Publications by authors named "P D Ambery"
Key Points: Increasing doses of the endothelin receptor antagonist zibotentan and lower eGFR were associated with a higher risk of fluid retention. The higher risk of fluid retention could be attenuated by the combination of zibotentan with the sodium-glucose cotransporter 2 inhibitor dapagliflozin.
Background: Endothelin receptor antagonists (ERAs) reduce albuminuria but are limited by fluid retention risk, particularly in patients with CKD.
Article Synopsis
- The first endothelin (ET)-1 receptor antagonist was approved over 20 years ago, mainly used for pulmonary arterial hypertension, a rare condition.
- Recent research has highlighted the ET system's potential in treating various cardiovascular diseases, including resistant hypertension and conditions stemming from COVID-19.
- New developments, such as a new ET receptor antagonist and innovative combinations with other drugs, may enhance treatment effectiveness and reduce side effects, expanding the therapeutic use of the ET-1 pathway.
Article Synopsis
- Endothelin-1 (ET-1) receptor A antagonists have potential benefits for kidney disease but are limited by fluid retention and heart failure risks.
- A mathematical model was used to simulate the effects of ETA antagonism in patients with type 2 diabetes and chronic kidney disease, analyzing various health indicators from the RADAR clinical trial.
- The study found that fluid retention is primarily due to venodilation and increased venous capacity, rather than a direct effect on kidney function, indicating a compensatory mechanism to maintain heart performance.
Article Synopsis
- The tutorial focuses on model-informed drug development (MIDD) as a critical approach in determining effective dosing strategies in drug trials, exemplified by the ZENITH trials.
- The case study highlights the combination of zibotentan and dapagliflozin, showing their significant impact on reducing albuminuria in chronic kidney disease patients and addressing challenges related to fluid retention.
- Through careful dose-response modeling and analysis, the trials successfully identified optimal dosages of zibotentan, paving the way for improved treatments in high-risk populations with kidney issues.
Endothelin A and B receptors, together with sodium-glucose cotransporter-2 (SGLT-2) channels are important targets in improving endothelial function and intervention with inhibitors has been the subject of multiple mechanistic and clinical outcome trials over recent years. Notable successes include the treatment of pulmonary hypertension with endothelin receptor antagonists, and the treatment of heart failure and chronic kidney disease with SGLT-2 inhibitors. With distinct and complementary mechanisms, in this review, we explore the logic of combination therapy for a number of diseases which have endothelial dysfunction at their heart.
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