Details

Autor(en) / Beteiligte

• Alahmari, Randh Ahmed

Titel

A Distinctive Metabolomics Pattern Associated with The Administration of Combined Dose of Sacubitril/Valsartan to Healthy Subjects - A Kinetic Approach

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2024

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• Background: Heart failure is a chronic condition associated with a decline in performance, which activates various compensatory mechanisms, including the natriuretic peptide and the renin-angiotensin-aldosterone (RAAS) system. Targeting these systems through pharmacological interventions can help improve patient’s health outcomes. This condition is treated with a drug combination of Sacubitril/Valsartan. The combined drug Sacubitril/Valsartan is a neprilysin inhibitor and angiotensin II receptor blocker (ARB), respectively, providing a dual-acting inhibition of RAAS and maintaining natriuretic peptides circulation. The Metabolomics approach has recently emerged as a means to create a predictive tool for assessing the efficacy of therapeutics and their potential side effects on humans in a dynamic manner.Objective: To comprehend the impact of imbalanced metabolites linked to the concurrent use of Sacubitril/Valsartan medication in a kinetic profile.Methodology: Healthy volunteers (n=14) were recruited to participate in this study after screening for any abnormalities and received a tablet combination of (97.2 mg of Sacubitril and 102.8 mg of Valsartan) twice “Phase I and Phase II” including a two-week washout period in between. Plasma samples were collected at eight-time points, pre-dose, before Cmax 1-3, Cmax, After Cmax 1 and 2, and after 48 hrs. 224 samples were extracted using MeOH: ACN (50:50) and analyzed using LC-QToF HRMS for untargeted metabolomics profiling in positive and negative ionization modes. Results: Positive and negative ionization modes collectively detected 20,472 mass ions for both phases, of which only 20,399 mass ions were shared features between Phase I and Phase II. After removing missing values, 13,840 features remained for one-way analysis of variance (ANOVA) with Tukey’s post hoc analysis (FDRp<0.05), which was performed among the eight-time points and revealed 315 significantly dysregulated metabolites compared to the background sample. Only 208 metabolites were identified by matching with the database” the Human Metabolome Database” using the Progenesis QI software, and 75 were considered human endogenous metabolites. Out of those metabolites, 15 were Sacubitril/Valsartan-dependent metabolites and were shown to be upregulated. Pyrimidine metabolism was the most impacted pathway.Conclusion: This untargeted metabolomics profile shows a solid dysregulation associated with the drug administration, which is believed to serve as a biochemical surrogate, and provide extensive knowledge regarding the disease therapeutic mechanism such as increases the UTP (Uridine-5'-triphosphate) and Cyclin D1 in heart failure patients.