Intravenous lecithin-coated microcrystals of dantrolene are effective in the treatment of malignant hyperthermia

An investigation in rats, dogs, and swine

Steven M. Karan, Edwin W. Lojeski, Duncan H. Haynes, Saiid Bina, David L. Wesche, Ben H Boedeker, Sheila M. Muldoon

Research output: Contribution to journalArticle

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Abstract

Dantrolene effectively treats malignant hyperthermia (MH) but 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 of 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.

Original languageEnglish (US)
Pages (from-to)796-802
Number of pages7
JournalAnesthesia and analgesia
Volume82
Issue number4
DOIs
StatePublished - Apr 19 1996

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Dantrolene
Malignant Hyperthermia
Lecithins
Swine
Dogs
Pulmonary Hypertension
Skeletal Muscle
Pharmacokinetics
Lung

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Intravenous lecithin-coated microcrystals of dantrolene are effective in the treatment of malignant hyperthermia : An investigation in rats, dogs, and swine. / Karan, Steven M.; Lojeski, Edwin W.; Haynes, Duncan H.; Bina, Saiid; Wesche, David L.; Boedeker, Ben H; Muldoon, Sheila M.

In: Anesthesia and analgesia, Vol. 82, No. 4, 19.04.1996, p. 796-802.

Research output: Contribution to journalArticle

Karan, Steven M. ; Lojeski, Edwin W. ; Haynes, Duncan H. ; Bina, Saiid ; Wesche, David L. ; Boedeker, Ben H ; Muldoon, Sheila M. / Intravenous lecithin-coated microcrystals of dantrolene are effective in the treatment of malignant hyperthermia : An investigation in rats, dogs, and swine. In: Anesthesia and analgesia. 1996 ; Vol. 82, No. 4. pp. 796-802.
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abstract = "Dantrolene effectively treats malignant hyperthermia (MH) but the current form, Dantrium{\circledR}, 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{\circledR} were similar: half-lives of 3.1 h, volume of 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{\circledR} were also similar (2.8 ± 0.4 vs 2.7 ± 0.6 mg/kg), but MC-D and Dantrium{\circledR} 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.",
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