Gitte Berkers1, Renske van der Meer2, Peter van Mourik1, Annelotte M Vonk3, Evelien Kruisselbrink3, Sylvia Wf Suen3, Harry Gm Heijerman4, Christof J Majoor5, Gerard H Koppelman6, Jolt Roukema7, Hettie M Janssens8, Yolanda B de Rijke9, E Marleen Kemper10, Jeffrey M Beekman3, Cornelis K van der Ent11, Hugo R de Jonge12. 1. Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. 2. Department of Pulmonology, Haga Teaching Hospital, The Hague, the Netherlands. 3. Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. 4. Department of Pulmonology, University Medical Center Utrecht, Utrecht, the Netherlands. 5. Department of Respiratory Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands. 6. Department of Pediatric Pulmonology and Pediatric Allergology and GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, the Netherlands. 7. Department of Pediatric Pulmonology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands. 8. Department of Pediatrics, division of Respiratory Medicine and Allergology, Erasmus Medical Center/Sophia Children's Hospital, University Hospital Rotterdam, the Netherlands. 9. Department of Clinical Chemistry, Erasmus Medical Center, University Hospital Rotterdam, the Netherlands. 10. Department of Pharmacy, Amsterdam University Medical Centers, Amsterdam, the Netherlands. 11. Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. Electronic address: K.vanderent@umcutrecht.nl. 12. Department of Gastroenterology and Hepatology, Erasmus Medical Center, University Hospital Rotterdam, the Netherlands.
Abstract
BACKGROUND: The natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein and ivacaftor, in different combinations. METHODS: In three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein. We evaluated change in lung function, sweat chloride concentration, CFQ-r, BMI and fecal elastase to determine the clinical effect. We evaluated the pharmacokinetic properties of the compounds by evaluating the concentration in plasma collected after treatment and the effect of the same plasma on the intestinal organoids. RESULTS: A clear clinical effect of treatment with ivacaftor was observed, evidenced by a significant improvement in clinical parameters. In contrast we observed no clear clinical effect of curcumin and/or genistein, except for a small but significant reduction in sweat chloride and airway resistance. Plasma concentrations of the food supplements were low, as was the response of the organoids to this plasma. CONCLUSIONS: We observed a clear clinical effect of treatment with ivacaftor, which is in line with the high responsiveness of the intestinal organoids to this drug. No clear clinical effect was observed of the treatment with curcumin and/or genistein, the low plasma concentration of these compounds emphasizes that pharmacokinetic properties of a compound have to be considered when in vitro experiments are performed.
BACKGROUND: The natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein and ivacaftor, in different combinations. METHODS: In three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein. We evaluated change in lung function, sweat chloride concentration, CFQ-r, BMI and fecal elastase to determine the clinical effect. We evaluated the pharmacokinetic properties of the compounds by evaluating the concentration in plasma collected after treatment and the effect of the same plasma on the intestinal organoids. RESULTS: A clear clinical effect of treatment with ivacaftor was observed, evidenced by a significant improvement in clinical parameters. In contrast we observed no clear clinical effect of curcumin and/or genistein, except for a small but significant reduction in sweat chloride and airway resistance. Plasma concentrations of the food supplements were low, as was the response of the organoids to this plasma. CONCLUSIONS: We observed a clear clinical effect of treatment with ivacaftor, which is in line with the high responsiveness of the intestinal organoids to this drug. No clear clinical effect was observed of the treatment with curcumin and/or genistein, the low plasma concentration of these compounds emphasizes that pharmacokinetic properties of a compound have to be considered when in vitro experiments are performed.
Authors: Justin D Anderson; Zhongyu Liu; L Victoria Odom; Latona Kersh; Jennifer S Guimbellot Journal: Am J Physiol Lung Cell Mol Physiol Date: 2021-05-19 Impact factor: 6.011
Authors: Sharon L Wong; Nikhil T Awatade; Miro A Astore; Katelin M Allan; Michael J Carnell; Iveta Slapetova; Po-Chia Chen; Alexander Capraro; Laura K Fawcett; Renee M Whan; Renate Griffith; Chee Y Ooi; Serdar Kuyucak; Adam Jaffe; Shafagh A Waters Journal: iScience Date: 2021-12-31