Summary of project PR000571
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000571. The data can be accessed directly via it's Project DOI: 10.21228/M8VM2M This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR000571 |
| Project DOI: | doi: 10.21228/M8VM2M |
| Project Title: | Pharmacometabolomics of L-Carnitine Treatment for Septic Shock |
| Project Type: | Quantitative NMR Metabolomics |
| Project Summary: | Rationale: Sepsis therapeutics have a poor history of success in clinical trials, due in part to the heterogeneity of enrolled patients. Pharmacometabolomics could differentiate drug response phenotypes and permit a precision medicine approach to sepsis. Objective: To utilize existing serum samples from the phase I clinical trial of L-carnitine treatment for severe sepsis to metabolically phenotype L-carnitine responders and non-responders. Methods: Serum samples collected prior to (T0) and after completion of the infusion (T24, T48) from patients randomized to either L-carnitine (12 g) or placebo for the treatment of vasopressor dependent septic shock were assayed by untargeted 1H-nuclear magnetic resonance metabolomics. The normalized, quantified metabolite data sets of L-carnitine and placebo treated patients at each time point were compared by ANOVA with post-hoc testing for multiple comparisons. Pathway analysis was performed to statistically rank metabolic networks. Measurements and main results: 38 metabolites were identified in all samples. Concentrations of 3-hydroxybutyrate, acetoacetate, 3-hydroxyisovalerate were different at T0 and over time in L-carnitine treated survivors versus non-survivors. Pathway analysis of pre-treatment metabolites revealed that synthesis and degradation of ketone bodies had the greatest impact in differentiating L-carnitine treatment response. Analysis of all patients based on pre-treatment 3-hydroxybutyrate concentration yielded distinct phenotypes. Using the T0 median 3-hydroxybutyrate level (153µM), patients were categorized as either high or low ketone. L-carnitine treated low ketone patients had greater utilization of carnitine as evidenced by lower post-treatment L-carnitine levels. The L-carnitine responders also had faster resolution of vasopressor requirement and a trend towards a greater improvement in mortality at 1 year (p = 0.038) compared with patients with higher 3-hydroxybutyrate. Conclusions: The results of this preliminary study, that were not readily apparent from the parent clinical trial, show a unique metabolite profile of L-carnitine responders and introduce pharmacometabolomics as a viable strategy for informing L-carnitine responsiveness. The approach taken in this study represents a concrete example for the application of precision medicine to sepsis therapeutics that warrants further study. This study was published: Ann Am Thorac Soc 2015;12:46-56. |
| Institute: | University of Michigan |
| Department: | Emergency Medicine |
| Laboratory: | University of Michigan NMR Metabolomics Laboratory |
| Last Name: | Stringer |
| First Name: | Kathleen |
| Address: | College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109 |
| Email: | NMRmetabolomics@umich.edu |
| Phone: | none |
| Funding Source: | This study was supported by the University of Michigan’s College of Pharmacy and its Biochemical Nuclear Magnetic Resonance Core and in part by the Michigan Regional Comprehensive Metabolomics Research Core (AK and Chenomx software), which is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; DK097153). The clinical trial was supported by a grant from the American Heart Association (10POST3560001) and the Cannon Foundation (SRG10-004). Dr. Jones’ effort was supported by a grant from the National Institute of General Medicine (NIGMS; R01GM103799). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIDDK, NIGMS or the National Institutes of Health. NIDDK (DK097153). |
Summary of all studies in project PR000571
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST000785 | Pharmacometabolomics of L-Carnitine Treatment Response Phenotypes in Patients with Septic Shock | Homo sapiens | University of Michigan | NMR | 2017-10-03 | 1 | 83 | Uploaded data (15.6M)* |
