title: Intravenous lecithin-coated microcrystals of dantrolene are effective in the treatment of malignant hyperthermia: an investigation in rats, dogs, and swine.
abstract: Dantrolene effectively treats malignant hyperthermia (MH) hut the current form, Dantrium, must be dissolved to a 0.33 mg/mL, pH 9.5 solution. This study describes lecithin-coated microcrystal formulations of sodium dantrolene (MC-NaD) and neutral dantrolene (MC-D) which reconstitute to 200 mg/mL within 1 min. In rats, the pharmacokinetics and pharmacodynamics of MC-NaD and Dantrium were similar: half-lives of 3.1 h, volume distributions of 0.54 and 0.59 L/kg, and 95% effective dose (ED95) values for depression of skeletal muscle twitch height (ED95T) of 2.6 +/- 0.7 and 2.8 +/- 0.5 mg/kg. In swine, the ED95T values for MC-NaD and Dantrium were also similar (2.8 +/- 0.4 vs 2.7 +/- 0.6 mg/kg), but MC-D and Dantrium were only similar at doses more than 2.5 mg/kg (ED95T: 3.5 +/- 0.4 vs 2.7 +/- 0.5 mg/kg). In susceptible swine, MC-NaD successfully treated five of six MH episodes and prevented MH in three of four swine. However, MC-NaD caused marked pulmonary hypertension in swine, while MC-D caused only a mild response that was eliminated by filtration. Likewise, MC-D caused no pulmonary response in dogs. These observations suggest that MC-D has potential to improve the treatment of MH.
authors.affiliation: Department of Anesthesiology, F. Edward Herbert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Karan
authors.forename: E W
authors.initials: EW
authors.lastname: Lojeski
authors.forename: D H
authors.initials: DH
authors.lastname: Haynes
authors.forename: S
authors.initials: S
authors.lastname: Bina
authors.forename: D L
authors.initials: DL
authors.lastname: Wesche
authors.forename: B H
authors.initials: BH
authors.lastname: Boedeker
authors.forename: S M
authors.initials: SM
authors.lastname: Muldoon
mesh_terms: D000818:Animals; D003460:Crystallization; D003620:Dantrolene / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D008305:Malignant Hyperthermia / Q000188:drug therapy*; D014677:Pharmaceutical Vehicles; D010713:Phosphatidylcholines; D051381:Rats; D013552:Swine
chemical_list: D014677:Pharmaceutical Vehicles; D010713:Phosphatidylcholines; D003620:Dantrolene