title: Ex vivo inhibition of beta-thromboglobulin release following administration to man of ABT-299, a novel prodrug of a potent platelet activating factor antagonist.
abstract: OBJECTIVE
  ABT-299 is a prodrug that is converted by serum esterase to a potent platelet activating factor (PAF) antagonist (A-85783). In order to evaluate the pharmacological activity of this antagonist in man the effect of ABT-299 given to healthy volunteers on ex vivo PAF-induced beta-thromboglobulin (beta-TG) release in blood was assessed.
  
  
  METHODS
  37 healthy male volunteers, age 18 to 40 (mean age of 23.6 years) and free of medication, participated in the study.
  
  
  METHODS
  Subjects were administered intravenously 0.8 mg, 2 mg, or 70 mg doses of ABT-299 (6-7 subjects per group) or placebo (9 subjects, pooled).
  
  
  METHODS
  Peripheral blood taken over 12 h after dosing was used for ex vivo beta-TG release and, in the case of the 70 mg dose, measurement of plasma drug concentration. Data were compared by Student's t-test.
  
  
  RESULTS
  All three doses produced highly significant inhibition (p < 0.005 compared to predose values) of PAF-induced beta-TG release (units/ml plasma +/- SEM) 12 h after drug administration (54 +/- 14 vs. 405 +/- 51, n = 8; 79 +/- 23 vs. 480 +/- 127, n = 7; 21 +/- 10 vs. 327 +/- 72, n = 6, respectively) whereas there was no significant difference in beta-TG release in the placebo group (449 +/- 90 vs. 307 +/- 49, n = 9). Inhibition was associated with the rapid appearance in plasma of A-85783 and the pyridine N-oxide metabolite of A-85783. Within 2 h, the plasma concentration of the metabolite exceeded that of the parent drug. Both the parent drug and the metabolite exhibited potent in vitro inhibition of PAF-induced beta-TG release (A2 values of 4 and 1 nM respectively).
  
  
  CONCLUSIONS
  These studies are the first to illustrate the utility of the beta-TG release assay for assessing ex vivo activity of PAF antagonists. These studies also demonstrate that the administration of ABT-299 to man results in potent, long lasting inhibition of PAF-mediated platelet activation, due in part to the pyridine-N-oxide metabolite, and support the potential therapeutic utility of this prodrug in treating PAF-mediated diseases.
authors.affiliation: Department 47J, Abbott Laboratories, Abbott Park, IL 60064-3500, USA. Dan.H.Albert@abbott.com
authors.forename: D H
authors.initials: DH
authors.lastname: Albert
authors.forename: T J
authors.initials: TJ
authors.lastname: Magoc
authors.forename: S D
authors.initials: SD
authors.lastname: Menacherry
authors.forename: D W
authors.initials: DW
authors.lastname: Morgan
authors.forename: E
authors.initials: E
authors.lastname: Sun
authors.forename: A E
authors.initials: AE
authors.lastname: Reyes
authors.forename: H D
authors.initials: HD
authors.lastname: Kleinert
authors.forename: G W
authors.initials: GW
authors.lastname: Carter
authors.forename: J B
authors.initials: JB
authors.lastname: Summers
mesh_terms: D000293:Adolescent; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism*; D007275:Injections, Intravenous; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013844:Thiazoles / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001620:beta-Thromboglobulin / Q000032:analysis*
chemical_list: D007211:Indoles; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; D011726:Pyridinium Compounds; D013844:Thiazoles; D001620:beta-Thromboglobulin; C093306:ABT 299; C093307:A 85783.0