Tags

Type your tag names separated by a space and hit enter

Comparison of Bromhexine and its Active Metabolite - Ambroxol as Potential Analgesics Reducing Oxaliplatin-Induced Neuropathic Pain - Pharmacodynamic and Molecular Docking Studies.
Curr Drug Metab. 2020 Jul 11 [Online ahead of print]CD

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 to 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 their ability to attenuate pain caused by oxaliplatin.

Authors+Show Affiliations

Department of Pharmacodynamics, Chair of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow. Poland.Department of Organic Chemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 2 dr. A. Jurasza St., 85-094 Bydgoszcz. Poland.Department of Organic Chemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 2 dr. A. Jurasza St., 85-094 Bydgoszcz. Poland.Department of Organic Chemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 2 dr. A. Jurasza St., 85-094 Bydgoszcz. Poland.Department of Pharmacodynamics, Chair of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow. Poland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32651960

Citation

Furgała-Wojas, Anna, et al. "Comparison of Bromhexine and Its Active Metabolite - Ambroxol as Potential Analgesics Reducing Oxaliplatin-Induced Neuropathic Pain - Pharmacodynamic and Molecular Docking Studies." Current Drug Metabolism, 2020.
Furgała-Wojas A, Kowalska M, Nowaczyk A, et al. Comparison of Bromhexine and its Active Metabolite - Ambroxol as Potential Analgesics Reducing Oxaliplatin-Induced Neuropathic Pain - Pharmacodynamic and Molecular Docking Studies. Curr Drug Metab. 2020.
Furgała-Wojas, A., Kowalska, M., Nowaczyk, A., Fijałkowski, Ł., & Sałat, K. (2020). Comparison of Bromhexine and its Active Metabolite - Ambroxol as Potential Analgesics Reducing Oxaliplatin-Induced Neuropathic Pain - Pharmacodynamic and Molecular Docking Studies. Current Drug Metabolism. https://doi.org/10.2174/1389200221666200711155632
Furgała-Wojas A, et al. Comparison of Bromhexine and Its Active Metabolite - Ambroxol as Potential Analgesics Reducing Oxaliplatin-Induced Neuropathic Pain - Pharmacodynamic and Molecular Docking Studies. Curr Drug Metab. 2020 Jul 11; PubMed PMID: 32651960.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparison of Bromhexine and its Active Metabolite - Ambroxol as Potential Analgesics Reducing Oxaliplatin-Induced Neuropathic Pain - Pharmacodynamic and Molecular Docking Studies. AU - Furgała-Wojas,Anna, AU - Kowalska,Magdalena, AU - Nowaczyk,Alicja, AU - Fijałkowski,Łukasz, AU - Sałat,Kinga, Y1 - 2020/07/11/ PY - 2020/01/06/received PY - 2020/04/30/revised PY - 2020/05/21/accepted PY - 2020/7/12/entrez PY - 2020/7/12/pubmed PY - 2020/7/12/medline KW - ambroxol KW - bromhexine KW - cold hyperalgesia KW - drug repurposing KW - molecular docking KW - oxaliplatin-induced neuropathy KW - sodium channels. KW - tactile allodynia JF - Current drug metabolism JO - Curr. Drug Metab. N2 - 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 to 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 their ability to attenuate pain caused by oxaliplatin. SN - 1875-5453 UR - https://www.unboundmedicine.com/medline/citation/32651960/Comparison_of_Bromhexine_and_its_Active_Metabolite_-_Ambroxol_as_Potential_Analgesics_Reducing_Oxaliplatin-Induced_Neuropathic_Pain_-_Pharmacodynamic_and_Molecular_Docking_Studies L2 - https://www.eurekaselect.com/183649/article DB - PRIME DP - Unbound Medicine ER -
Try the Free App:
Prime PubMed app for iOS iPhone iPad
Prime PubMed app for Android
Prime PubMed is provided
free to individuals by:
Unbound Medicine.