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Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5230
ISSN (Online): 1875-614X

Research Article

Effects of Acylhydrazone Derivatives on Experimental Pulmonary Inflammation by Chemical Sensitization

Author(s): Katharina Rodrigues de Lima Porto Ramos, Sandra Cabral da Silva, Pascal Marchand, Fernanda Virgínia Barreto Mota, Julyanne Cunha de Assis Correia, Jéssica de Andrade Gomes Silva, George Torres de Lima, Marllon Alex Santana, Willian Charles da Silva Moura, Vanda Lúcia dos Santos, Ricardo Olímpio Moura and Teresinha Gonçalves da Silva*

Volume 21, Issue 2, 2022

Published on: 29 August, 2022

Page: [135 - 151] Pages: 17

DOI: 10.2174/1871523021666220729141608

Price: $65

Abstract

Background: Chronic lung diseases are characterized by airway inflammation and remodelling of the lung parenchyma that triggers considerable impairment of respiratory function.

Objective: In this study, two compounds belonging to the N-acylhydrazone class were evaluated, aiming to identify new therapeutic agents for pulmonary inflammatory diseases.

Materials and Methods: The acute toxicity of 2-cyano-N'-(3-ethoxy-4-hydroxybenzylidene)- acetohydrazide (JR-12) and N'-benzylidene-2-cyano-3-phenylacrylohydrazide (JR09-Bz) was evaluated. Afterwards, they were tested in models of ovalbumin (OVA)-induced allergic asthma and pleurisy, bleomycin-induced pulmonary fibrosis, in addition to mucolytic activity.

Results and Discussion: The compounds did not show toxicity at the dose of 2,000 mg/kg, and no animal died. On OVA-induced pleurisy, animals treated with JR-12 or JR09-Bz at a dose of 10 mg/kg (orally) showed significant inhibition of the leukocyte infiltrate in the bronchoalveolar lavage by 62.5% and 61.5%, respectively, compared to the control group. The compounds JR-12 and JR09-Bz were also active in blocking the allergic asthmatic response triggered by OVA, reducing the leukocyte infiltrate by 73.1% and 69.8%, respectively. Histopathological changes and mast cell migration in treated animals with JR-12 or JR09-Bz were similar to treatment with the reference drugs dexamethasone and montelukast. JR-12 and JR09-Bz also reversed airway remodeling in animals on the bleomycin-induced fibrosis model compared to the control group. Furthermore, it was observed that N-arylhydrazone derivatives showed expectorant and mucolytic activities, increasing mucus secretion by 45.6% and 63.8% for JR-12 and JR09-Bz, respectively.

Conclusion: Together, the results show that JR-12 and JR09-Bz showed promising activity against airway inflammation, as well as low toxicity.

Keywords: Remodeling, Asthma, cell migration, histopatology, pulmonary fibrosis, Acylhidrazone.

Graphical Abstract

[1]
Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; Cheng, Z.; Yu, T.; Xia, J.; Wei, Y.; Wu, W.; Xie, X.; Yin, W.; Li, H.; Liu, M.; Xiao, Y.; Gao, H.; Guo, L.; Xie, J.; Wang, G.; Jiang, R.; Gao, Z.; Jin, Q.; Wang, J.; Cao, B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet, 2020, 395(10223), 497-506.
[http://dx.doi.org/10.1016/S0140-6736(20)30183-5] [PMID: 31986264]
[2]
Wu, C.Y.; Lin, Y.S.; Yang, Y.H.; Shu, L.H.; Cheng, Y.C.; Liu, H.T. GB-2 inhibits ACE2 and TMPRSS2 expression: In vivo and in vitro studies. Biomed. Pharmacother., 2020, 132, 110816.
[http://dx.doi.org/10.1016/j.biopha.2020.110816] [PMID: 33049583]
[3]
Zhou, P.; Yang, X.L.; Wang, X.G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.R.; Zhu, Y.; Li, B.; Huang, C.L.; Chen, H.D.; Chen, J.; Luo, Y.; Guo, H.; Jiang, R.D.; Liu, M.Q.; Chen, Y.; Shen, X.R.; Wang, X.; Zheng, X.S.; Zhao, K.; Chen, Q.J.; Deng, F.; Liu, L.L.; Yan, B.; Zhan, F.X.; Wang, Y.Y.; Xiao, G.F.; Shi, Z.L. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 2020, 579(7798), 270-273.
[http://dx.doi.org/10.1038/s41586-020-2012-7] [PMID: 32015507]
[4]
The Lancet. GBD 2020 Chronic Respiratory Disease Collaborators. Global health: Time for radical change? Lancet, 2020, 396(10258), 396-e1125.
[http://dx.doi.org/10.1016/S0140-6736(20)32131-0]
[5]
Alhassan, S.; Hattab, Y.; Bajwa, O.; Bihler, E.; Singh, A.C. Asthma. Crit. Care Nurs. Q., 2016, 39(2), 110-123.
[http://dx.doi.org/10.1097/CNQ.0000000000000104] [PMID: 26919672]
[6]
Taniguchi, H.; Kondoh, Y. Acute and subacute idiopathic interstitial pneumonias. Respirology, 2016, 21(5), 810-820.
[http://dx.doi.org/10.1111/resp.12786] [PMID: 27123874]
[7]
Kolb, M.; Bondue, B.; Pesci, A.; Miyazaki, Y.; Song, J.W.; Bhatt, N.Y.; Huggins, J.T.; Oldham, J.M.; Padilla, M.L.; Roman, J.; Shapera, S. Acute exacerbations of progressive-fibrosing interstitial lung diseases. Eur. Respir. Rev., 2018, 27(150), e180071.
[http://dx.doi.org/10.1183/16000617.0071-2018] [PMID: 30578331]
[8]
Wang, H.; Naghavi, M.; Allen, C.; Barber, R.M.; Bhutta, Z.A.; Carter, A.; Casey, D.C.; Charlson, F.J.; Chen, A.Z.; Coates, M.M.; Coggeshall, M.; Dandona, L.; Dicker, D.J.; Erskine, H.E.; Ferrari, A.J.; Fitzmaurice, C.; Foreman, K.; Forouzanfar, M.H.; Fraser, M.S.; Fullman, N.; Gething, P.W.; Goldberg, E.M.; Graetz, N.; Haagsma, J.A.; Hay, S.I.; Huynh, C.; Johnson, C.O.; Kassebaum, N.J.; Kinfu, Y.; Kulikoff, X.R.; Kutz, M.; Kyu, H.H.; Larson, H.J.; Leung, J.; Liang, X.; Lim, S.S.; Lind, M.; Lozano, R.; Marquez, N.; Mensah, G.A.; Mikesell, J.; Mokdad, A.H.; Mooney, M.D.; Nguyen, G.; Nsoesie, E.; Pigott, D.M.; Pinho, C.; Roth, G.A.; Salomon, J.A.; Sandar, L.; Silpakit, N.; Sligar, A.; Sorensen, R.J.D.; Stanaway, J.; Steiner, C.; Teeple, S.; Thomas, B.A.; Troeger, C.; VanderZanden, A.; Vollset, S.E.; Wanga, V.; Whiteford, H.A.; Wolock, T.; Zoeckler, L.; Abate, K.H.; Abbafati, C.; Abbas, K.M.; Abd-Allah, F.; Abera, S.F.; Abreu, D.M.X.; Abu-Raddad, L.J.; Abyu, G.Y.; Achoki, T.; Adelekan, A.L.; Ademi, Z.; Adou, A.K.; Adsuar, J.C.; Afanvi, K.A.; Afshin, A.; Agardh, E.E.; Agarwal, A.; Agrawal, A.; Kiadaliri, A.A.; Ajala, O.N.; Akanda, A.S.; Akinyemi, R.O.; Akinyemiju, T.F.; Akseer, N.; Lami, F.H.A.; Alabed, S.; Al-Aly, Z.; Alam, K.; Alam, N.K.M.; Alasfoor, D.; Aldhahri, S.F.; Aldridge, R.W.; Alegretti, M.A.; Aleman, A.V.; Alemu, Z.A.; Alexander, L.T.; Alhabib, S.; Ali, R.; Alkerwi, A.; Alla, F.; Allebeck, P.; Al-Raddadi, R.; Alsharif, U.; Altirkawi, K.A.; Martin, E.A.; Alvis-Guzman, N.; Amare, A.T.; Amegah, A.K.; Ameh, E.A.; Amini, H.; Ammar, W.; Amrock, S.M.; Andersen, H.H.; Anderson, B.O.; Anderson, G.M.; Antonio, C.A.T.; Aregay, A.F.; Ärnlöv, J.; Arsenijevic, V.S.A.; Artaman, A.; Asayesh, H.; Asghar, R.J.; Atique, S.; Avokpaho, E.F.G.A.; Awasthi, A.; Azzopardi, P.; Bacha, U.; Badawi, A.; Bahit, M.C.; Balakrishnan, K.; Banerjee, A.; Barac, A.; Barker-Collo, S.L.; Bärnighausen, T.; Barregard, L.; Barrero, L.H.; Basu, A.; Basu, S.; Bayou, Y.T.; Bazargan-Hejazi, S.; Beardsley, J.; Bedi, N.; Beghi, E.; Belay, H.A.; Bell, B.; Bell, M.L.; Bello, A.K.; Bennett, D.A.; Bensenor, I.M.; Berhane, A.; Bernabé, E.; Betsu, B.D.; Beyene, A.S.; Bhala, N.; Bhalla, A.; Biadgilign, S.; Bikbov, B.; Abdulhak, A.A.B.; Biroscak, B.J.; Biryukov, S.; Bjertness, E.; Blore, J.D.; Blosser, C.D.; Bohensky, M.A.; Borschmann, R.; Bose, D.; Bourne, R.R.A.; Brainin, M.; Brayne, C.E.G.; Brazinova, A.; Breitborde, N.J.K.; Brenner, H.; Brewer, J.D.; Brown, A.; Brown, J.; Brugha, T.S.; Buckle, G.C.; Butt, Z.A.; Calabria, B.; Campos-Nonato, I.R.; Campuzano, J.C.; Carapetis, J.R.; Cárdenas, R.; Carpenter, D.O.; Carrero, J.J.; Castañeda-Orjuela, C.A.; Rivas, J.C.; Catalá-López, F.; Cavalleri, F.; Cercy, K.; Cerda, J.; Chen, W.; Chew, A.; Chiang, P.P-C.; Chibalabala, M.; Chibueze, C.E.; Chimed-Ochir, O.; Chisumpa, V.H.; Choi, J-Y.J.; Chowdhury, R.; Christensen, H.; Christopher, D.J.; Ciobanu, L.G.; Cirillo, M.; Cohen, A.J.; Colistro, V.; Colomar, M.; Colquhoun, S.M.; Cooper, C.; Cooper, L.T.; Cortinovis, M.; Cowie, B.C.; Crump, J.A.; Damsere-Derry, J.; Danawi, H.; Dandona, R.; Daoud, F.; Darby, S.C.; Dargan, P.I. das Neves, J.; Davey, G.; Davis, A.C.; Davitoiu, D.V.; de Castro, E.F.; de Jager, P.; Leo, D.D.; Degenhardt, L.; Dellavalle, R.P.; Deribe, K.; Deribew, A.; Dharmaratne, S.D.; Dhillon, P.K.; Diaz-Torné, C.; Ding, E.L.; dos Santos, K.P.B.; Dossou, E.; Driscoll, T.R.; Duan, L.; Dubey, M.; Duncan, B.B.; Ellenbogen, R.G.; Ellingsen, C.L.; Elyazar, I.; Endries, A.Y.; Ermakov, S.P.; Eshrati, B.; Esteghamati, A.; Estep, K.; Faghmous, I.D.A.; Fahimi, S.; Faraon, E.J.A.; Farid, T.A.; Farinha, C.S.S.; Faro, A.; Farvid, M.S.; Farzadfar, F.; Feigin, V.L.; Fereshtehnejad, S-M.; Fernandes, J.G.; Fernandes, J.C.; Fischer, F.; Fitchett, J.R.A.; Flaxman, A.; Foigt, N.; Fowkes, F.G.R.; Franca, E.B.; Franklin, R.C.; Friedman, J.; Frostad, J.; Fürst, T.; Futran, N.D.; Gall, S.L.; Gambashidze, K.; Gamkrelidze, A.; Ganguly, P.; Gankpé, F.G.; Gebre, T.; Gebrehiwot, T.T.; Gebremedhin, A.T.; Gebru, A.A.; Geleijnse, J.M.; Gessner, B.D.; Ghoshal, A.G.; Gibney, K.B.; Gillum, R.F.; Gilmour, S.; Giref, A.Z.; Giroud, M.; Gishu, M.D.; Giussani, G.; Glaser, E.; Godwin, W.W.; Gomez-Dantes, H.; Gona, P.; Goodridge, A.; Gopalani, S.V.; Gosselin, R.A.; Gotay, C.C.; Goto, A.; Gouda, H.N.; Greaves, F.; Gugnani, H.C.; Gupta, R.; Gupta, R.; Gupta, V.; Gutiérrez, R.A.; Hafezi-Nejad, N.; Haile, D.; Hailu, A.D.; Hailu, G.B.; Halasa, Y.A.; Hamadeh, R.R.; Hamidi, S.; Hancock, J.; Handal, A.J.; Hankey, G.J.; Hao, Y.; Harb, H.L.; Harikrishnan, S.; Haro, J.M.; Havmoeller, R.; Heckbert, S.R.; Heredia-Pi, I.B.; Heydarpour, P.; Hilderink, H.B.M.; Hoek, H.W.; Hogg, R.S.; Horino, M.; Horita, N.; Hosgood, H.D.; Hotez, P.J.; Hoy, D.G.; Hsairi, M.; Htet, A.S.; Htike, M.M.T.; Hu, G.; Huang, C.; Huang, H.; Huiart, L.; Husseini, A.; Huybrechts, I.; Huynh, G.; Iburg, K.M.; Innos, K.; Inoue, M.; Iyer, V.J.; Jacobs, T.A.; Jacobsen, K.H.; Jahanmehr, N.; Jakovljevic, M.B.; James, P.; Javanbakht, M.; Jayaraman, S.P.; Jayatilleke, A.U.; Jeemon, P.; Jensen, P.N.; Jha, V.; Jiang, G.; Jiang, Y.; Jibat, T.; Jimenez-Corona, A.; Jonas, J.B.; Joshi, T.K.; Kabir, Z.; Kamal, R.; Kan, H.; Kant, S.; Karch, A.; Karema, C.K.; Karimkhani, C.; Karletsos, D.; Karthikeyan, G.; Kasaeian, A.; Katibeh, M.; Kaul, A.; Kawakami, N.; Kayibanda, J.F.; Keiyoro, P.N.; Kemmer, L.; Kemp, A.H.; Kengne, A.P.; Keren, A.; Kereselidze, M.; Kesavachandran, C.N.; Khader, Y.S.; Khalil, I.A.; Khan, A.R.; Khan, E.A.; Khang, Y-H.; Khera, S.; Khoja, T.A.M.; Kieling, C.; Kim, D.; Kim, Y.J.; Kissela, B.M.; Kissoon, N.; Knibbs, L.D.; Knudsen, A.K.; Kokubo, Y.; Kolte, D.; Kopec, J.A.; Kosen, S.; Koul, P.A.; Koyanagi, A.; Krog, N.H.; Defo, B.K.; Bicer, B.K.; Kudom, A.A.; Kuipers, E.J.; Kulkarni, V.S.; Kumar, G.A.; Kwan, G.F.; Lal, A.; Lal, D.K.; Lalloo, R.; Lallukka, T.; Lam, H.; Lam, J.O.; Langan, S.M.; Lansingh, V.C.; Larsson, A.; Laryea, D.O.; Latif, A.A.; Lawrynowicz, A.E.B.; Leigh, J.; Levi, M.; Li, Y.; Lindsay, M.P.; Lipshultz, S.E.; Liu, P.Y.; Liu, S.; Liu, Y.; Lo, L-T.; Logroscino, G.; Lotufo, P.A.; Lucas, R.M.; Lunevicius, R.; Lyons, R.A.; Ma, S.; Machado, V.M.P.; Mackay, M.T.; MacLachlan, J.H.; Razek, H.M.A.E.; Magdy, M.; Razek, A.E.; Majdan, M.; Majeed, A.; Malekzadeh, R.; Manamo, W.A.A.; Mandisarisa, J.; Mangalam, S.; Mapoma, C.C.; Marcenes, W.; Margolis, D.J.; Martin, G.R.; Martinez-Raga, J.; Marzan, M.B.; Masiye, F.; Mason-Jones, A.J.; Massano, J.; Matzopoulos, R.; Mayosi, B.M.; McGarvey, S.T.; McGrath, J.J.; McKee, M.; McMahon, B.J.; Meaney, P.A.; Mehari, A.; Mehndiratta, M.M.; Mejia-Rodriguez, F.; Mekonnen, A.B.; Melaku, Y.A.; Memiah, P.; Memish, Z.A.; Mendoza, W.; Meretoja, A.; Meretoja, T.J.; Mhimbira, F.A.; Micha, R.; Millear, A.; Miller, T.R.; Mirarefin, M.; Misganaw, A.; Mock, C.N.; Mohammad, K.A.; Mohammadi, A.; Mohammed, S.; Mohan, V.; Mola, G.L.D.; Monasta, L.; Hernandez, J.C.M.; Montero, P.; Montico, M.; Montine, T.J.; Moradi-Lakeh, M.; Morawska, L.; Morgan, K.; Mori, R.; Mozaffarian, D.; Mueller, U.O.; Murthy, G.V.S.; Murthy, S.; Musa, K.I.; Nachega, J.B.; Nagel, G.; Naidoo, K.S.; Naik, N.; Naldi, L.; Nangia, V.; Nash, D.; Nejjari, C.; Neupane, S.; Newton, C.R.; Newton, J.N.; Ng, M.; Ngalesoni, F.N.; de Dieu Ngirabega, J.; Nguyen, Q.L.; Nisar, M.I.; Pete, P.M.N.; Nomura, M.; Norheim, O.F.; Norman, P.E.; Norrving, B.; Nyakarahuka, L.; Ogbo, F.A.; Ohkubo, T.; Ojelabi, F.A.; Olivares, P.R.; Olusanya, B.O.; Olusanya, J.O.; Opio, J.N.; Oren, E.; Ortiz, A.; Osman, M.; Ota, E.; Ozdemir, R.; Pa, M.; Pain, A.; Pandian, J.D.; Pant, P.R.; Papachristou, C.; Park, E-K.; Park, J-H.; Parry, C.D.; Parsaeian, M.; Caicedo, A.J.P.; Patten, S.B.; Patton, G.C.; Paul, V.K.; Pearce, N.; Pedro, J.M.; Stokic, L.P.; Pereira, D.M.; Perico, N.; Pesudovs, K.; Petzold, M.; Phillips, M.R.; Piel, F.B.; Pillay, J.D.; Plass, D.; Platts-Mills, J.A.; Polinder, S.; Pope, C.A.; Popova, S.; Poulton, R.G.; Pourmalek, F.; Prabhakaran, D.; Qorbani, M.; Quame-Amaglo, J.; Quistberg, D.A.; Rafay, A.; Rahimi, K.; Rahimi-Movaghar, V.; Rahman, M.; Rahman, M.H.U.; Rahman, S.U.; Rai, R.K.; Rajavi, Z.; Rajsic, S.; Raju, M.; Rakovac, I.; Rana, S.M.; Ranabhat, C.L.; Rangaswamy, T.; Rao, P.; Rao, S.R.; Refaat, A.H.; Rehm, J.; Reitsma, M.B.; Remuzzi, G.; Resnikoff, S.; Ribeiro, A.L.; Ricci, S.; Blancas, M.J.R.; Roberts, B.; Roca, A.; Rojas-Rueda, D.; Ronfani, L.; Roshandel, G.; Rothenbacher, D.; Roy, A.; Roy, N.K.; Ruhago, G.M.; Sagar, R.; Saha, S.; Sahathevan, R.; Saleh, M.M.; Sanabria, J.R.; Sanchez-Niño, M.D.; Sanchez-Riera, L.; Santos, I.S.; Sarmiento-Suarez, R.; Sartorius, B.; Satpathy, M.; Savic, M.; Sawhney, M.; Schaub, M.P.; Schmidt, M.I.; Schneider, I.J.C.; Schöttker, B.; Schutte, A.E.; Schwebel, D.C.; Seedat, S.; Sepanlou, S.G.; Servan-Mori, E.E.; Shackelford, K.A.; Shaddick, G.; Shaheen, A.; Shahraz, S.; Shaikh, M.A.; Shakh-Nazarova, M.; Sharma, R.; She, J.; Sheikhbahaei, S.; Shen, J.; Shen, Z.; Shepard, D.S.; Sheth, K.N.; Shetty, B.P.; Shi, P.; Shibuya, K.; Shin, M-J.; Shiri, R.; Shiue, I.; Shrime, M.G.; Sigfusdottir, I.D.; Silberberg, D.H.; Silva, D.A.S.; Silveira, D.G.A.; Silverberg, J.I.; Simard, E.P.; Singh, A.; Singh, G.M.; Singh, J.A.; Singh, O.P.; Singh, P.K.; Singh, V.; Soneji, S.; Søreide, K.; Soriano, J.B.; Sposato, L.A.; Sreeramareddy, C.T.; Stathopoulou, V.; Stein, D.J.; Stein, M.B.; Stranges, S.; Stroumpoulis, K.; Sunguya, B.F.; Sur, P.; Swaminathan, S.; Sykes, B.L.; Szoeke, C.E.I.; Tabarés-Seisdedos, R.; Tabb, K.M.; Takahashi, K.; Takala, J.S.; Talongwa, R.T.; Tandon, N.; Tavakkoli, M.; Taye, B.; Taylor, H.R.; Ao, B.J.T.; Tedla, B.A.; Tefera, W.M.; Have, M.T.; Terkawi, A.S.; Tesfay, F.H.; Tessema, G.A.; Thomson, A.J.; Thorne-Lyman, A.L.; Thrift, A.G.; Thurston, G.D.; Tillmann, T.; Tirschwell, D.L.; Tonelli, M.; Topor-Madry, R.; Topouzis, F.; Towbin, J.A.; Traebert, J.; Tran, B.X.; Truelsen, T.; Trujillo, U.; Tura, A.K.; Tuzcu, E.M.; Uchendu, U.S.; Ukwaja, K.N.; Undurraga, E.A.; Uthman, O.A.; Dingenen, R.V.; van Donkelaar, A.; Vasankari, T.; Vasconcelos, A.M.N.; Venketasubramanian, N.; Vidavalur, R.; Vijayakumar, L.; Villalpando, S.; Violante, F.S.; Vlassov, V.V.; Wagner, J.A.; Wagner, G.R.; Wallin, M.T.; Wang, L.; Watkins, D.A.; Weichenthal, S.; Weiderpass, E.; Weintraub, R.G.; Werdecker, A.; Westerman, R.; White, R.A.; Wijeratne, T.; Wilkinson, J.D.; Williams, H.C.; Wiysonge, C.S.; Woldeyohannes, S.M.; Wolfe, C.D.A.; Won, S.; Wong, J.Q.; Woolf, A.D.; Xavier, D.; Xiao, Q.; Xu, G.; Yakob, B.; Yalew, A.Z.; Yan, L.L.; Yano, Y.; Yaseri, M.; Ye, P.; Yebyo, H.G.; Yip, P.; Yirsaw, B.D.; Yonemoto, N.; Yonga, G.; Younis, M.Z.; Yu, S.; Zaidi, Z.; Zaki, M.E.S.; Zannad, F.; Zavala, D.E.; Zeeb, H.; Zeleke, B.M.; Zhang, H.; Zodpey, S.; Zonies, D.; Zuhlke, L.J.; Vos, T.; Lopez, A.D.; Murray, C.J.L. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet, 2016, 388(10053), 1459-1544.
[http://dx.doi.org/10.1016/S0140-6736(16)31012-1] [PMID: 27733281]
[9]
Venkata, A.N. Asthma-COPD overlap: Review of diagnosis and management. Curr. Opin. Pulm. Med., 2020, 26(2), 155-161.
[http://dx.doi.org/10.1097/MCP.0000000000000649] [PMID: 31714273]
[10]
Cañas, J.A.; Sastre, B.; Rodrigo-Muñoz, J.M.; Fernández-Nieto, M.; Barranco, P.; Quirce, S.; Sastre, J.; Del Pozo, V. Eosinophil-derived exosomes contribute to asthma remodelling by activating structural lung cells. Clin. Exp. Allergy, 2018, 48(9), 1173-1185.
[http://dx.doi.org/10.1111/cea.13122] [PMID: 29451337]
[11]
Banno, A.; Reddy, A.T.; Lakshmi, S.P.; Reddy, R.C. PPARs: Key regulators of airway inflammation and potential therapeutic targets in asthma. Nucl. Receptor Res., 2018, 5, e101306.
[http://dx.doi.org/10.11131/2018/101306] [PMID: 29450204]
[12]
O’Byrne, P.; Fabbri, L.M.; Pavord, I.D.; Papi, A.; Petruzzelli, S.; Lange, P. Asthma progression and mortality: The role of inhaled corticosteroids. Eur. Respir. J., 2019, 54(1), e1900491.
[http://dx.doi.org/10.1183/13993003.00491-2019] [PMID: 31048346]
[13]
Durham, A.L.; Caramori, G.; Chung, K.F.; Adcock, I.M. Targeted anti-inflammatory therapeutics in asthma and chronic obstructive lung disease. Transplant. Res., 2016, 167(1), 192-203.
[http://dx.doi.org/10.1016/j.trsl.2015.08.004] [PMID: 26334389]
[14]
McCracken, J.L.; Veeranki, S.P.; Ameredes, B.T.; Calhoun, W.J. Diagnosis and management of asthma in adults: A review. JAMA, 2017, 318(3), 279-290.
[http://dx.doi.org/10.1001/jama.2017.8372] [PMID: 28719697]
[15]
Cernak, T.; Dykstra, K.D.; Tyagarajan, S.; Vachal, P.; Krska, S.W. The medicinal chemist’s toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev., 2016, 45(3), 546-576.
[http://dx.doi.org/10.1039/C5CS00628G] [PMID: 26507237]
[16]
Driscoll, D.; Farnia, S.; Kefalas, P.; Maziarz, R.T. Concise Review: The high cost of high-tech medicine: Planning ahead for market access. Stem Cells Transl. Med., 2017, 6(8), 1723-1729.
[http://dx.doi.org/10.1002/sctm.16-0487] [PMID: 28749065]
[17]
Fraga, C.A.; Barreiro, E.J. Medicinal chemistry of N-acylhydrazones: New lead-compounds of analgesic, antiinflammatory and antithrombotic drugs. Curr. Med. Chem., 2006, 13(2), 167-198.
[http://dx.doi.org/10.2174/092986706775197881] [PMID: 16472212]
[18]
Rostom, S.A.; Shalaby, M.A.; El-Demellawy, M.A. Polysubstituted pyrazoles, part 5. Synthesis of new 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid hydrazide analogs and some derived ring systems. A novel class of potential antitumor and anti-HCV agents. Eur. J. Med. Chem., 2003, 38(11-12), 959-974.
[http://dx.doi.org/10.1016/j.ejmech.2003.08.003] [PMID: 14642328]
[19]
Júnior, W.B.; Alexandre-Moreira, M.S.; Alves, M.A.; Perez-Rebolledo, A.; Parrilha, G.L.; Castellano, E.E.; Piro, O.E.; Barreiro, E.J.; Lima, L.M.; Beraldo, H. Analgesic and anti-inflammatory activities of salicylaldehyde 2-chlorobenzoyl hydrazone (H(2)LASSBio-466), salicylaldehyde 4-chlorobenzoyl hydrazone (H(2)LASSBio-1064) and their zinc(II) complexes. Molecules, 2011, 16(8), 6902-6915.
[http://dx.doi.org/10.3390/molecules16086902] [PMID: 21844840]
[20]
Chelucci, R.C.; Dutra, L.A.; Lopes Pires, M.E.; de Melo, T.R.F.; Bosquesi, P.L.; Chung, M.C.; Dos Santos, J.L. Antiplatelet and antithrombotic activities of non-steroidal anti-inflammatory drugs containing an N-acyl hydrazone subunit. Molecules, 2014, 19(2), 2089-2099.
[http://dx.doi.org/10.3390/molecules19022089] [PMID: 24549233]
[21]
El-Din, N.S.; Barseem, A. Synthesis, bioactivity and docking study of some new índole-hydrazone derivatives. J. Appl. Pharm. Sci., 2016, 6, 75-83.
[http://dx.doi.org/10.7324/JAPS.2016.601211]
[22]
Shen, F.Q.; Wang, Z.C.; Wu, S.Y.; Ren, S.Z.; Man, R.J.; Wang, B.Z.; Zhu, H.L. Synthesis of novel hybrids of pyrazole and coumarin as dual inhibitors of COX-2 and 5-LOX. Bioorg. Med. Chem. Lett., 2017, 27(16), 3653-3660.
[http://dx.doi.org/10.1016/j.bmcl.2017.07.020] [PMID: 28720504]
[23]
Mohsin, N.A.; Ahmad, M. Hybrid organic molecules as antiinammatory agents; a review of structural features and biological activity. Turk. J. Chem., 2018, 42, 1-20.
[http://dx.doi.org/10.3906/kim-1706-58]
[24]
Ribeiro, N.E.; Pereira, P.S.; de Oliveira, T.B.; de Arruda Lima, S.M.; Silva, T.M.S.; Santana, A.L.B.D.; do Nascimento, M.S.; Santisteban, R.M.; Teixeira, A.A.C.; da Silva, T.G. Acute and repeated dose 28-day oral toxicity of Chrysobalanusicaco L. leaf aqueous extract. Regul. Toxicol. Pharmacol., 2020, 113, 104643.
[http://dx.doi.org/10.1016/j.yrtph.2020.104643] [PMID: 32199870]
[25]
OECD - Guidelines for the Testing of Chemicals. OECD 423. Acute oral toxicitY-acute toxic class method; organisation for economic cooperation and development: Paris. 2001.
[26]
Bezerra-Santos, C.R.; Vieira-de-Abreu, A.; Barbosa-Filho, J.M.; Bandeira-Melo, C.; Piuvezam, M.R.; Bozza, P.T. Anti-allergic properties of Cissampelos sympodialis and its isolated alkaloid warifteine. Int. Immunopharmacol., 2006, 6(7), 1152-1160.
[http://dx.doi.org/10.1016/j.intimp.2006.02.007] [PMID: 16714219]
[27]
de Barros Alves, G.M.; de Sousa Maia, M.B.; de Souza Franco, E.; Galvão, A.M.; da Silva, T.G.; Gomes, R.M.; Martins, M.B.; da Silva Falcão, E.P.; de Castro, C.M.; da Silva, N.H. Expectorant and antioxidant activities of purified fumarprotocetraric acid from Cladonia verticillaris lichen in mice. Pulm. Pharmacol. Ther., 2014, 27(2), 139-143.
[http://dx.doi.org/10.1016/j.pupt.2013.07.002] [PMID: 23872116]
[28]
Melgert, B.N.; Postma, D.S.; Kuipers, I.; Geerlings, M.; Luinge, M.A.; van der Strate, B.W.A.; Kerstjens, H.A.M.; Timens, W.; Hylkema, M.N. Female mice are more susceptible to the development of allergic airway inflammation than male mice. Clin. Exp. Allergy, 2005, 35(11), 1496-1503.
[http://dx.doi.org/10.1111/j.1365-2222.2005.02362.x] [PMID: 16297148]
[29]
Takeda, M.; Tanabe, M.; Ito, W.; Ueki, S.; Konnno, Y.; Chihara, M.; Itoga, M.; Kobayashi, Y.; Moritoki, Y.; Kayaba, H.; Chihara, J. Gender difference in allergic airway remodelling and immunoglobulin production in mouse model of asthma. Respirology, 2013, 18(5), 797-806.
[http://dx.doi.org/10.1111/resp.12078] [PMID: 23490273]
[30]
Lee, K.S.; Kim, S.R.; Park, S.J.; Min, K.H.; Lee, K.Y.; Jin, S.M.; Yoo, W.H.; Lee, Y.C. Antioxidant down-regulates interleukin-18 expression in asthma. Mol. Pharmacol., 2006, 70(4), 1184-1193.
[http://dx.doi.org/10.1124/mol.106.024737] [PMID: 16822930]
[31]
Motohiro, A.; Furukawa, T.; Yasumoto, K.; Inokuchi, K. Mechanisms involved in acute lung edema induced in dogs by oleic acid. Eur. Surg. Res., 1986, 18(1), 50-57.
[http://dx.doi.org/10.1159/000128505] [PMID: 3510875]
[32]
Lossos, I.S.; Izbicki, G.; Or, R.; Goldstein, R.H.; Breuer, R. The effect of suramin on bleomycin-induced lung injury. Life Sci., 2000, 67(23), 2873-2881.
[http://dx.doi.org/10.1016/S0024-3205(00)00865-1] [PMID: 11106002]
[33]
Arnaud, R.R.; Soares, M.S.M.; Santos, M.G.C.; Lira, C.C. Density of mast cells in lesions of actinic cheilitis. Rev. Cubana Estomatol., 2014, 51, 378-387.
[34]
Heinemann, F.; Birk, G.; Schoenberger, T.; Stierstorfer, B. Deep neural network based histological scoring of lung fibrosis and inflammation in the mouse model system. PLoS One, 2018, 13(8), e0202708.
[http://dx.doi.org/10.1371/journal.pone.0202708] [PMID: 30138413]
[35]
Murakami, K.; Kohno, M.; Kadoya, M.; Nagahara, H.; Fujii, W.; Seno, T.; Yamamoto, A.; Oda, R.; Fujiwara, H.; Kubo, T.; Morita, S.; Nakada, H.; Hla, T.; Kawahito, Y. Knock out of S1P3 receptor signaling attenuates inflammation and fibrosis in bleomycin-induced lung injury mice model. PLoS One, 2014, 9(9), e106792.
[http://dx.doi.org/10.1371/journal.pone.0106792] [PMID: 25198418]
[36]
Palla, G.; Pelizzi, C.; Predieri, G.; Vignali, C. Conformational study on N-acylhydrazones of aromatic aldehydes by NMR spectroscopy. Gazz. Chim. Ital., 1982, 112, 339-341.
[37]
Palla, G.; Predieri, G.; Domiano, P.; Vignali, C.; Turner, W. Conformational behaviour and E/Z isomerization of N-acyl and N-aroylhydrazones. Tetrahedron, 1986, 42(13), 3649-3654.
[http://dx.doi.org/10.1016/S0040-4020(01)87332-4]
[38]
Rahman, V.P.; Mukhtar, S.; Ansari, W.H.; Lemiere, G. Synthesis, stereochemistry and biological activity of some novel long alkyl chain substituted thiazolidin-4-ones and thiazan-4-one from 10-undecenoic acid hydrazide. Eur. J. Med. Chem., 2005, 40(2), 173-184.
[http://dx.doi.org/10.1016/j.ejmech.2004.10.003] [PMID: 15694652]
[39]
Tian, B.; He, M.; Tang, S.; Hewlett, I.; Tan, Z.; Li, J.; Jin, Y.; Yang, M. Synthesis and antiviral activities of novel acylhydrazone derivatives targeting HIV-1 capsid protein. Bioorg. Med. Chem. Lett., 2009, 19(8), 2162-2167.
[http://dx.doi.org/10.1016/j.bmcl.2009.02.116] [PMID: 19297155]
[40]
Quattropani, A.; Dorbais, J.; Covini, D.; Pittet, P.A.; Colovray, V.; Thomas, R.J.; Coxhead, R.; Halazy, S.; Scheer, A.; Missotten, M.; Ayala, G.; Bradshaw, C.; De Raemy-Schenk, A.M.; Nichols, A.; Cirillo, R.; Tos, E.G.; Giachetti, C.; Golzio, L.; Marinelli, P.; Church, D.J.; Barberis, C.; Chollet, A.; Schwarz, M.K. Discovery and development of a new class of potent, selective, orally active oxytocin receptor antagonists. J. Med. Chem., 2005, 48(24), 7882-7905.
[http://dx.doi.org/10.1021/jm050645f] [PMID: 16302826]
[41]
Lopes, A.B.; Miguez, E.; Kümmerle, A.E.; Rumjanek, V.M.; Fraga, C.A.M.; Barreiro, E.J. Characterization of amide bond conformers for a novel heterocyclic template of N-acylhydrazone derivatives. Molecules, 2013, 18(10), 11683-11704.
[http://dx.doi.org/10.3390/molecules181011683] [PMID: 24071978]
[42]
Nguyen, B.T.; Anslyn, E.V. Indicator-displacement assays. Coord. Chem. Rev., 2006, 250(23-24), 3118-3127.
[http://dx.doi.org/10.1016/j.ccr.2006.04.009]
[43]
Woutersen, M.; Muller, A.; Pronk, M.E.J.; Cnubben, N.H.P.; Hakkert, B.C. Regulating human safety: How dose selection in toxicity studies impacts human health hazard assessment and subsequent risk management options. Regul. Toxicol. Pharmacol., 2020, 114, 104660.
[http://dx.doi.org/10.1016/j.yrtph.2020.104660] [PMID: 32334039]
[44]
Sookvanichsilp, N.; Nakornchai, S.; Weerapradist, W. Toxicological study of pyridoxal isonicotinoyl hydrazone: Acute and subchronic toxicity. Drug Chem. Toxicol., 1991, 14(4), 395-403.
[http://dx.doi.org/10.3109/01480549109011641] [PMID: 1811960]
[45]
Jayalakshmi, N.; Nanjundan, S. Synthesis, characterization and pharmacological studies of selenadiazole and hydrazone derivatives of 2, 6–diphenyl –4–piperidone. Int. J. Chem. Sci., 2008, 6, 1177-1188.
[46]
Boonpiyathad, T.; Sözener, Z.C.; Satitsuksanoa, P.; Akdis, C.A. Immunologic mechanisms in asthma. Semin. Immunol., 2019, 46, 101333.
[http://dx.doi.org/10.1016/j.smim.2019.101333] [PMID: 31703832]
[47]
Agra, L.C.; Lins, M.P.; da Silva Marques, P.; Smaniotto, S.; Bandeira de Melo, C.; Lagente, V.; Barreto, E. Uvaol attenuates pleuritis and eosinophilic inflammation in ovalbumin-induced allergy in mice. Eur. J. Pharmacol., 2016, 780, 232-242.
[http://dx.doi.org/10.1016/j.ejphar.2016.03.056] [PMID: 27038519]
[48]
Sousa, L.P.; Carmo, A.F.; Rezende, B.M.; Lopes, F.; Silva, D.M.; Alessandri, A.L.; Bonjardim, C.A.; Rossi, A.G.; Teixeira, M.M.; Pinho, V.; Pinho, V. Cyclic AMP enhances resolution of allergic pleurisy by promoting inflammatory cell apoptosis via inhibition of PI3K/Akt and NF-kappaB. Biochem. Pharmacol., 2009, 78(4), 396-405.
[http://dx.doi.org/10.1016/j.bcp.2009.04.030] [PMID: 19422809]
[49]
Zimecki, M.; Artym, J.; Kocięba, M.; Kaleta-Kuratewicz, K.; Kruzel, M.L. Lactoferrin restrains allergen-induced pleurisy in mice. Inflamm. Res., 2012, 61(11), 1247-1255.
[http://dx.doi.org/10.1007/s00011-012-0522-y] [PMID: 22810368]
[50]
Reis, A.C.; Alessandri, A.L.; Athayde, R.M.; Perez, D.A.; Vago, J.P.; Ávila, T.V.; Ferreira, T.P.T.; de Arantes, A.C.; Coutinho, D.S.; Rachid, M.A.; Sousa, L.P.; Martins, M.A.; Menezes, G.B.; Rossi, A.G.; Teixeira, M.M.; Pinho, V. Induction of eosinophil apoptosis by hydrogen peroxide promotes the resolution of allergic inflammation. Cell Death Dis., 2015, 6(2), e1632.
[http://dx.doi.org/10.1038/cddis.2014.580] [PMID: 25675292]
[51]
Boucher, R.C. Muco-obstructive lung diseases. N. Engl. J. Med., 2019, 380(20), 1941-1953.
[http://dx.doi.org/10.1056/NEJMra1813799] [PMID: 31091375]
[52]
Shen, Y.; Huang, S.; Kang, J.; Lin, J.; Lai, K.; Sun, Y.; Xiao, W.; Yang, L.; Yao, W.; Cai, S.; Huang, K.; Wen, F. Management of airway mucus hypersecretion in chronic airway inflammatory disease: Chinese expert consensus (English edition). Int. J. Chron. Obstruct. Pulmon. Dis., 2018, 13, 399-407.
[http://dx.doi.org/10.2147/COPD.S144312] [PMID: 29430174]
[53]
Tian, P.W.; Wen, F.Q. Clinical significance of airway mucus hypersecretion in chronic obstructive pulmonary disease. J. Transl. Int. Med., 2015, 3(3), 89-92.
[http://dx.doi.org/10.1515/jtim-2015-0013] [PMID: 27847895]
[54]
Allinson, J.P.; Hardy, R.; Donaldson, G.C.; Shaheen, S.O.; Kuh, D.; Wedzicha, J.A. The presence of chronic mucus hypersecretion across adult life in relation to chronic obstructive pulmonary disease development. Am. J. Respir. Crit. Care Med., 2016, 193(6), 662-672.
[http://dx.doi.org/10.1164/rccm.201511-2210OC] [PMID: 26695373]
[55]
Gubernatorova, E.O.; Namakanova, O.A.; Tumanov, A.V.; Drutskaya, M.S.; Nedospasov, S.A. Mouse models of severe asthma for evaluation of therapeutic cytokine targeting. Immunol. Lett., 2019, 207, 73-83.
[http://dx.doi.org/10.1016/j.imlet.2018.11.012] [PMID: 30659868]
[56]
Vuolo, F.; Abreu, S.C.; Michels, M.; Xisto, D.G.; Blanco, N.G.; Hallak, J.E.C.; Zuardi, A.W.; Crippa, J.A.; Reis, C.; Bahl, M.; Pizzichinni, E.; Maurici, R.; Pizzichinni, M.M.M.; Rocco, P.R.M.; Dal-Pizzol, F. Cannabidiol reduces airway inflammation and fibrosis in experimental allergic asthma. Eur. J. Pharmacol., 2019, 843, 251-259.
[http://dx.doi.org/10.1016/j.ejphar.2018.11.029] [PMID: 30481497]
[57]
Yun, C.; Chang, M.; Hou, G.; Lan, T.; Yuan, H.; Su, Z.; Zhu, D.; Liang, W.; Li, Q.; Zhu, H.; Zhang, J.; Lu, Y.; Deng, J.; Guo, H. Mangiferin suppresses allergic asthma symptoms by decreased Th9 and Th17 responses and increased Treg response. Mol. Immunol., 2019, 114, 233-242.
[http://dx.doi.org/10.1016/j.molimm.2019.07.025] [PMID: 31386980]
[58]
McBrien, C.N.; Menzies-Gow, A. The biology of eosinophils and their role in asthma. Front. Med. (Lausanne), 2017, 4, 93.
[http://dx.doi.org/10.3389/fmed.2017.00093] [PMID: 28713812]
[59]
Steinsvoll, S.; Helgeland, K.; Schenck, K. Mast cells--a role in periodontal diseases? J. Clin. Periodontol., 2004, 31(6), 413-419.
[http://dx.doi.org/10.1111/j.1600-051X.2004.00516.x] [PMID: 15142208]
[60]
Cerqueira, J.V.; Meira, C.S.; Santos, E.S.; de Aragão França, L.S.; Vasconcelos, J.F.; Nonaka, C.K.V.; de Melo, T.L.; Dos Santos Filho, J.M.; Moreira, D.R.M.; Soares, M.B.P. Anti-inflammatory activity of SintMed65, an N-acylhydrazone derivative, in a mouse model of allergic airway inflammation. Int. Immunopharmacol., 2019, 75, 105735.
[http://dx.doi.org/10.1016/j.intimp.2019.105735] [PMID: 31306982]
[61]
Nakajima, H.; Iwamoto, I.; Tomoe, S.; Matsumura, R.; Tomioka, H.; Takatsu, K.; Yoshida, S. CD4+ T-lymphocytes and interleukin-5 mediate antigen-induced eosinophil infiltration into the mouse trachea. Am. Rev. Respir. Dis., 1992, 146(2), 374-377.
[http://dx.doi.org/10.1164/ajrccm/146.2.374] [PMID: 1362635]
[62]
Kips, J.C.; Brusselle, G.G.; Joos, G.F.; Peleman, R.A.; Devos, R.R.; Tavernier, J.H.; Pauwels, R.A. Importance of interleukin-4 and interleukin-12 in allergen-induced airway changes in mice. Int. Arch. Allergy Immunol., 1995, 107(1-3), 115-118.
[http://dx.doi.org/10.1159/000236947] [PMID: 7613115]
[63]
Foster, P.S.; Hogan, S.P.; Ramsay, A.J.; Matthaei, K.I.; Young, I.G. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J. Exp. Med., 1996, 183(1), 195-201.
[http://dx.doi.org/10.1084/jem.183.1.195] [PMID: 8551223]
[64]
Hamelmann, E.; Schwarze, J.; Takeda, K.; Oshiba, A.; Larsen, G.L.; Irvin, C.G.; Gelfand, E.W. Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am. J. Respir. Crit. Care Med., 1997, 156(3 Pt 1), 766-775.
[http://dx.doi.org/10.1164/ajrccm.156.3.9606031] [PMID: 9309991]
[65]
Mattes, J.; Yang, M.; Mahalingam, S.; Kuehr, J.; Webb, D.C.; Simson, L.; Hogan, S.P.; Koskinen, A.; McKenzie, A.N.; Dent, L.A.; Rothenberg, M.E.; Matthaei, K.I.; Young, I.G.; Foster, P.S. Intrinsic defect in T cell production of interleukin (IL)-13 in the absence of both IL-5 and eotaxin precludes the development of eosinophilia and airways hyperreactivity in experimental asthma. J. Exp. Med., 2002, 195(11), 1433-1444.
[http://dx.doi.org/10.1084/jem.20020009] [PMID: 12045241]
[66]
Hall, S.; Agrawal, D.K. Key mediators in the immunopathogenesis of allergic asthma. Int. Immunopharmacol., 2014, 23(1), 316-329.
[http://dx.doi.org/10.1016/j.intimp.2014.05.034] [PMID: 24933589]
[67]
Duvall, M.G.; Krishnamoorthy, N.; Levy, B.D. Non-type 2 inflammation in severe asthma is propelled by neutrophil cytoplasts and maintained by defective resolution. Allergol. Int., 2019, 68(2), 143-149.
[http://dx.doi.org/10.1016/j.alit.2018.11.006] [PMID: 30573389]
[68]
Hernandez, J.D.; Yu, M.; Sibilano, R.; Tsai, M.; Galli, S.J. Development of multiple features of antigen-induced asthma pathology in a new strain of mast cell deficient BALB/c-KitW-sh/W-sh mice. Lab. Invest., 2020, 100(4), 516-526.
[http://dx.doi.org/10.1038/s41374-019-0354-2] [PMID: 31857699]
[69]
Reber, L.L.; Fahy, J.V. Mast cells in asthma: Biomarker and therapeutic target. Eur. Respir. J., 2016, 47, 1040-1042.
[http://dx.doi.org/10.1183/13993003.00065-2016]
[70]
Bentley, A.M.; Hamid, Q.; Robinson, D.S.; Schotman, E.; Meng, Q.; Assoufi, B.; Kay, A.B.; Durham, S.R. Prednisolone treatment in asthma. Reduction in the numbers of eosinophils, T cells, tryptase-only positive mast cells, and modulation of IL-4, IL-5, and interferon-gamma cytokine gene expression within the bronchial mucosa. Am. J. Respir. Crit. Care Med., 1996, 153(2), 551-556.
[http://dx.doi.org/10.1164/ajrccm.153.2.8564096] [PMID: 8564096]
[71]
James, A.L.; Maxwell, P.S.; Pearce-Pinto, G.; Elliot, J.G.; Carroll, N.G. The relationship of reticular basement membrane thickness to airway wall remodeling in asthma. Am. J. Respir. Crit. Care Med., 2002, 166(12 Pt 1), 1590-1595.
[http://dx.doi.org/10.1164/rccm.2108069] [PMID: 12471074]
[72]
Raymond, M.; Ching-A-Sue, G.; Van Hecke, O. Mast cell stabilisers, leukotriene antagonists and antihistamines: A rapid review of the evidence for their use in COVID19; Centre Evid-Based Med, 2020.
[73]
Anderson, S.D.; Caillaud, C.; Brannan, J.D. β2-agonists and exercise-induced asthma. Clin. Rev. Allergy Immunol., 2006, 31(2-3), 163-180.
[http://dx.doi.org/10.1385/CRIAI:31:2:163] [PMID: 17085791]
[74]
Makhija, I.K.; Shreedhara, C.S.; Ram, H.N. Mast cell stabilization potential of Sitopaladi churna: An ayurvedic formulation. Pharmacognosy Res., 2013, 5(4), 306-308.
[http://dx.doi.org/10.4103/0974-8490.118824] [PMID: 24174826]
[75]
You, X-Y.; Xue, Q.; Fang, Y.; Liu, Q.; Zhang, C.F.; Zhao, C.; Zhang, M.; Xu, X-H. Preventive effects of Ecliptae Herba extract and its component, ecliptasaponin A, on bleomycin-induced pulmonary fibrosis in mice. J. Ethnopharmacol., 2015, 175, 172-180.
[http://dx.doi.org/10.1016/j.jep.2015.08.034] [PMID: 26385580]
[76]
Xiang, J.; Cheng, S.; Feng, T.; Wu, Y.; Xie, W.; Zhang, M.; Xu, X.; Zhang, C. Neotuberostemonine attenuates bleomycin-induced pulmonary fibrosis by suppressing the recruitment and activation of macrophages. Int. Immunopharmacol., 2016, 36, 158-164.
[http://dx.doi.org/10.1016/j.intimp.2016.04.016] [PMID: 27144994]
[77]
Wang, X.; Ouyang, Z.; You, Q.; He, S.; Meng, Q.; Hu, C.; Wu, X.; Shen, Y.; Sun, Y.; Wu, X.; Xu, Q. Obaculactone protects against bleomycin-induced pulmonary fibrosis in mice. Toxicol. Appl. Pharmacol., 2016, 303(303), 21-29.
[http://dx.doi.org/10.1016/j.taap.2016.05.005] [PMID: 27180239]
[78]
Liu, Y.L.; Chen, B.Y.; Nie, J.; Zhao, G.H.; Zhuo, J.Y.; Yuan, J.; Li, Y.C.; Wang, L.L.; Chen, Z.W. Polydatin prevents bleomycin-induced pulmonary fibrosis by inhibiting the TGF-β/Smad/ERK signaling pathway. Exp. Ther. Med., 2020, 20(5), 62.
[http://dx.doi.org/10.3892/etm.2020.9190] [PMID: 32952652]
[79]
Abidi, A.; Bahri, S.; Khamsa, S.B.; Legrand, A. Nigella sativa fixed oil, attenuates bleomycin-induced pulmonary fibrosis in a rat model. Eur. Respir. J., 2018, 52, PA4796.
[http://dx.doi.org/10.1183/13993003.congress-2018.PA4796]
[80]
Ruan, Q.; Yang, K.; Wang, W.; Jiang, L.; Song, J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Int. Care Med., 2020, 46(5), 846-848.
[http://dx.doi.org/10.1007/s00134-020-05991-x] [PMID: 32125452]
[81]
Winters, N.I.; Burman, A.; Kropski, J.A.; Blackwell, T.S. Epithelial injury and dysfunction in the pathogenesis of idiopathic pulmonary fibrosis. Am. J. Med. Sci., 2019, 357(5), 374-378.
[http://dx.doi.org/10.1016/j.amjms.2019.01.010] [PMID: 31010463]
[82]
Weiskirchen, R.; Weiskirchen, S.; Tacke, F. Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications. Mol. Aspects Med., 2019, 65, 2-15.
[http://dx.doi.org/10.1016/j.mam.2018.06.003] [PMID: 29958900]
[83]
Hu, X.; Xu, Q.; Wan, H.; Hu, Y.; Xing, S.; Yang, H.; Gao, Y.; He, Z. PI3K-Akt-mTOR/PFKFB3 pathway mediated lung fibroblast aerobic glycolysis and collagen synthesis in lipopolysaccharide-induced pulmonary fibrosis. Lab. Invest., 2020, 100(6), 801-811.
[http://dx.doi.org/10.1038/s41374-020-0404-9] [PMID: 32051533]
[84]
Baddini-Martinez, J.; Baldi, B.G.; Costa, C.H.; Jezler, S.; Lima, M.S.; Rufino, R. Update on diagnosis and treatment of idiopathic pulmonary fibrosis. J. Bras. Pneumol., 2015, 41(5), 454-466.
[http://dx.doi.org/10.1590/S1806-37132015000000152] [PMID: 26578138]
[85]
Knüppel, L.; Ishikawa, Y.; Aichler, M.; Heinzelmann, K.; Hatz, R.; Behr, J.; Walch, A.; Bächinger, H.P.; Eickelberg, O.; Staab-Weijnitz, C.A. A novel antifibrotic mechanism of nintedanib and pirfenidone. Am. J. Respir. Cell Mol. Biol., 2017, 57(1), 77-90.
[http://dx.doi.org/10.1165/rcmb.2016-0217OC] [PMID: 28257580]

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    5.33s
    1 x Booting (24.52%)
    1.73s
    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
    36 statements were executed, 4 of which were duplicates, 32 unique. Show only duplicated4.82s
    • 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 ('314567762','',1,1740774226,1740774226) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740774226
      699msalphaeurekaselec_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 ('314567762','/article/125231',1,1740774226,1740774226)
      240μsalphaeurekaselec_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 >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) 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 >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) 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 >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) 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 >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) 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 >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) 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 >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 314567762 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314567762) limit 1
      351msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 314567762
      • 1: 314567762
      • 2: 314567762
      • 3: 314567762
      • 4: 314567762
      • 5: 314567762
      • 6: 314567762
      • 7: 314567762
      • 8: 314567762
      • 9: 314567762
      • 10: 314567762
      • 11: 314567762
      • 12: 314567762
      • 13: 314567762
      • 14: 314567762
      • 15: 314567762
      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=125231
      26.92msalphaeurekaselec_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` = 2 limit 1
      7.78msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 2
      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=2) and sj.journal_id!=2 group by `j`.`nid`) as `aggregate_table`
      1.02salphaeurekaselec_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=2) and sj.journal_id!=2 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      3.43msalphaeurekaselec_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=2) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      1.44salphaeurekaselec_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=2) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      31.2msalphaeurekaselec_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` = '125231'
      42.62msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 125231
      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` = '125231'
      21.95msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 125231
      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` = '125231' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      18.33msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 125231
      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
      11.5msalphaeurekaselec_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
      810μsalphaeurekaselec_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 = 2 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      415msalphaeurekaselec_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 = 2 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      94.25msalphaeurekaselec_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 = 2 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      4.51msalphaeurekaselec_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` = 125231 limit 1
      11.39msalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 125231
      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 = 125231 and content_type = 'article' order by status desc limit 1
      430μsalphaeurekaselec_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 * from `node_meta` where `nid` = 207127 limit 1
      310μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 207127
      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
      330μsalphaeurekaselec_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` = 'AIAAMC' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      370μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: AIAAMC
      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 = '125231' 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) )
      480μsalphaeurekaselec_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 = '11827' 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) )
      490μsalphaeurekaselec_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 = '3167' 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) )
      410μsalphaeurekaselec_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 <= 314567762 and j.to_ip >=314567762 )) and ((j.from_date <= 1740774230 and j.to_date >= 1740774230 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3167) 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 <= 314567762 and j.to_ip >=314567762 )) and ((j.from_date <= 1740774230 and j.to_date >= 1740774230 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3167) 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 <= 314567762 and j.to_ip >=314567762 )) and ((j.from_date <= 1740774230 and j.to_date >= 1740774230 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3167)
      575msalphaeurekaselec_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 <= 314567762 and j.to_ip >=314567762 )) and ((j.from_date <= 1740774231 and j.to_date >= 1740774231 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11827) 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 <= 314567762 and j.to_ip >=314567762 )) and ((j.from_date <= 1740774231 and j.to_date >= 1740774231 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11827) 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 <= 314567762 and j.to_ip >=314567762 )) and ((j.from_date <= 1740774231 and j.to_date >= 1740774231 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11827)
      930μsalphaeurekaselec_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 <= 314567762 and j.to_ip >=314567762 )) and ((j.from_date <= 1740774231 and j.to_date >= 1740774231 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 125231) 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 <= 314567762 and j.to_ip >=314567762 )) and ((j.from_date <= 1740774231 and j.to_date >= 1740774231 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 125231) 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 <= 314567762 and j.to_ip >=314567762 )) and ((j.from_date <= 1740774231 and j.to_date >= 1740774231 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 125231)
      1.17msalphaeurekaselec_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` < '135' and is_uploaded = 1 and issue_id = 11827 order by cast(first_page as SIGNED) desc limit 1
      1.48msalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 135
      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` > '151' and is_uploaded = 1 and issue_id = 11827 order by cast(first_page as SIGNED) asc limit 1
      940μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 151
      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'
      400μsalphaeurekaselec_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
      490μsalphaeurekaselec_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` = 125231 limit 1
      5.47msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 125231
      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` = 2 and `b`.`banner_from_date` <= 1740774231 and `b`.`banner_to_date` >= 1740774231 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      32.05msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 2
      • 3: 1740774231
      • 4: 1740774231
      • 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` = 2 and `b`.`banner_from_date` <= 1740774231 and `b`.`banner_to_date` >= 1740774231 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      3.14msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 2
      • 3: 1740774231
      • 4: 1740774231
      • 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='62335f47f6a4493bb939946e453abab0'
      320μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:291
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
        _token
        V8OzWfV4BCgd4r0ddzFYiqwMmGrpebUvXYQeFpXG
        uc_cart_id
        62335f47f6a4493bb939946e453abab0
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/125231" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/125231
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:8 [ "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        request_cookies
        []
        
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