title: Systemic efficacy of nodulisporamides against fleas on dogs.
abstract: Nodulisporic acid A (NSA) has been shown previously to be safe in dogs and to deliver >90% flea control for 4 days following a single oral administration. Three newly prepared nodulisporamide derivatives were subsequently identified from an artificial membrane flea feeding system as exhibiting potency substantially greater than NSA. To determine if they have superior in vivo activity, these 3 nodulisporamides, as well as NSA, were evaluated in dogs at 15 mg/kg/os. Parasite challenges were made by placing 100 live Ctenocephalides felis fleas onto the dorsum of dogs every 48 hr and examining efficacy at each of those intervals over a 22-day period. Results showed that NSA produced >90% efficacy at day 2 and 81% efficacy at day 4, and its residual flea killing fell to approximately 50% by day 6 posttreatment. All dogs treated with the 3 new experimental nodulisporamides were 100% protected from flea challenges to day 8 posttreatment, and 2 of the compounds continued to produce >90% residual activity to 2 wk posttreatment. Pharmacokinetic analysis showed that plasma profiles and half-lives of NSA and these 3 new compounds correlated closely with flea efficacy. These results demonstrate that specific substitutions to the pharmacophore of NSA can substantially increase the duration of activity against fleas.
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065, USA. wesley_shoop@merch.com
authors.forename: W L
authors.initials: WL
authors.lastname: Shoop
authors.forename: M
authors.initials: M
authors.lastname: Zakson-Aiken
authors.forename: L M
authors.initials: LM
authors.lastname: Gregory
authors.forename: B F
authors.initials: BF
authors.lastname: Michael
authors.forename: J
authors.initials: J
authors.lastname: Pivnichny
authors.forename: P T
authors.initials: PT
authors.lastname: Meinke
authors.forename: M H
authors.initials: MH
authors.lastname: Fisher
authors.forename: M J
authors.initials: MJ
authors.lastname: Wyvratt
authors.forename: B
authors.initials: B
authors.lastname: Pikounis
authors.forename: D M
authors.initials: DM
authors.lastname: Schmatz
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D004283:Dog Diseases / Q000188:drug therapy / Q000378:metabolism / Q000469:parasitology*; D004285:Dogs; D006207:Half-Life; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D007306:Insecticides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D011897:Random Allocation; D005423:Siphonaptera
chemical_list: D000577:Amides; D007211:Indoles; D007306:Insecticides; C110703:nodulisporic acid A