Dantrolene Dose Response in Malignant Hyperthermia-susceptible (MHS) Swine

Flewellen, E. H.; Nelson, Thomas E.

doi:10.1097/00000542-198004000-00003

Cited by 39 publications

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“…Additional support for a primary lesion in skeletal muscle of MH-affected man and pigs is the fact that dantrolene, a unique skeletal muscle relaxant is an effective prophylactic and therapeutic agent for MH in man (15) and pigs (16). The exact site of action of dantrolene is unknown but it does act directly on skeletal muscle (17) and diminishes the amount of calcium released to the myoplasm (18)(19)(20).…”

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confidence: 99%

Abnormality in calcium release from skeletal sarcoplasmic reticulum of pigs susceptible to malignant hyperthermia.

Nelson¹

1983

J. Clin. Invest.

137

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A B S T R A C T Two fractions of sarcoplasmic reticulum, one light (LSR) and one heavy (HSR), were isolated from gracilis muscle of control and malignant hyperthermia (MH)-susceptible pigs. Part of the gracilis muscle biopsy was used to compare the contracture sensitivity of the muscle to the calcium-releasing effects of caffeine on isolated SR membranes. Gracilis muscle of MH pigs was more sensitive to the contracture-producing effects of caffeine than control pig muscle. The caffeine dose-cumulative contracture response curve for MH muscle was shifted left of that for controls.The amount of caffeine-induced calcium released from SR is a function of the amount of calcium preload and this did not differ between LSR of MH and control muscle. When LSR fractions were optimally loaded with calcium for caffeine-induced calcium release, no difference in calcium-releasing effects of varying caffeine doses was observed between MH and control LSR. At calcium preloads below optimal, the MH-LSR appeared to be more sensitive to caffeine-induced calcium release. The HSR fractions could not be loaded with calcium in a manner similar to the LSR fractions because of an apparent calcium-induced calcium release phenomenon. Therefore, calcium threshold for calcium-induced calcium release was compared between MH and control HSR fraction. The effect of caffeine on the calcium-induced calcium release was also studied. The average calcium concentration threshold for calcium-induced calcium release was markedly lower for MH vs. control HSR; 20 vs. 63 nmol Ca2+/mg, respectively. Caffeine decreased the threshold for calcium-induced calcium release more in the MH than in control HSR. Under all conditions studied, the amount of calcium released did not differ INTRODUCTIONMalignant hyperthermia (MH)' is a life threatening hypermetabolic syndrome occurring in genetically predisposed man and swine (1-3). In man, MH is usually associated with the administration of certain anesthetic agents (4, 5); whereas in swine the MH syndrome can also be triggered by stress alone (6, 7). The primary defect associated with MH susceptibility in man and pigs appears to be located in skeletal muscle (8-10). Abnormal metabolic (8,11,12) and contracture (13,14) responses of skeletal muscle from MH-susceptible man and swine have produced a working hypothesis that abnormal increases in myoplasmic calcium ion concentration stimulate the hypermetabolism and skeletal muscle rigidity observed with the MH syndrome.Additional support for a primary lesion in skeletal muscle of MH-affected man and pigs is the fact that dantrolene, a unique skeletal muscle relaxant is an effective prophylactic and therapeutic agent for MH in man (15) Immedi-ately after biopsy, the muscle was placed on ice and minced with scissors into small pieces and placed in 35-ml centrifuge tubes containing 1.4 ml of 20 mM histidine (pH 6.8) per g of muscle. The muscle was homogenized 15 s X 2, setting of 5, using a Polytron homogenizer with a PT 20 generator (Brinkmann Instruments, Inc., Westbury, ...

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confidence: 99%

Abnormality in calcium release from skeletal sarcoplasmic reticulum of pigs susceptible to malignant hyperthermia.

Nelson¹

1983

J. Clin. Invest.

137

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“…Although there is a paucity of data regarding an optimal systemic dose of dantrolene in the intact rat, data from other animal species demonstrate that the dose of dantrolene used in our study was relevant. First, a systemic dose of 3.5 mg/kg dantrolene, slightly above the therapeutic dose in humans (2.5 mg/kg) for the treatment of malignant hyperthermia (MH), provides adequate protection from malignant hyperthermia in swine (24). Secondly, systemic dantrolene at 10 mg/kg has been found to be cardioprotective in guinea pigs or rabbits, which is about 3–4× greater than the therapeutic dose to treat MH in both animals and humans.…”

Section: Discussionmentioning

confidence: 99%

Mannitol But Not Dantrolene Prevents Myocardial Dysfunction Following Intra‐cranial Hypertension in Rats

Hall

Wang

Milne

et al. 2005

American Journal of Transplantation

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Cardiac complications stemming from intra-cranial hypertension may result from impaired intra-cellular Ca 2+ homeostasis. The aim of this study was to examine the effects of dantrolene, a blocker of sarcoplasmic reticulum (SR) Ca 2+ release, on myocardial dysfunction associated with intra-cranial hypertension in rats. Dantrolene (10 mg) with and without 15% mannitol was administered to halothane-anesthetized rats prior to induction of intra-cranial hypertension by subdural balloon inflation. Its effects were compared to 3% and 15% mannitol and 5% Pentaspan ® . Dantrolene with mannitol or 15% mannitol alone prevented the transient intra-cranial hypertension-induced hyperdynamic response and ensuing circulatory collapse that was found in animals pre-treated with 3% mannitol solution or pentaspan. Moreover, hemodynamic function was preserved irrespective of TnI cleavage. However, only animals treated with high dose 15% mannitol exhibited lower lipid peroxidation content in the heart. In contrast, pre-treatment with dantrolene alone did not prevent the cardiac complications associated with intra-cranial hypertension. In conclusion, 15% mannitol attenuated the cardiopulmonary complications associated with intra-cranial hypertension. Dantrolene without mannitol was without effect. Since mannitol exhibits free radical scavenging properties, protection could be the result of a decrease in oxidative stress after intra-cranial hypertension.

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“…Clinically, dantrolene is most commonly known for its use as a life-saving antidote to the muscle hyperexcitability associated with malignant hyperthermia and has a well-documented efficacy in the treatment of this condition in humans, horses, dogs, and swine (Flewellen & Nelson, 1980;Waldron-Mease et al, 1981;Ward et al, 1986;Nelson, 1991). Dantrolene was initially used in humans as a muscle relaxant for the long-term treatment of skeletal muscle spasticity (Krause et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic evaluation of oral dantrolene in the dog

Haraschak

Langston

Wang

et al. 2013

Vet Pharm & Therapeutics

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The pharmacokinetics of dantrolene and its active metabolite, 5-hydroxydantrolene, after a single oral dose of either 5 mg/kg or 10 mg/kg of dantrolene were determined. The effects of exposure to dantrolene and 5-hydroxydantrolene on activated whole blood gene expression of the cytokines interleukin-2 (IL-2) and interferon-γ (IFN-γ) were also investigated. When dantrolene was administered at a 5 mg/kg dose, peak plasma concentration (Cmax) was 0.43 µg/ml, terminal half-life (t1/2) was 1.26 hrs, and area under the time-concentration curve (AUC) was 3.87 µg hr/mL. For the 10 mg/kg dose, Cmax was 0.65 µg/ml, t1/2 was 1.21 hrs, and AUC was 5.94 µg hr/mL. For all calculated parameters, however, there were large standard deviations and wide ranges noted between and within individual dogs: t1/2, for example, ranged from 0.43 to 6.93 hrs, Cmax ratios ranged from 1.05 to 3.39, and relative bioavailability (rF) values ranged from 0.02 to 1.56. While activated whole blood expression of IL-2 and IFN-γ as measured by qRT-PCR was markedly suppressed following exposure to very high concentrations (30 µg/mL and 50 µg/mL, respectively) of both dantrolene and 5-hydroxydantrolene, biologically and therapeutically relevant suppression of cytokine expression did not occur at the much lower drug concentrations achieved with oral dantrolene dosing.

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Dantrolene Dose Response in Malignant Hyperthermia-susceptible (MHS) Swine

Cited by 39 publications

References 0 publications

Abnormality in calcium release from skeletal sarcoplasmic reticulum of pigs susceptible to malignant hyperthermia.

Abnormality in calcium release from skeletal sarcoplasmic reticulum of pigs susceptible to malignant hyperthermia.

Mannitol But Not Dantrolene Prevents Myocardial Dysfunction Following Intra‐cranial Hypertension in Rats

Pharmacokinetic evaluation of oral dantrolene in the dog

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