Oral hymecromone decreases hyaluronan in human study participants
BACKGROUND Hyaluronan (HA), an extracellular matrix glycosaminoglycan, has been implicated in the pathophysiology of COVID-19 infection, pulmonary hypertension, pulmonary fibrosis, and other diseases, but is not targeted by any approved drugs. We asked whether hymecromone (4-methylumbelliferone [4-M...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-05-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI157983 |
| _version_ | 1818242778052689920 |
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| author | Joelle I. Rosser Nadine Nagy Riya Goel Gernot Kaber Sally Demirdjian Jamie Saxena Jennifer B. Bollyky Adam R. Frymoyer Ana E. Pacheco-Navarro Elizabeth B. Burgener Jayakumar Rajadas Zhe Wang Olga Arbach Colleen E. Dunn Anissa Kalinowski Carlos E. Milla Paul L. Bollyky |
| author_facet | Joelle I. Rosser Nadine Nagy Riya Goel Gernot Kaber Sally Demirdjian Jamie Saxena Jennifer B. Bollyky Adam R. Frymoyer Ana E. Pacheco-Navarro Elizabeth B. Burgener Jayakumar Rajadas Zhe Wang Olga Arbach Colleen E. Dunn Anissa Kalinowski Carlos E. Milla Paul L. Bollyky |
| author_sort | Joelle I. Rosser |
| collection | DOAJ |
| description | BACKGROUND Hyaluronan (HA), an extracellular matrix glycosaminoglycan, has been implicated in the pathophysiology of COVID-19 infection, pulmonary hypertension, pulmonary fibrosis, and other diseases, but is not targeted by any approved drugs. We asked whether hymecromone (4-methylumbelliferone [4-MU]), an oral drug approved in Europe for biliary spasm treatment that also inhibits HA in vitro and in animal models, could be repurposed as an inhibitor of HA synthesis in humans.METHODS We conducted an open-label, single-center, dose-response study of hymecromone in healthy adults. Subjects received hymecromone at 1200 (n = 8), 2400 (n = 9), or 3600 (n = 9) mg/d divided into 3 doses daily, administered orally for 4 days. We assessed safety and tolerability of hymecromone and analyzed HA, 4-MU, and 4-methylumbelliferyl glucuronide (4-MUG; the main metabolite of 4-MU) concentrations in sputum and serum.RESULTS Hymecromone was well tolerated up to doses of 3600 mg/d. Both sputum and serum drug concentrations increased in a dose-dependent manner, indicating that higher doses lead to greater exposures. Across all dose arms combined, we observed a significant decrease in sputum HA from baseline after 4 days of treatment. We also observed a decrease in serum HA. Additionally, higher baseline sputum HA levels were associated with a greater decrease in sputum HA.CONCLUSION After 4 days of exposure to oral hymecromone, healthy human subjects experienced a significant reduction in sputum HA levels, indicating this oral therapy may have potential in pulmonary diseases where HA is implicated in pathogenesis.TRIAL REGISTRATION ClinicalTrials.gov NCT02780752.FUNDING Stanford Medicine Catalyst, Stanford SPARK, Stanford Innovative Medicines Accelerator program, NIH training grants 5T32AI052073-14 and T32HL129970. |
| first_indexed | 2024-12-12T13:50:38Z |
| format | Article |
| id | doaj.art-f748f673d08f429f9f1becca4580831e |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-12-12T13:50:38Z |
| publishDate | 2022-05-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-f748f673d08f429f9f1becca4580831e2022-12-22T00:22:34ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-05-011329Oral hymecromone decreases hyaluronan in human study participantsJoelle I. RosserNadine NagyRiya GoelGernot KaberSally DemirdjianJamie SaxenaJennifer B. BollykyAdam R. FrymoyerAna E. Pacheco-NavarroElizabeth B. BurgenerJayakumar RajadasZhe WangOlga ArbachColleen E. DunnAnissa KalinowskiCarlos E. MillaPaul L. BollykyBACKGROUND Hyaluronan (HA), an extracellular matrix glycosaminoglycan, has been implicated in the pathophysiology of COVID-19 infection, pulmonary hypertension, pulmonary fibrosis, and other diseases, but is not targeted by any approved drugs. We asked whether hymecromone (4-methylumbelliferone [4-MU]), an oral drug approved in Europe for biliary spasm treatment that also inhibits HA in vitro and in animal models, could be repurposed as an inhibitor of HA synthesis in humans.METHODS We conducted an open-label, single-center, dose-response study of hymecromone in healthy adults. Subjects received hymecromone at 1200 (n = 8), 2400 (n = 9), or 3600 (n = 9) mg/d divided into 3 doses daily, administered orally for 4 days. We assessed safety and tolerability of hymecromone and analyzed HA, 4-MU, and 4-methylumbelliferyl glucuronide (4-MUG; the main metabolite of 4-MU) concentrations in sputum and serum.RESULTS Hymecromone was well tolerated up to doses of 3600 mg/d. Both sputum and serum drug concentrations increased in a dose-dependent manner, indicating that higher doses lead to greater exposures. Across all dose arms combined, we observed a significant decrease in sputum HA from baseline after 4 days of treatment. We also observed a decrease in serum HA. Additionally, higher baseline sputum HA levels were associated with a greater decrease in sputum HA.CONCLUSION After 4 days of exposure to oral hymecromone, healthy human subjects experienced a significant reduction in sputum HA levels, indicating this oral therapy may have potential in pulmonary diseases where HA is implicated in pathogenesis.TRIAL REGISTRATION ClinicalTrials.gov NCT02780752.FUNDING Stanford Medicine Catalyst, Stanford SPARK, Stanford Innovative Medicines Accelerator program, NIH training grants 5T32AI052073-14 and T32HL129970.https://doi.org/10.1172/JCI157983Inflammation |
| spellingShingle | Joelle I. Rosser Nadine Nagy Riya Goel Gernot Kaber Sally Demirdjian Jamie Saxena Jennifer B. Bollyky Adam R. Frymoyer Ana E. Pacheco-Navarro Elizabeth B. Burgener Jayakumar Rajadas Zhe Wang Olga Arbach Colleen E. Dunn Anissa Kalinowski Carlos E. Milla Paul L. Bollyky Oral hymecromone decreases hyaluronan in human study participants The Journal of Clinical Investigation Inflammation |
| title | Oral hymecromone decreases hyaluronan in human study participants |
| title_full | Oral hymecromone decreases hyaluronan in human study participants |
| title_fullStr | Oral hymecromone decreases hyaluronan in human study participants |
| title_full_unstemmed | Oral hymecromone decreases hyaluronan in human study participants |
| title_short | Oral hymecromone decreases hyaluronan in human study participants |
| title_sort | oral hymecromone decreases hyaluronan in human study participants |
| topic | Inflammation |
| url | https://doi.org/10.1172/JCI157983 |
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