Dantrolene Dose Response in Awake Man

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Abstract
Dantrolene sodium [a muscle relaxant] was administered i.v. to 12 adult volunteers to assess muscular and cardiopulmonary response. Pharmacokinetic results were obtained from whole blood drug concentration. Indirectly evoked thumb adduction was quantitated. Handgrip strength and subjective weakness score (10 equal to full strength, 0 equal to paralyzed) were assessed. Cardiopulmonary variables included forced vital capacity (FVC), peak expiratory flow rate (PEFR), percentage of end-tidal CO2 (ETCO2), indirect mean arterial pressure (MAP) and heart rate (HR). Commercially available dantrolene for i.v. administration 0.33 mg/ml was administered in bolus doses of 0.1 mg/kg every 5 min until a plateau in twitch depression was achieved. Monitored variables were assessed either after each dose or following each cumulative 0.2 mg/kg dose over approximately 2 h. Intermittently during the subsequent 46 h, grip strength, subjective weakness and blood levels were assessed. An average maximal twitch depression of 75% was reached at 2.2-2.5 mg/kg cumulative dantrolene dose. Significant depression of grip strength was observed after a dantrolene dose of 1.0 mg/kg and remained for 20 h. Subjective weakness score was 4.7 after dantrolene and slowly returned to 10 by 48 h. FVC and PEFR were not depressed significantly from control levels. ETCO2, MAP and HR were unchanged. Maximum dantrolene blood level was 4.2 .mu.g/ml at 2.9 h after the initial dantrolene dose. A near steady state existed for 5.5 h following the last dantrolene dose with a blood level of 3.6 .mu.g/ml. Then blood levels declined slowly following first-order kinetics with a t1/2 [half-life] elimination of 12.1 h. The acute i.v. administration of dantrolene, 2.4 mg/kg, will apparently achieve MH prophylaxis or therapeusis in humans.

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