INTRAVENOUS LECITHIN-COATED MICROCRYSTALS OF DANTROLENE ARE EFFECTIVEIN THE TREATMENT OF MALIGNANT HYPERTHERMIA - AN INVESTIGATION IN RATS, DOGS, AND SWINE

Dantrolene effectively treats malignant hyperthermia (MH) but the curr ent form, Dantrium(R), must be dissolved to a 0.33 mg/mL, pH 9.5 solut ion. This study describes lecithin-coated microcrystal formulations of sodium dantrolene (MC-NaD) and neutral dantrolene (MC-D) which recons titute to 200 mg/mL within 1 min. In rats, the pharmacokinetics and ph armacodynamics of MC-NaD and Dantrium(R) were similar: half-lives of 3 .1 h, volume of distributions of 0.54 and 0.59 L/kg, and 95% effective dose (ED(95)) values for depression of skeletal muscle twitch height (ED(95)T) of 2.6 +/- 0.7 and 2.8 +/- 0.5 mg/kg. In swine, the ED(95)T values for MC-NaD and Dantrium(R) were also similar (2.8 +/- 0.4 vs 2. 7 +/- 0.6 mg/kg), but MC-D and Dantrium(R) were only similar at doses more than 2.5 mg/kg (ED(95)T: 3.5 +/- 0.4 vs 2.7 +/- 0.5 mg/kg). In su sceptible swine, MC-NaD successfully treated five of six MH episodes a nd prevented MH in three of four swine. However, MC-NaD caused marked pulmonary hypertension in swine, while MC-D caused only a mild respons e that was eliminated by filtration. Likewise, MC-D caused no pulmonar y response in dogs. These observations suggest that MC-D has potential to improve the treatment of MH.