title: Acute and subacute toxicity studies of CMICE-013, a novel iodinated rotenone-based myocardial perfusion tracer, in Sprague Dawley rats and Gottingen minipigs.
abstract: OBJECTIVE
  Extensive acute and subacute toxicities studies are required to evaluate the toxicological profile of the novel cardiac perfusion imaging tracer (123)I-CMICE-013 to support applications for clinical trials.
  
  
  METHODS
  Sprague-Dawley rats and Gottingen minipigs received injections of non-radioactive 127I-CMICE-013 at two dosage levels of 1 and 5 μg/kg, and vehicle buffer as control. In the acute toxicity studies, each animal was injected on two occasions 24 h apart and then underwent a 14-day recovery period; in the subacute study, animals received daily injections for 14 days continuously. The health status and mortality of test animals were monitored daily and body weight, food consumption, physiological and biochemical parameters were measured at various time points during the study. Animals were euthanized at the end of the studies and dissected for pathologic examination of organs and tissues.
  
  
  RESULTS
  The acute and subacute administrations of injections of the non-radioactive CMICE-013 in rats and minipigs were well tolerated. Little to no dosing-related adverse effects were observed in animal body and organ weights, hematology, coagulation, clinical chemistry, urinalysis, ophthalmoscopy, electrocardiograms, heart rates, blood pressure, macroscopic and microscopic examination of the preserved animal tissues including the brain.
  
  
  CONCLUSIONS
  The lack of adverse effects from acute and subacute dosing suggest that the CMICE-013 injection solution has a reasonable safety margin within the designed concentration range to be utilized in imaging applications. The dosage level of 5 μg/kg was considered the no adverse effect level for both rats and minipigs based on our acute and subacute studies.
authors.affiliation: Nordion Inc., 447 March Road, Ottawa, ON K2K 1X8, Canada; Canadian Molecular Imaging Center of Excellence (CMICE), University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada. Electronic address: dyduan81@gmail.com.
authors.forename: Yin
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Nordion Inc., 447 March Road, Ottawa, ON K2K 1X8, Canada; Canadian Molecular Imaging Center of Excellence (CMICE), University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada.
authors.forename: Xuxu
authors.initials: X
authors.lastname: Yan
authors.affiliation: Nordion Inc., 447 March Road, Ottawa, ON K2K 1X8, Canada; Canadian Molecular Imaging Center of Excellence (CMICE), University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada; Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada.
authors.forename: Lihui
authors.initials: L
authors.lastname: Wei
authors.affiliation: Nordion Inc., 447 March Road, Ottawa, ON K2K 1X8, Canada; Canadian Molecular Imaging Center of Excellence (CMICE), University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada; Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada.
authors.forename: Corinne
authors.initials: C
authors.lastname: Bensimon
authors.affiliation: Nordion Inc., 447 March Road, Ottawa, ON K2K 1X8, Canada; Canadian Molecular Imaging Center of Excellence (CMICE), University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada; Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Pasan
authors.initials: P
authors.lastname: Fernando
authors.affiliation: Canadian Molecular Imaging Center of Excellence (CMICE), University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada; Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada.
authors.forename: Terrence D
authors.initials: TD
authors.lastname: Ruddy
mesh_terms: D000818:Animals; D002867:Chromones / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000633:toxicity*; D007275:Injections, Intravenous; D008297:Male; D055414:Myocardial Perfusion Imaging / Q000009:adverse effects* / Q000379:methods; D019055:No-Observed-Adverse-Effect Level; D011237:Predictive Value of Tests; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D023382:Toxicity Tests, Acute / Q000379:methods*; D059551:Toxicity Tests, Subacute / Q000379:methods*
chemical_list: C000599676:CMICE-013; D002867:Chromones; D006576:Heterocyclic Compounds, 4 or More Rings; D019275:Radiopharmaceuticals
keywords: CMICE-013; Iodinated rotenone; Myocardial perfusion tracer; Preclinical toxicity study