Pharmacometabolomics of <scp>l</scp>-Carnitine Treatment Response Phenotypes in Patients with Septic Shock

Puskarich, Michael A.; Finkel, Michael A.; Karnovsky, Alla; Jones, Alan E.; Trexel, Julie; Harris, Brooke N.; Stringer, Kathleen A.

doi:10.1513/annalsats.201409-415oc

Cited by 59 publications

(85 citation statements)

References 46 publications

(52 reference statements)

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“…In addition, a major logistical challenge in studying critical ill patients is their unscheduled presentation into relatively poorly controlled areas of the health care systems (e.g., the emergency department, the operating room, the ICU), which may contribute to delays, and technical variation inherent in sample handling and processing even in a clinical research setting. Nevertheless, metabolomics holds promise to inform of underlying etiology and may be a more sensitive gauge of illness severity and outcome than traditional biomarkers (e.g., SOFA scores) (17). This makes the implications of our findings particularly relevant to sepsis because the employment of sound metabolomics approaches are critical for the generation of reliable metabolomics data, though these findings are also likely to be relevant in any number of disease states notable for alterations in blood rheology.…”

Section: Discussionmentioning

confidence: 99%

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Whole Blood Reveals More Metabolic Detail of the Human Metabolome than Serum as Measured by 1H-NMR Spectroscopy

Stringer¹,

Younger²,

McHugh³

et al. 2015

Shock

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Serum is a common sample of convenience for metabolomics studies. Its processing time can be lengthy and may result in the loss of metabolites including those of red blood cells (RBC). Unlike serum, whole blood (WB) is quickly processed, minimizing the influence of variable hemolysis while including RBC metabolites. To determine differences between serum and WB metabolomes, both sample types, collected from healthy volunteers, were assayed by 1H-NMR spectroscopy. A total of 34 and 50 aqueous metabolites were quantified from serum and WB, respectively. Free hemoglobin (Hgb) levels in serum were measured and the correlation between Hgb and metabolite concentrations was determined. All metabolites detected in serum were at higher concentrations in WB with the exception of acetoacetate and propylene glycol. The 18 unique metabolites of WB included adenosine, AMP, ADP and ATP, which are associated with RBC metabolism. The use of serum results in the underrepresentation of a number of metabolic pathways including branched chain amino acid degradation and glycolysis and gluconeogenesis. The range of free Hgb in serum was 0.03-0.01 g/dL and 8 metabolites were associated (p ≤ 0.05) with free Hgb. The range of free Hgb in serum samples from 18 sepsis patients was 0.02-0.46 g/dL. WB and serum have unique aqueous metabolite profiles but the use of serum may introduce potential pathway bias. Use of WB for metabolomics may be particularly important for studies in diseases like sepsis in which RBC metabolism is altered and mechanical and sepsis-induced hemolysis contributes to variance in the metabolome.

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Section: Discussionmentioning

confidence: 99%

“…At the time of assay, frozen samples were thawed on ice and macromolecules were removed by the addition of methanol:chloroform (1:1) as previously described (17). Following extraction, the resulting aqueous phase of each sample was assayed by 1 H-NMR spectroscopy.…”

Section: Methodsmentioning

confidence: 99%

Whole Blood Reveals More Metabolic Detail of the Human Metabolome than Serum as Measured by 1H-NMR Spectroscopy

Stringer¹,

Younger²,

McHugh³

et al. 2015

Shock

Self Cite

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“…Taken together with the fact that sepsis, as mentioned above, is a global health concern, this underlines the significance of metabolomics for public health. More specifically, by complementing other “-omics” technologies, employment of metabolomics has the potential to radically transform the research and clinical landscape in sepsis by enabling effective risk stratification and diagnosis [100], prognosis [101], and, with pharmacometabolomics, even targeted therapeutic approaches [102]. …”

Section: Impact On Public Healthmentioning

confidence: 99%

Metabolomics in Sepsis and Its Impact on Public Health

Evangelatos

Bauer

Reumann

et al. 2017

Public Health Genomics

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Sepsis, with its often devastating consequences for patients and their families, remains a major public health concern that poses an increasing financial burden. Early resuscitation together with the elucidation of the biological pathways and pathophysiological mechanisms with the use of “-omics” technologies have started changing the clinical and research landscape in sepsis. Metabolomics (i.e., the study of the metabolome), an “-omics” technology further down in the “-omics” cascade between the genome and the phenome, could be particularly fruitful in sepsis research with the potential to alter the clinical practice. Apart from its benefit for the individual patient, metabolomics has an impact on public health that extends beyond its applications in medicine. In this review, we present recent developments in metabolomics research in sepsis, with a focus on pneumonia, and we discuss the impact of metabolomics on public health, with a focus on free/libre open source software.

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“…Puskarich et al [73] used 500 MHz 1 H NMR of pre-dose serum samples to show that lower baseline blood serum levels of 3-hydroxybutyrate (p < 0.001), acetoacetate (p < 0.001) and 3-hydroxyisovalerate (p < 0.001) were significantly associated with survival for septic shock patients on L-carnitine therapy (4 g bolus followed by 8 g infusion over 12 hours). The 31 patients were randomised between placebo (n = 15) and drug treatment (n = 16).…”

Section: Prediction Of Drug Efficacy Studiesmentioning

confidence: 99%

“…It is striking that pharmacometabonomics approaches are now being used to predict drug efficacy in situations that are literally life-and-death, such as the report by Puskarich et al [73] involving septic shock patients on L-carnitine therapy. Many of the studies reported are early stage and exploratory, rather than large-scale clinical trials, and many of the studies will require validation in larger cohorts of subjects.…”

Section: Conclusion and The Future For Pharmacometabonomicsmentioning

confidence: 99%

NMR-based pharmacometabonomics: A new paradigm for personalised or precision medicine

Everett

2017

Progress in Nuclear Magnetic Resonance Spectroscopy

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Metabolic profiling by NMR spectroscopy or hyphenated mass spectrometry, known as metabonomics or metabolomics, is an important tool for systemsbased approaches in biology and medicine. The experiments are typically done in a diagnostic fashion where changes in metabolite profiles are interpreted as a consequence of an intervention or event; be that a change in diet, the administration of a drug, physical exertion or the onset of a disease. By contrast, pharmacometabonomics takes a prognostic approach to metabolic profiling, in order to predict the effects of drug dosing before it occurs. Differences in predose metabolite profiles between groups of subjects are used to predict postdose differences in response to drug administration. Thus the paradigm is inverted and pharmacometabonomics is the metabolic equivalent of pharmacogenomics. Although the field is still in its infancy, it is expected that pharmacometabonomics, alongside pharmacogenomics, will assist with the delivery of personalised or precision medicine to patients, which is a critical goal of 21 st century healthcare. Highlights metabonomics or metabolomics involves metabolic profiling by NMR or MS methods  metabonomics is used in a diagnostic mode to study the effects of an intervention  pharmacometabonomics is a prognostic method to predict the effects of drugs  pharmacometabonomics is a special case of predictive metabonomics  pharmacometabonomics will help to deliver personalised medicine in the future Graphical AbstractNMR-Based Pharmacometabonomics PNMRS 2017

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Pharmacometabolomics of l-Carnitine Treatment Response Phenotypes in Patients with Septic Shock

Cited by 59 publications

References 46 publications

Whole Blood Reveals More Metabolic Detail of the Human Metabolome than Serum as Measured by 1H-NMR Spectroscopy

Whole Blood Reveals More Metabolic Detail of the Human Metabolome than Serum as Measured by 1H-NMR Spectroscopy

Metabolomics in Sepsis and Its Impact on Public Health

NMR-based pharmacometabonomics: A new paradigm for personalised or precision medicine

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