Category
JFL 261A
Description
Background: Cystic fibrosis is a life-limiting genetic disorder that primarily affects the lungs and digestive system. Cystic fibrosis (CF) is caused by over 2000 different mutations in the CFTR anion channel. Trikafta is a lifesaving, highly effective triple drug combination consisting of two trafficking correctors (Elexacaftor and Tezacaftor) and the channel potentiator Ivacaftor. However, these drugs produce significant side effects, including gastroesophageal reflux disease, abdominal pain, diarrhea, constipation, and nausea. Elexacaftor has significant off-target effects on various potassium channels which could explain some of these adverse events. Therefore, we sought to characterize the enteric motility effects of Elexacaftor using a murine model. Methods: C57Bl/6 mice were used to assess lower esophageal sphincter and jejunal circular muscle in vitro spontaneous circular muscle contractions. Additionally, in vivo upper gastrointestinal motility was assessed by orally feeding non-digestible FITC-dextran (70 kDa) and generating gastrointestinal transit distribution histograms with calculated geometric centers (GC) after 80 min. Results: Elexacaftor (5.97 and 17.93 mg/kg) was given at clinically relevant dosages intraperitoneally 30 minutes before the assessment of gastrointestinal motility. The subsequent gastrointestinal transit distribution histograms demonstrated a significant delay with a calculated geometric center of 8.44 and 5.50 compared to control 10.4 (N=4, p<0.05). In vitro Elexacaftor (10 µM) caused a significant relaxation of the lower esophageal sphincter spontaneously generated tonic muscle contractions (N=3). Additionally, the spontaneous jejunal circular muscle phasic contractions were also significantly inhibited by both 10 and 30 µM concentrations of Elexacaftor. Conclusion: These data demonstrate that Elexacaftor has significant inhibitory effects on upper gastrointestinal motility. Elexacaftor induced lower esophageal sphincter relaxation would allow gastric acid reflux leading to the clinical diagnosis of GERD. And a delay in upper intestinal transit could also further potentiate acid reflux into the esophagus. Interestingly, these results may explain the gastrointestinal adverse events in patients with CF.
Effect of the Cystic Fibrosis Drug Elexacaftor on the Murine Lower Esophageal Sphincter May Explain the GERD Symptoms of Patients
JFL 261A
Background: Cystic fibrosis is a life-limiting genetic disorder that primarily affects the lungs and digestive system. Cystic fibrosis (CF) is caused by over 2000 different mutations in the CFTR anion channel. Trikafta is a lifesaving, highly effective triple drug combination consisting of two trafficking correctors (Elexacaftor and Tezacaftor) and the channel potentiator Ivacaftor. However, these drugs produce significant side effects, including gastroesophageal reflux disease, abdominal pain, diarrhea, constipation, and nausea. Elexacaftor has significant off-target effects on various potassium channels which could explain some of these adverse events. Therefore, we sought to characterize the enteric motility effects of Elexacaftor using a murine model. Methods: C57Bl/6 mice were used to assess lower esophageal sphincter and jejunal circular muscle in vitro spontaneous circular muscle contractions. Additionally, in vivo upper gastrointestinal motility was assessed by orally feeding non-digestible FITC-dextran (70 kDa) and generating gastrointestinal transit distribution histograms with calculated geometric centers (GC) after 80 min. Results: Elexacaftor (5.97 and 17.93 mg/kg) was given at clinically relevant dosages intraperitoneally 30 minutes before the assessment of gastrointestinal motility. The subsequent gastrointestinal transit distribution histograms demonstrated a significant delay with a calculated geometric center of 8.44 and 5.50 compared to control 10.4 (N=4, p<0.05). In vitro Elexacaftor (10 µM) caused a significant relaxation of the lower esophageal sphincter spontaneously generated tonic muscle contractions (N=3). Additionally, the spontaneous jejunal circular muscle phasic contractions were also significantly inhibited by both 10 and 30 µM concentrations of Elexacaftor. Conclusion: These data demonstrate that Elexacaftor has significant inhibitory effects on upper gastrointestinal motility. Elexacaftor induced lower esophageal sphincter relaxation would allow gastric acid reflux leading to the clinical diagnosis of GERD. And a delay in upper intestinal transit could also further potentiate acid reflux into the esophagus. Interestingly, these results may explain the gastrointestinal adverse events in patients with CF.
Comments
Undergraduate