Comparative Evaluation of Cyclooxygenase Inhibition Profiles Across Various NSAID Forms and Doses: Implications for Efficacy and Adverse Effects
Abstract Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for pain disorders and exert pharmacological effects by inhibiting cyclooxygenase (COX). Although previous studies have evaluated the COX inhibitory activity and selectivity of NSAIDs, none has compared COX inhibit...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Adis, Springer Healthcare
2024-12-01
|
| Series: | Pain and Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s40122-024-00687-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832586041517670400 |
|---|---|
| author | Kenshu Shirakawa Masafumi Takeno Hidekazu Kuma Takaaki Terahara Shigeki Yamaguchi |
| author_facet | Kenshu Shirakawa Masafumi Takeno Hidekazu Kuma Takaaki Terahara Shigeki Yamaguchi |
| author_sort | Kenshu Shirakawa |
| collection | DOAJ |
| description | Abstract Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for pain disorders and exert pharmacological effects by inhibiting cyclooxygenase (COX). Although previous studies have evaluated the COX inhibitory activity and selectivity of NSAIDs, none has compared COX inhibitory concentrations with the plasma concentrations of clinical doses or investigated the efficacy and adverse effects of different dosage forms. Therefore, in this study we evaluated the COX inhibitory activities and inhibition rates of clinical doses of the various NSAID formulations, especially diclofenac sodium. Methods Human blood and the drug (diclofenac sodium, celecoxib, ibuprofen, flurbiprofen, or etodolac) were mixed and incubated, and the supernatant was collected and quantified the COX inhibitory activity of each drug by ELISA. Logistic regression analyses were used to calculate the inhibition rates at maximum plasma drug concentration (C max) of clinical doses of marketed formulations. For diclofenac sodium, we also calculated the concentrations at which COX inhibition rates were 50% and 80% (IC50 and IC80). Results COX-2 inhibition rate at C max of clinical doses exceeded 50% except celecoxib 100 mg. For diclofenac sodium, the C max at the clinical doses of the oral and suppository formulations showed almost complete inhibition of COX-2 and an inhibition rate exceeding IC80 for COX-1. The C max at repeated doses of the transdermal formulation showed an inhibition rate above IC80 for COX-2 but below IC80 for COX-1. Discussion This result explains why gastrointestinal disorders frequently occur with oral and suppository formulations of diclofenac sodium despite its relatively high COX-2 selectivity. Although the plasma drug concentration of the transdermal formulation is lower than oral and suppository formulations, it has an inhibition rate above IC50 for COX-2, which is required for analgesic efficacy, and has a lower COX-1 inhibition rate than these formulations. Conclusion The findings explain why the transdermal formulation exerts an analgesic effect despite having a lower C max than other diclofenac sodium formulations. |
| format | Article |
| id | doaj-art-2923c4570d484070a96606685a5f2bed |
| institution | Kabale University |
| issn | 2193-8237 2193-651X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Adis, Springer Healthcare |
| record_format | Article |
| series | Pain and Therapy |
| spelling | doaj-art-2923c4570d484070a96606685a5f2bed2025-01-26T12:13:47ZengAdis, Springer HealthcarePain and Therapy2193-82372193-651X2024-12-0114132933810.1007/s40122-024-00687-2Comparative Evaluation of Cyclooxygenase Inhibition Profiles Across Various NSAID Forms and Doses: Implications for Efficacy and Adverse EffectsKenshu Shirakawa0Masafumi Takeno1Hidekazu Kuma2Takaaki Terahara3Shigeki Yamaguchi4Department of Anesthesiology and Pain Medicine, Dokkyo Medical University School of MedicineHisamitsu Pharmaceutical Co., Inc.Hisamitsu Pharmaceutical Co., Inc.Hisamitsu Pharmaceutical Co., Inc.Department of Anesthesiology and Pain Medicine, Dokkyo Medical University School of MedicineAbstract Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for pain disorders and exert pharmacological effects by inhibiting cyclooxygenase (COX). Although previous studies have evaluated the COX inhibitory activity and selectivity of NSAIDs, none has compared COX inhibitory concentrations with the plasma concentrations of clinical doses or investigated the efficacy and adverse effects of different dosage forms. Therefore, in this study we evaluated the COX inhibitory activities and inhibition rates of clinical doses of the various NSAID formulations, especially diclofenac sodium. Methods Human blood and the drug (diclofenac sodium, celecoxib, ibuprofen, flurbiprofen, or etodolac) were mixed and incubated, and the supernatant was collected and quantified the COX inhibitory activity of each drug by ELISA. Logistic regression analyses were used to calculate the inhibition rates at maximum plasma drug concentration (C max) of clinical doses of marketed formulations. For diclofenac sodium, we also calculated the concentrations at which COX inhibition rates were 50% and 80% (IC50 and IC80). Results COX-2 inhibition rate at C max of clinical doses exceeded 50% except celecoxib 100 mg. For diclofenac sodium, the C max at the clinical doses of the oral and suppository formulations showed almost complete inhibition of COX-2 and an inhibition rate exceeding IC80 for COX-1. The C max at repeated doses of the transdermal formulation showed an inhibition rate above IC80 for COX-2 but below IC80 for COX-1. Discussion This result explains why gastrointestinal disorders frequently occur with oral and suppository formulations of diclofenac sodium despite its relatively high COX-2 selectivity. Although the plasma drug concentration of the transdermal formulation is lower than oral and suppository formulations, it has an inhibition rate above IC50 for COX-2, which is required for analgesic efficacy, and has a lower COX-1 inhibition rate than these formulations. Conclusion The findings explain why the transdermal formulation exerts an analgesic effect despite having a lower C max than other diclofenac sodium formulations.https://doi.org/10.1007/s40122-024-00687-2Diclofenac sodiumNSAIDCyclooxygenase (COX)Whole blood assay (WBA)Gastrointestinal disorders |
| spellingShingle | Kenshu Shirakawa Masafumi Takeno Hidekazu Kuma Takaaki Terahara Shigeki Yamaguchi Comparative Evaluation of Cyclooxygenase Inhibition Profiles Across Various NSAID Forms and Doses: Implications for Efficacy and Adverse Effects Pain and Therapy Diclofenac sodium NSAID Cyclooxygenase (COX) Whole blood assay (WBA) Gastrointestinal disorders |
| title | Comparative Evaluation of Cyclooxygenase Inhibition Profiles Across Various NSAID Forms and Doses: Implications for Efficacy and Adverse Effects |
| title_full | Comparative Evaluation of Cyclooxygenase Inhibition Profiles Across Various NSAID Forms and Doses: Implications for Efficacy and Adverse Effects |
| title_fullStr | Comparative Evaluation of Cyclooxygenase Inhibition Profiles Across Various NSAID Forms and Doses: Implications for Efficacy and Adverse Effects |
| title_full_unstemmed | Comparative Evaluation of Cyclooxygenase Inhibition Profiles Across Various NSAID Forms and Doses: Implications for Efficacy and Adverse Effects |
| title_short | Comparative Evaluation of Cyclooxygenase Inhibition Profiles Across Various NSAID Forms and Doses: Implications for Efficacy and Adverse Effects |
| title_sort | comparative evaluation of cyclooxygenase inhibition profiles across various nsaid forms and doses implications for efficacy and adverse effects |
| topic | Diclofenac sodium NSAID Cyclooxygenase (COX) Whole blood assay (WBA) Gastrointestinal disorders |
| url | https://doi.org/10.1007/s40122-024-00687-2 |
| work_keys_str_mv | AT kenshushirakawa comparativeevaluationofcyclooxygenaseinhibitionprofilesacrossvariousnsaidformsanddosesimplicationsforefficacyandadverseeffects AT masafumitakeno comparativeevaluationofcyclooxygenaseinhibitionprofilesacrossvariousnsaidformsanddosesimplicationsforefficacyandadverseeffects AT hidekazukuma comparativeevaluationofcyclooxygenaseinhibitionprofilesacrossvariousnsaidformsanddosesimplicationsforefficacyandadverseeffects AT takaakiterahara comparativeevaluationofcyclooxygenaseinhibitionprofilesacrossvariousnsaidformsanddosesimplicationsforefficacyandadverseeffects AT shigekiyamaguchi comparativeevaluationofcyclooxygenaseinhibitionprofilesacrossvariousnsaidformsanddosesimplicationsforefficacyandadverseeffects |