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Current Drug Metabolism

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ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

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General Research Article

Comparison of Bromhexine and its Active Metabolite - Ambroxol as Potential Analgesics Reducing Oxaliplatin-induced Neuropathic Pain - Pharmacodynamic and Molecular Docking Studies

Author(s): Anna Furgała-Wojas, Magdalena Kowalska, Alicja Nowaczyk, Łukasz Fijałkowski and Kinga Sałat*

Volume 21, Issue 7, 2020

Page: [548 - 561] Pages: 14

DOI: 10.2174/1389200221666200711155632

Price: $65

Abstract

Background: Painful peripheral neuropathy is a dose-limiting adverse effect of the antitumor drug oxaliplatin. The main symptoms of neuropathy: tactile allodynia and cold hyperalgesia, appear in more than 80% of patients on oxaliplatin therapy and are due to the overexpression of neuronal sodium channels (Navs) and neuroinflammation.

Objective: This study assessed antiallodynic and antihyperalgesic properties of two repurposed drugs with antiinflammatory and Nav-blocking properties (bromhexine and its pharmacologically active metabolite - ambroxol) in a mouse model of neuropathic pain induced by oxaliplatin. Using molecular docking techniques, we predicted targets implicated in the observed in vivo activity of bromhexine.

Methods: Oxaliplatin (a single intraperitoneal dose of 10 mg/kg) induced tactile allodynia and cold hyperalgesia in CD-1 mice and the effectiveness of single-dose or repeated-dose bromhexine and ambroxol to attenuate pain hypersensitivity was assessed in von Frey and cold plate tests. Additionally, Veber analysis and molecular docking experiments of bromhexine on mouse (m) and human (h) Nav1.6-1.9 were carried out.

Results: At the corresponding doses, ambroxol was more effective than bromhexine as an antiallodynic agent. However, at the dose of 150 mg/kg, ambroxol induced motor impairments in mice. Repeated-dose bromhexine and ambroxol partially attenuated the development of late-phase tactile allodynia in oxaliplatin-treated mice. Only 7-day administration of bromhexine attenuated the development of late-phase cold hyperalgesia. Bromhexine was predicted to be a strong inhibitor of mNav1.6, mNav1.7, mNav1.9, and hNav1.7-hNav1.9.

Conclusion: The conversion of bromhexine to other than ambroxol active metabolites should be considered when interpreting some of its in vivo effects. Nav-blocking properties of bromhexine (and previously also predicted for ambroxol) might underlie its ability to attenuate pain caused by oxaliplatin.

Keywords: Drug repurposing, bromhexine, ambroxol, oxaliplatin-induced neuropathy, tactile allodynia, cold hyperalgesia, molecular docking, sodium channels.

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[1]
Fura, A. Role of pharmacologically active metabolites in drug discovery and development. Drug Discov. Today, 2006, 11(3-4), 133-142.
[http://dx.doi.org/10.1016/S1359-6446(05)03681-0 ] [PMID: 16533711]
[2]
Kern, K.U.; Schwickert, M. Ambroxol for the treatment of fibromyalgia: science or fiction? J. Pain Res., 2017, 10, 1905-1929.
[http://dx.doi.org/10.2147/JPR.S139223 ] [PMID: 28860846]
[3]
Zanasi, A.; Mazzolini, M.; Kantar, A. A reappraisal of the mucoactive activity and clinical efficacy of bromhexine. Multidiscip. Respir. Med., 2017, 12(1), 7.
[http://dx.doi.org/10.1186/s40248-017-0088-1 ] [PMID: 28331610]
[4]
Meijer, L.A.; Verstegen, J.C.M.; Bull, S.; Fink-Gremmels, J. Metabolism of bromhexine in pig hepatocyte cultures. J. Vet. Pharmacol. Ther., 2004, 27(4), 219-225.
[http://dx.doi.org/10.1111/j.1365-2885.2004.00584.x ] [PMID: 15305850]
[5]
Liu, J.; Chen, X.; Hu, Y.; Cheng, G.; Zhong, D. Quantification of the major metabolites of bromhexine in human plasma using RRLC-MS/MS and its application to pharmacokinetics. J. Pharm. Biomed. Anal., 2010, 51(5), 1134-1141.
[http://dx.doi.org/10.1016/j.jpba.2009.11.024 ] [PMID: 20031363]
[6]
Kopitar, Z.; Jauch, R.; Hankwitz, R.; Pelzer, H. Species differences in metabolism and excretion of bromhexine in mice, rats, rabbits, dogs and man. Eur. J. Pharmacol., 1973, 21(1), 6-10.
[http://dx.doi.org/10.1016/0014-2999(73)90198-2 ] [PMID: 4709208]
[7]
Dube, A.K.; Kumar, M.S. Biotransformation of bromhexine by Cunninghamella elegans, C. echinulata and C. blakesleeana. Braz. J. Microbiol., 2017, 48(2), 259-267.
[http://dx.doi.org/10.1016/j.bjm.2016.11.003 ] [PMID: 27988088]
[8]
Schraven, E.; Koss, F.W.; Keck, J.; Beisenherz, G. Excretion, isolation and identification of the metabolites of bisolvon. Eur. J. Pharmacol., 1967, 1(5), 445-451.
[http://dx.doi.org/10.1016/0014-2999(67)90108-2 ] [PMID: 5587560]
[9]
Weiser, T. Comparison of the effects of four Na+ channel analgesics on TTX-resistant Na+ currents in rat sensory neurons and recombinant Nav1.2 channels. Neurosci. Lett., 2006, 395(3), 179-184.
[http://dx.doi.org/10.1016/j.neulet.2005.10.058 ] [PMID: 16293367]
[10]
Malerba, M.; Ragnoli, B. Ambroxol in the 21st century: pharmacological and clinical update. Expert Opin. Drug Metab. Toxicol., 2008, 4(8), 1119-1129.
[http://dx.doi.org/10.1517/17425255.4.8.1119 ] [PMID: 18680446]
[11]
Paleari, D.; Rossi, G.A.; Nicolini, G.; Olivieri, D. Ambroxol: a multifaceted molecule with additional therapeutic potentials in respiratory disorders of childhood. Expert Opin. Drug Discov., 2011, 6(11), 1203-1214.
[http://dx.doi.org/10.1517/17460441.2011.629646 ] [PMID: 22646987]
[12]
Hull, J.D.; Lyon, R.A. In vitro pharmacology of ambroxol: potential serotonergic sites of action. Life Sci., 2018, 197, 67-72.
[http://dx.doi.org/10.1016/j.lfs.2018.02.002 ] [PMID: 29412172]
[13]
Hama, A.T.; Plum, A.W.; Sagen, J. Antinociceptive effect of ambroxol in rats with neuropathic spinal cord injury pain. Pharmacol. Biochem. Behav., 2010, 97(2), 249-255.
[http://dx.doi.org/10.1016/j.pbb.2010.08.006 ] [PMID: 20732348]
[14]
Furgała, A.; Fijałkowski, Ł.; Nowaczyk, A.; Sałat, R.; Sałat, K. Time-shifted co-administration of sub-analgesic doses of ambroxol and pregabalin attenuates oxaliplatin-induced cold allodynia in mice. Biomed. Pharmacother., 2018, 106, 930-940.
[http://dx.doi.org/10.1016/j.biopha.2018.07.039 ] [PMID: 30119265]
[15]
Martínez-Martínez, L-A.; Pérez, L-F.; Becerril-Mendoza, L-T.; Rodríguez-Henriquez, P.; Muñoz, O-E.; Acosta, G.; Silveira, L.H.; Vargas, A.; Barrera-Villalpando, M-I.; Martínez-Lavín, M. Ambroxol for fibromyalgia: one group pretest-posttest open-label pilot study. Clin. Rheumatol., 2017, 36(8), 1879-1884.
[http://dx.doi.org/10.1007/s10067-017-3664-z ] [PMID: 28466418]
[16]
Kern, K-U.; Schwickert-Nieswandt, M.; Maihöfner, C.; Gaul, C. Topical ambroxol 20% for the treatment of classical trigeminal neuralgia - a new option? initial clinical case observations. Headache, 2019, 59(3), 418-429.
[http://dx.doi.org/10.1111/head.13475 ] [PMID: 30653673]
[17]
Kern, K.U.; Weiser, T. Topical ambroxol for the treatment of neuropathic pain: a first clinical observation. Schmerz, 2015, 29(6), 632-640.
[http://dx.doi.org/10.1007/s00482-015-0065-6 ] [PMID: 26597641]
[18]
Latli, B.; Hrapchak, M.; Switek, H.K.; Retz, D.M.; Krishnamurthy, D.; Senanayake, C.H. Synthesis of labeled ambroxol and its major metabolites. J. Labelled Comp. Radiopharm., 2010, 53(1), 15-23.
[http://dx.doi.org/10.1002/jlcr.1694]
[19]
Sittl, R.; Lampert, A.; Huth, T.; Schuy, E.T.; Link, A.S.; Fleckenstein, J.; Alzheimer, C.; Grafe, P.; Carr, R.W. Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current. Proc. Natl. Acad. Sci. USA, 2012, 109(17), 6704-6709.
[http://dx.doi.org/10.1073/pnas.1118058109 ] [PMID: 22493249]
[20]
Deuis, J.R.; Zimmermann, K.; Romanovsky, A.A.; Possani, L.D.; Cabot, P.J.; Lewis, R.J.; Vetter, I. An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways. Pain, 2013, 154(9), 1749-1757.
[http://dx.doi.org/10.1016/j.pain.2013.05.032 ] [PMID: 23711479]
[21]
Forstenpointner, J.; Oberlojer, V.C.; Naleschinski, D.; Höper, J.; Helfert, S.M.; Binder, A.; Gierthmühlen, J.; Baron, R. A fibers mediate cold hyperalgesia in patients with oxaliplatin-induced neuropathy. Pain Pract., 2018, 18(6), 758-767.
[http://dx.doi.org/10.1111/papr.12670 ] [PMID: 29222932]
[22]
Binder, A.; Stengel, M.; Maag, R.; Wasner, G.; Schoch, R.; Moosig, F.; Schommer, B.; Baron, R. Pain in oxaliplatin-induced neuropathy-sensitisation in the peripheral and central nociceptive system. Eur. J. Cancer, 2007, 43(18), 2658-2663.
[http://dx.doi.org/10.1016/j.ejca.2007.07.030 ] [PMID: 17855072]
[23]
Sisignano, M.; Baron, R.; Scholich, K.; Geisslinger, G. Mechanism-based treatment for chemotherapy-induced peripheral neuropathic pain. Nat. Rev. Neurol., 2014, 10(12), 694-707.
[http://dx.doi.org/10.1038/nrneurol.2014.211 ] [PMID: 25366108]
[24]
Sałat, K.; Cios, A.; Wyska, E.; Sałat, R.; Mogilski, S.; Filipek, B.; Więckowski, K.; Malawska, B. Antiallodynic and antihyperalgesic activity of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one compared to pregabalin in chemotherapy-induced neuropathic pain in mice. Pharmacol. Biochem. Behav., 2014, 122, 173-181.
[http://dx.doi.org/10.1016/j.pbb.2014.03.025 ] [PMID: 24726707]
[25]
Sałat, K.; Furgała, A.; Sałat, R. Evaluation of cebranopadol, a dually acting nociceptin/orphanin FQ and opioid receptor agonist in mouse models of acute, tonic, and chemotherapy-induced neuropathic pain. Inflammopharmacology, 2018, 26(2), 361-374.
[http://dx.doi.org/10.1007/s10787-017-0405-5 ] [PMID: 29071457]
[26]
Zhao, M.; Isami, K.; Nakamura, S.; Shirakawa, H.; Nakagawa, T.; Kaneko, S. Acute cold hypersensitivity characteristically induced by oxaliplatin is caused by the enhanced responsiveness of trpa1 in mice. Mol. Pain, 2012, 8(1)
[http://dx.doi.org/10.1186/1744-8069-8-55]
[27]
Furgała, A. Acute cold allodynia induced by oxaliplatin is attenuated by amitriptyline. Acta Neurobiol, 2018, 78, 325-331.
[28]
Sakurai, M.; Egashira, N.; Kawashiri, T.; Yano, T.; Ikesue, H.; Oishi, R. Oxaliplatin-induced neuropathy in the rat: involvement of oxalate in cold hyperalgesia but not mechanical allodynia. Pain, 2009, 147(1-3), 165-174.
[http://dx.doi.org/10.1016/j.pain.2009.09.003 ] [PMID: 19782472]
[29]
Sałat, K.; Kołaczkowski, M.; Furgała, A.; Rojek, A.; Śniecikowska, J.; Varney, M.A.; Newman-Tancredi, A. Antinociceptive, antiallodynic and antihyperalgesic effects of the 5-HT1A receptor selective agonist, NLX-112 in mouse models of pain. Neuropharmacology, 2017, 125, 181-188.
[http://dx.doi.org/10.1016/j.neuropharm.2017.07.022 ] [PMID: 28751195]
[30]
Sałat, K.; Furgała, A.; Malikowska-Racia, N. Searching for analgesic drug candidates alleviating oxaliplatin-induced cold hypersensitivity in mice. Chem. Biol. Drug Des., 2019, 93(6), 1061-1072.
[http://dx.doi.org/10.1111/cbdd.13507 ] [PMID: 30900821]
[31]
Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Montgomery, J.A.; Vreven, T.; Kudin, K.N.; Burant, J.C.; Millam, J.M.; Iyengar, S.S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G.A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, H.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J.E.; Hratchian, H.P.; Cross, J.B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.E.; Yazyev, O.; Austin, A.J.; Cammi, R.; Pomelli, C.; Ochterski, J.; Ayala, P.Y.; Morokuma, K.; Voth, G.A.; Salvador, P.; Dannenberg, J.J.; Zakrzewski, V.G.; Dapprich, S.; Daniels, A.D.; Strain, M.C.; Farkas, O.; Malick, D.K.; Rabuck, A.D.; Raghavachari, K.; Foresman, J.B.; Ortiz, J.V.; Cui, Q.; Baboul, A.G.; Clifford, S.; Cioslowski, J.; Stefanov, B.B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R.L.; Fox, D.J.; Keith, T.; Al-Laham, M.A.; Peng, C.Y.; Nanayakkara, A.; Challacombe, M.; Gill, P.M.W.; Johnson, B.; Chen, W.; Wong, M.W.; Gonzalez, C.; Pople, J.A. G09W Tutorial Gaussian 09 (Revision D.2); Gaussian, Inc.: Pittsburgh, PA, 2009.
[32]
Irwin, J.J.; Sterling, T.; Mysinger, M.M.; Bolstad, E.S.; Coleman, R.G. ZINC: a free tool to discover chemistry for biology. J. Chem. Inf. Model., 2012, 52(7), 1757-1768.
[http://dx.doi.org/10.1021/ci3001277 ] [PMID: 22587354]
[33]
Song, I.K.; Kang, Y.K. Conformational preferences of γ-aminobutyric acid in the gas phase and in water. J. Mol. Struct., 2012, 1024, 163-169.
[http://dx.doi.org/10.1016/j.molstruc.2012.04.080]
[34]
Rodrigo, M.M.; Esteso, M.A.; Barros, M.F.; Verissimo, L.M.P.; Romero, C.M.; Suarez, A.F.; Ramos, M.L.; Valente, A.J.M.; Burrows, H.D.; Ribeiro, A.C.F. The structure and diffusion behaviour of the neurotransmitter γ-aminobutyric acid (GABA) in neutral aqueous solutions. J. Chem. Thermodyn., 2017, 104, 110-117.
[http://dx.doi.org/10.1016/j.jct.2016.09.014]
[35]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256 ] [PMID: 19399780]
[36]
Boeckmann, B.; Bairoch, A.; Apweiler, R.; Blatter, M-C.; Estreicher, A.; Gasteiger, E.; Martin, M.J.; Michoud, K.; O’Donovan, C.; Phan, I.; Pilbout, S.; Schneider, M. The SWISS-PROT protein knowledgebase and its supplement TrEMBL in 2003. Nucleic Acids Res., 2003, 31(1), 365-370.
[http://dx.doi.org/10.1093/nar/gkg095 ] [PMID: 12520024]
[37]
Sula, A.; Booker, J.; Ng, L.C.T.; Naylor, C.E.; DeCaen, P.G.; Wallace, B.A. The complete structure of an activated open sodium channel. Nat. Commun., 2017, 8, 14205.
[http://dx.doi.org/10.1038/ncomms14205 ] [PMID: 28205548]
[38]
Carrithers, M.D.; Chatterjee, G.; Carrithers, L.M.; Offoha, R.; Iheagwara, U.; Rahner, C.; Graham, M.; Waxman, S.G. Regulation of podosome formation in macrophages by a splice variant of the sodium channel SCN8A. J. Biol. Chem., 2009, 284(12), 8114-8126.
[http://dx.doi.org/10.1074/jbc.M801892200 ] [PMID: 19136557]
[39]
Nassar, M.A.; Stirling, L.C.; Forlani, G.; Baker, M.D.; Matthews, E.A.; Dickenson, A.H.; Wood, J.N. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc. Natl. Acad. Sci. USA, 2004, 101(34), 12706-12711.
[http://dx.doi.org/10.1073/pnas.0404915101 ] [PMID: 15314237]
[40]
Spampanato, J.; Escayg, A.; Meisler, M.H.; Goldin, A.L. Generalized epilepsy with febrile seizures plus type 2 mutation W1204R alters voltage-dependent gating of Na(v)1.1 sodium channels. Neuroscience, 2003, 116(1), 37-48.
[http://dx.doi.org/10.1016/S0306-4522(02)00698-X ] [PMID: 12535936]
[41]
Jeong, S-Y.; Goto, J.; Hashida, H.; Suzuki, T.; Ogata, K.; Masuda, N.; Hirai, M.; Isahara, K.; Uchiyama, Y.; Kanazawa, I. Identification of a novel human voltage-gated sodium channel α subunit gene, SCN12A. Biochem. Biophys. Res. Commun., 2000, 267(1), 262-270.
[http://dx.doi.org/10.1006/bbrc.1999.1916 ] [PMID: 10623608]
[42]
Osorio, N.; Korogod, S.; Delmas, P. Specialized functions of Nav1.5 and Nav1.9 channels in electrogenesis of myenteric neurons in intact mouse ganglia. J. Neurosci., 2014, 34(15), 5233-5244.
[http://dx.doi.org/10.1523/JNEUROSCI.0057-14.2014 ] [PMID: 24719102]
[43]
Ahuja, S.; Mukund, S.; Deng, L.; Khakh, K.; Chang, E.; Ho, H.; Shriver, S.; Young, C.; Lin, S.; Johnson, J.P., Jr; Wu, P.; Li, J.; Coons, M.; Tam, C.; Brillantes, B.; Sampang, H.; Mortara, K.; Bowman, K.K.; Clark, K.R.; Estevez, A.; Xie, Z.; Verschoof, H.; Grimwood, M.; Dehnhardt, C.; Andrez, J-C.; Focken, T.; Sutherlin, D.P.; Safina, B.S.; Starovasnik, M.A.; Ortwine, D.F.; Franke, Y.; Cohen, C.J.; Hackos, D.H.; Koth, C.M.; Payandeh, J. Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist. Science, 2015, 350(6267), aac5464
[http://dx.doi.org/10.1126/science.aac5464 ] [PMID: 26680203]
[44]
Facer, P.; Punjabi, P.P.; Abrari, A.; Kaba, R.A.; Severs, N.J.; Chambers, J.; Kooner, J.S.; Anand, P. Localisation of SCN10A gene product Na(v)1.8 and novel pain-related ion channels in human heart. Int. Heart J., 2011, 52(3), 146-152.
[http://dx.doi.org/10.1536/ihj.52.146 ] [PMID: 21646736]
[45]
Uboh, C.E.; Rudy, J.A.; Soma, L.R.; Fennell, M.; May, L.; Sams, R.; Railing, F.A.; Shellenberger, J.; Kahler, M. Characterization of bromhexine and ambroxol in equine urine: effect of furosemide on identification and confirmation. J. Pharm. Biomed. Anal., 1991, 9(1), 33-39.
[http://dx.doi.org/10.1016/0731-7085(91)80234-Z ] [PMID: 2043720]
[46]
Takeda, H.; Misawa, M.; Yanaura, S. A role of lysosomal enzymes in the mechanism of mucolytic action of bromhexine. Jpn. J. Pharmacol., 1983, 33(2), 455-461.
[http://dx.doi.org/10.1254/jjp.33.455 ] [PMID: 6887650]
[47]
Colombo, L.; Marcucci, F.; Marini, G.M.; Pierfederici, P.; Mussini, E. Determination of ambroxol in biological material by gas chromatography with electron-capture detection. J. Chromatogr. A, 1990, 530(1), 141-147.
[http://dx.doi.org/10.1016/S0378-4347(00)82313-0 ] [PMID: 2277104]
[48]
Bazylak, G.; Nagels, L.J. Simultaneous high-throughput determination of clenbuterol, ambroxol and bromhexine in pharmaceutical formulations by HPLC with potentiometric detection. J. Pharm. Biomed. Anal., 2003, 32(4-5), 887-903.
[http://dx.doi.org/10.1016/S0731-7085(03)00191-2 ] [PMID: 12899975]
[49]
Srivastava, V.; Singh, P.K.; Kanaujia, S.; Singh, P.P. Photoredox catalysed synthesis of amino alcohol. New J. Chem., 2018, 42(1), 688-691.
[http://dx.doi.org/10.1039/C7NJ03068A]
[50]
Gaida, W.; Klinder, K.; Arndt, K.; Weiser, T. Ambroxol, a Nav1.8-preferring Na(+) channel blocker, effectively suppresses pain symptoms in animal models of chronic, neuropathic and inflammatory pain. Neuropharmacology, 2005, 49(8), 1220-1227.
[http://dx.doi.org/10.1016/j.neuropharm.2005.08.004 ] [PMID: 16182323]
[51]
Veber, D.F.; Johnson, S.R.; Cheng, H-Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
[http://dx.doi.org/10.1021/jm020017n ] [PMID: 12036371]
[52]
Han, C.; Estacion, M.; Huang, J.; Vasylyev, D.; Zhao, P.; Dib-Hajj, S.D.; Waxman, S.G. Human Na(v)1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons. J. Neurophysiol., 2015, 113(9), 3172-3185.
[http://dx.doi.org/10.1152/jn.00113.2015 ] [PMID: 25787950]
[53]
Shah, K.; Mujwar, S.; Gupta, J.K.; Shrivastava, S.K.; Mishra, P. Molecular docking and in silico cogitation validate mefenamic acid prodrugs as human cyclooxygenase-2 inhibitor. Assay Drug Dev. Technol., 2019, 17(6), 285-291.
[http://dx.doi.org/10.1089/adt.2019.943 ] [PMID: 31532713]
[54]
Trott, O.; Olson, A.J. AutoDock vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[55]
Turner, P.V.; Brabb, T.; Pekow, C.; Vasbinder, M.A. Administration of substances to laboratory animals: routes of administration and factors to consider. J. Am. Assoc. Lab. Anim. Sci., 2011, 50(5), 600-613.
[PMID: 22330705]
[56]
Starobova, H.; Vetter, I. Pathophysiology of chemotherapy-induced peripheral neuropathy. Front. Mol. Neurosci., 2017, 10, 174.
[http://dx.doi.org/10.3389/fnmol.2017.00174 ] [PMID: 28620280]
[57]
Ewertz, M.; Qvortrup, C.; Eckhoff, L. Chemotherapy-induced peripheral neuropathy in patients treated with taxanes and platinum derivatives. Acta Oncol., 2015, 54(5), 587-591.
[http://dx.doi.org/10.3109/0284186X.2014.995775 ] [PMID: 25751757]
[58]
Nakagawa, T.; Kaneko, S. Roles of transient receptor potential ankyrin 1 in oxaliplatin-induced peripheral neuropathy. Biol. Pharm. Bull., 2017, 40(7), 947-953.
[http://dx.doi.org/10.1248/bpb.b17-00243 ] [PMID: 28674258]
[59]
Ndrugs. Bromhexine hydrochloride actions, administration, pharmacology. Available at:. https://www.ndrugs.com/?s=bromhexine
[60]
Mahan, M.C.; Jildeh, T.R.; Tenbrunsel, T.; Adelman, B.T.; Davis, J.J. Time of return of neurologic function after spinal anesthesia for total knee arthroplasty: mepivacaine vs bupivacaine in a randomized controlled trial. Arthroplast. Today, 2019, 5(2), 226-233.
[http://dx.doi.org/10.1016/j.artd.2019.03.003 ] [PMID: 31286049]
[61]
Gozdemir, M.; Muslu, B.; Sert, H.; Usta, B.; Demircioglu, R.I.; Kasikara, H. Transient neurological symptoms after spinal anesthesia. Clin. Invest. Med., 2016, 39(6), 27512.
[http://dx.doi.org/10.25011/cim.v39i6.27512 ] [PMID: 27917802]
[62]
O., Cathasaigh, M. Read, M.R.; Atilla, A.; Schiller, T.; Kwong, G.P.S.. Blood concentration of bupivacaine and duration of sensory and motor block following ultrasound-guided femoral and sciatic nerve blocks in dogs. PLoS One, 2018, 13(3), e0193400
[http://dx.doi.org/10.1371/journal.pone.0193400 ] [PMID: 29505566]
[63]
Moldovan, M.; Rosberg, M.R.; Alvarez, S.; Klein, D.; Martini, R.; Krarup, C. Aging-associated changes in motor axon voltage-gated Na(+) channel function in mice. Neurobiol. Aging, 2016, 39, 128-139.
[http://dx.doi.org/10.1016/j.neurobiolaging.2015.12.005 ] [PMID: 26923409]
[64]
Montilla-García, Á.; Tejada, M.Á.; Perazzoli, G.; Entrena, J.M.; Portillo-Salido, E.; Fernández-Segura, E.; Cañizares, F.J.; Cobos, E.J. Grip strength in mice with joint inflammation: a rheumatology function test sensitive to pain and analgesia. Neuropharmacology, 2017, 125, 231-242.
[http://dx.doi.org/10.1016/j.neuropharm.2017.07.029 ] [PMID: 28760650]
[65]
Pereira, A.F.; de Oliveira, F.F.B.; de Freitas Alves, B.W.; de Menezes, K.L.S.; de Mesquita, A.K.V.; Lisboa, M.R.P.; de Sousa, K.K.O.; Vale, M.L. Neurotoxic effect of oxaliplatin: comparison with its oxalate-free analogue cis-[PtII(1R,2R-DACH)(3-acetoxy-1,1-cyclobutanedicar-boxylato)] (LLC-1402) in mice. Toxicol. Appl. Pharmacol., 2018, 340, 77-84.
[http://dx.doi.org/10.1016/j.taap.2018.01.001 ] [PMID: 29307816]
[66]
Park, S.B.; Kiernan, M.C. Oxaliplatin and neuropathy: a role for sodium channels. Clin. Neurophysiol., 2018, 129(3), 670-671.
[http://dx.doi.org/10.1016/j.clinph.2017.12.028 ] [PMID: 29343414]
[67]
Leffler, A.; Reckzeh, J.; Nau, C. Block of sensory neuronal Na+ channels by the secreolytic ambroxol is associated with an interaction with local anesthetic binding sites. Eur. J. Pharmacol., 2010, 630(1-3), 19-28.
[http://dx.doi.org/10.1016/j.ejphar.2009.12.027 ] [PMID: 20044988]
[68]
Weiser, T.; Wilson, N. Inhibition of tetrodotoxin (TTX)-resistant and TTX-sensitive neuronal Na(+) channels by the secretolytic ambroxol. Mol. Pharmacol., 2002, 62(3), 433-438.
[http://dx.doi.org/10.1124/mol.62.3.433 ] [PMID: 12181417]
[69]
Schoenwald, R.D.; Barfknecht, C.F.; Shirolkar, S.; Xia, E.; Ignace, C.C. Identification of sigma receptors in lacrimocytes and their therapeutic implication in dry eye syndrome; Springer: Boston, MA, 1994.
[http://dx.doi.org/10.1007/978-1-4615-2417-5_24]
[70]
Helmut Heinrich Buschman EP1787679A1,. 2005.
[71]
Bruna, J.; Velasco, R. Sigma-1 receptor: a new player in neuroprotection against chemotherapy-induced peripheral neuropathy. Neural Regen. Res., 2018, 13(5), 775-778.
[http://dx.doi.org/10.4103/1673-5374.232459 ] [PMID: 29862996]
[72]
Bruna, J.; Videla, S.; Argyriou, A.A.; Velasco, R.; Villoria, J.; Santos, C.; Nadal, C.; Cavaletti, G.; Alberti, P.; Briani, C.; Kalofonos, H.P.; Cortinovis, D.; Sust, M.; Vaqué, A.; Klein, T.; Plata-Salamán, C. Efficacy of a novel sigma-1 receptor antagonist for oxaliplatin-induced neuropathy: a randomized, double-blind, placebo-controlled phase IIa clinical trial. Neurotherapeutics, 2018, 15(1), 178-189.
[http://dx.doi.org/10.1007/s13311-017-0572-5 ] [PMID: 28924870]
[73]
Merlos, M.; Romero, L.; Zamanillo, D.; Plata-Salamán, C.; Vela, J.M. Sigma-1 receptor and pain. In: Handbook of experimental pharmacology;; Springer: Cham , 2017, Vol. 244 , pp. 131-161.

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