title: In vitro and in vivo evaluation of macrofilaricidal activity of GABA and 1,3-dipalmitoyl-2-(4-aminobutyryl)glycerol HCl: a diglyceride prodrug.
abstract: A new therapeutic target has been identified from the filaria Molinema dessetae: the gabaergic system. gamma-aminobutyric acid (GABA) itself showed antifilarial effect in vitro and a macrofilaricidal action in vivo at high dose by intraperitoneal route (10(-2) M). Nevertheless, no action was observed by oral route. The study we report here consists to obtain an antifilarial effect by oral route using a diglyceride prodrug. Such a strategy is based on the triglycerides metabolism. A diglyceride prodrug of gamma-aminobutyric acid has been synthesized and its filaricidal activity compared with that of GABA, in vitro on adults of Molinema dessetae and in vivo on Molinema dessetae infected Proechimys oris. In vitro, GABA at 2.5 x 10(-3) M induced a temporary paralysis and the ester drug at the same concentration was fully active on adults. In vivo, no significant activity was observed by oral administration of a daily dose of GABA (10(-2) M). A five day course of GABA at 10(-2) M via the intraperitoneal route induced a significant reduction of male and female worms. We did not find any activity of the prodrug in vivo, either by the oral route (10(-2) M) or after an intraperitoneal administration (10(-3) M). The interest of GABA and GABA derivatives as potential filaricidal drugs was discussed.
authors: Laboratoire de Physicochimie des Surfaces et Innovation en Pharmacotechnie, URA CNRS 1218, Université de Paris XI, Chatenay-Malabry, France.
authors: J R
authors: JR
authors: Deverre
authors: P
authors: P
authors: Loiseau
authors: P
authors: P
authors: Gayral
authors: Y
authors: Y
authors: Letourneux
authors: P
authors: P
authors: Couvreur
authors: J P
authors: JP
authors: Benoit
mesh_terms: D000818:Animals; D005260:Female; D005368:Filariasis / Q000188:drug therapy / Q000469:parasitology; D005369:Filaricides / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008842:Microfilariae / Q000187:drug effects; D011355:Prodrugs / Q000494:pharmacology*; D012377:Rodentia; D014280:Triglycerides / Q000494:pharmacology* / Q000627:therapeutic use; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D005369:Filaricides; D011355:Prodrugs; D014280:Triglycerides; C060252:1,3-dipalmitoyl-2-(4-aminobutyryl)glycerol; D005680:gamma-Aminobutyric Acid