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Author Notes:

Address correspondence to: Laura L. Dugan, MD, Department of Medicine, Division of Geriatric Medicine, Vanderbilt University, 2215 Garland Av., 529 LH, Nashville, TN 37232, USA, laura.l.dugan@vanderbilt.edu, ph: 001-615-936-8303, fax: 001-615-936-2661

All of authors (Joshua I. Hardt; Joel S. Perlmutter; Christopher J. Smith; Kevin L. Quick; Subhasish K. Chakraborty and Laura L. Dugan) have no conflicts of interest.

Subjects:

Research Funding:

This study was supported by NIH/NINDS grants NS37688, NS050425, NS39913, NS41509 and NS058714; the American Parkinson Disease Association (APDA) Advanced Research Center at Washington University, the Greater St. Louis Chapter of the APDA and the Barnes-Jewish Hospital Foundation (Elliot Stein Family Fund for PD Research and the Jack Buck Fund for PD Research), the Larry L. Hillblom Foundation, the Hartke Fund and a Paul Beeson Physician Scholars Award (LLD).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Pharmacology & Pharmacy
  • IN-VIVO
  • FULLERENE
  • CARBOXYFULLERENE
  • SERTRALINE
  • NEURONS
  • STRESS

Pharmacokinetics and Toxicology of the Neuroprotective e,e,e-Methanofullerene(60)-63-tris Malonic Acid[C-3] in Mice and Primates

Tools:

Journal Title:

European Journal of Drug Metabolism and Pharmacokinetics

Volume:

Volume 43, Number 5

Publisher:

, Pages 543-554

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Background and Objectives: Fullerene-based compounds are a novel class of molecules being developed for a variety of biomedical applications, with nearly 1000 publications in this area in the last 4 years alone. One such compound, the e,e,e-methanofullerene(60)-63-tris malonic acid (designated C3), is a potent catalytic superoxide dismutase mimetic which has shown neuroprotective efficacy in a number of animal models of neurologic disease, including Parkinsonian Macaca fascicularis monkeys. The aim of this study was to characterize its toxicity and pharmacokinetics in mice and monkeys. Methods: To assess pharmacokinetics in mice, we synthesized and administered 14C-C3 to mice using various routes of delivery, including orally. To assess potential toxicity in primates, serial blood studies and electrocardiograms (ECGs) were obtained from monkeys treated with C3 (3 or 7 mg/kg/day) for 2 months. Results and Conclusions: The plasma half-life of C3 was 8.2 ± 0.2 h, and there was wide tissue distribution, including uptake into brain. The compound was cleared by both hepatic and renal excretion. C3 was quite stable, with minimal metabolism of the compound even after 7 days of treatment. The LD50 in mice was 80 mg/kg for a single intraperitoneal injection, and was > 30 mg/kg/day for sustained administration; therapeutic doses are 1–5 mg/kg/day. For primates, no evidence of renal, hepatic, electrolyte, or hematologic abnormalities were noted, and serial ECGs demonstrated no alteration in cardiac electrical activity. Thus, doses of C3 that have therapeutic efficacy appear to be well tolerated after 2 years (mice) or 2 months (non-human primates) of treatment.

Copyright information:

© 2018, Springer International Publishing AG, part of Springer Nature.

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