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Current Neuropharmacology

Editor-in-Chief

ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

General Review Article

Relevance of CYP2C9 Function in Valproate Therapy

Author(s): Katalin Monostory*, Andrea Nagy, Katalin Tóth, Tamás Bűdi , Ádám Kiss, Máté Déri and Gábor Csukly

Volume 17, Issue 1, 2019

Page: [99 - 106] Pages: 8

DOI: 10.2174/1570159X15666171109143654

open access plus

Abstract

Background: Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity; however, inferring a patient’s drug metabolizing capacity merely from his or her genotype can lead to false prediction. Non-genetic host factors (age, sex, disease states) and environmental factors (nutrition, comedication) can transiently alter the enzyme expression and activities resulting in genotypephenotype mismatch. Although valproic acid is a well-tolerated anticonvulsant, pediatric patients are particularly vulnerable to valproate injury that can be partly attributed to the age-related differences in metabolic pathways.

Methods: CYP2C9 mediated oxidation of valproate, which is the minor metabolic pathway in adults, appears to become the principal route in children. Genetic and non-genetic variations in CYP2C9 activity can result in significant inter- and intra-individual differences in valproate pharmacokinetics and valproate induced adverse reactions.

Results: The loss-of-function alleles, CYP2C9*2 or CYP2C9*3, display significant reduction in valproate metabolism in children; furthermore, low CYP2C9 expression in patients with CYP2C9*1/*1 genotype also leads to a decrease in valproate metabolizing capacity. Due to phenoconversion, the homozygous wild genotype, expected to be translated to CYP2C9 enzyme with normal activity, is transiently switched into poor (or extensive) metabolizer phenotype.

Conclusion: Novel strategy for valproate therapy adjusted to CYP2C9-status (CYP2C9 genotype and CYP2C9 expression) is strongly recommended in childhood. The early knowledge of pediatric patients’ CYP2C9-status facilitates the optimization of valproate dosing which contributes to the avoidance of misdosing induced adverse reactions, such as abnormal blood levels of ammonia and alkaline phosphatase, and improves the safety of children’s anticonvulsant therapy.

Keywords: Valproic acid, epilepsy, psychiatric disorders, CYP2C9 genotype, CYP2C9 expression, personalized medication, pediatric patients.

Graphical Abstract

[1]
Shah, R.R.; Smith, R.L. Addressing phenoconversion: the Achilles’ heel of personalized medicine. Br. J. Clin. Pharmacol., 2015, 79(2), 222-240. [http://dx.doi.org/10.1111/bcp.12441]. [PMID: 24913012].
[2]
Squassina, A.; Manchia, M.; Manolopoulos, V.G.; Artac, M.; Lappa-Manakou, C.; Karkabouna, S.; Mitropoulos, K.; Del Zompo, M.; Patrinos, G.P. Realities and expectations of pharmacogenomics and personalized medicine: impact of translating genetic knowledge into clinical practice. Pharmacogenomics, 2010, 11(8), 1149-1167. [http://dx.doi.org/10.2217/pgs.10.97]. [PMID: 20712531].
[3]
Gervasini, G.; Benítez, J.; Carrillo, J.A. Pharmacogenetic testing and therapeutic drug monitoring are complementary tools for optimal individualization of drug therapy. Eur. J. Clin. Pharmacol., 2010, 66(8), 755-774. [http://dx.doi.org/10.1007/s00228-010-0857-7]. [PMID: 20582584].
[4]
Shah, R.R.; Shah, D.R. Personalized medicine: is it a pharmacogenetic mirage? Br. J. Clin. Pharmacol., 2012, 74(4), 698-721. [http://dx.doi.org/10.1111/j.1365-2125.2012.04328.x]. [PMID: 22591598].
[5]
Sim, S.C.; Kacevska, M.; Ingelman-Sundberg, M. Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects. Pharmacogenomics J., 2013, 13(1), 1-11. [http://dx.doi.org/10.1038/tpj.2012.45]. [PMID: 23089672].
[6]
Lipscomb, J.C.; Poet, T.S. In vitro measurements of metabolism for application in pharmacokinetic modeling. Pharmacol. Ther., 2008, 118(1), 82-103. [http://dx.doi.org/10.1016/j.pharmthera.2008.01. 006]. [PMID: 18374419].
[7]
Wilk-Zasadna, I.; Bernasconi, C.; Pelkonen, O.; Coecke, S. Biotransformation in vitro: An essential consideration in the quantitative in vitro-to-in vivo extrapolation (QIVIVE) of toxicity data. Toxicology, 2015, 332, 8-19. [http://dx.doi.org/10.1016/j.tox. 2014.10.006]. [PMID: 25456264].
[8]
Tóth, K.; Sirok, D.; Kiss, Á.; Mayer, A.; Pátfalusi, M.; Hirka, G.; Monostory, K. Utility of in vitro pharmacokinetic data in prediction of in vivo hepatic clearance of psychopharmacons. Microchem. J., 2018, 136, 193-199. [http://dx.doi.org/10.1016/j.microc.2016.10.028].
[9]
Cederbaum, A.I. Molecular mechanisms of the microsomal mixed function oxidases and biological and pathological implications. Redox Biol., 2015, 4, 60-73. [http://dx.doi.org/10.1016/j.redox. 2014.11.008]. [PMID: 25498968].
[10]
Lewis, D.F. 57 varieties: the human cytochromes P450. Pharmacogenomics, 2004, 5(3), 305-318. [http://dx.doi.org/10.1517/phgs. 5.3.305.29827]. [PMID: 15102545].
[11]
Zanger, U.M.; Turpeinen, M.; Klein, K.; Schwab, M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal. Bioanal. Chem., 2008, 392(6), 1093-1108. [http://dx.doi.org/10.1007/s00216-008-2291-6]. [PMID: 18695978].
[12]
Guengerich, F.P. Human Cytochrome P450 Enzymes Cytochrome P450, Structure, Mechanism, and Biochemistry; P.R, F.P., Ed.; Springer: Dordrecht, 2015, pp. 523-785. [http://dx.doi.org/10.1007/ 978-3-319-12108-6_9]
[13]
Zhou, S.F.; Liu, J.P.; Chowbay, B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab. Rev., 2009, 41(2), 89-295. [http://dx.doi.org/10.1080/03602530902843483]. [PMID: 19514967].
[14]
Temesvári, M.; Kóbori, L.; Paulik, J.; Sárváry, E.; Belic, A.; Monostory, K. Estimation of drug-metabolizing capacity by cytochrome P450 genotyping and expression. J. Pharmacol. Exp. Ther., 2012, 341(1), 294-305. [http://dx.doi.org/10.1124/jpet.111.189597]. [PMID: 22262920].
[15]
Zanger, U.M.; Schwab, M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther., 2013, 138(1), 103-141. [http://dx.doi.org/10.1016/j.pharmthera.2012.12.007]. [PMID: 23333322].
[16]
Samer, C.F.; Lorenzini, K.I.; Rollason, V.; Daali, Y.; Desmeules, J.A. Applications of CYP450 testing in the clinical setting. Mol. Diagn. Ther., 2013, 17(3), 165-184. [http://dx.doi.org/10.1007/ s40291-013-0028-5]. [PMID: 23588782].
[17]
Rendic, S.; Guengerich, F.P. Update information on drug metabolism systems--2009, part II: summary of information on the effects of diseases and environmental factors on human cytochrome P450 (CYP) enzymes and transporters. Curr. Drug Metab., 2010, 11(1), 4-84. [http://dx.doi.org/10.2174/138920010791110917]. [PMID: 20302566].
[18]
Löscher, W. Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs, 2002, 16(10), 669-694. [http://dx.doi.org/10.2165/00023210-200216100-00003]. [PMID: 12269861].
[19]
Peterson, G.M.; Naunton, M. Valproate: a simple chemical with so much to offer. J. Clin. Pharm. Ther., 2005, 30(5), 417-421. [http:// dx.doi.org/10.1111/j.1365-2710.2005.00671.x]. [PMID: 16164485].
[20]
Chiu, C.T.; Wang, Z.; Hunsberger, J.G.; Chuang, D.M. Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder. Pharmacol. Rev., 2013, 65(1), 105-142. [http://dx. doi.org/10.1124/pr.111.005512]. [PMID: 23300133].
[21]
Tseng, P.T.; Chen, Y.W.; Chung, W.; Tu, K.Y.; Wang, H.Y.; Wu, C.K.; Lin, P.Y. Significant effect of valproate augmentation therapy in patients with schizophrenia: A meta-analysis study. Medicine (Baltimore), 2016, 95(4), e2475. [http://dx.doi.org/10.1097/ MD.0000000000002475]. [PMID: 26825886].
[22]
Sztajnkrycer, M.D. Valproic acid toxicity: overview and management. J. Toxicol. Clin. Toxicol., 2002, 40(6), 789-801. [http://dx. doi.org/10.1081/CLT-120014645]. [PMID: 12475192].
[23]
Perucca, E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs, 2002, 16(10), 695-714. [http://dx.doi.org/10.2165/00023210-200216100-00004]. [PMID: 12269862].
[24]
Chateauvieux, S.; Morceau, F.; Dicato, M.; Diederich, M. Molecular and therapeutic potential and toxicity of valproic acid. J. Biomed. Biotechnol., 2010, 2010, 479364. [http://dx.doi.org/10.1155/ 2010/479364]. [PMID: 20798865].
[25]
Nanau, R.M.; Neuman, M.G. Adverse drug reactions induced by valproic acid. Clin. Biochem., 2013, 46(15), 1323-1338. [http://dx. doi.org/10.1016/j.clinbiochem.2013.06.012]. [PMID: 23792104].
[26]
König, S.A.; Siemes, H.; Bläker, F.; Boenigk, E.; Gross-Selbeck, G.; Hanefeld, F.; Haas, N.; Köhler, B.; Koelfen, W.; Korinthenberg, R.; Kurek, E.; Lenard, H-G.; Penin, H.; Penzien, J.M.; Schünke, W.; Schultze, C.; Stephani, U.; Stute, M.; Traus, M.; Weinmann, H-M.; Scheffner, W. Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities. Epilepsia, 1994, 35(5), 1005-1015. [http://dx.doi.org/10.1111/j.1528-1157.1994.tb02546.x]. [PMID: 7925143].
[27]
Guerrini, R. Valproate as a mainstay of therapy for pediatric epilepsy. Paediatr. Drugs, 2006, 8(2), 113-129. [http://dx.doi.org/10. 2165/00148581-200608020-00004]. [PMID: 16608372].
[28]
Kochen, W.; Schneider, A.; Ritz, A. Abnormal metabolism of valproic acid in fatal hepatic failure. Eur. J. Pediatr., 1983, 141(1), 30-35. [http://dx.doi.org/10.1007/BF00445664]. [PMID: 6416845].
[29]
Fisher, E.; Siemes, H.; Pund, R.; Wittfoht, W.; Nau, H. Valproate metabolites in serum and urine during antiepileptic therapy in children with infantile spasms: abnormal metabolite pattern associated with reversible hepatotoxicity. Epilepsia, 1992, 33(1), 165-171. [http://dx.doi.org/10.1111/j.1528-1157.1992.tb02301.x]. [PMID: 1733752].
[30]
Siemes, H.; Nau, H.; Schultze, K.; Wittfoht, W.; Drews, E.; Penzien, J.; Seidel, U. Valproate (VPA) metabolites in various clinical conditions of probable VPA-associated hepatotoxicity. Epilepsia, 1993, 34(2), 332-346. [http://dx.doi.org/10.1111/j.1528-1157.1993. tb02419.x]. [PMID: 8453944].
[31]
Silva, M.F.; Aires, C.C.; Luis, P.B.; Ruiter, J.P.; IJlst, L.; Duran, M.; Wanders, R.J.; Tavares de Almeida, I. Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review. J. Inherit. Metab. Dis., 2008, 31(2), 205-216. [http://dx.doi.org/10. 1007/s10545-008-0841-x]. [PMID: 18392741].
[32]
Abbott, F.S.; Anari, M.R. Chemistry and Biotransformation. Milestones in Drug Therapy: Valproate; Löscher, W. , Ed.; Birkhauser Verlag:; Basel, 1999, pp. 47-75.
[33]
Sadeque, A.J.; Fisher, M.B.; Korzekwa, K.R.; Gonzalez, F.J.; Rettie, A.E. Human CYP2C9 and CYP2A6 mediate formation of the hepatotoxin 4-ene-valproic acid. J. Pharmacol. Exp. Ther., 1997, 283(2), 698-703. [PMID: 9353388].
[34]
Kiang, T.K.; Ho, P.C.; Anari, M.R.; Tong, V.; Abbott, F.S.; Chang, T.K. Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1/*1 genotype. Toxicol. Sci., 2006, 94(2), 261-271. [http://dx.doi.org/10.1093/toxsci/kfl096]. [PMID: 16945988].
[35]
Strassburg, C.P.; Strassburg, A.; Kneip, S.; Barut, A.; Tukey, R.H.; Rodeck, B.; Manns, M.P. Developmental aspects of human hepatic drug glucuronidation in young children and adults. Gut, 2002, 50(2), 259-265. [http://dx.doi.org/10.1136/gut.50.2.259]. [PMID: 11788570].
[36]
Ginsberg, G.; Hattis, D.; Sonawane, B.; Russ, A.; Banati, P.; Kozlak, M.; Smolenski, S.; Goble, R. Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature. Toxicol. Sci., 2002, 66(2), 185-200. [http://dx.doi.org/10.1093/toxsci/66.2.185]. [PMID: 11896285].
[37]
Reith, D.M.; Andrews, J.; Parker-Scott, S.; Eadie, M.J. Urinary excretion of valproate metabolites in children and adolescents. Biopharm. Drug Dispos., 2000, 21(8), 327-330. [http://dx.doi.org/10. 1002/bdd.247]. [PMID: 11514952].
[38]
Ponchaut, S.; van Hoof, F.; Veitch, K. In vitro effects of valproate and valproate metabolites on mitochondrial oxidations. Relevance of CoA sequestration to the observed inhibitions. Biochem. Pharmacol., 1992, 43(11), 2435-2442. [http://dx.doi.org/10.1016/0006-2952(92)90324-C]. [PMID: 1610408].
[39]
Stewart, C.F.; Hampton, E.M. Effect of maturation on drug disposition in pediatric patients. Clin. Pharm., 1987, 6(7), 548-564. [PMID: 3319364].
[40]
Zhou, S.F.; Zhou, Z.W.; Huang, M. Polymorphisms of human cytochrome P450 2C9 and the functional relevance. Toxicology, 2010, 278(2), 165-188. [http://dx.doi.org/10.1016/j.tox.2009.08.013]. [PMID: 19715737].
[41]
Kurose, K.; Sugiyama, E.; Saito, Y. Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. Drug Metab. Pharmacokinet., 2012, 27(1), 9-54. [http://dx.doi.org/10.2133/dmpk.DMPK-11-RV-111]. [PMID: 22123129].
[42]
Hirota, T.; Eguchi, S.; Ieiri, I. Impact of genetic polymorphisms in CYP2C9 and CYP2C19 on the pharmacokinetics of clinically used drugs. Drug Metab. Pharmacokinet., 2013, 28(1), 28-37. [http:// dx.doi.org/10.2133/dmpk.DMPK-12-RV-085]. [PMID: 23165865].
[43]
Gotoh, O. Substrate recognition sites in cytochrome P450 family 2 (CYP2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences. J. Biol. Chem., 1992, 267(1), 83-90. [PMID: 1730627].
[44]
Crespi, C.L.; Miller, V.P. The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH: cytochrome P450 oxidoreductase. Pharmacogenetics, 1997, 7(3), 203-210. [http://dx.doi.org/10.1097/00008571-199706000-00005]. [PMID: 9241660].
[45]
Wei, L.; Locuson, C.W.; Tracy, T.S. Polymorphic variants of CYP2C9: mechanisms involved in reduced catalytic activity. Mol. Pharmacol., 2007, 72(5), 1280-1288. [http://dx.doi.org/10.1124/ mol.107.036178]. [PMID: 17686967].
[46]
Ho, P.C.; Abbott, F.S.; Zanger, U.M.; Chang, T.K. Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes. Pharmacogenomics J., 2003, 3(6), 335-342. [http://dx.doi.org/10.1038/sj.tpj.6500210]. [PMID: 14597963].
[47]
Tan, L.; Yu, J.T.; Sun, Y.P.; Ou, J.R.; Song, J.H.; Yu, Y. The influence of cytochrome oxidase CYP2A6, CYP2B6, and CYP2C9 polymorphisms on the plasma concentrations of valproic acid in epileptic patients. Clin. Neurol. Neurosurg., 2010, 112(4), 320-323. [http:// dx.doi.org/10.1016/j.clineuro.2010.01.002]. [PMID: 20089352].
[48]
Tóth, K.; Bűdi, T.; Kiss, Á.; Temesvári, M.; Háfra, E.; Nagy, A.; Szever, Z.; Monostory, K. Phenoconversion of CYP2C9 in epilepsy limits the predictive value of CYP2C9 genotype in optimizing valproate therapy. Per. Med., 2015, 12(3), 199-207. [http://dx.doi. org/10.2217/pme.14.82]. [PMID: 29771647].
[49]
Tanaka, E. Clinically significant pharmacokinetic drug interactions between antiepileptic drugs. J. Clin. Pharm. Ther., 1999, 24(2), 87-92. [http://dx.doi.org/10.1046/j.1365-2710.1999.00201.x]. [PMID: 10380060].
[50]
Amini-Shirazi, N.; Ghahremani, M.H.; Ahmadkhaniha, R.; Mandegary, A.; Dadgar, A.; Abdollahi, M.; Shadnia, S.; Pakdaman, H.; Kebriaeezadeh, A. Influence of CYP2C9 polymorphism on metabolism of valproate and its hepatotoxin metabolite in Iranian patients. Toxicol. Mech. Methods, 2010, 20(8), 452-457. [http://dx. doi.org/10.3109/15376516.2010.497977]. [PMID: 20602621].
[51]
Levy, R.H.; Rettenmeier, A.W.; Anderson, G.D.; Wilensky, A.J.; Friel, P.N.; Baillie, T.A.; Acheampong, A.; Tor, J.; Guyot, M.; Loiseau, P. Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4-ene-valproate, a hepatotoxic metabolite of valproic acid. Clin. Pharmacol. Ther., 1990, 48(3), 225-235. [http://dx.doi.org/10.1038/clpt.1990.144]. [PMID: 2119269].
[52]
Star, K.; Edwards, I.R.; Choonara, I. Valproic acid and fatalities in children: a review of individual case safety reports in VigiBase. PLoS One, 2014, 9(10), e108970. [http://dx.doi.org/10.1371/ journal.pone.0108970]. [PMID: 25302991].
[53]
Yu, N.; Di, Q.; Hu, Y.; Zhang, Y.F.; Su, L.Y.; Liu, X.H.; Li, L.C. A meta-analysis of pro-inflammatory cytokines in the plasma of epileptic patients with recent seizure. Neurosci. Lett., 2012, 514(1), 110-115. [http://dx.doi.org/10.1016/j.neulet.2012.02.070]. [PMID: 22402188].
[54]
Uludag, I.F.; Bilgin, S.; Zorlu, Y.; Tuna, G.; Kirkali, G. Interleukin-6, interleukin-1 beta and interleukin-1 receptor antagonist levels in epileptic seizures. Seizure, 2013, 22(6), 457-461. [http://dx.doi. org/10.1016/j.seizure.2013.03.004]. [PMID: 23566695].
[55]
Aitken, A.E.; Morgan, E.T. Gene-specific effects of inflammatory cytokines on cytochrome P450 2C, 2B6 and 3A4 mRNA levels in human hepatocytes. Drug Metab. Dispos., 2007, 35(9), 1687-1693. [http://dx.doi.org/10.1124/dmd.107.015511]. [PMID: 17576808].
[56]
Pascussi, J.M.; Gerbal-Chaloin, S.; Pichard-Garcia, L.; Daujat, M.; Fabre, J.M.; Maurel, P.; Vilarem, M.J. Interleukin-6 negatively regulates the expression of pregnane X receptor and constitutively activated receptor in primary human hepatocytes. Biochem. Biophys. Res. Commun., 2000, 274(3), 707-713. [http://dx.doi.org/10. 1006/bbrc.2000.3219]. [PMID: 10924340].
[57]
Pascussi, J.M.; Dvorák, Z.; Gerbal-Chaloin, S.; Assenat, E.; Maurel, P.; Vilarem, M.J. Pathophysiological factors affecting CAR gene expression. Drug Metab. Rev., 2003, 35(4), 255-268. [http:// dx.doi.org/10.1081/DMR-120026394]. [PMID: 14705859].
[58]
Monostory, K.; Pascussi, J.M. Regulation of drug-metabolizing human cytochrome P450s. Acta Chim. Slov., 2008, 55, 20-37.
[59]
Pascussi, J.M.; Gerbal-Chaloin, S.; Duret, C.; Daujat-Chavanieu, M.; Vilarem, M.J.; Maurel, P. The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences. Annu. Rev. Pharmacol. Toxicol., 2008, 48, 1-32. [http:// dx.doi.org/10.1146/annurev.pharmtox.47.120505.105349]. [PMID: 17608617].
[60]
Kobayashi, K.; Hashimoto, M.; Honkakoski, P.; Negishi, M. Regulation of gene expression by CAR: an update. Arch. Toxicol., 2015, 89(7), 1045-1055. [http://dx.doi.org/10.1007/s00204-015-1522-9]. [PMID: 25975989].
[61]
Prakash, C.; Zuniga, B.; Song, C.S.; Jiang, S.; Cropper, J.; Park, S.; Chatterjee, B. Nuclear Receptors in drug metabolism, drug response and drug interactions. Nucl. Receptor Res., 2015, 2, 101178. [http://dx.doi.org/10.11131/2015/101178]. [PMID: 27478824].
[62]
Anderson, G.D. Children versus adults: pharmacokinetic and adverse-effect differences. Epilepsia, 2002, 43(Suppl. 3), 53-59. [http:// dx.doi.org/10.1046/j.1528-1157.43.s.3.5.x]. [PMID: 12060006].
[63]
Nagy, A.; Bűdi, T.; Temesvári, M.; Szever, Z.; Szabó, P.T.; Monostory, K. Adverse events in a newborn on valproate therapy due to loss-of-function mutations in CYP2C9. Epilepsy Behav. Case Rep., 2015, 4, 86-87. [http://dx.doi.org/10.1016/j.ebcr.2015. 08.006]. [PMID: 26543813].
[64]
Dreifuss, F.E.; Langer, D.H. Hepatic considerations in the use of antiepileptic drugs. Epilepsia, 1987, 28(Suppl. 2), S23-S29. [http:// dx.doi.org/10.1111/j.1528-1157.1987.tb05768.x]. [PMID: 3121292].
[65]
Scheffner, D.; König, S.; Rauterberg-Ruland, I.; Kochen, W.; Hofmann, W.J.; Unkelbach, S. Fatal liver failure in 16 children with valproate therapy. Epilepsia, 1988, 29(5), 530-542. [http://dx. doi.org/10.1111/j.1528-1157.1988.tb03757.x]. [PMID: 3137017].
[66]
Bűdi, T.; Tóth, K.; Nagy, A.; Szever, Z.; Kiss, Á.; Temesvári, M.; Háfra, E.; Garami, M.; Tapodi, A.; Monostory, K. Clinical significance of CYP2C9-status guided valproic acid therapy in children. Epilepsia, 2015, 56(6), 849-855. [http://dx.doi.org/10.1111/epi. 13011]. [PMID: 25967074].
[67]
Yamamoto, Y.; Takahashi, Y.; Suzuki, E.; Mishima, N.; Inoue, K.; Itoh, K.; Kagawa, Y.; Inoue, Y. Risk factors for hyperammonemia associated with valproic acid therapy in adult epilepsy patients. Epilepsy Res., 2012, 101(3), 202-209. [http://dx.doi.org/10.1016/ j.eplepsyres.2012.04.001]. [PMID: 22542569].
[68]
Yamamoto, Y.; Takahashi, Y.; Imai, K.; Mishima, N.; Yazawa, R.; Inoue, K.; Itoh, K.; Kagawa, Y.; Inoue, Y. Risk factors for hyperammonemia in pediatric patients with epilepsy. Epilepsia, 2013, 54(6), 983-989. [http://dx.doi.org/10.1111/epi.12125]. [PMID: 23409971].
[69]
Tseng, Y.L.; Huang, C.R.; Lin, C.H.; Lu, Y.T.; Lu, C.H.; Chen, N.C.; Chang, C.C.; Chang, W.N.; Chuang, Y.C. Risk factors of hyperammonemia in patients with epilepsy under valproic acid therapy. Medicine (Baltimore), 2014, 93(11), e66. [http://dx.doi. org/10.1097/MD.0000000000000066]. [PMID: 25192484].
[70]
Monostory, K.; Bűdi, T.; Tóth, K.; Nagy, A.; Szever, Z.; Kiss, Á.; Temesvári, M.; Háfra, E.; Tapodi, A.; Garami, M. In response: Commentary on clinical significance of CYP2C9-status-guided valproic acid therapy in children. Epilepsia, 2016, 57(8), 1339-1340. [http://dx.doi.org/10.1111/epi.13451]. [PMID: 27485380].

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    • 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
    32 statements were executed, 4 of which were duplicates, 28 unique. Show only duplicated575ms
    • 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 ('221924030','',1,1739959681,1739959681) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1739959681
      20.18msalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 11. middleware::check_user_access:24
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address_detail (ip_address,visitor_url,visitor_count, created_on,updated_on) VALUES ('221924030','/article/86796',1,1739959681,1739959681)
      260μsalphaeurekaselec_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 >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) 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 >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) 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 >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) 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 >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) 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 >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) 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 >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 221924030 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221924030) limit 1
      59.25msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 221924030
      • 1: 221924030
      • 2: 221924030
      • 3: 221924030
      • 4: 221924030
      • 5: 221924030
      • 6: 221924030
      • 7: 221924030
      • 8: 221924030
      • 9: 221924030
      • 10: 221924030
      • 11: 221924030
      • 12: 221924030
      • 13: 221924030
      • 14: 221924030
      • 15: 221924030
      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=86796
      1.19msalphaeurekaselec_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` = 26 limit 1
      1.21msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 26
      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=26) and sj.journal_id!=26 group by `j`.`nid`) as `aggregate_table`
      1.53msalphaeurekaselec_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=26) and sj.journal_id!=26 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.24msalphaeurekaselec_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=26) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      2.19msalphaeurekaselec_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=26) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      32.78msalphaeurekaselec_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` = '86796'
      10.94msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 86796
      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` = '86796'
      36.46msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 86796
      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` = '86796' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      21.63msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 86796
      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
      370μsalphaeurekaselec_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
      710μsalphaeurekaselec_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 = 26 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      97.81msalphaeurekaselec_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 = 26 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      88.97msalphaeurekaselec_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 = 26 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      39.9msalphaeurekaselec_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` = 86796 limit 1
      9.01msalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 86796
      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 = 86796 and content_type = 'article' order by status desc limit 1
      550μsalphaeurekaselec_live_10_06_2022Article.php#751
      Backtrace
      • 11. app/Models/Article.php:751
      • 12. app/Http/Controllers/ArticleController.php:2094
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid article_nid,a.title article_title,j.title journal_title from content_by_diseases cd inner join article a on a.article_id=cd.content_id inner join journal j on j.journal_id=a.journal_id where cd.pid = 281 and cd.sub_disease_id = 522 and content_id!=86796 and cd.content_type = 'article' order by rand() limit 20
      120msalphaeurekaselec_live_10_06_2022Article.php#769
      Backtrace
      • 11. app/Models/Article.php:769
      • 12. app/Http/Controllers/ArticleController.php:2098
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `node_meta` where `nid` = 156975 limit 1
      18.21msalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 156975
      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
      360μsalphaeurekaselec_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` = 'CN' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      410μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CN
      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 = '86796' 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) )
      590μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2186
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `first_page` < '99' and is_uploaded = 1 and issue_id = 8752 order by cast(first_page as SIGNED) desc limit 1
      720μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 99
      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` > '106' and is_uploaded = 1 and issue_id = 8752 order by cast(first_page as SIGNED) asc limit 1
      630μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 106
      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
      320μsalphaeurekaselec_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` = 86796 limit 1
      3.98msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 86796
      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` = 26 and `b`.`banner_from_date` <= 1739959682 and `b`.`banner_to_date` >= 1739959682 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.67msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 26
      • 3: 1739959682
      • 4: 1739959682
      • 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` = 26 and `b`.`banner_from_date` <= 1739959682 and `b`.`banner_to_date` >= 1739959682 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.75msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 26
      • 3: 1739959682
      • 4: 1739959682
      • 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='a06844ac31907ef8e8436f59f9248662'
      330μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
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        []
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        status_text
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        0 of 0
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        ClearShow all
        Date ↕MethodURLData
        #12025-02-19 10:08:02GET/article/86796314321