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Pharmacokinetics and local tissue response to local instillation of vocacapsaicin, a novel capsaicin prodrug, in rat and rabbit osteotomy models

Vocacapsaicin is a novel prodrug of trans‐capsaicin (trans‐8‐methyl‐N‐vanillyl‐6‐nonenamide) being developed as a nonopioid, long‐lasting, site‐specific treatment for postsurgical pain management. The objective of these studies was to examine the safety and tolerability of vocacapsaicin in an osteot...

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Autores principales: Knotts, Tarra, Mease, Kirsten, Sangameswaran, Lakshmi, Felx, Melanie, Kramer, Susan, Donovan, John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9790453/
https://www.ncbi.nlm.nih.gov/pubmed/35128722
http://dx.doi.org/10.1002/jor.25271
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author Knotts, Tarra
Mease, Kirsten
Sangameswaran, Lakshmi
Felx, Melanie
Kramer, Susan
Donovan, John
author_facet Knotts, Tarra
Mease, Kirsten
Sangameswaran, Lakshmi
Felx, Melanie
Kramer, Susan
Donovan, John
author_sort Knotts, Tarra
collection PubMed
description Vocacapsaicin is a novel prodrug of trans‐capsaicin (trans‐8‐methyl‐N‐vanillyl‐6‐nonenamide) being developed as a nonopioid, long‐lasting, site‐specific treatment for postsurgical pain management. The objective of these studies was to examine the safety and tolerability of vocacapsaicin in an osteotomy model in two animal species and to evaluate bone healing parameters. Rats undergoing unilateral femoral osteotomy received a single perioperative administration (by instillation) of vocacapsaicin (vehicle, 0.15, 0.3, and 0.6 mg/kg). Rabbits undergoing unilateral ulnar osteotomy received a single perioperative administration (by infiltration and instillation) of vocacapsaicin (vehicle, 0.256 and 0.52 mg) alone or in combination with 0.5% ropivacaine. Clinical signs, body weights, food consumption, radiography, histopathologic examinations, ex vivo bone mineral density measurements (rats only), and biomechanical testing were evaluated at 4 and 8 weeks in rats and at 2 and 10 weeks in rabbits. Plasma samples were also collected in rabbits. There were no vocacapsaicin‐related effects on mortality, clinical observations, body weight, or food consumption in either species. Systemic exposure to vocacapsaicin and its metabolites, including capsaicin, was transient. In rats, vocacapsaicin was devoid of deleterious effects on bone healing parameters, and there was a trend for enhanced bone healing in rats treated with the mid‐dose. In rabbits, vocacapsaicin administered alone or in combination with ropivacaine did not adversely affect bone healing parameters. In conclusion, a single perioperative administration of vocacapsaicin in unilateral osteotomy models was well tolerated, locally and systemically, supporting its continued development as a novel, nonopioid treatment for postsurgical pain management.
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spelling pubmed-97904532022-12-28 Pharmacokinetics and local tissue response to local instillation of vocacapsaicin, a novel capsaicin prodrug, in rat and rabbit osteotomy models Knotts, Tarra Mease, Kirsten Sangameswaran, Lakshmi Felx, Melanie Kramer, Susan Donovan, John J Orthop Res Research Articles Vocacapsaicin is a novel prodrug of trans‐capsaicin (trans‐8‐methyl‐N‐vanillyl‐6‐nonenamide) being developed as a nonopioid, long‐lasting, site‐specific treatment for postsurgical pain management. The objective of these studies was to examine the safety and tolerability of vocacapsaicin in an osteotomy model in two animal species and to evaluate bone healing parameters. Rats undergoing unilateral femoral osteotomy received a single perioperative administration (by instillation) of vocacapsaicin (vehicle, 0.15, 0.3, and 0.6 mg/kg). Rabbits undergoing unilateral ulnar osteotomy received a single perioperative administration (by infiltration and instillation) of vocacapsaicin (vehicle, 0.256 and 0.52 mg) alone or in combination with 0.5% ropivacaine. Clinical signs, body weights, food consumption, radiography, histopathologic examinations, ex vivo bone mineral density measurements (rats only), and biomechanical testing were evaluated at 4 and 8 weeks in rats and at 2 and 10 weeks in rabbits. Plasma samples were also collected in rabbits. There were no vocacapsaicin‐related effects on mortality, clinical observations, body weight, or food consumption in either species. Systemic exposure to vocacapsaicin and its metabolites, including capsaicin, was transient. In rats, vocacapsaicin was devoid of deleterious effects on bone healing parameters, and there was a trend for enhanced bone healing in rats treated with the mid‐dose. In rabbits, vocacapsaicin administered alone or in combination with ropivacaine did not adversely affect bone healing parameters. In conclusion, a single perioperative administration of vocacapsaicin in unilateral osteotomy models was well tolerated, locally and systemically, supporting its continued development as a novel, nonopioid treatment for postsurgical pain management. John Wiley and Sons Inc. 2022-02-06 2022-10 /pmc/articles/PMC9790453/ /pubmed/35128722 http://dx.doi.org/10.1002/jor.25271 Text en © 2022 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Knotts, Tarra
Mease, Kirsten
Sangameswaran, Lakshmi
Felx, Melanie
Kramer, Susan
Donovan, John
Pharmacokinetics and local tissue response to local instillation of vocacapsaicin, a novel capsaicin prodrug, in rat and rabbit osteotomy models
title Pharmacokinetics and local tissue response to local instillation of vocacapsaicin, a novel capsaicin prodrug, in rat and rabbit osteotomy models
title_full Pharmacokinetics and local tissue response to local instillation of vocacapsaicin, a novel capsaicin prodrug, in rat and rabbit osteotomy models
title_fullStr Pharmacokinetics and local tissue response to local instillation of vocacapsaicin, a novel capsaicin prodrug, in rat and rabbit osteotomy models
title_full_unstemmed Pharmacokinetics and local tissue response to local instillation of vocacapsaicin, a novel capsaicin prodrug, in rat and rabbit osteotomy models
title_short Pharmacokinetics and local tissue response to local instillation of vocacapsaicin, a novel capsaicin prodrug, in rat and rabbit osteotomy models
title_sort pharmacokinetics and local tissue response to local instillation of vocacapsaicin, a novel capsaicin prodrug, in rat and rabbit osteotomy models
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9790453/
https://www.ncbi.nlm.nih.gov/pubmed/35128722
http://dx.doi.org/10.1002/jor.25271
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