HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Safety assessment of 4'-thio-beta-D-arabinofuranosylcytosine in the beagle dog suggests a drug-induced centrally mediated effect on the hypothalamic-pituitary-adrenal axis.

Abstract
4'-Thio-beta-D-arabinofuranosylcytosine (OSI-7836) is a nucleoside analogue with structural similarity to gemcitabine and cytarabine (ara-C). Myelosuppression, reversible transaminase elevations, and flu-like symptoms are common side effects associated with human use of gemcitabine and ara-C. Fatigue is also associated with the use of gemcitabine and OSI-7836 in humans. To better understand the toxicity of OSI-7836, subchronic studies were conducted in dogs. OSI-7836 was administered on days 1 and 8 or on days 1, 2, and 3 of a 21-day dose regimen. These schedules attempted to match clinical trial dosing regimens. Routine toxicity study end points demonstrated that OSI-7836 was primarily cytotoxic to the gastrointestinal tract, bone marrow, and testes; the myelotoxicity was mild and reversible. Plasma pharmacokinetics were dose-linear with an elimination half-life of 2.2 h. Follow-up single dose experiments in dogs assessed drug effects on lymphocyte subpopulations and on adrenal and thyroid function. Populations of T and B cells were equally reduced following OSI-7836 administration. There were no adverse effects on thyroid function, but there were marked reductions in circulating cortisol and adrenocorticotropic hormone concentrations suggesting a centrally mediated impairment of the hypothalamic-pituitary-adrenal axis. These findings show a toxicological profile with OSI-7836 similar to other nucleoside analogues and suggest that the beagle is a model for studying one possible cause of OSI-7836-related fatigue, impaired function of the hypothalamic-pituitary-adrenal axis.
AuthorsDorothy B Colagiovanni, Daniel W Drolet, Larry Dihel, Dennis J Meyer, Karen Hart, Julie Wolf
JournalInternational journal of toxicology (Int J Toxicol) 2006 Mar-Apr Vol. 25 Issue 2 Pg. 119-26 ISSN: 1091-5818 [Print] United States
PMID16597550 (Publication Type: Journal Article)
Chemical References
  • Antineoplastic Agents
  • Arabinonucleosides
  • Adrenocorticotropic Hormone
  • Thyroxine
  • Hydrocortisone
  • 4'-thio-arabinofuranosylcytosine
Topics
  • Adrenal Glands (drug effects, metabolism)
  • Adrenocorticotropic Hormone (blood)
  • Animals
  • Antineoplastic Agents (administration & dosage, blood, pharmacokinetics, toxicity)
  • Arabinonucleosides (administration & dosage, blood, pharmacokinetics, toxicity)
  • Blood Cell Count
  • Dogs
  • Drug Evaluation, Preclinical
  • Female
  • Hydrocortisone (blood)
  • Hypothalamo-Hypophyseal System (drug effects, metabolism)
  • Male
  • Pituitary-Adrenal System (drug effects, metabolism)
  • Testis (drug effects, pathology)
  • Thyroid Gland (drug effects, metabolism)
  • Thyroxine (blood)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: