Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Review Article

Drug Delivery System Approaches for Rheumatoid Arthritis Treatment: A Review

Author(s): Anushka Garhwal, Priyadarshi Kendya, Sakshi Soni, Shivam Kori, Vandana Soni and Sushil Kumar Kashaw*

Volume 24, Issue 7, 2024

Published on: 09 October, 2023

Page: [704 - 720] Pages: 17

DOI: 10.2174/1389557523666230913105803

Price: $65

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that has traditionally been treated using a variety of pharmacological compounds. However, the effectiveness of these treatments is often limited due to challenges associated with their administration. Oral and parenteral routes of drug delivery are often restricted due to issues such as low bioavailability, rapid metabolism, poor absorption, first-pass effect, and severe side effects. In recent years, nanocarrier-based delivery methods have emerged as a promising alternative for overcoming these challenges. Nanocarriers, including nanoparticles, dendrimers, micelles, nanoemulsions, and stimuli-sensitive carriers, possess unique properties that enable efficient drug delivery and targeted therapy. Using nanocarriers makes it possible to circumvent traditional administration routes' limitations. One of the key advantages of nanocarrier- based delivery is the ability to overcome resistance or intolerance to traditional antirheumatic therapies. Moreover, nanocarriers offer improved drug stability, controlled release kinetics, and enhanced solubility, optimizing the therapeutic effect. They can also protect the encapsulated drug, prolonging its circulation time and facilitating sustained release at the target site. This targeted delivery approach ensures a higher concentration of the therapeutic agent at the site of inflammation, leading to improved therapeutic outcomes. This article explores potential developments in nanotherapeutic regimens for RA while providing a comprehensive summary of current approaches based on novel drug delivery systems. In conclusion, nanocarrier-based drug delivery systems have emerged as a promising solution for improving the treatment of rheumatoid arthritis. Further advancements in nanotechnology hold promise for enhancing the efficacy and safety of RA therapies, offering new hope for patients suffering from this debilitating disease.

Graphical Abstract

[1]
Klareskog, L.; Padyukov, L.; Lorentzen, J.; Alfredsson, L. Mechanisms of disease: Genetic susceptibility and environmental triggers in the development of rheumatoid arthritis. Nat. Clin. Pract. Rheumatol., 2006, 2(8), 425-433.
[http://dx.doi.org/10.1038/ncprheum0249] [PMID: 16932734]
[2]
Lawrence, T.; Natoli, G. Transcriptional regulation of macrophage polarization: Enabling diversity with identity. Nat. Rev. Immunol., 2011, 11(11), 750-761.
[http://dx.doi.org/10.1038/nri3088] [PMID: 22025054]
[3]
Dolati, S.; Sadreddini, S.; Rostamzadeh, D.; Ahmadi, M.; Jadidi-Niaragh, F.; Yousefi, M. Utilization of nanoparticle technology in rheumatoid arthritis treatment. Biomed. Pharmacother., 2016, 80, 30-41.
[http://dx.doi.org/10.1016/j.biopha.2016.03.004] [PMID: 27133037]
[4]
Machin, A.R.; Babatunde, O.; Haththotuwa, R.; Scott, I.; Blagojevic-Bucknall, M.; Corp, N.; Chew-Graham, C.A.; Hider, S.L. Correction to: The association between anxiety and disease activity and quality of life in rheumatoid arthritis: A systematic review and meta-analysis. Clin. Rheumatol., 2020, 39(4), 1373-1375.
[http://dx.doi.org/10.1007/s10067-020-04954-3] [PMID: 32020442]
[5]
Firestein, G.S. Evolving concepts of rheumatoid arthritis. Nature, 2003, 423(6937), 356-361.
[http://dx.doi.org/10.1038/nature01661] [PMID: 12748655]
[6]
Wegner, N.; Lundberg, K.; Kinloch, A.; Fisher, B.; Malmström, V.; Feldmann, M.; Venables, P.J. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol. Rev., 2010, 233(1), 34-54.
[http://dx.doi.org/10.1111/j.0105-2896.2009.00850.x] [PMID: 20192991]
[7]
Philippou, E.; Nikiphorou, E. Are we really what we eat? Nutrition and its role in the onset of rheumatoid arthritis. Autoimmun. Rev., 2018, 17(11), 1074-1077.
[http://dx.doi.org/10.1016/j.autrev.2018.05.009] [PMID: 30213695]
[8]
Viatte, S.; Barton, A. Genetics of rheumatoid arthritis susceptibility, severity, and treatment response. Semin. Immunopathol., 2017, 39(4), 395-408.
[http://dx.doi.org/10.1007/s00281-017-0630-4] [PMID: 28555384]
[9]
Song, Y.; Huang, Y.; Zhou, F.; Ding, J.; Zhou, W. Macrophage-targeted nanomedicine for chronic diseases immunotherapy. Chin. Chem. Lett., 2022, 33(2), 597-612.
[http://dx.doi.org/10.1016/j.cclet.2021.08.090]
[10]
Zhao, J.; Chen, X.; Ho, K.H.; Cai, C.; Li, C.W.; Yang, M.; Yi, C. Nanotechnology for diagnosis and therapy of rheumatoid arthritis: Evolution towards theranostic approaches. Chin. Chem. Lett., 2021, 32(1), 66-86.
[http://dx.doi.org/10.1016/j.cclet.2020.11.048]
[11]
Gregersen, P.K.; Silver, J.; Winchester, R.J. The shared epitope hypothesis. an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum., 1987, 30(11), 1205-1213.
[http://dx.doi.org/10.1002/art.1780301102] [PMID: 2446635]
[12]
Raychaudhuri, S. Recent advances in the genetics of rheumatoid arthritis. Curr. Opin. Rheumatol., 2010, 22(2), 109-118.
[http://dx.doi.org/10.1097/BOR.0b013e328336474d] [PMID: 20075733]
[13]
Tan, E.M.; Smolen, J.S. Historical observations contributing insights on etiopathogenesis of rheumatoid arthritis and role of rheumatoid factor. J. Exp. Med., 2016, 213(10), 1937-1950.
[http://dx.doi.org/10.1084/jem.20160792] [PMID: 27621417]
[14]
Scher, J.U.; Sczesnak, A.; Longman, R.S.; Segata, N.; Ubeda, C. Bielski, C Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife, 2013, 2, e01202.
[15]
Klareskog, L.; Stolt, P.; Lundberg, K.; Källberg, H.; Bengtsson, C.; Grunewald, J.; Rönnelid, J.; Erlandsson Harris, H.; Ulfgren, A.K. Rantapää-Dahlqvist, S.; Eklund, A.; Padyukov, L.; Alfredsson, L. A new model for an etiology of rheumatoid arthritis: Smoking may trigger HLA–DR (shared epitope)–restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum., 2006, 54(1), 38-46.
[http://dx.doi.org/10.1002/art.21575] [PMID: 16385494]
[16]
Stolt, P.; Yahya, A.; Bengtsson, C.; Källberg, H.; Rönnelid, J.; Lundberg, I.; Klareskog, L.; Alfredsson, L. Silica exposure among male current smokers is associated with a high risk of developing ACPA-positive rheumatoid arthritis. Ann. Rheum. Dis., 2010, 69(6), 1072-1076.
[http://dx.doi.org/10.1136/ard.2009.114694] [PMID: 19966090]
[17]
Mohamed, B.M.; Verma, N.K.; Davies, A.M.; McGowan, A.; Crosbie-Staunton, K.; Prina-Mello, A.; Kelleher, D.; Botting, C.H.; Causey, C.P.; Thompson, P.R.; Pruijn, G.J.M.; Kisin, E.R.; Tkach, A.V.; Shvedova, A.A.; Volkov, Y. Citrullination of proteins: A common post-translational modification pathway induced by different nanoparticles in vitro and in vivo. Nanomedicine, 2012, 7(8), 1181-1195.
[http://dx.doi.org/10.2217/nnm.11.177] [PMID: 22625207]
[18]
Too, C.L.; Muhamad, N.A.; Ilar, A.; Padyukov, L.; Alfredsson, L.; Klareskog, L.; Murad, S.; Bengtsson, C. Occupational exposure to textile dust increases the risk of rheumatoid arthritis: Results from a Malaysian population-based case–control study. Ann. Rheum. Dis., 2016, 75(6), 997-1002.
[http://dx.doi.org/10.1136/annrheumdis-2015-208278] [PMID: 26681695]
[19]
De Rycke, L.; Peene, I.; Hoffman, I.E.A.; Kruithof, E.; Union, A.; Meheus, L.; Lebeer, K.; Wyns, B.; Vincent, C.; Mielants, H.; Boullart, L.; Serre, G.; Veys, E.M.; De Keyser, F. Rheumatoid factor and anticitrullinated protein antibodies in rheumatoid arthritis: Diagnostic value, associations with radiological progression rate, and extra-articular manifestations. Ann. Rheum. Dis., 2004, 63(12), 1587-1593.
[http://dx.doi.org/10.1136/ard.2003.017574] [PMID: 15547083]
[20]
Elshabrawy, H.A.; Chen, Z.; Volin, M.V.; Ravella, S.; Virupannavar, S.; Shahrara, S. The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis, 2015, 18(4), 433-448.
[http://dx.doi.org/10.1007/s10456-015-9477-2] [PMID: 26198292]
[21]
Bouta, E.M.; Li, J.; Ju, Y.; Brown, E.B.; Ritchlin, C.T.; Xing, L.; Schwarz, E.M. The role of the lymphatic system in inflammatory-erosive arthritis. Semin. Cell Dev. Biol., 2015, 38, 90-97.
[http://dx.doi.org/10.1016/j.semcdb.2015.01.001] [PMID: 25598390]
[22]
Capellino, S.; Cosentino, M.; Wolff, C.; Schmidt, M.; Grifka, J.; Straub, R.H. Catecholamine-producing cells in the synovial tissue during arthritis: modulation of sympathetic neurotransmitters as new therapeutic target. Ann. Rheum. Dis., 2010, 69(10), 1853-1860.
[http://dx.doi.org/10.1136/ard.2009.119701] [PMID: 20498218]
[23]
Bizzaro, N.; Bartoloni, E.; Morozzi, G.; Manganelli, S.; Riccieri, V.; Sabatini, P.; Filippini, M.; Tampoia, M.; Afeltra, A.; Sebastiani, G.; Alpini, C.; Bini, V.; Bistoni, O.; Alunno, A.; Gerli, R. Anti-cyclic citrullinated peptide antibody titer predicts time to rheumatoid arthritis onset in patients with undifferentiated arthritis: Results from a 2-year prospective study. Arthritis Res. Ther., 2013, 15(1), R16.
[http://dx.doi.org/10.1186/ar4148] [PMID: 23339296]
[24]
Krishnamurthy, A.; Joshua, V.; Haj Hensvold, A.; Jin, T.; Sun, M.; Vivar, N.; Ytterberg, A.J.; Engström, M.; Fernandes-Cerqueira, C.; Amara, K.; Magnusson, M.; Wigerblad, G.; Kato, J.; Jiménez-Andrade, J.M.; Tyson, K.; Rapecki, S.; Lundberg, K.; Catrina, S.B.; Jakobsson, P.J.; Svensson, C.; Malmström, V.; Klareskog, L.; Wähämaa, H.; Catrina, A.I. Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann. Rheum. Dis., 2016, 75(4), 721-729.
[http://dx.doi.org/10.1136/annrheumdis-2015-208093] [PMID: 26612338]
[25]
Wigerblad, G.; Bas, D.B.; Fernades-Cerqueira, C.; Krishnamurthy, A.; Nandakumar, K.S.; Rogoz, K.; Kato, J.; Sandor, K.; Su, J.; Jimenez-Andrade, J.M.; Finn, A.; Bersellini Farinotti, A.; Amara, K.; Lundberg, K.; Holmdahl, R.; Jakobsson, P-J.; Malmström, V.; Catrina, A.I.; Klareskog, L.; Svensson, C.I. Autoantibodies to citrullinated proteins may induce joint pain independent of inflammation. Ann. Rheum. Dis., 2016, 75(4), 730-738.
[http://dx.doi.org/10.1136/annrheumdis-2015-208094] [PMID: 26613766]
[26]
McInnes, I.B.; Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med., 2011, 365(23), 2205-2219.
[http://dx.doi.org/10.1056/NEJMra1004965] [PMID: 22150039]
[27]
Aletaha, D.; Smolen, J.S. Diagnosis and management of rheumatoid arthritis: A review. JAMA, 2018, 320(13), 1360-1372.
[http://dx.doi.org/10.1001/jama.2018.13103] [PMID: 30285183]
[28]
Sabeh, F.; Fox, D.; Weiss, S.J. Membrane-type I matrix metalloproteinase-dependent regulation of rheumatoid arthritis synoviocyte function. J. Immunol., 2010, 184(11), 6396-6406.
[http://dx.doi.org/10.4049/jimmunol.0904068] [PMID: 20483788]
[29]
Mitragotri, S.; Yoo, J.W. Designing micro- and nano-particles for treating rheumatoid arthritis. Arch. Pharm. Res., 2011, 34(11), 1887-1897.
[http://dx.doi.org/10.1007/s12272-011-1109-9] [PMID: 22139688]
[30]
Anaya, JM; Shoenfeld, Y; Rojas-Villarraga, A; Levy, RA; Cervera, R Autoimmunity: from bench to bedside,
[31]
Hadwen, B.; Stranges, S.; Barra, L. Risk factors for hypertension in rheumatoid arthritis patients–A systematic review. Autoimmun. Rev., 2021, 20(4), 102786.
[http://dx.doi.org/10.1016/j.autrev.2021.102786] [PMID: 33609791]
[32]
Hu, C.J.; Zhang, L.; Zhou, S.; Jiang, N.; Zhao, J.L.; Wang, Q.; Tian, X.P.; Zeng, X.F. Effectiveness of iguratimod as monotherapy or combined therapy in patients with rheumatoid arthritis: A systematic review and meta-analysis of RCTs. J. Orthop. Surg. Res., 2021, 16(1), 457.
[http://dx.doi.org/10.1186/s13018-021-02603-2] [PMID: 34271950]
[33]
Xie, Z.; Yang, X.; Duan, Y.; Han, J.; Liao, C. Small-molecule kinase inhibitors for the treatment of nononcologic diseases. J. Med. Chem., 2021, 64(3), 1283-1345.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01511] [PMID: 33481605]
[34]
Šenolt, L.; Vencovský, J.; Pavelka, K.; Ospelt, C.; Gay, S. Prospective new biological therapies for rheumatoid arthritis. Autoimmun. Rev., 2009, 9(2), 102-107.
[http://dx.doi.org/10.1016/j.autrev.2009.03.010] [PMID: 19328245]
[35]
Mysler, E.; Pineda, C.; Horiuchi, T.; Singh, E.; Mahgoub, E.; Coindreau, J.; Jacobs, I. Clinical and regulatory perspectives on biosimilar therapies and intended copies of biologics in rheumatology. Rheumatol. Int., 2016, 36(5), 613-625.
[http://dx.doi.org/10.1007/s00296-016-3444-0] [PMID: 26920148]
[36]
Sarnola, K.; Merikoski, M.; Jyrkkä, J.; Hämeen-Anttila, K. Physicians’ perceptions of the uptake of biosimilars: A systematic review. BMJ Open, 2020, 10(5), e034183.
[http://dx.doi.org/10.1136/bmjopen-2019-034183] [PMID: 32371511]
[37]
Katz-Talmor, D.; Katz, I.; Porat-Katz, B.S.; Shoenfeld, Y. Cannabinoids for the treatment of rheumatic diseases — where do we stand? Nat. Rev. Rheumatol., 2018, 14(8), 488-498.
[http://dx.doi.org/10.1038/s41584-018-0025-5] [PMID: 29884803]
[38]
Laprairie, R.B.; Bagher, A.M.; Kelly, M.E.M.; Denovan-Wright, E.M. Cannabidiol is a negative allosteric modulator of the cannabinoid CB 1 receptor. Br. J. Pharmacol., 2015, 172(20), 4790-4805.
[http://dx.doi.org/10.1111/bph.13250] [PMID: 26218440]
[39]
Kaur, I.; Behl, T.; Bungau, S.; Zengin, G.; Kumar, A.; El-Esawi, M.A.; Khullar, G.; Venkatachalam, T.; Arora, S. The endocannabinoid signaling pathway as an emerging target in pharmacotherapy, earmarking mitigation of destructive events in rheumatoid arthritis. Life Sci., 2020, 257(118109), 118109.
[http://dx.doi.org/10.1016/j.lfs.2020.118109] [PMID: 32698072]
[40]
Bryk, M.; Starowicz, K. Cannabinoid-based therapy as a future for joint degeneration. Focus on the role of CB2 receptor in the arthritis progression and pain: An updated review. Pharmacol. Rep., 2021, 73(3), 681-699.
[http://dx.doi.org/10.1007/s43440-021-00270-y] [PMID: 34050525]
[41]
Vandana, K.R.; Yalavarthi, P.; Sundaresan, C.R.; Sriramaneni, R.; Vadlamudi, H. In-vitro assessment and pharmacodynamics of nimesulide incorporated Aloe vera transemulgel. Curr. Drug Discov. Technol., 2014, 11(2), 162-167.
[http://dx.doi.org/10.2174/1570163810666131202233721] [PMID: 24295369]
[42]
Danhier, F.; Ansorena, E.; Silva, J.M.; Coco, R.; Le Breton, A.; Préat, V. PLGA-based nanoparticles: An overview of biomedical applications. J. Control. Release, 2012, 161(2), 505-522.
[http://dx.doi.org/10.1016/j.jconrel.2012.01.043] [PMID: 22353619]
[43]
Goindi, S.; Narula, M.; Kalra, A. Microemulsion-based topical hydrogels of tenoxicam for treatment of arthritis. AAPS PharmSciTech, 2016, 17(3), 597-606.
[http://dx.doi.org/10.1208/s12249-015-0383-0] [PMID: 26285672]
[44]
Akbari, E.; Mousazadeh, H.; Sabet, Z.; Fattahi, T.; Dehnad, A.; Akbarzadeh, A.; Alizadeh, E. Dual drug delivery of trapoxin A and methotrexate from biocompatible PLGA-PEG polymeric nanoparticles enhanced antitumor activity in breast cancer cell line. J. Drug Deliv. Sci. Technol., 2021, 61(102294), 102294.
[http://dx.doi.org/10.1016/j.jddst.2020.102294]
[45]
Ganguly, K.; Patel, D.K.; Dutta, S.D.; Shin, W.C.; Lim, K.T. Stimuli-responsive self-assembly of cellulose nanocrystals (CNCs): Structures, functions, and biomedical applications. Int. J. Biol. Macromol., 2020, 155, 456-469.
[http://dx.doi.org/10.1016/j.ijbiomac.2020.03.171] [PMID: 32222290]
[46]
Remtulla, A.H. Reactive oxygen species in protein sulphenic acid formation during T cell activation; implications for rheumatoid arthritis. Doctoral dissertation: Aston University 2019.
[47]
Adepu, S.; Ramakrishna, S. Controlled drug delivery systems: Current status and future directions. Molecules, 2021, 26(19), 5905.
[http://dx.doi.org/10.3390/molecules26195905] [PMID: 34641447]
[48]
Syed, U.T.; Dias, A.M.A.; de Sousa, H.C.; Crespo, J.; Brazinha, C. Greening perfluorocarbon based nanoemulsions by direct membrane emulsification: Comparative studies with ultrasound emulsification. J. Clean. Prod., 2022, 357(131966), 131966.
[http://dx.doi.org/10.1016/j.jclepro.2022.131966]
[49]
Janakiraman, K.; Krishnaswami, V.; Rajendran, V.; Natesan, S.; Kandasamy, R. Novel nano therapeutic materials for the effective treatment of rheumatoid arthritis-recent insights. Mater. Today Commun., 2018, 17, 200-213.
[http://dx.doi.org/10.1016/j.mtcomm.2018.09.011] [PMID: 32289062]
[50]
Wang, J.; Zeng, J.; Liu, Z.; Zhou, Q.; Wang, X.; Zhao, F.; Zhang, Y.; Wang, J.; Liu, M.; Du, R. Promising strategies for transdermal delivery of arthritis drugs: Microneedle systems. Pharmaceutics, 2022, 14(8), 1736.
[http://dx.doi.org/10.3390/pharmaceutics14081736] [PMID: 36015362]
[51]
Yang, D.; Chen, M.; Sun, Y.; Jin, Y.; Lu, C.; Pan, X.; Quan, G.; Wu, C. Microneedle-mediated transdermal drug delivery for treating diverse skin diseases. Acta Biomater., 2021, 121, 119-133.
[http://dx.doi.org/10.1016/j.actbio.2020.12.004] [PMID: 33285323]
[52]
Camilleri, J.P.; Williams, A.S.; Amos, N.; Douglas-Jones, A.G.; Love, W.G.; Williams, B.D. The effect of free and liposome-encapsulated clodronate on the hepatic mononuclear phagocyte system in the rat. Clin. Exp. Immunol., 2008, 99(2), 269-275.
[http://dx.doi.org/10.1111/j.1365-2249.1995.tb05544.x] [PMID: 7851021]
[53]
Ren, H.; He, Y.; Liang, J.; Cheng, Z.; Zhang, M.; Zhu, Y.; Hong, C.; Qin, J.; Xu, X.; Wang, J. Role of liposome size, surface charge, and PEGylation on rheumatoid arthritis targeting therapy. ACS Appl. Mater. Interfaces, 2019, 11(22), 20304-20315.
[http://dx.doi.org/10.1021/acsami.8b22693] [PMID: 31056910]
[54]
Williams, A.S.; Camilleri, J.P.; Williams, B.D. Suppression of adjuvant-induced arthritis by liposomally conjugated methotrexate in the rat. Rheumatology, 1994, 33(6), 530-533.
[http://dx.doi.org/10.1093/rheumatology/33.6.530] [PMID: 8205400]
[55]
Thakur, S.; Riyaz, B.; Patil, A.; Kaur, A.; Kapoor, B.; Mishra, V. Novel drug delivery systems for NSAIDs in management of rheumatoid arthritis: An overview. Biomed. Pharmacother., 2018, 106, 1011-1023.
[http://dx.doi.org/10.1016/j.biopha.2018.07.027] [PMID: 30119166]
[56]
Montazeri Aliabadi, H.; Brocks, D.R.; Lavasanifar, A. Polymeric micelles for the solubilization and delivery of cyclosporine A: pharmacokinetics and biodistribution. Biomaterials, 2005, 26(35), 7251-7259.
[http://dx.doi.org/10.1016/j.biomaterials.2005.05.042] [PMID: 16005061]
[57]
Bernardi, A.; Zilberstein, A.C.C.V.; Jäger, E.; Campos, M.M.; Morrone, F.B.; Calixto, J.B.; Pohlmann, A.R.; Guterres, S.S.; Battastini, A.M.O. Effects of indomethacin-loaded nanocapsules in experimental models of inflammation in rats. Br. J. Pharmacol., 2009, 158(4), 1104-1111.
[http://dx.doi.org/10.1111/j.1476-5381.2009.00244.x] [PMID: 19422380]
[58]
Sharma, G.; Saini, M.K.; Thakur, K.; Kapil, N.; Garg, N.K.; Raza, K.; Goni, V.G.; Pareek, A.; Katare, O.P. Aceclofenac cocrystal nanoliposomes for rheumatoid arthritis with better dermatokinetic attributes: A preclinical study. Nanomedicine, 2017, 12(6), 615-638.
[http://dx.doi.org/10.2217/nnm-2016-0405] [PMID: 28186461]
[59]
Chandrasekar, D.; Sistla, R.; Ahmad, F.J.; Khar, R.K.; Diwan, P.V. Folate coupled poly(ethyleneglycol) conjugates of anionic poly(amidoamine) dendrimer for inflammatory tissue specific drug delivery. J. Biomed. Mater. Res. A, 2007, 82A(1), 92-103.
[http://dx.doi.org/10.1002/jbm.a.31122] [PMID: 17269145]
[60]
Suk, J.S.; Xu, Q.; Kim, N.; Hanes, J.; Ensign, L.M. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv. Drug Deliv. Rev., 2016, 99(Pt A), 28-51.
[http://dx.doi.org/10.1016/j.addr.2015.09.012] [PMID: 26456916]
[61]
Quan, L.; Zhang, Y.; Crielaard, B.J.; Dusad, A.; Lele, S.M.; Rijcken, C.J.F.; Metselaar, J.M.; Kostková, H.; Etrych, T.; Ulbrich, K.; Kiessling, F.; Mikuls, T.R.; Hennink, W.E.; Storm, G.; Lammers, T.; Wang, D. Nanomedicines for inflammatory arthritis: Head-to-head comparison of glucocorticoid-containing polymers, micelles, and liposomes. ACS Nano, 2014, 8(1), 458-466.
[http://dx.doi.org/10.1021/nn4048205] [PMID: 24341611]
[62]
Hwang, J.; Rodgers, K.; Oliver, J.C.; Schluep, T. α-methylprednisolone conjugated cyclodextrin polymer-based nanoparticles for rheumatoid arthritis therapy. Int. J. Nanomed., 2008, 3(3), 359-371.
[PMID: 18990945]
[63]
Ishihara, T.; Kubota, T.; Choi, T.; Higaki, M. Treatment of experimental arthritis with stealth-type polymeric nanoparticles encapsulating betamethasone phosphate. J. Pharmacol. Exp. Ther., 2009, 329(2), 412-417.
[http://dx.doi.org/10.1124/jpet.108.150276] [PMID: 19244548]
[64]
Williams, A.; Goodfellow, R.; Topley, N.; Amos, N.; Williams, B. The suppression of rat collagen-induced arthritis and inhibition of macrophage derived mediator release by liposomal methotrexate formulations. Inflamm. Res., 2000, 49(4), 155-161.
[http://dx.doi.org/10.1007/s000110050575] [PMID: 10858015]
[65]
Barrera, P.; Blom, A.; Van Lent, P.L.E.M.; Van Bloois, L.; Beijnen, J.H.; Van Rooijen, N.; De Waal Malefijt, M.C.; Van De Putte, L.B.A.; Storm, G.; Van Den Berg, W.B. Synovial macrophage depletion with clodronate‐containing liposomes in rheumatoid arthritis. Arthritis Rheum., 2000, 43(9), 1951-1959.
[http://dx.doi.org/10.1002/1529-0131(200009)43:9<1951:AID-ANR5>3.0.CO;2-K] [PMID: 11014344]
[66]
Jung, Y.S.; Park, W.; Na, K. Temperature-modulated noncovalent interaction controllable complex for the long-term delivery of etanercept to treat rheumatoid arthritis. J. Control. Release, 2013, 171(2), 143-151.
[http://dx.doi.org/10.1016/j.jconrel.2013.07.012] [PMID: 23880471]
[67]
Fernandes, J.C.; Wang, H.; Jreyssaty, C.; Benderdour, M.; Lavigne, P.; Qiu, X.; Winnik, F.M.; Zhang, X.; Dai, K.; Shi, Q. Bone-protective effects of nonviral gene therapy with folate-chitosan DNA nanoparticle containing interleukin-1 receptor antagonist gene in rats with adjuvant-induced arthritis. Mol. Ther., 2008, 16(7), 1243-1251.
[http://dx.doi.org/10.1038/mt.2008.99] [PMID: 18500247]
[68]
Lee, H.; Lee, M.Y.; Bhang, S.H.; Kim, B.S.; Kim, Y.S.; Ju, J.H.; Kim, K.S.; Hahn, S.K. Hyaluronate-gold nanoparticle/tocilizumab complex for the treatment of rheumatoid arthritis. ACS Nano, 2014, 8(5), 4790-4798.
[http://dx.doi.org/10.1021/nn500685h] [PMID: 24730974]
[69]
Heo, R.; Park, J.S.; Jang, H.J.; Kim, S.H.; Shin, J.M.; Suh, Y.D.; Jeong, J.H.; Jo, D.G.; Park, J.H. Hyaluronan nanoparticles bearing γ-secretase inhibitor: in vivo therapeutic effects on rheumatoid arthritis. J. Control. Release, 2014, 192, 295-300.
[http://dx.doi.org/10.1016/j.jconrel.2014.07.057] [PMID: 25109660]
[70]
Zhou, H.; Chan, H.W.; Wickline, S.A.; Lanza, G.M.; Pham, C.T.N. α v β 3 –Targeted nanotherapy suppresses inflammatory arthritis in mice. FASEB J., 2009, 23(9), 2978-2985.
[http://dx.doi.org/10.1096/fj.09-129874] [PMID: 19376816]
[71]
Vanniasinghe, A.S.; Manolios, N.; Schibeci, S.; Lakhiani, C.; Kamali-Sarvestani, E.; Sharma, R.; Kumar, V.; Moghaddam, M.; Ali, M.; Bender, V. Targeting fibroblast-like synovial cells at sites of inflammation with peptide targeted liposomes results in inhibition of experimental arthritis. Clin. Immunol., 2014, 151(1), 43-54.
[http://dx.doi.org/10.1016/j.clim.2014.01.005] [PMID: 24513809]
[72]
Kim, H.J.; Lee, S.M.; Park, K.H.; Mun, C.H.; Park, Y.B.; Yoo, K.H. Drug-loaded gold/iron/gold plasmonic nanoparticles for magnetic targeted chemo-photothermal treatment of rheumatoid arthritis. Biomaterials, 2015, 61, 95-102.
[http://dx.doi.org/10.1016/j.biomaterials.2015.05.018] [PMID: 26001074]
[73]
Lee, S.M.; Kim, H.J.; Ha, Y.J.; Park, Y.N.; Lee, S.K.; Park, Y.B.; Yoo, K.H. Targeted chemo-photothermal treatments of rheumatoid arthritis using gold half-shell multifunctional nanoparticles. ACS Nano, 2013, 7(1), 50-57.
[http://dx.doi.org/10.1021/nn301215q] [PMID: 23194301]
[74]
Wang, Y.; Liu, Z.; Li, T.; Chen, L.; Lyu, J.; Li, C.; Lin, Y.; Hao, N.; Zhou, M.; Zhong, Z. Enhanced therapeutic effect of RGD-modified polymeric micelles loaded with low-dose methotrexate and nimesulide on rheumatoid arthritis. Theranostics, 2019, 9(3), 708-720.
[http://dx.doi.org/10.7150/thno.30418] [PMID: 30809303]
[75]
Koo, O.M.Y.; Rubinstein, I.; Önyüksel, H. Actively targeted low-dose camptothecin as a safe, long-acting, disease-modifying nanomedicine for rheumatoid arthritis. Pharm. Res., 2011, 28(4), 776-787.
[http://dx.doi.org/10.1007/s11095-010-0330-4] [PMID: 21132352]
[76]
Jain, S.; Tran, T.H.; Amiji, M. Macrophage repolarization with targeted alginate nanoparticles containing IL-10 plasmid DNA for the treatment of experimental arthritis. Biomaterials, 2015, 61, 162-177.
[http://dx.doi.org/10.1016/j.biomaterials.2015.05.028] [PMID: 26004232]
[77]
Meka, R.R.; Venkatesha, S.H.; Acharya, B.; Moudgil, K.D. Peptide-targeted liposomal delivery of dexamethasone for arthritis therapy. Nanomedicine, 2019, 14(11), 1455-1469.
[http://dx.doi.org/10.2217/nnm-2018-0501] [PMID: 30938236]
[78]
Katsumata, K; Ishihara, J; Mansurov, A; Ishihara, A; Raczy, MM; Yuba, E; Hubbell, JA Targeting inflammatory sites through collagen affinity enhances the therapeutic efficacy of anti-inflammatory antibodies. Sci. Adv., 2019, 5(11), eaay1971.
[http://dx.doi.org/10.1126/sciadv.aay1971]
[79]
He, Y.; Li, R.; Liang, J.; Zhu, Y.; Zhang, S.; Zheng, Z.; Qin, J.; Pang, Z.; Wang, J. Drug targeting through platelet membrane-coated nanoparticles for the treatment of rheumatoid arthritis. Nano Res., 2018, 11(11), 6086-6101.
[http://dx.doi.org/10.1007/s12274-018-2126-5]
[80]
Zhang, N.; Xu, C.; Li, N.; Zhang, S.; Fu, L.; Chu, X.; Hua, H.; Zeng, X.; Zhao, Y. Folate receptor-targeted mixed polysialic acid micelles for combating rheumatoid arthritis: in vitro and in vivo evaluation. Drug Deliv., 2018, 25(1), 1182-1191.
[http://dx.doi.org/10.1080/10717544.2018.1472677] [PMID: 29790372]
[81]
Li, Z.; Zhou, X.; Wei, M.; Gao, X.; Zhao, L.; Shi, R.; Sun, W.; Duan, Y.; Yang, G.; Yuan, L. In vitro and in vivo RNA inhibition by CD9-HuR functionalized exosomes encapsulated with miRNA or CRISPR/dCas9. Nano Lett., 2019, 19(1), 19-28.
[http://dx.doi.org/10.1021/acs.nanolett.8b02689] [PMID: 30517011]
[82]
Shi, Y.; Xie, F.; Rao, P.; Qian, H.; Chen, R.; Chen, H.; Li, D.; Mu, D.; Zhang, L.; Lv, P.; Shi, G.; Zheng, L.; Liu, G. TRAIL-expressing cell membrane nanovesicles as an anti-inflammatory platform for rheumatoid arthritis therapy. J. Control. Release, 2020, 320, 304-313.
[http://dx.doi.org/10.1016/j.jconrel.2020.01.054] [PMID: 32004586]
[83]
Graversen, J.H.; Svendsen, P.; Dagnæs-Hansen, F.; Dal, J.; Anton, G.; Etzerodt, A.; Petersen, M.D.; Christensen, P.A.; Møller, H.J.; Moestrup, S.K. Targeting the hemoglobin scavenger receptor CD163 in macrophages highly increases the anti-inflammatory potency of dexamethasone. Mol. Ther., 2012, 20(8), 1550-1558.
[http://dx.doi.org/10.1038/mt.2012.103] [PMID: 22643864]
[84]
Liu, L.; Hu, F.; Wang, H.; Wu, X.; Eltahan, A.S.; Stanford, S.; Bottini, N.; Xiao, H.; Bottini, M.; Guo, W.; Liang, X.J. Secreted protein acidic and rich in cysteine mediated biomimetic delivery of methotrexate by albumin-based nanomedicines for rheumatoid arthritis therapy. ACS Nano, 2019, 13(5), 5036-5048.
[http://dx.doi.org/10.1021/acsnano.9b01710] [PMID: 30978282]
[85]
Moura, C.C.; Segundo, M.A.; Neves, Jd.; Reis, S.; Sarmento, B. Co-association of methotrexate and SPIONs into anti-CD64 antibody-conjugated PLGA nanoparticles for theranostic application. Int. J. Nanomed., 2014, 9, 4911-4922.
[PMID: 25364249]
[86]
Bilthariya, U.; Jain, N.; Rajoriya, V.; Jain, A.K. Folate-conjugated albumin nanoparticles for rheumatoid arthritis-targeted delivery of etoricoxib. Drug Dev. Ind. Pharm., 2015, 41(1), 95-104.
[http://dx.doi.org/10.3109/03639045.2013.850705] [PMID: 24164469]
[87]
Qi, R.; Majoros, I.; Misra, A.C.; Koch, A.E.; Campbell, P.; Marotte, H.; Bergin, I.L.; Cao, Z.; Goonewardena, S.; Morry, J.; Zhang, S.; Beer, M.; Makidon, P.; Kotlyar, A.; Thomas, T.P.; Baker, J.R., Jr Folate receptor-targeted dendrimer-methotrexate conjugate for inflammatory arthritis. J. Biomed. Nanotechnol., 2015, 11(8), 1431-1441.
[http://dx.doi.org/10.1166/jbn.2015.2077] [PMID: 26295143]
[88]
Verma, A.; Jain, A.; Tiwari, A.; Saraf, S.; Panda, P.K.; Agrawal, G.P.; Jain, S.K. Folate conjugated double liposomes bearing prednisolone and methotrexate for targeting rheumatoid arthritis. Pharm. Res., 2019, 36(8), 123.
[http://dx.doi.org/10.1007/s11095-019-2653-0] [PMID: 31218557]
[89]
Nogueira, E.; Freitas, J.; Loureiro, A.; Nogueira, P.; Gomes, A.C.; Preto, A.; Carmo, A.M.; Moreira, A.; Cavaco-Paulo, A. Neutral PEGylated liposomal formulation for efficient folate-mediated delivery of MCL1 siRNA to activated macrophages. Colloids Surf. B Biointerfaces, 2017, 155, 459-465.
[http://dx.doi.org/10.1016/j.colsurfb.2017.04.023] [PMID: 28472749]
[90]
Pandey, P.K.; Maheshwari, R.; Raval, N.; Gondaliya, P.; Kalia, K.; Tekade, R.K. Nanogold-core multifunctional dendrimer for pulsatile chemo-, photothermal- and photodynamic- therapy of rheumatoid arthritis. J. Colloid Interface Sci., 2019, 544, 61-77.
[http://dx.doi.org/10.1016/j.jcis.2019.02.073] [PMID: 30825801]
[91]
Sultana, F.; Neog, M.K.; Rasool, M. Targeted delivery of morin, a dietary bioflavanol encapsulated mannosylated liposomes to the macrophages of adjuvant-induced arthritis rats inhibits inflammatory immune response and osteoclastogenesis. Eur. J. Pharm. Biopharm., 2017, 115, 229-242.
[http://dx.doi.org/10.1016/j.ejpb.2017.03.009] [PMID: 28315446]
[92]
Poh, S.; Chelvam, V.; Kelderhouse, L.E.; Ayala-López, W.; Vaitilingam, B.; Putt, K.S.; Low, P.S. Folate-conjugated liposomes target and deliver therapeutics to immune cells in a rat model of rheumatoid arthritis. Nanomedicine, 2017, 12(20), 2441-2451.
[http://dx.doi.org/10.2217/nnm-2017-0166] [PMID: 28972462]
[93]
Zeb, A.; Qureshi, O.S.; Yu, C.H.; Akram, M.; Kim, H.S.; Kim, M.S.; Kang, J.H.; Majid, A.; Chang, S.Y.; Bae, O.N.; Kim, J.K. Enhanced anti-rheumatic activity of methotrexate-entrapped ultradeformable liposomal gel in adjuvant-induced arthritis rat model. Int. J. Pharm., 2017, 525(1), 92-100.
[http://dx.doi.org/10.1016/j.ijpharm.2017.04.032] [PMID: 28428089]
[94]
Neog, M.K.; Rasool, M. Targeted delivery of p-coumaric acid encapsulated mannosylated liposomes to the synovial macrophages inhibits osteoclast formation and bone resorption in the rheumatoid arthritis animal model. Eur. J. Pharm. Biopharm., 2018, 133, 162-175.
[http://dx.doi.org/10.1016/j.ejpb.2018.10.010] [PMID: 30339889]
[95]
Hu, L.; Luo, X.; Zhou, S.; Zhu, J.; Xiao, M.; Li, C.; Zheng, H.; Qiu, Q.; Lai, C.; Liu, X.; Deng, Y.; Song, Y. Neutrophil-mediated delivery of dexamethasone palmitate-loaded liposomes decorated with a sialic acid conjugate for rheumatoid arthritis treatment. Pharm. Res., 2019, 36(7), 97.
[http://dx.doi.org/10.1007/s11095-019-2609-4] [PMID: 31076925]
[96]
Cao, J.; Naeem, M.; Noh, J.K.; Lee, E.H.; Yoo, J.W. Dexamethasone phosphate-loaded folate-conjugated polymeric nanoparticles for selective delivery to activated macrophages and suppression of inflammatory responses. Macromol. Res., 2015, 23(5), 485-492.
[http://dx.doi.org/10.1007/s13233-015-3065-6]
[97]
Shi, Q.; Rondon-Cavanzo, E.P.; Dalla Picola, I.P.; Tiera, M.J.; Zhang, X.; Dai, K.; Benabdoune, H.A.; Benderdour, M.; Fernandes, J.C. In vivo therapeutic efficacy of TNFα silencing by folate-PEG-chitosan-DEAE/siRNA nanoparticles in arthritic mice. Int. J. Nanomed., 2018, 13, 387-402.
[http://dx.doi.org/10.2147/IJN.S146942] [PMID: 29391796]
[98]
Xu, X.L.; Li, W.S.; Wang, X.J.; Du, Y.L.; Kang, X.Q.; Hu, J.B.; Li, S.J.; Ying, X.Y.; You, J.; Du, Y.Z. Endogenous sialic acid-engineered micelles: A multifunctional platform for on-demand methotrexate delivery and bone repair of rheumatoid arthritis. Nanoscale, 2018, 10(6), 2923-2935.
[http://dx.doi.org/10.1039/C7NR08430G] [PMID: 29369319]
[99]
Li, P.; Yang, X.; Yang, Y.; He, H.; Chou, C.K.; Chen, F.; Pan, H.; Liu, L.; Cai, L.; Ma, Y.; Chen, X. Synergistic effect of all-trans-retinal and triptolide encapsulated in an inflammation-targeted nanoparticle on collagen-induced arthritis in mice. J. Control. Release, 2020, 319, 87-103.
[http://dx.doi.org/10.1016/j.jconrel.2019.12.025] [PMID: 31862360]
[100]
Shin, J.M.; Kim, S.H.; Thambi, T.; You, D.G.; Jeon, J.; Lee, J.O.; Chung, B.Y.; Jo, D.G.; Park, J.H. A hyaluronic acid–methotrexate conjugate for targeted therapy of rheumatoid arthritis. Chem. Commun., 2014, 50(57), 7632-7635.
[http://dx.doi.org/10.1039/c4cc02595d] [PMID: 24893961]
[101]
Gouveia, V.M.; Lopes-de-Araújo, J.; Costa Lima, S.A.; Nunes, C.; Reis, S. Hyaluronic acid-conjugated pH-sensitive liposomes for targeted delivery of prednisolone on rheumatoid arthritis therapy. Nanomedicine, 2018, 13(9), 1037-1049.
[http://dx.doi.org/10.2217/nnm-2017-0377] [PMID: 29790395]
[102]
Yang, M.; Ding, J.; Feng, X.; Chang, F.; Wang, Y.; Gao, Z.; Zhuang, X.; Chen, X. Scavenger receptor-mediated targeted treatment of collagen-induced arthritis by dextran sulfate-methotrexate prodrug. Theranostics, 2017, 7(1), 97-105.
[http://dx.doi.org/10.7150/thno.16844] [PMID: 28042319]
[103]
Xu, Y.; Mu, J.; Xu, Z.; Zhong, H.; Chen, Z.; Ni, Q.; Liang, X.J.; Guo, S. Modular acid-activatable acetone-based ketal-linked nanomedicine by dexamethasone prodrugs for enhanced anti-rheumatoid arthritis with low side effects. Nano Lett., 2020, 20(4), 2558-2568.
[http://dx.doi.org/10.1021/acs.nanolett.9b05340] [PMID: 32167768]
[104]
Chen, M. Su; Guissi; Xiao; Zong; Ping; Ping, Q. Folate receptor-targeting and reactive oxygen species-responsive liposomal formulation of methotrexate for treatment of rheumatoid arthritis. Pharmaceutics, 2019, 11(11), 582.
[http://dx.doi.org/10.3390/pharmaceutics11110582] [PMID: 31698794]
[105]
Friedrich, R.B.; Coradini, K.; Fonseca, F.N.; Guterres, S.S.; Beck, R.C.R.; Pohlmann, A.R. Lipid-core nanocapsules improved antiedematogenic activity of tacrolimus in adjuvant-induced arthritis model. J. Nanosci. Nanotechnol., 2016, 16(2), 1265-1274.
[http://dx.doi.org/10.1166/jnn.2016.11673] [PMID: 27433576]
[106]
Boechat, A.L.; de Oliveira, C.P.; Tarragô, A.M.; da Costa, A.G.; Malheiro, A.; Guterres, S.S.; Pohlmann, A.R. Methotrexate-loaded lipid-core nanocapsules are highly effective in the control of inflammation in synovial cells and a chronic arthritis model. Int. J. Nanomed., 2015, 10, 6603-6614.
[PMID: 26543364]
[107]
Coradini, K.; Friedrich, R.B.; Fonseca, F.N.; Vencato, M.S.; Andrade, D.F.; Oliveira, C.M.; Battistel, A.P.; Guterres, S.S.; da Rocha, M.I.U.M.; Pohlmann, A.R.; Beck, R.C.R. A novel approach to arthritis treatment based on resveratrol and curcumin co-encapsulated in lipid-core nanocapsules: in vivo studies. Eur. J. Pharm. Sci., 2015, 78, 163-170.
[http://dx.doi.org/10.1016/j.ejps.2015.07.012] [PMID: 26206297]
[108]
Rollett, A.; Reiter, T.; Nogueira, P.; Cardinale, M.; Loureiro, A.; Gomes, A.; Cavaco-Paulo, A.; Moreira, A.; Carmo, A.M.; Guebitz, G.M. Folic acid-functionalized human serum albumin nanocapsules for targeted drug delivery to chronically activated macrophages. Int. J. Pharm., 2012, 427(2), 460-466.
[http://dx.doi.org/10.1016/j.ijpharm.2012.02.028] [PMID: 22374516]
[109]
Mello, S.B.; Tavares, E.R.; Bulgarelli, A.; Bonfá, E.; Maranhão, R.C. Intra-articular methotrexate associated to lipid nanoemulsions: anti-inflammatory effect upon antigen-induced arthritis. Int. J. Nanomed., 2013, 8, 443-449.
[PMID: 23439784]
[110]
Hoscheid, J.; Outuki, P.M.; Kleinubing, S.A.; Silva, M.F.; Bruschi, M.L.; Cardoso, M.L.C. Development and characterization of Pterodon pubescens oil nanoemulsions as a possible delivery system for the treatment of rheumatoid arthritis. Colloids Surf. A Physicochem. Eng. Asp., 2015, 484, 19-27.
[http://dx.doi.org/10.1016/j.colsurfa.2015.07.040]
[111]
Pathan, I.; Mangle, M.; Bairagi, S. Design and characterization of nanoemulsion for transdermal delivery of meloxicam. Anal. Chem. Lett., 2016, 6(3), 286-295.
[http://dx.doi.org/10.1080/22297928.2016.1209126]
[112]
Hao, F.; Lee, R.J.; Zhong, L.; Dong, S.; Yang, C.; Teng, L.; Meng, Q.; Lu, J.; Xie, J.; Teng, L. Hybrid micelles containing methotrexate-conjugated polymer and co-loaded with microRNA-124 for rheumatoid arthritis therapy. Theranostics, 2019, 9(18), 5282-5297.
[http://dx.doi.org/10.7150/thno.32268] [PMID: 31410215]
[113]
Wang, Q.; Jiang, H.; Li, Y.; Chen, W.; Li, H.; Peng, K.; Zhang, Z.; Sun, X. Targeting NF-kB signaling with polymeric hybrid micelles that co-deliver siRNA and dexamethasone for arthritis therapy. Biomaterials, 2017, 122, 10-22.
[http://dx.doi.org/10.1016/j.biomaterials.2017.01.008] [PMID: 28107661]
[114]
Wang, X.; Feng, Y.; Fu, J.; Wu, C.; He, B.; Zhang, H.; Wang, X.; Dai, W.; Sun, Y.; Zhang, Q. A lipid micellar system loaded with dexamethasone palmitate alleviates rheumatoid arthritis. AAPS PharmSciTech, 2019, 20(8), 316.
[http://dx.doi.org/10.1208/s12249-019-1449-1] [PMID: 31602546]
[115]
Zhang, Q.; Dehaini, D.; Zhang, Y.; Zhou, J.; Chen, X.; Zhang, L.; Fang, R.H.; Gao, W.; Zhang, L. Neutrophil membrane-coated nanoparticles inhibit synovial inflammation and alleviate joint damage in inflammatory arthritis. Nat. Nanotechnol., 2018, 13(12), 1182-1190.
[http://dx.doi.org/10.1038/s41565-018-0254-4] [PMID: 30177807]
[116]
Ma, G.; Wu, C. Microneedle, bio-microneedle and bio-inspired microneedle: A review. J. Control. Release, 2017, 251, 11-23.
[http://dx.doi.org/10.1016/j.jconrel.2017.02.011] [PMID: 28215667]
[117]
Cho, W.K.; Ankrum, J.A.; Guo, D.; Chester, S.A.; Yang, S.Y.; Kashyap, A.; Campbell, G.A.; Wood, R.J.; Rijal, R.K.; Karnik, R.; Langer, R.; Karp, J.M. Microstructured barbs on the North American porcupine quill enable easy tissue penetration and difficult removal. Proc. Natl. Acad. Sci., 2012, 109(52), 21289-21294.
[http://dx.doi.org/10.1073/pnas.1216441109] [PMID: 23236138]
[118]
Alimardani, V.; Abolmaali, S.S.; Yousefi, G.; Rahiminezhad, Z.; Abedi, M.; Tamaddon, A.; Ahadian, S. Microneedle arrays combined with nanomedicine approaches for transdermal delivery of therapeutics. J. Clin. Med., 2021, 10(2), 181.
[http://dx.doi.org/10.3390/jcm10020181] [PMID: 33419118]
[119]
Tas, C.; Joyce, J.C.; Nguyen, H.X.; Eangoor, P.; Knaack, J.S.; Banga, A.K.; Prausnitz, M.R. Dihydroergotamine mesylate-loaded dissolving microneedle patch made of polyvinylpyrrolidone for management of acute migraine therapy. J. Control. Release, 2017, 268, 159-165.
[http://dx.doi.org/10.1016/j.jconrel.2017.10.021] [PMID: 29051065]
[120]
Jamaledin, R.; Di Natale, C.; Onesto, V.; Taraghdari, Z.; Zare, E.; Makvandi, P.; Vecchione, R.; Netti, P. Progress in microneedle-mediated protein delivery. J. Clin. Med., 2020, 9(2), 542.
[http://dx.doi.org/10.3390/jcm9020542] [PMID: 32079212]
[121]
Yang, J.; Liu, X.; Fu, Y.; Song, Y. Recent advances of microneedles for biomedical applications: Drug delivery and beyond. Acta Pharm. Sin. B, 2019, 9(3), 469-483.
[http://dx.doi.org/10.1016/j.apsb.2019.03.007] [PMID: 31193810]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version301msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[15:18:00] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[15:18:00] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • warninglog[15:18:00] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[15:18:00] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (94.87ms)time
  • Application (206ms)time
  • 1 x Application (68.48%)
    206ms
    1 x Booting (31.52%)
    94.87ms
    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 duplicated116ms
    • 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 ('59772390','',1,1740496680,1740496680) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740496680
      1.24msalphaeurekaselec_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 ('59772390','/article/134485',1,1740496680,1740496680)
      160μsalphaeurekaselec_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 >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) 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 >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) 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 >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) 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 >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) 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 >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) 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 >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 59772390 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59772390) limit 1
      11.71msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 59772390
      • 1: 59772390
      • 2: 59772390
      • 3: 59772390
      • 4: 59772390
      • 5: 59772390
      • 6: 59772390
      • 7: 59772390
      • 8: 59772390
      • 9: 59772390
      • 10: 59772390
      • 11: 59772390
      • 12: 59772390
      • 13: 59772390
      • 14: 59772390
      • 15: 59772390
      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=134485
      780μsalphaeurekaselec_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` = 56 limit 1
      820μsalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 56
      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=56) and sj.journal_id!=56 group by `j`.`nid`) as `aggregate_table`
      1.1msalphaeurekaselec_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=56) and sj.journal_id!=56 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      900μsalphaeurekaselec_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=56) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      1.33msalphaeurekaselec_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=56) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      1.22msalphaeurekaselec_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` = '134485'
      800μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 134485
      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` = '134485'
      6.47msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 134485
      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` = '134485' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      3.92msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 134485
      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
      210μsalphaeurekaselec_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
      440μsalphaeurekaselec_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 = 56 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      39.91msalphaeurekaselec_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 = 56 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      10.44msalphaeurekaselec_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 = 56 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      10.33msalphaeurekaselec_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` = 134485 limit 1
      300μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 134485
      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 = 134485 and content_type = 'article' order by status desc limit 1
      410μsalphaeurekaselec_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` = 221005 limit 1
      360μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 221005
      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
      280μsalphaeurekaselec_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` = 'MRMC' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      390μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: MRMC
      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 = '134485' 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) )
      500μsalphaeurekaselec_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 = '12970' 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) )
      380μsalphaeurekaselec_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 = '3467' 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) )
      370μsalphaeurekaselec_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 <= 59772390 and j.to_ip >=59772390 )) and ((j.from_date <= 1740496680 and j.to_date >= 1740496680 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3467) 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 <= 59772390 and j.to_ip >=59772390 )) and ((j.from_date <= 1740496680 and j.to_date >= 1740496680 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3467) 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 <= 59772390 and j.to_ip >=59772390 )) and ((j.from_date <= 1740496680 and j.to_date >= 1740496680 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3467)
      9.54msalphaeurekaselec_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 <= 59772390 and j.to_ip >=59772390 )) and ((j.from_date <= 1740496680 and j.to_date >= 1740496680 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 12970) 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 <= 59772390 and j.to_ip >=59772390 )) and ((j.from_date <= 1740496680 and j.to_date >= 1740496680 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 12970) 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 <= 59772390 and j.to_ip >=59772390 )) and ((j.from_date <= 1740496680 and j.to_date >= 1740496680 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 12970)
      1.05msalphaeurekaselec_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 <= 59772390 and j.to_ip >=59772390 )) and ((j.from_date <= 1740496680 and j.to_date >= 1740496680 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 134485) 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 <= 59772390 and j.to_ip >=59772390 )) and ((j.from_date <= 1740496680 and j.to_date >= 1740496680 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 134485) 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 <= 59772390 and j.to_ip >=59772390 )) and ((j.from_date <= 1740496680 and j.to_date >= 1740496680 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 134485)
      910μsalphaeurekaselec_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` < '704' and is_uploaded = 1 and issue_id = 12970 order by cast(first_page as SIGNED) desc limit 1
      750μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 704
      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` > '720' and is_uploaded = 1 and issue_id = 12970 order by cast(first_page as SIGNED) asc limit 1
      670μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 720
      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'
      260μsalphaeurekaselec_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
      300μsalphaeurekaselec_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` = 134485 limit 1
      3.88msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 134485
      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` = 56 and `b`.`banner_from_date` <= 1740496680 and `b`.`banner_to_date` >= 1740496680 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      2.13msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 56
      • 3: 1740496680
      • 4: 1740496680
      • 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` = 56 and `b`.`banner_from_date` <= 1740496680 and `b`.`banner_to_date` >= 1740496680 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.56msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 56
      • 3: 1740496680
      • 4: 1740496680
      • 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='b153626699e39315e7fd0a4337d1f2d9'
      270μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
        _token
        zchu4QVxxOdH2yQMio5p5n0pwF0uUtr71u88oluw
        uc_cart_id
        b153626699e39315e7fd0a4337d1f2d9
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/134485" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/134485
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:9 [ "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6InF6clM1aWIyNldnNmtRRWF6YjdXbWc9PSIsInZhbHVlIjoibVZHMThQQUlWRHlDNEt4YW56OHVUTGFpZ1dxOUtNTnRrbEFZaFhPK0IwND0iLCJtYWMiOiJiMDYwNjg1MWQ4NDZiMjc5ZjUyZGVmMjIxMTkyMTFmNjkwNmYxYmRhYzZhODc0ODg2NWViMGJkMmM1Njk2MjhhIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6InF6clM1aWIyNldnNmtRRWF6YjdXbWc9PSIsInZhbHVlIjoibVZHMThQQUlWRHlDNEt4YW56OHVUTGFpZ1dxOUtNTnRrbEFZaFhPK0IwND0iLCJtYWMiOiJiMDYwNjg1MWQ4NDZi" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 15:18:00 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImpUUU1kUmx6aCthZUd4U003SlF2b3c9PSIsInZhbHVlIjoicTBLa3BiYjRFY2oyMk9qZWJ2VS94RU43bWc5WlZRR3lqU2FTWEJBdDRXTDJSU2MwVXI2L2VlM0xjWDExSzdoRFVIWURqYm5FdDZ0V0l1S3Y2eGlyQk1CaFFlRGh0OWxlc2xoMWZpaWJwZk5iUnNiTnRyY3B6VHN0VjFQbmUyQ1oiLCJtYWMiOiIxNzhjMWEwYmE3OTVmYjAxOTlmNWJiMjk0NjIxMjEzMzc2NjZlMzA4ZjMxYmU5YzI2MjE1Yzc4Nzk4N2M0ZmVjIiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 03:18:00 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6ImpUUU1kUmx6aCthZUd4U003SlF2b3c9PSIsInZhbHVlIjoicTBLa3BiYjRFY2oyMk9qZWJ2VS94RU43bWc5WlZRR3lqU2FTWEJBdDRXTDJSU2MwVXI2L2VlM0xjWDExSzdoRFVIWURqY" 1 => "alphaeurekaselectnet_session=eyJpdiI6ImhHaWNjZkk3OFg5Rnd6N2VTeVJFTmc9PSIsInZhbHVlIjoiOU5oNTk2QmFxQy9CcHlGdHdOdmdQdkphNm5rQnA3TDVYZTVJUTdlVWxXakh6eXpac1h1aDRndkJzaktxT3pwNE51WFZQN01TamlDc05KZXhYcmNJKzBIMVBvb3JpWXNjS2JQK0s4Q3VUV2xCV0ZYOTVSQWNPd1p6Y1B4UjNOZ0MiLCJtYWMiOiI3ZDE3MzhlOGQyY2RjYzRjZDNmMDUxODUwZWViZTIzNDEwYjhmNjBhOWExNTkyMDM3YmFjNWFmNzNmZmY0NmFkIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6ImhHaWNjZkk3OFg5Rnd6N2VTeVJFTmc9PSIsInZhbHVlIjoiOU5oNTk2QmFxQy9CcHlGdHdOdmdQdkphNm5rQnA3TDVYZTVJUTdlVWxXakh6eXpac1h1aDRndkJ" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImpUUU1kUmx6aCthZUd4U003SlF2b3c9PSIsInZhbHVlIjoicTBLa3BiYjRFY2oyMk9qZWJ2VS94RU43bWc5WlZRR3lqU2FTWEJBdDRXTDJSU2MwVXI2L2VlM0xjWDExSzdoRFVIWURqYm5FdDZ0V0l1S3Y2eGlyQk1CaFFlRGh0OWxlc2xoMWZpaWJwZk5iUnNiTnRyY3B6VHN0VjFQbmUyQ1oiLCJtYWMiOiIxNzhjMWEwYmE3OTVmYjAxOTlmNWJiMjk0NjIxMjEzMzc2NjZlMzA4ZjMxYmU5YzI2MjE1Yzc4Nzk4N2M0ZmVjIiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 03:18:00 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6ImpUUU1kUmx6aCthZUd4U003SlF2b3c9PSIsInZhbHVlIjoicTBLa3BiYjRFY2oyMk9qZWJ2VS94RU43bWc5WlZRR3lqU2FTWEJBdDRXTDJSU2MwVXI2L2VlM0xjWDExSzdoRFVIWURqY" 1 => "alphaeurekaselectnet_session=eyJpdiI6ImhHaWNjZkk3OFg5Rnd6N2VTeVJFTmc9PSIsInZhbHVlIjoiOU5oNTk2QmFxQy9CcHlGdHdOdmdQdkphNm5rQnA3TDVYZTVJUTdlVWxXakh6eXpac1h1aDRndkJzaktxT3pwNE51WFZQN01TamlDc05KZXhYcmNJKzBIMVBvb3JpWXNjS2JQK0s4Q3VUV2xCV0ZYOTVSQWNPd1p6Y1B4UjNOZ0MiLCJtYWMiOiI3ZDE3MzhlOGQyY2RjYzRjZDNmMDUxODUwZWViZTIzNDEwYjhmNjBhOWExNTkyMDM3YmFjNWFmNzNmZmY0NmFkIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6ImhHaWNjZkk3OFg5Rnd6N2VTeVJFTmc9PSIsInZhbHVlIjoiOU5oNTk2QmFxQy9CcHlGdHdOdmdQdkphNm5rQnA3TDVYZTVJUTdlVWxXakh6eXpac1h1aDRndkJ" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "zchu4QVxxOdH2yQMio5p5n0pwF0uUtr71u88oluw" "uc_cart_id" => "b153626699e39315e7fd0a4337d1f2d9" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/134485" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 15:18:00GET/article/134485414361