Optimization of Long-Acting Bronchodilator Dose Ratios Using Isolated Guinea Pig Tracheal Rings for Synergistic Combination Therapy in Asthma and COPD
Abstract
:1. Introduction
2. Results
2.1. Individual Relaxant Effect
2.2. Interaction between LABA and LAMA Based on a Non-Constant Dose Ratio
2.3. Interaction between LABA and LAMA Based on a Constant Dose Ratio
2.4. Interaction between LABA and LAMA Over Time
3. Discussion
4. Materials and Methods
4.1. Drugs
4.2. Animals
4.3. Preparation of Isolated Tracheal Rings from Dunkin Hartley Guinea Pig
4.4. Experimental Protocol
4.4.1. Cumulative Dose Fashion
4.4.2. Study Design
Interaction between LABA and LAMA Based on a Non-Constant Dose Ratio
Interaction between LABA and LAMA Based on a Constant Dose Ratio
Interaction between LABA and LAMA Over Time
4.5. Drug Interaction Analysis
4.6. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ANOVA | Analysis of variance |
ASM | Airway smooth muscle |
BI | Bliss independence |
CI | Combination index |
COPD | Chronic obstructive pulmonary disease |
ΔE | Delta effect |
DRI | Dose reduction index |
EC50-70 | Submaximal effective concentration size between 50% and 70% of the maximum concentration |
FOR | Formoterol fumarate dihydrate |
IND | Indacaterol maleate |
LABA | Long-acting β2-agonist |
LAMA | Long-acting muscarinic antagonist |
pEC50 | Negative logarithm of the half maximal effective concentration |
SEM | Standard error of the mean |
TIO | Tiotropium bromide monohydrate |
UT | Unified theory |
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A | Tiotropium bromide monohydrate | Formoterol fumarate dihydrate | Relaxant effect (%) | CI | Interaction magnitude |
1.55 nM | 0.45 nM | 35.12 | 3.522 | − − − − − | |
1.55 nM | 0.90 nM | 69.49 | 0.834 | + + | |
1.55 nM | 1.81 nM | 86.51 | 0.294 | + + + + | |
1.55 nM | 2.71 nM | 95.34 | 0.102 | + + + + | |
1.55 nM | 3.62 nM | 98.64 | 0.035 | + + + + + | |
1.55 nM | 7.24 nM | 99.3 | 0.020 | + + + + + | |
1.55 nM | 9.04 nM | 99.7 | 0.009 | + + + + + | |
B | Tiotropium bromide monohydrate | Formoterol fumarate dihydrate | Relaxant effect (%) | CI | Interaction magnitude |
0.41 nM | 0.12 nM | 10.49 | 2.158 | − − − − | |
0.61 nM | 0.35 nM | 33.20 | 1.174 | − − | |
0.81 nM | 0.94 nM | 59.17 | 0.652 | + + + | |
1.02 nM | 1.79 nM | 79.21 | 0.337 | + + + | |
1.55 nM | 3.62 nM | 91.34 | 0.183 | + + + + | |
2.08 nM | 9.69 nM | 97.35 | 0.080 | + + + + + | |
2.60 nM | 15.19 nM | 99.59 | 0.060 | + + + + + | |
C | Tiotropium bromide monohydrate | Indacaterol maleate | Relaxant effect (%) | CI | Interaction magnitude |
1.55 nM | 1.50 nM | 36445,00 | 3.865 | − − − − − | |
1.55 nM | 2.99 nM | 69.54 | 0.928 | + | |
1.55 nM | 7.48 nM | 83.93 | 0.385 | + + + | |
1.55 nM | 14.96 nM | 91.03 | 0.190 | + + + + | |
1.55 nM | 29.91 nM | 96.59 | 0.076 | + + + + + | |
1.55 nM | 59.82 nM | 99.06 | 0.025 | + + + + + | |
1.55 nM | 74.78 nM | 99.64 | 0.011 | + + + + + | |
1.55 nM | 0.15 mM | 99.86 | 0.005 | + + + + + | |
D | Tiotropium bromide monohydrate | Indacaterol maleate | Relaxant effect (%) | CI | Interaction magnitude |
0.41 nM | 0.39 nM | 9.92 | 18.707 | − − − − − − | |
0.61 nM | 1.17 nM | 27.91 | 1.779 | − − − − | |
0.81 nM | 3.90 nM | 48.10 | 0.895 | + | |
1.02 nM | 9.88 nM | 71.56 | 0.440 | + + + | |
1.55 nM | 29.91 nM | 90.30 | 0.203 | + + + + | |
2.08 nM | 80.14 nM | 97.99 | 0.067 | + + + + + | |
2.60 nM | 0.13 mM | 99.12 | 0.041 | + + + + + | |
3.13 nM | 0.30 mM | 99,59 | 0.025 | + + + + + |
DRI50 | |||
---|---|---|---|
LABA/LAMA Combination | TIO | FOR | IND |
FOR/TIO 2:1 (w/w) | 1.38 | 4 338 | / |
FOR/TIO 3:1 (w/w) | 1.23 | 2 586 | / |
IND/TIO 10:1 (w/w) | 1.27 | / | 4 484 |
IND/TIO 20:1 (w/w) | 1.35 | / | 2 370 |
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Menchi, E.; El Khattabi, C.; Pochet, S.; Denis, O.; Amighi, K.; Wauthoz, N. Optimization of Long-Acting Bronchodilator Dose Ratios Using Isolated Guinea Pig Tracheal Rings for Synergistic Combination Therapy in Asthma and COPD. Pharmaceuticals 2022, 15, 963. https://doi.org/10.3390/ph15080963
Menchi E, El Khattabi C, Pochet S, Denis O, Amighi K, Wauthoz N. Optimization of Long-Acting Bronchodilator Dose Ratios Using Isolated Guinea Pig Tracheal Rings for Synergistic Combination Therapy in Asthma and COPD. Pharmaceuticals. 2022; 15(8):963. https://doi.org/10.3390/ph15080963
Chicago/Turabian StyleMenchi, Elena, Charaf El Khattabi, Stéphanie Pochet, Olivier Denis, Karim Amighi, and Nathalie Wauthoz. 2022. "Optimization of Long-Acting Bronchodilator Dose Ratios Using Isolated Guinea Pig Tracheal Rings for Synergistic Combination Therapy in Asthma and COPD" Pharmaceuticals 15, no. 8: 963. https://doi.org/10.3390/ph15080963
APA StyleMenchi, E., El Khattabi, C., Pochet, S., Denis, O., Amighi, K., & Wauthoz, N. (2022). Optimization of Long-Acting Bronchodilator Dose Ratios Using Isolated Guinea Pig Tracheal Rings for Synergistic Combination Therapy in Asthma and COPD. Pharmaceuticals, 15(8), 963. https://doi.org/10.3390/ph15080963