Linde Buntinx1, Lin Chang1, Aasim Amin1, Bart Morlion2, Jan de Hoon1. 1. Centre for Clinical Pharmacology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. 2. Department of Cardiovascular Sciences, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
Abstract
AIM: To develop a non-invasive, safe and reproducible target-engagement biomarker for future TRPA1 antagonists in healthy volunteers. METHODS: Dose finding (n = 11): 3%, 10%, and 30% cinnamaldehyde (CA) and placebo (= vehicle) was topically applied on the right forearm. One-way ANOVA with post-hoc Bonferroni was used to compare between doses. Reproducibility: 10% CA doses were topically applied during one visit on both arms (n = 10) or during two visits (n = 23) separated by a washout period of 7 days. CA-induced dermal blood flow (DBF) was assessed by laser Doppler imaging (LDI) at baseline and at 10, 20, 30, 40 and 50 min post-CA. Paired t-test was used to compare between arms or visits. Concordance correlation coefficient (CCC) was calculated to assess reproducibility. Data are expressed as percent change from baseline (mean ± 95% CI). RESULTS: All three doses increased DBF compared to vehicle at all time-points, with the maximum response at 10-20 min post-CA. Dose response was found when comparing AUC0-50min of 30% CA (51 364 ± 8475%*min) with 10% CA (32 239 ± 8034%*min, P = 0.03) and 3% CA (30 226 ± 11 958%*min, P = 0.015). 10% CA was chosen as an effective and safe dose. DBF response to 10% CA was found to be reproducible between arms (AUC0-50min , CCC = 0.91) and visits (AUC0-50min , CCC = 0.83). Based on sample size calculations, this model allows a change in CA-induced DBF of 30-50% to be detected between two independent groups of maximum 10-15 subjects with 80% power. CONCLUSIONS: Evaluation of CA-induced changes in DBF offers a safe, non-invasive and reproducible target-engagement biomarker in vivo in humans to evaluate TRPA1 antagonists.
RCT Entities:
AIM: To develop a non-invasive, safe and reproducible target-engagement biomarker for future TRPA1 antagonists in healthy volunteers. METHODS: Dose finding (n = 11): 3%, 10%, and 30% cinnamaldehyde (CA) and placebo (= vehicle) was topically applied on the right forearm. One-way ANOVA with post-hoc Bonferroni was used to compare between doses. Reproducibility: 10% CA doses were topically applied during one visit on both arms (n = 10) or during two visits (n = 23) separated by a washout period of 7 days. CA-induced dermal blood flow (DBF) was assessed by laser Doppler imaging (LDI) at baseline and at 10, 20, 30, 40 and 50 min post-CA. Paired t-test was used to compare between arms or visits. Concordance correlation coefficient (CCC) was calculated to assess reproducibility. Data are expressed as percent change from baseline (mean ± 95% CI). RESULTS: All three doses increased DBF compared to vehicle at all time-points, with the maximum response at 10-20 min post-CA. Dose response was found when comparing AUC0-50min of 30% CA (51 364 ± 8475%*min) with 10% CA (32 239 ± 8034%*min, P = 0.03) and 3% CA (30 226 ± 11 958%*min, P = 0.015). 10% CA was chosen as an effective and safe dose. DBF response to 10% CA was found to be reproducible between arms (AUC0-50min , CCC = 0.91) and visits (AUC0-50min , CCC = 0.83). Based on sample size calculations, this model allows a change in CA-induced DBF of 30-50% to be detected between two independent groups of maximum 10-15 subjects with 80% power. CONCLUSIONS: Evaluation of CA-induced changes in DBF offers a safe, non-invasive and reproducible target-engagement biomarker in vivo in humans to evaluate TRPA1 antagonists.
Authors: Stephen Ph Alexander; Doriano Fabbro; Eamonn Kelly; Neil Marrion; John A Peters; Helen E Benson; Elena Faccenda; Adam J Pawson; Joanna L Sharman; Christopher Southan; Jamie A Davies Journal: Br J Pharmacol Date: 2015-12 Impact factor: 8.739
Authors: Thiago A F Ferro; Eliene B Souza; Mariela A M Suarez; João F S Rodrigues; Domingos M S Pereira; Saulo J F Mendes; Laoane F Gonzaga; Márcia C A M Machado; Maria R Q Bomfim; João B Calixto; Jack L Arbiser; Valério Monteiro-Neto; Eunice André; Elizabeth S Fernandes Journal: Molecules Date: 2019-04-25 Impact factor: 4.411