title: Acetylcholinesterase inhibition by zifrosilone: pharmacokinetics and pharmacodynamics.
abstract: OBJECTIVE
  To determine the pharmacokinetics, pharmacodynamics and safety of the acetylcholinesterase inhibitor zifrosilone in healthy male volunteers.
  
  
  METHODS
  Pharmacokinetics, pharmacodynamics, and tolerance of zifrosilone were studied in a double-blind, sequential, single-escalating-dose, randomized panel design. Each panel consisted of six subjects, with four subjects receiving zifrosilone (10, 30, 60, 90, 120, 150, 200, 250, and 300 mg orally) and two subjects receiving matching placebo. Serial blood samples were obtained for zifrosilone plasma concentrations and red blood cell acetylcholinesterase and butyrylcholinesterase activities. Participating subjects (n = 54) were men between the ages of 18 and 45 years. Each subject had a normal physical examination, electrocardiogram, serum chemistries, hematology, urinalysis, and test for human immunodeficiency virus at screening.
  
  
  RESULTS
  A greater than proportionate increase in mean plasma concentration values for area under the curve from time zero to infinity was observed over the 200 to 300 mg dose range groups. Red blood cell acetylcholinesterase showed a dose-inhibition relationship, with a mean maximum inhibition of 20.9% at 10 mg that increased to 62.1% at 300 mg. Butyrylcholinesterase activity was relatively unaffected by zifrosilone (< 20% inhibition at 300 mg). For doses > or = 200 mg, an Emax pharmacodynamic model was used to describe the relationship between zifrosilone plasma concentration and red blood cell acetylcholinesterase inhibition (Emax = 83.8%; EC50 = 0.65 ng/ml).
  
  
  CONCLUSIONS
  Zifrosilone showed dose-dependent pharmacokinetics after oral administration and was effective in causing selective inhibition of red blood cell acetylcholinesterase.
authors.affiliation: California Clinical Trials, Beverly Hills 90211, USA.
authors.forename: N R
authors.initials: NR
authors.lastname: Cutler
authors.forename: R D
authors.initials: RD
authors.lastname: Seifert
authors.forename: M M
authors.initials: MM
authors.lastname: Schleman
authors.forename: J J
authors.initials: JJ
authors.lastname: Sramek
authors.forename: O J
authors.initials: OJ
authors.lastname: Szylleyko
authors.forename: D R
authors.initials: DR
authors.lastname: Howard
authors.forename: A
authors.initials: A
authors.lastname: Barchowsky
authors.forename: T S
authors.initials: TS
authors.lastname: Wardle
authors.forename: E P
authors.initials: EP
authors.lastname: Brass
mesh_terms: D000098:Acetophenones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D008297:Male; D014297:Trimethylsilyl Compounds / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000098:Acetophenones; D002800:Cholinesterase Inhibitors; D014297:Trimethylsilyl Compounds; C082826:zifrosilone