Abstract |
CMX-2043 is an α- lipoic acid analogue targeted to reduction of cellular injury and organ damage due to ischaemia- reperfusion injury (IRI). It has been shown to be effective in a rat model of cardiac IRI. The studies here reported evaluate its safety and pharmacokinetic profile in preparation for human clinical studies in procedures associated with IRI. Safety and tolerability were tested in standard pre-clinical in vitro and animal models and in a Phase 1 human clinical trial. CMX-2043 did not bind to a wide range of receptors and specific targets at approximately 4 μg/mL (10 μM). It was not mutagenic by Ames assay, did not produce chromosome aberrations in Chinese hamster ovary (CHO) cells, and was negative for clastogenic potential. Toxicological studies in rats including both single and 14-day repeat intravenous doses and in dogs (single intravenous dose) with a 2-week recovery period were conducted. The NOAEL in rats and dogs was 30 and >10 mg/kg, respectively. No serious adverse events were reported in a placebo-controlled, sequential dose escalation Phase 1 clinical trial. The low toxicity in the pre-clinical studies and the absence of adverse events in the Phase 1 trial have supported investigation of CMX-2043 in a human efficacy trial.
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Authors | Steven A Kates, Alan S Lader, Ralph Casale, Reinier Beeuwkes 3rd |
Journal | Basic & clinical pharmacology & toxicology
(Basic Clin Pharmacol Toxicol)
Vol. 115
Issue 5
Pg. 456-64
(Nov 2014)
ISSN: 1742-7843 [Electronic] England |
PMID | 24751172
(Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial)
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Copyright | © 2014 Ischemix LLC. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of [Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). |
Chemical References |
- Dipeptides
- alpha-N-(1,2-dithiolane-3-pentanoyl)glutamylalanine
- Thioctic Acid
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Topics |
- Administration, Intravenous
- Adolescent
- Adult
- Animals
- CHO Cells
- Cricetinae
- Cricetulus
- Dipeptides
(administration & dosage, therapeutic use)
- Dogs
- Dose-Response Relationship, Drug
- Drug Administration Schedule
- Female
- Humans
- Male
- Mutagenicity Tests
- Rats
- Rats, Sprague-Dawley
- Rats, Wistar
- Reperfusion Injury
(drug therapy)
- Thioctic Acid
(administration & dosage, analogs & derivatives, therapeutic use)
- Young Adult
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