National CounterACT Initiative

NCT03597438 | Completed

• 2 other identifiers: 18-0150561R21NS103826-01
• Study Type: observational
• Target: 236
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Mitochondrial Alteration

Outcome Measures

Primary Outcomes (1)

• Attenuation by the succinate prodrug of toxin-induced decrease in mitochondrial respiration.

  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

  by end of 2018

Secondary Outcomes (1)

• Attenuation of toxin-induced decrease in mitochondrial membrane potential and attenuate lactate production by the succinate prodrug.

  by end of 2018

Study Arms (2)

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

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients scheduled for elective surgery will be screened for eligibility. Volunteers who are employees, trainees, and students will be screened for eligibility.

You may qualify if:

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

You may not qualify if:

• Known primary mitochondrial disorder.
• Use of an investigational drug within 30 days prior to enrollment.
• Parents/guardians or subjects who in the opinion of the Investigator, may be non-compliant with study schedules or procedures.
• Males or females \> 18 years of age
• Employee, trainee, or student informed consent
• Prior enrollment in this study.
• Known primary mitochondrial disorder.
• Use of an investigational drug within 30 days prior to enrollment.

Sponsors & Collaborators

• Children's Hospital of Philadelphia: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (1)

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (14)

• 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.

  PMID: 1471148 BACKGROUND

• 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.

  PMID: 27502960 BACKGROUND

• Degli Esposti M. Inhibitors of NADH-ubiquinone reductase: an overview. Biochim Biophys Acta. 1998 May 6;1364(2):222-35. doi: 10.1016/s0005-2728(98)00029-2.

  PMID: 9593904 BACKGROUND

• Mesnage R, Arno M, Costanzo M, Malatesta M, Seralini GE, Antoniou MN. Transcriptome profile analysis reflects rat liver and kidney damage following chronic ultra-low dose Roundup exposure. Environ Health. 2015 Aug 25;14:70. doi: 10.1186/s12940-015-0056-1.

  PMID: 26302742 BACKGROUND

• Friedrich T, van Heek P, Leif H, Ohnishi T, Forche E, Kunze B, Jansen R, Trowitzsch-Kienast W, Hofle G, Reichenbach H, et al. Two binding sites of inhibitors in NADH: ubiquinone oxidoreductase (complex I). Relationship of one site with the ubiquinone-binding site of bacterial glucose:ubiquinone oxidoreductase. Eur J Biochem. 1994 Jan 15;219(1-2):691-8. doi: 10.1111/j.1432-1033.1994.tb19985.x.

  PMID: 8307034 BACKGROUND

• Lim S, Ahn SY, Song IC, Chung MH, Jang HC, Park KS, Lee KU, Pak YK, Lee HK. Chronic exposure to the herbicide, atrazine, causes mitochondrial dysfunction and insulin resistance. PLoS One. 2009;4(4):e5186. doi: 10.1371/journal.pone.0005186. Epub 2009 Apr 13.

  PMID: 19365547 BACKGROUND

• 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.

  PMID: 18060860 BACKGROUND

• Hollingworth RM, Ahammadsahib KI, Gadelhak G, McLaughlin JL. New inhibitors of complex I of the mitochondrial electron transport chain with activity as pesticides. Biochem Soc Trans. 1994 Feb;22(1):230-3. doi: 10.1042/bst0220230. No abstract available.

  PMID: 8206238 BACKGROUND

• Satoh T, Miyoshi H, Sakamoto K, Iwamura H. Comparison of the inhibitory action of synthetic capsaicin analogues with various NADH-ubiquinone oxidoreductases. Biochim Biophys Acta. 1996 Jan 11;1273(1):21-30. doi: 10.1016/0005-2728(95)00131-x.

  PMID: 8573592 BACKGROUND

• Gassner B, Wuthrich A, Scholtysik G, Solioz M. The pyrethroids permethrin and cyhalothrin are potent inhibitors of the mitochondrial complex I. J Pharmacol Exp Ther. 1997 May;281(2):855-60.

  PMID: 9152394 BACKGROUND

• 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.

  PMID: 18154668 BACKGROUND

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

  PMID: 6329674 BACKGROUND

• Tawara T, Fukushima T, Hojo N, Isobe A, Shiwaku K, Setogawa T, Yamane Y. Effects of paraquat on mitochondrial electron transport system and catecholamine contents in rat brain. Arch Toxicol. 1996;70(9):585-9. doi: 10.1007/s002040050316.

  PMID: 8831909 BACKGROUND

• Eckerman I. THE BHOPAL SAGA: Universities Press (India); 2005.

  BACKGROUND

Study Officials

• Todd J Kilbaugh, MD

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 13, 2018
• First Posted: July 24, 2018
• Study Start: May 7, 2018
• Primary Completion: April 18, 2023
• Study Completion: February 22, 2024
• Last Updated: February 23, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)