meta-analysis. Eur. J. Nucl. Med. Mol. Imaging, 2016, 43(2), 374-385.
[11]
Catafau, A.M.; Bullich, S. Amyloid PET imaging: Applications beyond Alzheimer’s disease. Clin. Transl. Imaging, 2015, 3(1), 39-55.
[12]
Furumoto, S.; Okamura, N.; Iwata, R.; Yanai, K.; Arai, H.; Kudo, Y. Recent advances in the development of amyloid imaging agents. Curr. Top. Med. Chem., 2007, 7(18), 1773-1789.
[13]
Kung, H.F.; Choi, S.R.; Qu, W.; Zhang, W.; Skovronsky, D. 18F stilbenes and styrylpyridines for PET imaging of A beta plaques in Alzheimer’s disease: A miniperspective. J. Med. Chem., 2010, 53(3), 933-941.
[14]
Choi, S.R.; Schneider, J.A.; Bennett, D.A.; Beach, T.G.; Bedell, B.J.; Zehntner, S.P.; Krautkramer, M.; Kung, H.F.; Skovronsky, D.M.; Hefti, F. Correlation of amyloid PET ligand florbetapir F 18 (18F-AV-45) binding with β-amyloid aggregation and neuritic plaque deposition in postmortem brain tissue. Alzheimer Dis. Assoc. Disord., 2012, 26(1), 8-16.
[15]
de Lartigue, J. Flutemetamol (18F): A β-amyloid positron emission tomography tracer for Alzheimer’s and dementia diagnosis. Drugs Today, 2014, 50(3), 219-229.
[16]
Villemagne, V.L.; Ong, K.; Mulligan, R.S.; Holl, G.; Pejoska, S.; Jones, G.; O’Keefe, G.; Ackerman, U.; Tochon-Danguy, H.; Chan, J.G. Amyloid imaging with 18F-florbetaben in Alzheimer disease and other dementias. J. Nucl. Med., 2011, 52(8), 1210-1217.
[17]
Ma, Y.; Hof, P.R.; Grant, S.C.; Blackband, S.J.; Bennett, R.; Slatest, L.; McGuigan, M.D.; Benveniste, H. A three-dimensional digital atlas database of the adult C57BL/6J mouse brain by magnetic resonance microscopy. Neuroscience, 2005, 135(4), 1203-1215.
[18]
Prabhakar, C.; Reddy, G.B.; Reddy, C.M.; Nageshwar, D.; Devi, A.S.; Babu, J.M.; Vyas, K.; Sarma, M.; Reddy, G.O. Process research and structural studies on nabumetone. Org. Process Res. Dev., 1999, 3(2), 121-125.
[19]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The Protein Data Bank, 1999; Springer: Dordrecht, 2006.
[20]
Hanwell, M.D.; Curtis, D.E.; Lonie, D.C.; Vandermeersch, T.; Zurek, E.; Hutchison, G.R. Avogadro: An advanced semantic chemical editor, visualization, and analysis platform. J. Cheminf., 2012, 4(1), 17.
[21]
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[22]
Hess, B.; Kutzner, C.; Van Der Spoel, D.; Lindahl, E. GROMACS 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation. J. Chem. Theory Comput., 2008, 4(3), 435-447.
[23]
Case, D.A.; Cheatham, T.E.; Darden, T.; Gohlke, H.; Luo, R.; Merz, K.M.; Onufriev, A.; Simmerling, C.; Wang, B.; Woods, R.J. The Amber biomolecular simulation programs. J. Comput. Chem., 2005, 26(16), 1668-1688.
[24]
Lemkul, J.A.; Allen, W.J.; Bevan, D.R. Practical considerations for building GROMOS-compatible small-molecule topologies. J. Chem. Inf. Model., 2010, 50(12), 2221-2235.
[25]
Klunk, W.E.; Wang, Y.; Huang, G.F.; Debnath, M.L.; Holt, D.P.; Mathis, C.A. Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain. Life Sciences., 2001, 69(13), 1471-1484.
[26]
Klunk, W.E.; Wang, Y.; Huang, G-f.; Debnath, M.L.; Holt, D.P.; Shao, L.; Hamilton, R.L.; Ikonomovic, M.D.; DeKosky, S.T.; Mathis, C.A. The binding of 2-(4′-methylaminophenyl) benzothiazole to postmortem brain homogenates is dominated by the amyloid component. J. Neurosci., 2003, 23(6), 2086-2092.
[27]
Wang, R.; Lai, L.; Wang, S. Further development and validation of empirical scoring functions for structure-based binding affinity prediction. J. Comput. Aided Mol. Des., 2002, 16(1), 11-26.
[28]
Sablón, M.; Rodriguez, C.; Rivera, S.; Pérez, R.; Perera, A.; López, R.M. Method for obtaining novel derivatives of naphthalene for in vivo diagnosis of Alzheimer's disease. Registered with the Cuban Industrial Property Office, under No. 2009/57 and registration number 23844 in the same office. This patent was granted by: European Patent Office (EPO 2 436 666 A20), Unitted State Patent (US 9,764,047), Instituto Mexicano de la Propiedad industrial (MX/a/2013/011331), Canadian intellectual Property Office (CA2789869 C), South African Patent Office (No. 2012/07005) and Intellectual Property Corporation of Malaysian (PI 2012003534). Also, the patent is requested in US (2012/0321560 A1), Brazil (PI0115172-0) and in Japan (9/2012), 2009.
[29]
Koelsch, F.C. 6-Bromo-2-naphthol. In: EC Horning; Organic Synthesis Collective Vol 3, A Revised Edition Of Annual Volumes 20-29. John Wiley & Sons, Inc., New York, 1995; pp. 132-133.
[30]
Dijkstra, G.; Kruizinga, W.H.; Kellogg, R.M. An assessment of the causes of the “cesium effect”. J. Org. Chem., 1987, 52(19), 4230-4234.
[31]
Fürstner, A.; Martin, R.; Krause, H.; Seidel, G.n.; Goddard, R.; Lehmann, C.W. Preparation, structure, and reactivity of nonstabilized organoiron compounds. Implications for iron-catalyzed cross coupling reactions. J. Am. Chem. Soc., 2008, 130(27), 8773-8787.
[32]
Fürstner, A.; Leitner, A. Iron‐catalyzed cross‐coupling reactions of alkyl‐grignard reagents with aryl chlorides, tosylates, and triflates. Angew. Chem. Int. Ed., 2002, 41(4), 609-612.
[33]
Fürstner, A.; Leitner, A.; Méndez, M.; Krause, H. Iron-catalyzed cross-coupling reactions. J. Am. Chem. Soc., 2002, 124(46), 13856-13863.
[34]
Cahiez, G.; Habiak, V.; Duplais, C.; Moyeux, A. Iron‐catalyzed alkylations of aromatic grignard reagents. Angew. Chem. Int. Ed., 2007, 46(23), 4364-4366.
[35]
Martin, R.; Fürstner, A. Cross‐coupling of alkyl halides with aryl grignard reagents catalyzed by a low‐valent iron complex. Angew. Chem., 2004, 116(30), 4045-4047.
[36]
Bedford, R.B.; Brenner, P.B. The development of iron catalysts for cross-coupling reactions. In: Iron Catalysis II; Springer, 2015; pp. 19-46.
[37]
Nagano, T.; Hayashi, T. Iron-catalyzed Grignard cross-coupling with alkyl halides possessing β-hydrogens. Org. Lett., 2004, 6(8), 1297-1299.
[38]
Tamura, M.; Kochi, J.K. Vinylation of Grignard reagents. Catalysis by iron. J. Am. Chem. Soc., 1971, 93(6), 1487-1489.
[39]
Kochi, J.K. Electron-transfer mechanisms for organometallic intermediates in catalytic reactions. Acc. Chem. Res., 1974, 7(10), 351-360.
[40]
Yamamoto, A. Organotransition-metal chemistry: Past development and future outlook. J. Organomet. Chem., 2000, 600(1), 159-167.
[41]
Uchino, M.; Yamamoto, A.; Ikeda, S. Preparation of a phenyl—nickel complex, phenyl (dipyridyl) nickel chloride, an olefin dimerization catalyst. J. Organomet. Chem., 1970, 24(3), C63-C64.
[42]
Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. Iron-catalyzed cross-coupling of primary and secondary alkyl halides with aryl Grignard reagents. J. Am. Chem. Soc., 2004, 126(12), 3686-3687.
[43]
Bedford, R.B.; Betham, M.; Bruce, D.W.; Danopoulos, A.A.; Frost, R.M.; Hird, M. Iron− Phosphine,− Phosphite,- Arsine, and- Carbene Catalysts for the Coupling of Primary and Secondary Alkyl Halides with Aryl Grignard Reagents. J. Org. Chem., 2006, 71(3), 1104-1110.
[44]
Nakamura, M.; Ito, S.; Matsuo, K.; Nakamura, E. Iron-catalyzed chemoselective cross-coupling of primary and secondary alkyl halides with arylzinc reagents. Synlett, 2005, 2005(11), 1794-1798.
[45]
Karlstroem, A.S.E.; Huerta, F.F.; Meuzelaar, G.J.; Bäckvall, J.-E. Ferrocenyl thiolates as ligands in the enantioselective copper-catalyzed substitution of allylic acetates with Grignard reagents. Synlett, 2001, 2001(Special Issue), 0923-0926.
[46]
Noda, D.; Sunada, Y.; Hatakeyama, T.; Nakamura, M.; Nagashima, H. Effect of TMEDA on iron-catalyzed coupling reactions of ArMgX with Alkyl halides. J. Am. Chem. Soc., 2009, 131(17), 6078-6079.
[47]
Kim, D.W.; Jeong, H-J.; Lim, S.T.; Sohn, M-H. Facile nucleophilic fluorination of primary alkyl halides using tetrabutylammonium fluoride in a tert-alcohol medium. Tetrahedron Lett., 2010, 51(2), 432-434.
[48]
Chang, W.E.; Takeda, T.; Raman, E.P.; Klimov, D.K. Molecular dynamics simulations of anti-aggregation effect of ibuprofen. Biophys. J., 2010, 98(11), 2662-2670.
[49]
Kim, S.; Chang, W.E.; Kumar, R.; Klimov, D.K. Naproxen interferes with the assembly of Aβ oligomers implicated in Alzheimer’s disease. Biophys. J., 2011, 100(8), 2024-2032.
[50]
Zhu, B-Y.; Cheng, Y.; Li, G-B.; Yang, S-Y.; Zhang, Z-R. Synthesis and evaluation of styrylpyran fluorophores for noninvasive detection of cerebral β-amyloid deposits. Bioorg. Med. Chem., 2016.
[51]
Tjernberg, L.O.; Callaway, D.J.; Tjernberg, A.; Hahne, S.; Lilliehöök, C.; Terenius, L.; Thyberg, J.; Nordstedt, C. A molecular model of Alzheimer amyloid β-peptide fibril formation. J. Biol. Chem., 1999, 274(18), 12619-12625.
[52]
Tjernberg, L.O.; Näslund, J.; Lindqvist, F.; Johansson, J.; Karlström, A.R.; Thyberg, J.; Terenius, L.; Nordstedt, C. Arrest of-amyloid fibril formation by a pentapeptide ligand. J. Biol. Chem., 1996, 271(15), 8545-8548.
[53]
Lührs, T.; Ritter, C.; Adrian, M.; Riek-Loher, D.; Bohrmann, B.; Döbeli, H.; Schubert, D.; Riek, R. 3D structure of Alzheimer’s amyloid-β (1–42) fibrils. Proc. Natl. Acad. Sci. USA, 2005, 102(48), 17342-17347.
[54]
Bjelic, S.; Nervall, M.; Gutiérrez-de-Terán, H.; Ersmark, K.; Hallberg, A.; Åqvist, J. Computational inhibitor design against malaria plasmepsins. Cell. Mol. Life Sci., 2007, 64(17), 2285-2305.
[55]
Oddo, S.; Caccamo, A.; Shepherd, J.D.; Murphy, M.P.; Golde, T.E.; Kayed, R.; Metherate, R.; Mattson, M.P.; Akbari, Y.; LaFerla, F.M. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron, 2003, 39(3), 409-421.
[56]
Cline, G.W.; Hanna, S.B. Kinetics and mechanisms of the aminolysis of N-hydroxysuccinimide esters in aqueous buffers. J. Org. Chem., 1988, 53(15), 3583-3586.
[57]
Choi, S.R.; Golding, G.; Zhuang, Z.; Zhang, W.; Lim, N.; Hefti, F.; Benedum, T.E.; Kilbourn, M.R.; Skovronsky, D.; Kung, H.F. Preclinical properties of 18F-AV-45: A PET agent for Aβ plaques in the brain. J. Nucl. Med., 2009, 50(11), 1887-1894.
[58]
Klunk, W.E.; Lopresti, B.J.; Ikonomovic, M.D.; Lefterov, I.M.; Koldamova, R.P.; Abrahamson, E.E.; Debnath, M.L.; Holt, D.P.; Huang, G-f.; Shao, L. Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-β in Alzheimer’s disease brain but not in transgenic mouse brain. J. Neurosci., 2005, 25(46), 10598-10606.
[59]
[60]
FDA Application number: 204677Orig1s000. Florbetaben. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204677Orig1s000PharmR.pdf
[61]
Mathis, C.A.; Wang, Y.; Holt, D.P.; Huang, G-F.; Debnath, M.L.; Klunk, W.E. Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J. Med. Chem., 2003, 46(13), 2740-2754.
[62]
Choi, S.R.; Golding, G.; Zhuang, Z.; Zhang, W.; Lim, N.; Hefti, F.; Benedum, T.E.; Kilbourn, M.R.; Skovronsky, D.; Kung, H.F. Preclinical properties of 18F-AV-45: A PET agent for Aβ plaques in the brain. J. Nucl. Med., 2009, 50(11), 1887-1894.
[63]
Sundaram, G.S.; Dhavale, D.; Prior, J.L.; Sivapackiam, J.; Laforest, R.; Kotzbauer, P.; Sharma, V. Synthesis, characterization, and preclinical validation of a PET radiopharmaceutical for interrogating Aβ (β-amyloid) plaques in Alzheimer’s disease. EJNMMI Res., 2015, 5(1), 33-46.
[64]
Heurling, K.; Leuzy, A.; Zimmer, E.R.; Lubberink, M.; Nordberg, A. Imaging β-amyloid using [18F] flutemetamol positron emission tomography: From dosimetry to clinical diagnosis. Eur. J. Nucl. Med. Mol. Imaging, 2016, 43(2), 362-373.
[65]
Zhang, W.; Oya, S.; Kung, M-P.; Hou, C.; Maier, D.L.; Kung, H.F. F-18 polyethyleneglycol stilbenes as PET imaging agents targeting Aβ aggregates in the brain. Nucl. Med. Biol., 2005, 32(8), 799-809.
[66]
Sundaram, G.S.; Dhavale, D.; Prior, J.L.; Sivapackiam, J.; Laforest, R.; Kotzbauer, P.; Sharma, V. Synthesis, characterization, and preclinical validation of a PET radiopharmaceutical for interrogating Aβ (β-amyloid) plaques in Alzheimer’s disease. EJNMMI Res., 2015, 5(1), 33.
[67]
Rosen, W.G.; Mohs, R.C.; Davis, K.L. A new rating scale for Alzheimer’s disease. Am. J. Psychiatry, 1984, 141(11), 1356-1364.
[68]
Ouyang, Y.; Tinianow, J.N.; Cherry, S.R.; Marik, J. Evaluation of 2-[18F] fluoroacetate kinetics in rodent models of cerebral hypoxia–ischemia. J. Cereb. Blood Flow Metab., 2014, 34(5), 836-844.

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    • (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
      12.65msalphaeurekaselec_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=95561
      770μsalphaeurekaselec_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` = 95 limit 1
      890μsalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 95
      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=95) and sj.journal_id!=95 group by `j`.`nid`) as `aggregate_table`
      660μsalphaeurekaselec_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=95) and sj.journal_id!=95 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      550μsalphaeurekaselec_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=95) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      1.24msalphaeurekaselec_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=95) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      1.08msalphaeurekaselec_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` = '95561'
      790μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 95561
      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` = '95561'
      1.56msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 95561
      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` = '95561' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      3.34msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 95561
      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
      270μsalphaeurekaselec_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
      500μsalphaeurekaselec_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 = 95 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      25.26msalphaeurekaselec_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 = 95 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      3.65msalphaeurekaselec_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 = 95 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      2.84msalphaeurekaselec_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` = 95561 limit 1
      260μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 95561
      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 = 95561 and content_type = 'article' order by status desc limit 1
      310μsalphaeurekaselec_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 = 281 and cd.sub_disease_id = 518 and content_id!=95561 and cd.content_type = 'article' order by rand() limit 20
      53.39msalphaeurekaselec_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` = 168721 limit 1
      260μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 168721
      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
      240μsalphaeurekaselec_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` = 'CRP' 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: CRP
      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 = '95561' 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) )
      400μsalphaeurekaselec_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 * from `article` where `first_page` < '58' and is_uploaded = 1 and issue_id = 8932 order by cast(first_page as SIGNED) desc limit 1
      650μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 58
      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` > '71' and is_uploaded = 1 and issue_id = 8932 order by cast(first_page as SIGNED) asc limit 1
      580μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 71
      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'
      220μsalphaeurekaselec_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
      250μsalphaeurekaselec_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` = 95561 limit 1
      3.83msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 95561
      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` = 95 and `b`.`banner_from_date` <= 1739972429 and `b`.`banner_to_date` >= 1739972429 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.62msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 95
      • 3: 1739972429
      • 4: 1739972429
      • 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` = 95 and `b`.`banner_from_date` <= 1739972429 and `b`.`banner_to_date` >= 1739972429 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.54msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 95
      • 3: 1739972429
      • 4: 1739972429
      • 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='abd3d25ced290c88fd809fd1c4cc8c09'
      280μsalphaeurekaselec_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#?
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        ClearShow all
        Date ↕MethodURLData
        #12025-02-19 13:40:29GET/article/95561314321