title: A randomized phase I study of methanesulfonyl fluoride, an irreversible cholinesterase inhibitor, for the treatment of Alzheimer's disease.
abstract: OBJECTIVE
  To ascertain the tolerability profile of single and repeated oral doses of methanesulfonyl fluoride (MSF, SNX-001) in healthy aged subjects, and to determine the degree of erythrocyte acetylcholinesterase (AChE) inhibition induced by MSF after single and repeated oral doses.
  
  
  METHODS
  To calculate properly the kinetics and the duration of AChE inhibition, the effects of MSF were also studied in rodents. These experiments suggested that MSF administered three times per week should provide safe and efficacious AChE inhibition. In a randomized placebo-controlled phase I study, 3.6 mg, 7.2 mg or 10.8 mg MSF were then orally administered to 27 consenting healthy volunteers (aged 50 to 72 years). After a single dose phase and a 1 week wash-out period, the subjects received the same doses three times per week for 2 weeks.
  
  
  RESULTS
  Twenty-two out of the 27 subjects completed the study. Four patients withdrew due to adverse events (AEs) and one for non-compliance. Erythrocyte AChE was inhibited by a total of 33%, 46%, and 62% after 2 weeks of 3.6 mg, 7.2 mg and 10.8 mg MSF, respectively. No serious AEs occurred. The most frequent AEs were headache (27%), nausea (11%) and diarrhoea (8%).
  
  
  CONCLUSIONS
  MSF proved to be well tolerated even with repeated oral dosing. It is estimated that MSF provided a degree of AChE inhibition that should effectively enhance memory. This molecule deserves to be tested for efficacy in a pilot randomized controlled study in patients with Alzheimer's disease.
authors.affiliation: University of Texas at El Paso, El Paso, TX 79968, USA. dmoss@utep.edu
authors.forename: Donald E
authors.initials: DE
authors.lastname: Moss
authors.forename: Ruggero G
authors.initials: RG
authors.lastname: Fariello
authors.forename: Jörg
authors.initials: J
authors.lastname: Sahlmann
authors.forename: Isabel
authors.initials: I
authors.lastname: Sumaya
authors.forename: Federica
authors.initials: F
authors.lastname: Pericle
authors.forename: Enrico
authors.initials: E
authors.lastname: Braglia
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004910:Erythrocyte Membrane / Q000201:enzymology; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D013450:Sulfones; C005109:methanesulfonyl fluoride; D000110:Acetylcholinesterase