Comparative toxicology of two enantiomers of the peripherally acting non-narcotic antitussive drug moguisteine.
Moguisteine (R,S(+/-)-2-(2-methoxyphenoxy)-methyl-3-ethoxycarbonylacetyl-1,3-t hiazolidine, CAS 119637-67-1), a new peripheral non-narcotic antitussive drug, is a racemate composed of an equimolar mixture of R(+) and S(-) enantiomers (BBR 2221 and BBR 2222, respectively). Since in some cases the use of only one enantiomer instead of a racemate may increase the efficacy and/or the tolerability of a compound, moguisteine enantiomers were submitted to toxicological evaluation. Given in a single oral (gavage) or intraperitoneal administration to mice and rats, both moguisteine enantiomers show very low general toxicity. Administered by gavage to rats and dogs for four consecutive weeks, BBR 221 and BBR 2222 are tolerated at up to the dose of 240 mg/kg/day in both sexes with no appreciable toxic changes. Finally, the mutagenicity tests show that both enantiomers are devoid of any mutagenic potential both in vitro and in vivo. Considering the overall results of the toxicological studies and comparing them with the data obtained from the previously performed studies with the racemate moguisteine, it can be affirmed that no differences can be identified between the two enantiomers and the racemate moguisteine. These findings justify the development of moguisteine as a racemate since neither enantiomer should offer any advantage over the racemate.
Cavalletti
E
E
Research Centre, Boehringer Mannheim Italia, Monza, Milan, Italy.
Montaguti
P
P
Sala
F
F
Ceserani
R
R
D000284:Administration, Oral; D000818:Animals; D000996:Antitussive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D004285:Dogs; D005260:Female; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D053778:Thiazolidines
D000996:Antitussive Agents; D009153:Mutagens; D013844:Thiazoles; D053778:Thiazolidines; C087933:moguisteine