National CounterACT Initiative

Overview

The purpose of the study is to determine in vitro effects on mitochondrial function of selected chemical agents in human cells, and assess the capability of a cell-permeable succinate prodrug to attenuate toxic effects The project aims at repurposing this recent pharmaceutical discovery, currently being developed for treatment of toxic exposure, for an expanded indication to treat chemically induced mitochondrial toxicity.

Full Title of Study: “Mitochondrial Targeted Biofuels as Countermeasures Against Chemical Threats”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: April 18, 2023

Detailed Description

The study duration per subject will be approximately 15 minutes to complete the one time blood collection.

Arms, Groups and Cohorts

  • Patient
    • patients scheduled for elective surgery who are patients either as an inpatient or arriving to the hospital on the day of scheduled surgery
  • Volunteer
    • Volunteers who are employees, trainees and students at the Children’s Hospital of Philadelphia (CHOP) will be introduced to the study via an informational study flyer to determine eligibility and desire to participate in the study

Clinical Trial Outcome Measures

Primary Measures

  • Attenuation by the succinate prodrug of toxin-induced decrease in mitochondrial respiration.
    • Time Frame: by end of 2018
    • Data will be assessed using 2-tailed Student’s t-test. Dose-response curves for respiration will be made for each toxin and IC50 calculated. In case of difficulties in demonstrating acute toxicity of chemical agents, dose-titration experiments and long-term incubation (up to 24 hours) will be performed

Secondary Measures

  • Attenuation of toxin-induced decrease in mitochondrial membrane potential and attenuate lactate production by the succinate prodrug.
    • Time Frame: by end of 2018
    • Data will be assessed using 2-tailed Student’s t-test. Dose-response curves for respiration will be made for each toxin and IC50 calculated. In case of difficulties in demonstrating acute toxicity of chemical agents, dose-titration experiments and long-term incubation (up to 24 h) will be performed

Participating in This Clinical Trial

Patient Inclusion Criteria:

1. Males or females age greater or equal 2 years of age 2. Weight greater or equal to 10 kg 3. Parental/guardian permission (informed consent) and if appropriate, child assent. Patient Exclusion Criteria:

1. Known primary mitochondrial disorder. 2. Use of an investigational drug within 30 days prior to enrollment. 3. Parents/guardians or subjects who in the opinion of the Investigator, may be non-compliant with study schedules or procedures. Volunteer Inclusion Criteria 1. Males or females > 18 years of age 2. Employee, trainee, or student informed consent Volunteer Exclusion Criteria:

1. Prior enrollment in this study. 2. Known primary mitochondrial disorder. 3. Use of an investigational drug within 30 days prior to enrollment.

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Children’s Hospital of Philadelphia
  • Collaborator
    • National Institute of Neurological Disorders and Stroke (NINDS)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Todd J Kilbaugh, MD, Principal Investigator, Childrens Hospital of Philadelphia

References

Jeevaratnam K, Vidya S, Vaidyanathan CS. In vitro and in vivo effect of methyl isocyanate on rat liver mitochondrial respiration. Toxicol Appl Pharmacol. 1992 Dec;117(2):172-9. doi: 10.1016/0041-008x(92)90234-j.

Ehinger JK, Piel S, Ford R, Karlsson M, Sjovall F, Frostner EA, Morota S, Taylor RW, Turnbull DM, Cornell C, Moss SJ, Metzsch C, Hansson MJ, Fliri H, Elmer E. Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency. Nat Commun. 2016 Aug 9;7:12317. doi: 10.1038/ncomms12317.

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Hase Y, Tatsuno M, Nishi T, Kataoka K, Kabe Y, Yamaguchi Y, Ozawa N, Natori M, Handa H, Watanabe H. Atrazine binds to F1F0-ATP synthase and inhibits mitochondrial function in sperm. Biochem Biophys Res Commun. 2008 Feb 1;366(1):66-72. doi: 10.1016/j.bbrc.2007.11.107. Epub 2007 Dec 4.

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Gunnell D, Eddleston M, Phillips MR, Konradsen F. The global distribution of fatal pesticide self-poisoning: systematic review. BMC Public Health. 2007 Dec 21;7:357. doi: 10.1186/1471-2458-7-357.

Bus JS, Gibson JE. Paraquat: model for oxidant-initiated toxicity. Environ Health Perspect. 1984 Apr;55:37-46. doi: 10.1289/ehp.845537.

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