Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024591 (malignant hyperthermia)
 2,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant hyperthermia (MH) is a hypermetabolic syndrome triggered in genetically susceptible individuals when certain potent inhalation anesthetics or succinylcholine are administered. The signs of MH include a greatly increased body metabolism, muscle rigidity and eventual hyperthermia that may exceed 110 degrees F. Death can result from cardiac arrest, brain damage, internal hemorrhaging or failure of other body systems. Dantrolene is given until the manifestations of MH abate. The initial dose is 2.5 mg/kg body weight; and repeated as needed. High-risk patients cannot always be identified by history, and preparation of every OR is essential. Supplies of dantrolene and other medications must be kept in the OR area. If MH develops, acting within minutes may save a life.
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PMID:Malignant hyperthermia: an OR emergency! 1202 57

Dantrolene is a drug that suppresses intracellular Ca(2+) release from sarcoplasmic reticulum (SR) in skeletal muscle and is used as a therapeutic agent in individuals susceptible to malignant hyperthermia. Although its precise mechanism of action has not been elucidated, we have identified the N-terminal region (amino acids 1-1400) of the skeletal muscle isoform of the ryanodine receptor (RyR1), the primary Ca(2+) release channel in SR, as a molecular target for dantrolene using the photoaffinity analog [(3)H]azidodantrolene. Here, we demonstrate that heterologously expressed RyR1 retains its capacity to be specifically labeled with [(3)H]azidodantrolene, indicating that muscle specific factors are not required for this ligand-receptor interaction. Synthetic domain peptides of RyR1 previously shown to affect RyR1 function in vitro and in vivo were exploited as potential drug binding site mimics and used in photoaffinity labeling experiments. Only DP1 and DP1-2s, peptides containing the amino acid sequence corresponding to RyR1 residues 590-609, were specifically labeled by [(3)H]azidodantrolene. A monoclonal anti-RyR1 antibody that recognizes RyR1 and its 1400-amino acid N-terminal fragment recognizes DP1 and DP1-2s in both Western blots and immunoprecipitation assays and specifically inhibits [(3)H]azidodantrolene photolabeling of RyR1 and its N-terminal fragment in SR. Our results indicate that synthetic domain peptides can mimic a native, ligand-binding conformation in vitro and that the dantrolene-binding site and the epitope for the monoclonal antibody on RyR1 are equivalent and composed of amino acids 590-609.
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PMID:Identification of a dantrolene-binding sequence on the skeletal muscle ryanodine receptor. 1216 62

Malignant hyperthermia is a potentially fatal pharmacogenetic disease triggered by volatile anesthetics and/or succinylcholine. Dysregulation of intracellular calcium homeostasis is the trigger of the acute crisis. Malignant hyperthermia crisis correspond to an hypermetabolic state, which occurred acutely and interesting skeletal muscular cell. Early manifestations grouped tachycardia, tachypnea, masseter spasm, mixed acidosis and raise of the end expiratory CO2 pressure. Hyperthermia is a late sign, rhabdomyolysis is a sign of the severity of the malignant hyperthermia. The successful treatment is based on an early diagnosis, immediately interruption of triggering agents, intravenous administration of Dantrolene in sufficient dosage and starting of adequate symptomatic treatment. Prevention of this complication is based on asking the patient about genetic predisposition to malignant hyperthermia. Confirmation of the susceptibility to malignant hyperthermia can be provided by in vitro contracture test with halothane or caffeine after muscle biopsy.
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PMID:[Malignant hyperthermia]. 1261 49

Malignant hyperthermia (MH) is a genetic, potentially life-threatening disorder of the skeletal muscle presenting during or following general anaesthesia. Trigger agents are volatile anaesthetics and depolarising muscle relaxants. Dantrolene is the only available drug for effective and specific MH therapy, which reduces significantly the mortality rate. Dantrolene is a skeletal muscle relaxant that depresses the excitation-contraction coupling,however, the specificity of action remains unknown. Recent studies identified the ryanodine receptor, the calcium release channel of the sarcoplasmic reticulum, as the direct molecular target of dantrolene. In addition to its use for MH, dantrolene is used in other disorders such as neuroleptic malignant syndrome and spasticity. Since dantrolene is weakly water soluble, the clinical preparation is time and manpower consuming. New agents have been synthesized, but because of economic considerations no registration for clinical usage has been realised.
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PMID:[Dantrolene. Pharmacological and therapeutic aspects]. 1266 6

Human malignant hyperthermia is a life-threatening genetic sensitivity of skeletal muscles to volatile anaesthetics and depolarizing neuromuscular blocking drugs occurring during or after anaesthesia. The skeletal muscle relaxant dantrolene is the only currently available drug for specific and effective therapy of this syndrome in man. After its introduction, the mortality of malignant hyperthermia decreased from 80% in the 1960s to < 10% today. It was soon discovered that dantrolene depresses the intrinsic mechanisms of excitation-contraction coupling in skeletal muscle. However, its precise mechanism of action and its molecular targets are still incompletely known. Recent studies have identified the ryanodine receptor as a dantrolene-binding site. A direct or indirect inhibition of the ryanodine receptor, the major calcium release channel of the skeletal muscle sarcoplasmic reticulum, is thought to be fundamental in the molecular action of dantrolene in decreasing intracellular calcium concentration. Dantrolene is not only used for the treatment of malignant hyperthermia, but also in the management of neuroleptic malignant syndrome, spasticity and Ecstasy intoxication. The main disadvantage of dantrolene is its poor water solubility, and hence difficulties are experienced in rapidly preparing intravenous solutions in emergency situations. Due to economic considerations, no other similar drugs have been introduced into routine clinical practice.
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PMID:Dantrolene--a review of its pharmacology, therapeutic use and new developments. 1547 27

We report on a 25-year old ASA physical status I patient, who developed within 20 minutes a full-blown malignant hyperthermia (MH) in the context of a living donor liver transplantation after 180 minutes of uneventful anaesthesia. The only trigger substance applied was Sevoflurane. The patient had already received a short, uneventful anaesthesia with Isoflurane a couple of years ago. In the context of the special constellation an initial dose of Dantrolene of 10 mg/kg body weight was administered. The patient was stabilised within 30 minutes, and the enzyme levels remained low compared with other case reports. The post-operative in vitro caffeine halothane contracture testing confirmed that son and mother were susceptible to MH, contracture testing in the father was negative. All known triggers may cause life-threatening MH crisis - even after hours and after inconspicuous multiple exposures to known trigger substances. Therefore all trigger substances must be avoided in all patients susceptible to MH.
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PMID:[Delayed onset of malignant hyperthermia crisis during a living donor liver transplantation caused by sevoflurane]. 1504 5

Interdomain interactions between N-terminal and central domains serving as a "domain switch" are believed to be essential to the functional regulation of the skeletal muscle ryanodine receptor-1 Ca(2+) channel. Mutational destabilization of the domain switch in malignant hyperthermia (MH), a genetic sensitivity to volatile anesthetics, causes functional instability of the channel. Dantrolene, a drug used to treat MH, binds to a region within this proposed domain switch. To explore its mechanism of action, the effect of dantrolene on MH-like channel activation by the synthetic domain peptide DP4 or anti-DP4 antibody was examined. A fluorescence probe, methylcoumarin acetate, was covalently attached to the domain switch using DP4 as a delivery vehicle. The magnitude of domain unzipping was determined from the accessibility of methylcoumarin acetate to a macromolecular fluorescence quencher. The Stern-Volmer quenching constant (K(Q)) increased with the addition of DP4 or anti-DP4 antibody. This increase was reversed by dantrolene at both 37 and 22 degrees C and was unaffected by calmodulin. [(3)H]Ryanodine binding to the sarcoplasmic reticulum and activation of sarcoplasmic reticulum Ca(2+) release, both measures of channel activation, were enhanced by DP4. These activities were inhibited by dantrolene at 37 degrees C, yet required the presence of calmodulin at 22 degrees C. These results suggest that the mechanism of action of dantrolene involves stabilization of domain-domain interactions within the domain switch, preventing domain unzipping-induced channel dysfunction. We suggest that temperature and calmodulin primarily affect the coupling between the domain switch and the downstream mechanism of regulation of Ca(2+) channel opening rather than the domain switch itself.
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PMID:Dantrolene stabilizes domain interactions within the ryanodine receptor. 1561 Nov 17

Ryanodine receptor (RyR) type 1 (RyR1) exhibits a markedly lower gain of Ca(2+)-induced Ca(2+) release (CICR) activity than RyR type 3 (RyR3) in the sarcoplasmic reticulum (SR) of mammalian skeletal muscle (selective stabilization of the RyR1 channel), and this reduction in the gain is largely eliminated using 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS). We have investigated whether the hypothesized interdomain interactions within RyR1 are involved in the selective stabilization of the channel using [(3)H]ryanodine binding, single-channel recordings, and Ca(2+) release from the SR vesicles. Like CHAPS, domain peptide 4 (DP4, a synthetic peptide corresponding to the Leu(2442)-Pro(2477) region of RyR1), which seems to destabilize the interdomain interactions, markedly stimulated RyR1 but not RyR3. Their activating effects were saturable and nonadditive. Dantrolene, a potent inhibitor of RyR1 used to treat malignant hyperthermia, reversed the effects of DP4 or CHAPS in an identical manner. These findings indicate that RyR1 is activated by DP4 and CHAPS through a common mechanism that is probably mediated by the interdomain interactions. DP4 greatly increased [(3)H]ryanodine binding to RyR1 with only minor alterations in the sensitivity to endogenous CICR modulators (Ca(2+), Mg(2+), and adenine nucleotide). However, DP4 sensitized RyR1 four- to six-fold to caffeine in the caffeine-induced Ca(2+) release. Thus the gain of CICR activity critically determines the magnitude and threshold of Ca(2+) release by drugs such as caffeine. These findings suggest that the low CICR gain of RyR1 is important in normal Ca(2+) handling in skeletal muscle and that perturbation of this state may result in muscle diseases such as malignant hyperthermia.
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PMID:Postulated role of interdomain interactions within the type 1 ryanodine receptor in the low gain of Ca2+-induced Ca2+ release activity of mammalian skeletal muscle sarcoplasmic reticulum. 1567 76

Malignant hyperthermia (MH) is an operative emergency associated with general anesthesia. Early diagnosis and prompt treatment are the keynotes in management of MH. Dantrolene is the only specific drug and all of the institutions where general anesthesia is a daily routine should have a stockpile of this drug for the rare occurrence of MH. Nonetheless, the enormous expenditure on stockpile and 3-year validity make a large reserve of the drug to forestall MH, a disorder of rare occurrence, seems disputable, especially in small hospitals where general anesthesia is seldom practiced. We herein report two cases of MH with excellent response to small doses of dantrolene and then discuss the way of practicable management and debate on the question of whether fewer stock of dantrolene is an alternative way for hospitals of smaller scale.
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PMID:Malignant hyperthermia with excellent response to small dose of dantrolene. 1567 36

Dantrolene is the only drug proven effective for prevention and treatment of malignant hyperthermia (MH). Current dosing recommendations are based on noncompartmental analyses and are largely empiric. They are also divergent, as evidenced by differing recommendations from the Malignant Hyperthermia Association of the United States (MHAUS) and European Sources. We determined the compartmental pharmacokinetics of dantrolene, simulated the concentration time course based on currently recommended dosing, and suggest an optimal regimen. Nine volunteers (55-89 kg) received IV infusions of dantrolene (5 mg/kg over 30 min followed by 0.05 mg.kg(-1) . h(-1) for 5 h). Venous blood samples were drawn for up to 60 h, and dantrolene plasma concentrations were determined by reverse phase, high-performance liquid chromatography. One, two, and three compartmental models were fitted to the data, and a covariate analysis was performed. All calculations were performed with NONMEM using the population approach. The data were adequately described by a two-compartment model with the following typical variable values (median +/- se): volumes of distribution V1= 3.24 +/- 0.61 L; V2= 22.9 +/- 1.53 L; plasma clearance CL el= 0.03 +/- 0.003 L/min; and distributional clearance CL dist= 1.24 +/- 0.22 L/min. All parameters were scaled linearly with weight. Simulations of European recommendations for treatment of MH lead to plasma concentrations converging to 14-18 mg/L within 24 h. Simulating MHAUS guidelines (intermittent bolus administration) yielded peak and trough plasma concentrations ranging from 6.7-22.6 mg/L. Based on our findings, we propose an infusion regimen adjusted to the initial bolus dose(s) required to control symptoms. This strategy maintains the individualized therapeutic concentrations and improves stability of plasma concentrations.
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PMID:Compartmental pharmacokinetics of dantrolene in adults: do malignant hyperthermia association dosing guidelines work? 1630 Dec 43


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