Capsaicin-Cyclodextrin Complex Enhances Mepivacaine Targeting and Improves Local Anesthesia in Inflamed Tissues
Acidic environments, such as in inflamed tissues, favor the charged form of local anesthetics (LA). Hence, these drugs show less cell permeation and diminished potency. Since the analgesic capsaicin (CAP) triggers opening of the TRPV1 receptor pore, its combination with LAs could result in better up...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-08-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/16/5741 |
| _version_ | 1797559076520984576 |
|---|---|
| author | Verônica Muniz Couto Laura de Oliveira-Nascimento Luiz Fernando Cabeça Danilo Costa Geraldes Juliana Souza Ribeiro Costa Karin A. Riske Michelle Franz-Montan Fabiano Yokaychiya Margareth K. K. Dias Franco Eneida de Paula |
| author_facet | Verônica Muniz Couto Laura de Oliveira-Nascimento Luiz Fernando Cabeça Danilo Costa Geraldes Juliana Souza Ribeiro Costa Karin A. Riske Michelle Franz-Montan Fabiano Yokaychiya Margareth K. K. Dias Franco Eneida de Paula |
| author_sort | Verônica Muniz Couto |
| collection | DOAJ |
| description | Acidic environments, such as in inflamed tissues, favor the charged form of local anesthetics (LA). Hence, these drugs show less cell permeation and diminished potency. Since the analgesic capsaicin (CAP) triggers opening of the TRPV1 receptor pore, its combination with LAs could result in better uptake and improved anesthesia. We tested the above hypothesis and report here for the first time the analgesia effect of a two-drug combination (LA and CAP) on an inflamed tissue. First, CAP solubility increased up to 20 times with hydroxypropyl-beta-cyclodextrin (HP-β-CD), as shown by the phase solubility study. The resulting complex (HP-β-CD-CAP) showed 1:1 stoichiometry and high association constant, according to phase-solubility diagrams and isothermal titration calorimetry data. The inclusion complex formation was also confirmed and characterized by differential scanning calorimetry (DSC), X-ray diffraction, and <sup>1</sup>H-NMR. The freeze-dried complex showed physicochemical stability for at least 12 months. To test in vivo performance, we used a pain model based on mouse paw edema. Results showed that 2% mepivacaine injection failed to anesthetize mice inflamed paw, but its combination with complexed CAP resulted in pain control up to 45 min. These promising results encourages deeper research of CAP as an adjuvant for anesthesia in inflamed tissues and cyclodextrin as a solubilizing agent for targeting molecules in drug delivery. |
| first_indexed | 2024-03-10T17:40:34Z |
| format | Article |
| id | doaj.art-3254aff3272f43aab5536261c6d91d8e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T17:40:34Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3254aff3272f43aab5536261c6d91d8e2023-11-20T09:43:11ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-08-012116574110.3390/ijms21165741Capsaicin-Cyclodextrin Complex Enhances Mepivacaine Targeting and Improves Local Anesthesia in Inflamed TissuesVerônica Muniz Couto0Laura de Oliveira-Nascimento1Luiz Fernando Cabeça2Danilo Costa Geraldes3Juliana Souza Ribeiro Costa4Karin A. Riske5Michelle Franz-Montan6Fabiano Yokaychiya7Margareth K. K. Dias Franco8Eneida de Paula9Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas 13083-862, SP, BrazilFaculty of Pharmaceutical Sciences, University of Campinas, Campinas 13083-871, SP, BrazilTechnologic Federal University of Parana, Londrina 80060-000, PR, BrazilFaculty of Pharmaceutical Sciences, University of Campinas, Campinas 13083-871, SP, BrazilFaculty of Pharmaceutical Sciences, University of Campinas, Campinas 13083-871, SP, BrazilDepartment of Biophysics, Federal University of Sao Paulo, Sao Paulo 04023-062, SP, BrazilDepartment of Physiological Sciences, Piracicaba Dental School, University of Campinas, Piracicaba 13414-903, SP, BrazilNuclear and Energy Research Institute, IPEN–CNEN/SP, Sao Paulo 05508-000, SP, BrazilNuclear and Energy Research Institute, IPEN–CNEN/SP, Sao Paulo 05508-000, SP, BrazilDepartment of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas 13083-862, SP, BrazilAcidic environments, such as in inflamed tissues, favor the charged form of local anesthetics (LA). Hence, these drugs show less cell permeation and diminished potency. Since the analgesic capsaicin (CAP) triggers opening of the TRPV1 receptor pore, its combination with LAs could result in better uptake and improved anesthesia. We tested the above hypothesis and report here for the first time the analgesia effect of a two-drug combination (LA and CAP) on an inflamed tissue. First, CAP solubility increased up to 20 times with hydroxypropyl-beta-cyclodextrin (HP-β-CD), as shown by the phase solubility study. The resulting complex (HP-β-CD-CAP) showed 1:1 stoichiometry and high association constant, according to phase-solubility diagrams and isothermal titration calorimetry data. The inclusion complex formation was also confirmed and characterized by differential scanning calorimetry (DSC), X-ray diffraction, and <sup>1</sup>H-NMR. The freeze-dried complex showed physicochemical stability for at least 12 months. To test in vivo performance, we used a pain model based on mouse paw edema. Results showed that 2% mepivacaine injection failed to anesthetize mice inflamed paw, but its combination with complexed CAP resulted in pain control up to 45 min. These promising results encourages deeper research of CAP as an adjuvant for anesthesia in inflamed tissues and cyclodextrin as a solubilizing agent for targeting molecules in drug delivery.https://www.mdpi.com/1422-0067/21/16/5741inflammationmepivacainecapsaicinanesthesiacyclodextrin |
| spellingShingle | Verônica Muniz Couto Laura de Oliveira-Nascimento Luiz Fernando Cabeça Danilo Costa Geraldes Juliana Souza Ribeiro Costa Karin A. Riske Michelle Franz-Montan Fabiano Yokaychiya Margareth K. K. Dias Franco Eneida de Paula Capsaicin-Cyclodextrin Complex Enhances Mepivacaine Targeting and Improves Local Anesthesia in Inflamed Tissues International Journal of Molecular Sciences inflammation mepivacaine capsaicin anesthesia cyclodextrin |
| title | Capsaicin-Cyclodextrin Complex Enhances Mepivacaine Targeting and Improves Local Anesthesia in Inflamed Tissues |
| title_full | Capsaicin-Cyclodextrin Complex Enhances Mepivacaine Targeting and Improves Local Anesthesia in Inflamed Tissues |
| title_fullStr | Capsaicin-Cyclodextrin Complex Enhances Mepivacaine Targeting and Improves Local Anesthesia in Inflamed Tissues |
| title_full_unstemmed | Capsaicin-Cyclodextrin Complex Enhances Mepivacaine Targeting and Improves Local Anesthesia in Inflamed Tissues |
| title_short | Capsaicin-Cyclodextrin Complex Enhances Mepivacaine Targeting and Improves Local Anesthesia in Inflamed Tissues |
| title_sort | capsaicin cyclodextrin complex enhances mepivacaine targeting and improves local anesthesia in inflamed tissues |
| topic | inflammation mepivacaine capsaicin anesthesia cyclodextrin |
| url | https://www.mdpi.com/1422-0067/21/16/5741 |
| work_keys_str_mv | AT veronicamunizcouto capsaicincyclodextrincomplexenhancesmepivacainetargetingandimproveslocalanesthesiaininflamedtissues AT lauradeoliveiranascimento capsaicincyclodextrincomplexenhancesmepivacainetargetingandimproveslocalanesthesiaininflamedtissues AT luizfernandocabeca capsaicincyclodextrincomplexenhancesmepivacainetargetingandimproveslocalanesthesiaininflamedtissues AT danilocostageraldes capsaicincyclodextrincomplexenhancesmepivacainetargetingandimproveslocalanesthesiaininflamedtissues AT julianasouzaribeirocosta capsaicincyclodextrincomplexenhancesmepivacainetargetingandimproveslocalanesthesiaininflamedtissues AT karinariske capsaicincyclodextrincomplexenhancesmepivacainetargetingandimproveslocalanesthesiaininflamedtissues AT michellefranzmontan capsaicincyclodextrincomplexenhancesmepivacainetargetingandimproveslocalanesthesiaininflamedtissues AT fabianoyokaychiya capsaicincyclodextrincomplexenhancesmepivacainetargetingandimproveslocalanesthesiaininflamedtissues AT margarethkkdiasfranco capsaicincyclodextrincomplexenhancesmepivacainetargetingandimproveslocalanesthesiaininflamedtissues AT eneidadepaula capsaicincyclodextrincomplexenhancesmepivacainetargetingandimproveslocalanesthesiaininflamedtissues |