title: Comparative effects of interferon alpha-2b and pegylated interferon alpha-2b on menstrual cycles and ovarian hormones in cynomolgus monkeys.
abstract: BACKGROUND
  The covalent modification of interferon (IFN) alpha2b with monomethyoxy polyethylene glycol (PEG) reduces its clearance rate and increases its half-life. High doses of interferon (IFN) alpha2b have previously been shown to affect maintenance of pregnancy in rhesus monkeys. Given the role of ovarian hormones in reproductive function and pregnancy, this study was conducted to assess the effects of PEG-IFNalpha2b or IFNalpha2b (comparative control) on ovarian hormones and menstrual cyclicity in cynomolgus monkeys. In addition, the potential for reversibility of PEG-IFNalpha2b or IFNalpha2b-related observations was assessed.
  
  
  METHODS
  Monkeys were administered 3,105 microg/m(2) human recombinant (hr) IFNalpha2b or 52, 262, or 4,239 microg/m(2) PEG-hr-IFNalpha2b every other day for one menstrual cycle, followed by a post-dose period of up to two menstrual cycles.
  
  
  RESULTS
  Monkeys administered 3,105 microg/m(2) hr-IFNalpha2b or 52, 262, or 4,239 microg/m(2) PEG-hr-IFNalpha2b exhibited transient decreases in food consumption, leukocyte and erythrocyte parameters. Monkeys administered 3,105 microg/m(2) hr-IFNalpha2b exhibited lengthened menstrual cycles that were associated with a delay in reaching peak ovarian hormone levels and lower respective peak concentrations. Similarly, monkeys administered 4,239 microg/m(2) PEG-hr-IFNalpha2b exhibited lengthened menstrual cycles and a delay in reaching peak ovarian hormone levels and slightly lower respective peak concentrations. Post-dosing menstrual cycle length, estradiol and progesterone profiles exhibited evidence of recovery in both the hr-IFNalpha2b and the high-dose PEG-hr-IFNalpha2b groups.
  
  
  CONCLUSIONS
  Administration of hr-IFNalpha2b or PEG-hr-IFNalpha2b at high doses to cynomolgus monkeys resulted in similar effects on menstrual cycles, estradiol and progesterone profiles, and exhibited evidence of reversibility upon cessation of dosing. These results suggest that the previously observed high-dose IFNalpha-related effects on the maintenance of pregnancy in monkeys are likely the result of altered ovarian function.
authors.affiliation: Schering-Plough Research Institute, 556 Morris Avenue, Summit, NJ 07901, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Enright
authors.forename: David R
authors.initials: DR
authors.lastname: Compton
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Collins
authors.forename: Thomas
authors.initials: T
authors.lastname: Davis
authors.forename: Barry S
authors.initials: BS
authors.lastname: McIntyre
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects; D004958:Estradiol / Q000097:blood; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000493:pharmacokinetics / Q000633:toxicity*; D007962:Leukocytes / Q000187:drug effects; D008252:Macaca fascicularis; D008597:Menstrual Cycle / Q000187:drug effects*; D009500:Neutralization Tests; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism; D011092:Polyethylene Glycols; D011374:Progesterone / Q000097:blood; D011994:Recombinant Proteins; D020127:Recovery of Function; D018675:Toxicity Tests; D028761:Withholding Treatment
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D011374:Progesterone; D004958:Estradiol; C417083:peginterferon alfa-2b