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Malignant hyperthermia (MH) is a rare but potentially life-threatening emergency characterized by a hypermetabolic state which leads to pyrexia and muscle rigidity. It is a genetic disorder that displays autosomal dominant inheritance. Defects of the RyR1 and CACNA1S genes cause dysregulated calcium release within skeletal myocytes on exposure to triggering agents, causing tetanic contraction of the myocyte. Triggering agents are the halogenated volatile anaesthetic agents and suxamethonium chloride. Diagnosing MH involves genetic testing and an in-vitro contracture test. This is performed at specialist MH centres. An unexplained rise in end-tidal CO 2 and tachycardia should prompt the anaesthetist to consider an MH crisis. This can occur at any time during an anaesthetic or within the ensuing hours. A previous uneventful general anaesthetic does not rule out a crisis happening on subsequent anaesthetics. Crisis management comprises of stopping the offending triggering agent and provision of a clean volatile-free anaesthetic circuit. Activated charcoal filters are useful for the sequestration of halogenated vapours. Dantrolene is the only available treatment and should be immediately available in every area providing anaesthetic assistance. Active body cooling should be implemented to target core body temperatures below 38.5°C. Supportive measures should be instigated until the reaction has subsided. Guidelines produced by the Association of Anaesthetists of Great Britain and Ireland and the European Malignant Hyperpyrexia Group are available to aid in the management of the MH-susceptible patient and an MH crisis. [ABSTRACT FROM AUTHOR]

Background: Right ventricular (RV) dysfunction and its associated arrhythmias are recognized as important determinants of the prognosis of pulmonary arterial hypertension (PAH).Objective: Here, we aimed to investigate whether direct pharmacological intervention in the RV muscle with dantrolene (DAN), a stabilizer of the cardiac ryanodine receptor (RyR2), has a protective effect against RV dysfunction and arrhythmia in a monocrotaline (MCT)-induced PAH rat model.Methods: Male 8-week-old Sprague-Dawley rats were injected with MCT for the induction of PAH. Induction of ventricular tachycardia (VT) by catecholamines was also evaluated in association with RyR2-mediated Ca2+ release properties in isolated cardiomyocytes. A pulmonary artery-banding model has also been established to assess the independent effects of chronic pressure overload on RV morphology and function.Results: In the MCT-induced PAH rat model, RV hypertrophy, dilation, and functional decline were observed, with a survival rate of 0% 2 months after MCT induction. In contrast, chronic DAN treatment improved all these RV parameters and increased survival by 80%. Chronic DAN treatment also prevented the dissociation of calmodulin from RyR2, thereby inhibiting Ca2+ sparks and spontaneous Ca2+ transients in MCT-induced hypertrophied RV cardiomyocytes. Epinephrine induced VT in more than 50% of rats with MCT-induced PAH, but complete suppression of VT was achieved by chronic DAN treatment.Conclusion: Stabilization of RyR2 by DAN has potential as a new therapeutic agent against the development of RV dysfunction and fatal arrhythmia associated with PAH. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We have previously shown that the intranasal administration of dantrolene ameliorated cognitive dysfunction in the 5XFAD mouse model of Alzheimer's disease. This study examines the morphology of the nasal mucosa after 10 months of intranasal dantrolene in 5XFAD mice. MATERIALS AND METHODS: 5XFAD mice were either treated with intranasal dantrolene (5 mg/kg, 3 times/wk) from 2 months to 12 months of age or given no treatment at all. The mice were euthanatized at 12 months of age and the snouts were processed for histological examination. The morphology of the nasal mucosa was assessed and compared between the two groups. RESULTS: There were no significant differences in the thickness of the olfactory epithelium or the proportion of the thickness of the glandular layer to the wall of mucosa and submucosa in the nasal passages. CONCLUSIONS: Long-term intranasal administration of dantrolene did not significantly change the nasal mucosa morphology in 5XFAD mice. [ABSTRACT FROM AUTHOR]

Dantrolene, an FDA approved drug to treat malignant hyperthermia and muscle spasm, has been demonstrated to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediated toxicity of host cells. Ryanodine receptor overactivation and associated disruption of intracellular Ca2+ homeostasis play important roles in SARS-CoV-2 infection and replication of host cells. Dantrolene, as an inhibitor of RyRs, is expected to ameliorate these detrimental effects of SARS-CoV-2 in host cells. Additionally, dantrolene has also been shown to inhibit multiple cell or organ damage induced by hypoxia/ischemia, mitochondria damage, oxidative stresses, inflammation, impairment of autophagy and apoptosis, etc., which are often the causes of severity and mortality of COVID-19 patients. We have repurposed that dantrolene has a high potential at treating COVID-19 patients and reducing its morbidity and mortality. [ABSTRACT FROM AUTHOR]

Malignant hyperthermia (MH) is a life-threatening condition characterized by signs of hypermetabolism during general anaesthesia. There is a wide variability in the magnitude of these signs. Early recognition and immediate management are essential in preventing morbidity and mortality. A MH crisis is a rare reaction caused by abnormal calcium movement within the skeletal muscle cells on exposure to volatile anaesthetic agents and/or succinylcholine. Diagnosing this condition preoperatively can be a challenge as a history of an uneventful exposure to the triggering agents does not exclude the possibility of developing the reaction. Despite the autosomal dominant pattern of inheritance, genetic testing is not a definitive diagnostic tool. The gold standard diagnostic test is the in-vitro contracture test (IVCT) that is usually performed in specialist MH centres using fresh muscle biopsies. A MH crisis can be fatal if mismanaged. Dantrolene is the only specific treatment available; it is crucial to ensure its availability in areas where triggering agents are administered. This article summarizes the pathophysiology and the safe perioperative approach in managing patients with MH. Both the European Malignant Hyperthermia Group (EMHG) and the Association of Anaesthetists have published comprehensive guidelines on the safe management of this condition. [ABSTRACT FROM AUTHOR]

• Ca2+ leakage through the ryanodine receptor (RyR2) is one of the causes of heart failure. • RyR2-targeting therapy by dantrolene suppresses the Ca2+ leakage through RyR2. • The trial will clarify the efficacy of dantrolene for heart failure and arrhythmia. Leakage of Ca2+ from the sarcoplasmic reticulum (SR) is a critical contributing factor to heart failure pathophysiology. Therefore, reducing SR Ca2+ leaks may provide significant additive benefits when used in combination with conventional therapies. Dantrolene, a drug routinely used to treat malignant hyperthermia, also stabilizes the cardiac isoform of the release channel (RyR2), thus decreasing SR Ca2+ leaks. The purpose of this study is to evaluate the effect of chronic administration of dantrolene on heart failure and lethal arrhythmia in patients with chronic heart failure and reduced ejection fraction in a multicenter, randomized, double-blind, controlled study. Patients with chronic heart failure who had functional status of New York Heart Association class II and III and a left ventricular ejection fraction <40% were treated according to the Japanese Circulation Society, the European Society of Cardiology, and the American Heart Association/the American College of Cardiology guidelines for diagnosis and treatment of acute and chronic heart failure. Patients were randomized and divided into two groups in a double-blind fashion: dantrolene group and placebo group (target sample size: 300 cases). These drugs were administered for 96 weeks. The primary endpoint is cardiovascular death, first hospitalization for exacerbation of heart failure, or lethal arrhythmia [ventricular tachycardia (VT) storm, sustained VT, ventricular fibrillation] for 2 years after starting administration of dantrolene 1 cap (25 mg) three times daily (if not tolerable, two times daily) or matching placebo. This paper presents the rationale and trial design of the study. Recruitment for the study started on 8 December 2017. The results of this trial will clarify the efficacy and safety of dantrolene for ventricular arrhythmia, as well as mortality and morbidity in patients with chronic heart failure and reduced ejection fraction during guideline-directed medical treatment. [ABSTRACT FROM AUTHOR]

Targeted temperature management (TTM) is used frequently in patients with a variety of diseases, especially those who have experienced brain injury and/or cardiac arrest. Shivering is one of the main adverse effects of TTM that can often limit its implementation and efficacy. Shivering is the body's natural response to hypothermia and its deleterious effects can negate the benefits of TTM. The purpose of this article is to provide an overview of TTM strategies and shivering management. [ABSTRACT FROM AUTHOR]

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A sepse é uma disfunção orgânica fatal com características clínicas inespecíficas que podem imitar outras condições clínicas com quadro hipermetabólico, como a hipertermia maligna. Os cenários são extremamente desafiadores para a anestesia perioperatória e requerem intervenção urgente. Ilustrar a necessidade de intervenção e consulta precoces para uma assistência adicional na abordagem e exclusão de hipertermia maligna e outras possíveis causas durante tal cenário. Paciente do sexo masculino, 63 anos, submetido à cistoscopia eletiva com cistoscópio flexível e biópsia transretal da próstata guiada por ultrassom sem intercorrências. No pós‐operatório, o paciente desenvolveu sintomas que levantaram a suspeita de hipertermia maligna. O protocolo de hipertermia maligna foi imediatamente iniciado, inclusive a administração de dantrolene e uma consulta pela linha direta da associação de hipertermia maligna, juntamente com outros diagnósticos e manejos intervencionistas com vistas ao aprimoramento do paciente. Enquanto a administração precoce de dantrolene ajudou na estabilização hemodinâmica do paciente, a consulta com outros anestesistas e com a Associação de Hipertermia Maligna, juntamente com repetidos exames físicos e laboratoriais, ajudou a excluir a hipertermia maligna como o possível diagnóstico. O paciente recuperou‐se mais tarde na unidade de terapia intensiva, onde recebeu tratamento para a bacteremia detectada em suas hemoculturas. A sepse compartilha sintomas clínicos que mimetizam a hipertermia maligna. Enquanto a sepse progride rapidamente para lesões secundárias, a hipertermia maligna é uma ameaça à vida. Proporcionar o tratamento ideal requer um bom julgamento clínico e um alto nível de suspeita quanto aos cuidados oportunos e apropriados, como a administração precoce de dantrolene e a consulta pela linha direta da Associação de Hipertermia Maligna para assistência adicional, que podem resultar em desfechos positivos. Sepsis is a life‐threatening organ dysfunction with non‐specific clinical features that can mimic other clinical conditions with hyper metabolic state such as malignant hyperthermia. Perioperatively anesthesia providers come across such scenarios, which are extremely challenging with the need for urgent intervention. To illustrate the need for early intervention and consultation for added assistance to approach and rule out malignant hyperthermia and other possible causes during such a scenario. A 63‐year‐old male underwent an uneventful elective flexible cystoscopy and transrectal ultrasound‐guided prostate biopsy. Postoperatively he developed symptoms raising suspicion for malignant hyperthermia. Immediately malignant hyperthermia protocol was initiated that included administration of dantrolene and consultation of malignant hyperthermia association hotline along with other diagnostic and interventional management aimed at patient optimization. While early administration of dantrolene helped in hemodynamically stabilizing the patient, the consultation with other providers and malignant hyperthermia association hotline along with repeated examinations and lab works helped in ruling out malignant hyperthermia as the possible diagnosis. The patient later recovered in the intensive care unit where he was treated for the bacteremia that grew in his blood cultures. Sepsis shares clinical symptoms that mimic malignant hyperthermia. While sepsis rapidly progresses to secondary injuries, malignant hyperthermia is life threatening. Providing ideal care requires good clinical judgment and a high level of suspicion where timely and appropriate care such as early administration of dantrolene and consultation of malignant hyperthermia association hotline for added assistance can influence positive outcomes. [ABSTRACT FROM AUTHOR]

Objectives:Traumatic spinal cord injury (SCI) is a significant clinical problem with numerous secondary complications and perpetual deficits. No potent treatment is currently available to fully repair motor and other neurological functions. We studied the effects of dantrolene (DNT) at different time points, on the motor-evoked potentials (MEPs) and the apoptosis response in spinal cord injury. Methods:The study was conducted on a total of 38 rabbits divided into five main groups.These were group 1 (sham): only laminectomy (n = 6), group 2 (SCI): laminectomy and traumatic SCI (n = 8), group 3 (DNT 0h): just after the SCI, DNT 10 mg/kg I.P. (n = 8), group 4 (DNT 1h): 1 h after the SCI, DNT 10 mg/kg I.P. (n = 8), and group 5 (DNT 4h): 4 h after the SCI, DNT 10 mg/kg I.P. (n = 8). Results: DNT, which was administered as the treatment, had a therapeutic effect on the motor function. This effect was observed by recording neural transmission obtained via the Tarlov test and a transcranial magnetic stimulator by using the values of the MEPs. A significant decrease was histopathologically observed in the apoptotic cell count. Discussion: The electrophysiological efficacy of our model of trauma as SCI has been complemented with the significant differences between the control group and the SCI group. This creates a need for electrophysiological studies to be conducted in the future because effects, even at a minimum level, may play an important role in finding an applicable medicine for SCI. [ABSTRACT FROM AUTHOR]

Malignant hyperthermia is a potentially life-threatening hypermetabolic disorder, often induced by exposure to volatile anesthetics and succinylcholine. There are few reports of malignant hyperthermia during cardiopulmonary bypass. Here the authors review available literature including case reports of malignant hyperthermia and cardiopulmonary bypass and discuss the potential implications of malignant hyperthermia diagnosis and management as it applies to cardiac surgery. [ABSTRACT FROM AUTHOR]

Background: Both vagal (VS) and sympathetic (SS) stimulations can increase atrial fibrillation (AF) inducibility, with VS being known as more arrhythmogenic in normal hearts. Heart failure (HF) results in autonomic dysfunction (characterized by sympathetic activation and vagal withdrawal) and is associated with an increased AF incidence. This study investigated whether failing hearts, compared with normal control hearts, respond differently to autonomic stimulation-induced AF arrhythmogenesis and the effect of dantrolene on SS-enhanced AF in HF.Methods and Results: A rat myocardial infarction (MI) HF model was used. In experiment 1, AF inducibility was compared in 9 MI-HF rats versus 10 sham-control animals at baseline, during VS, and during SS with isoproterenol infusion. In experiment 2, dantrolene treatment (n = 8) was compared with placebo-control (n = 9) on SS-induced AF inducibility in HF. Compared with the sham-control, baseline AF inducibility was higher in the MI-HF group. AF inducibility was augmented in both groups by autonomic stimulation. However, under VS the increased magnitude was less in the MI-HF group (49% ± 11% vs 80% ± 10%; P = .029), but under SS was significantly more (53% ± 8% vs 6% ± 7%; P < .001), compared with sham-control. Dantrolene significantly attenuated SS-enhanced AF in HF (69% ± 6% vs 29% ± 9%; P = .006).Conclusions: Failing hearts are less sensitive to VS, but more vulnerable to SS-induced AF compared with normal-control hearts. Dantrolene can significantly attenuate SS-enhanced AF in HF, indicating that cardiac ryanodine receptor dysfunction may play a critical role in SS-enhanced AF in HF, and stabilizing leaky ryanodine receptor with the use of dantrolene may be a new treatment option in this condition. [ABSTRACT FROM AUTHOR]

Copyright of Colombian Journal of Anesthesiology is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Pesquisa Veterinaria Brasileira is the property of Colegio Brasileiro de Patologia Animal - CBPA and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: The mechanisms underlying spontaneous atrial fibrillation (AF) associated with atrial ischemia/infarction are incompletely elucidated. Here, we investigate the mechanisms underlying spontaneous AF in an ovine model of left atrial myocardial infarction (LAMI).Methods and Results: LAMI was created by ligating the atrial branch of the left anterior descending coronary artery. ECG loop recorders were implanted to monitor AF episodes. In 7 sheep, dantrolene-a ryanodine receptor blocker-was administered in vivo during the 8-day observation period (LAMI-D, 2.5 mg/kg, IV, BID). LAMI animals experienced numerous spontaneous AF episodes during the 8-day monitoring period that were suppressed by dantrolene (LAMI, 26.1±5.1; sham, 4.3±1.1; LAMI-D, 2.8±0.8; mean±SEM episodes per sheep, P<0.01). Optical mapping showed spontaneous focal discharges (SFDs) originating from the ischemic/normal-zone border. SFDs were calcium driven, rate dependent, and enhanced by isoproterenol (0.03 µmol/L, from 210±87 to 3816±1450, SFDs per sheep) but suppressed by dantrolene (to 55.8±32.8, SFDs per sheep, mean±SEM). SFDs initiated AF-maintaining reentrant rotors anchored by marked conduction delays at the ischemic/normal-zone border. NOS1 (NO synthase-1) protein expression decreased in ischemic zone myocytes, whereas NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) oxidase and xanthine oxidase enzyme activities and reactive oxygen species (DCF [6-carboxy-2',7'-dichlorodihydrofluorescein diacetate]-fluorescence) increased. CaM (calmodulin) aberrantly increased [3H]ryanodine binding to cardiac RyR2 (ryanodine receptors) in the ischemic zone. Dantrolene restored the physiological binding of CaM to RyR2.Conclusions: Atrial ischemia causes spontaneous AF episodes in sheep, caused by SFDs that initiate reentry. Nitroso-redox imbalance in the ischemic zone is associated with intense reactive oxygen species production and altered RyR2 responses to CaM. Dantrolene administration normalizes the CaM response, prevents LAMI-related SFDs, and AF initiation. These findings provide novel insights into the mechanisms underlying ischemia-related atrial arrhythmias. [ABSTRACT FROM AUTHOR]

During anesthetic procedures in pediatrics, especially when inhaled drugs or neuromuscular blockers are needed, adverse events related to the interaction of the pharmacological agent with the patient's sensitivity and susceptibility, such as malignant hyperthermia, are possible. Such a condition is considered an anesthetic emergency, requiring a high degree of diagnostic suspicion, a specific propaedeutic approach, and early and targeted treatment. Although rare, MH is relatively more prevalent among children, and in most cases, its diagnosis occurs during clinical signs such as localized or generalized hypertonia, hypercapnia, tachycardia, and fever. Nevertheless, many patients may not present hyperthermia during these events. In the following report, we describe the characteristics of a burn victim child who, during a bandaging procedure requiring anesthetic agents for induction, presented clinical manifestations during and after the surgical procedure compatible with the diagnosis of malignant hyperthermia but without fever, promptly treated with dantrolene, with satisfactory clinical and laboratory results. Increased sensitivity in the suspicion of drug-related complications may favor the early recognition of certain diseases and allow earlier therapy and favorable outcomes. [ABSTRACT FROM AUTHOR]

With the increase in need for anesthesia services outside the operating room, nonoperating room personnel are exposed to situations unique to the surgical environment. Malignant hyperthermia (MH) is an inherited genetic disorder that is triggered specifically by drugs and gases used to induce and maintain anesthesia. If left untreated, this disorder can progress into a cascade of events that can ultimately lead to death. The purpose of this review is to provide radiology and imaging personnel with the knowledge to assist anesthesia providers in the diagnosis, evaluation, and treatment of MH. [ABSTRACT FROM AUTHOR]

The present study was performed to determine the effect of Zn exposure influencing endoplasmic reticulum (ER) stress, explore the underlying molecular mechanism of Zn-induced hepatic lipolysis in a fish species of significance for aquaculture, yellow catfish Pelteobagrus fulvidraco . We found that waterborne Zn exposure evoked ER stress and unfolded protein response (UPR), and activated cAMP/PKA pathway, and up-regulated hepatic lipolysis. The increase in ER stress and lipolysis were associated with activation of cAMP/PKA signaling pathway. Zn also induced an increase in intracellular Ca 2+ level, which could be partially prevented by dantrolene (RyR receptor inhibitor) and 2-APB (IP3 receptor inhibitor), demonstrating that the disturbed Ca 2+ homeostasis in ER contributed to ER stress and dysregulation of lipolysis. Inhibition of ER stress by PBA attenuated UPR, inhibited the activation of cAMP/PKA pathway and resulted in down-regulation of lipolysis. Inhibition of protein kinase RNA-activated-like ER kinase (PERK) by GSK2656157 and inositol-requiring enzyme (IRE) by STF-083010 differentially influenced Zn-induced changes of lipid metabolism, indicating that PERK and IRE pathways played different regulatory roles in Zn-induced lipolysis. Inhibition of PKA by H89 blocked the Zn-induced activation of cAMP/PKA pathway with a concomitant inhibition of ER stress-mediated lipolysis. Taken together, our findings highlight the importance of the ER stress–cAMP/PKA axis in Zn-induced lipolysis, which provides new insights into Zn toxicology in fish and probably in other vertebrates. [ABSTRACT FROM AUTHOR]

Background: Cardiac type 2 ryanodine receptors (RyR2s) play a pivotal role in cellular electrophysiology and contractility. Increased RyR2-mediated diastolic sarcoplasmic reticulum (SR) Ca2+ release is linked to heart failure (HF) and arrhythmias. Dantrolene, a drug used for the treatment of malignant hyperthermia, is known to stabilize RyRs in skeletal muscle.Objective: The purpose of this study was to investigate the effects of dantrolene on arrhythmogenic triggers and contractile function in human atrial fibrillation (AF) and HF cardiomyocytes (CM).Methods: Human CM were isolated from either patients with HF (ventricular) or patients with AF (atrial), and Ca2+ imaging, patch-clamp, or muscle strip experiments were performed.Results: After exposure to dantrolene, human atrial AF and left ventricular HF CM showed significant reductions in proarrhythmic SR Ca2+ spark frequency and diastolic SR Ca2+ leak. Moreover, dantrolene decreased the frequency of Ca2+ waves and spontaneous Ca2+ transients in HF CM. Patch-clamp experiments revealed that dantrolene significantly suppressed delayed afterdepolarizations in HF and AF CM. Importantly, dantrolene had no effect on action potential duration in AF or in HF CM. In addition, dantrolene had neutral effects on contractile force of human isometrically twitching ventricular HF trabeculae.Conclusion: Our study showed that dantrolene beneficially influenced disrupted SR Ca2+ homeostasis in human HF and AF CM. Cellular arrhythmogenic triggers were potently suppressed by dantrolene, whereas action potential duration and contractility were not affected. As a clinically approved drug for the treatment of malignant hyperthermia, dantrolene may be a potential antiarrhythmic drug for patients with rhythm disorders and merits further clinical investigation. [ABSTRACT FROM AUTHOR]

Malignant hyperthermia (MH) is a life-threatening disease that occurs during general anaesthesia following exposure to succinylcholine (SCh), a depolarizing muscle relaxant, and volatile anaesthetics. Susceptibility to MH most commonly arises from mutations in the RyR1 gene, the Ca2+ release channel of skeletal muscle. Fulminant MH (f-MH) is the most dangerous form of MH, which presents a hypermetabolic cascade state, including very high temperature and carbon dioxide production, increased heart rate and oxygen consumption, mixed acidosis, rigid muscles, and rhabdomyolysis. Dantrolene is the only specific drug therapy for MH on the market. Without dantrolene, the reported mortality of f-MH is as high as 42.3%. Based on the participation of catecholamine in the hyperhaemodynamic response of f-MH and the demonstrated effective control of catecholamine release of magnesium sulfate, combined with the fact that magnesium and calcium have opposite effects on muscle contraction, I hypothesized that magnesium sulfate could be a choice for delaying the progression of f-MH while waiting for dantrolene treatment. [ABSTRACT FROM AUTHOR]

A 3-yr-old spayed female coyote (Canis latrans) developed clinical signs of exertional myopathy after fighting with a conspecific. A diagnosis of exertional myopathy was made based on physical examination findings, probable myoglobinuria, and elevations in serum creatinine kinase activity, alanine aminotransferase activity, and potassium concentration. Dantrolene, a hydantoin analog, as well as supportive and symptomatic therapies, was used to successfully treat exertional myopathy. This is the first reported use of dantrolene in wildlife or zoo animals. [ABSTRACT FROM AUTHOR]

In this study, we investigated the long-term treatment of dantrolene on amyloid and tau neuropathology, brain volume, and cognitive function in aged triple transgenic Alzheimer (3xTg-AD) mice. Fifteen-month old 3xTg-AD mice and wild-type controls were treated with oral dantrolene (5 mg/kg) or vehicle control twice a week for 6 months. Learning and memory were examined using the Morris Water Maze at 21 and 22 months of age. After the behavioral testing, hippocampal and cortical brain volumes were calculated with magnetic resonance imaging and motor function was evaluated using the rotorod. The amyloid burden and tau neurofibrillary tangles in the hippocampus were determined using immunohistochemistry. We found that dantrolene significantly decreased the intraneuronal amyloid accumulation by as much as 76% compared with its corresponding vehicle control, together with a trend to reduce phosphorylated tau in the hippocampus. No significant differences could be detected in hippocampal or cortical brain volume, motor function or cognition among all experimental groups, indicating that the mice were still presymptomatic for Alzheimer disease. Thus, presymptomatic and long-term dantrolene treatment significantly decreased the intraneuronal amyloid burden in aged 3xTg-AD mice before significant changes in brain volume, or cognition. [ABSTRACT FROM AUTHOR]

Alzheimer disease (AD) is a fatal progressive disease and the most common form of dementia without effective treatments. Previous studies support that the disruption of endoplasmic reticulum Ca2+ through overactivation of ryanodine receptors plays an important role in the pathogenesis of AD. Normalization of intracellular Ca2+ homeostasis could be an effective strategy for AD therapies. Dantrolene, an antagonist of ryanodine receptors and an FDA-approved drug for clinical treatment of malignant hyperthermia and muscle spasms, exhibits neuroprotective effects in multiple models of neurodegenerative disorders. Recent preclinical studies consistently support the therapeutic effects of dantrolene in various types of AD animal models and were summarized in the current review. [ABSTRACT FROM AUTHOR]

Malignant hyperthermia (MH) is a pharmacogenetic disorder. Indeed, it was among the first group of pharmacogenetic conditions reviewed in the anaesthetic literature. Most patients who are susceptible to MH have no overt manifestations of the condition until they are exposed to the triggering drugs, which comprise the potent inhalational anaesthetics and suxamethonium. There is currently no valid population screening test for MH and the key to avoiding mortality or chronic morbidity rests with anaesthetists recognizing the early features of a developing MH reaction and then intervening appropriately. There are no clinical pathognomonic features of MH but an understanding of the cellular and systemic events underlying the reaction is most useful in making the provisional diagnosis. This article will focus on these pathophysiological mechanisms and the rationale for published management guidelines. As MH is fundamentally a disorder of skeletal muscle calcium regulation it is necessary first to summarize the physiology of skeletal muscle calcium release and reuptake. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The regulatory mechanisms responsible for acute exercise-induced expression of monocarboxylate transporters MCT1 and MCT4 mRNA in skeletal muscle remain unclear. 5′-adenosine-activated protein kinase (AMPK) is a key signaling molecule that regulates gene expression at the mRNA level. We examined whether AMPK activation is involved in acute exercise-induced expression of MCT1 and MCT4 mRNA in fast-twitch muscle. Materials/Methods: Male Sprague–Dawley rats were subjected to an acute bout of either 5min high-intensity intermittent swimming (HIS) or 6-h low-intensity prolonged swimming (LIS). The effects of acute exercise on the phosphorylation of AMPK (p-AMPK), calcium/calmodulin pendent kinase II (p-CaMKII), p38 mitogen-activated protein kinase (p-p38MAPK), and MCTs mRNA were analyzed in vivo. To observe the direct effects of AMPK activation on MCTs mRNA, the effects of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), caffeine, and dantrolene were analyzed in vitro using an isolated muscle incubation model. Results: The p-AMPK increased in response to both HIS and LIS, although the p-CaMKII and p-p38MAPK were increased only following HIS. Irrespective of exercise intensity, MCT1 and MCT4 mRNA was also transiently upregulated by both HIS and LIS. Direct exposure of the epitrochlearis muscle to 0.5mmol/L AICAR or 1mmol/L caffeine, which activated p-AMPK increased both MCT1 and MCT4 mRNA levels. When pAMPK was inhibited by dantrolene, neither MCT1 nor MCT4 mRNA was increased. Conclusion: These results suggest that acute exercise-induced increases in MCT1 and MCT4 mRNA expression may be possibly mediated by AMPK activation, at least in part in fast-twitch muscle. [Copyright &y& Elsevier]

Malignant hyperthermia (MH) has been described as a rare inherited autosomal dominant metabolic syndrome triggered in patients after exposure to certain inhalation anesthetics and depolarizing muscle relaxants. Typically MH is seen within the operating room and postanesthesia care environment. This case study will discuss a patient with an atypical MH crisis in the intensive care unit. Pathophysiology, genetic basis of and testing for MH-susceptibility as well as the role of the critical care nurse in the management of this potentially fatal disorder will be discussed. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 9 year-old diagnosed with the condition of malignant hyperthermia (MH). Malignant hyperthermia is a hereditary disorder that can be accelerated by volatile anesthetic agents and depolarizing muscle relaxants. Muscle biopsy or genetic testing is the best method for anticipating MH. Dantrolene 1 mg/kg IV every 4-6 hours should be administered, and continued for 24-48 hours after an incident of MH.

Abstract: Kim JY, Chun S, Bang MS, Shin H-I, Lee S-U. Safety of low-dose oral dantrolene sodium on hepatic function. Objective: To investigate the incidence of hepatobiliary dysfunction after administration of low-dose dantrolene sodium. Design: A retrospective survey of medical records. Setting: One secondary and 2 tertiary hospitals. Participants: Patients (N=243; 144 men, 27 children; mean age ± SD, 47.8±19.7y) who were administered dantrolene at a daily dose of 12.5 to 400mg for more than 4 weeks. Interventions: Not applicable. Main Outcome Measures: Liver function test (LFT) results, including serum total bilirubin, aspartate transaminase, alanine transaminase, and alkaline phosphatase, were recorded before and at least 1 month after the initial dose of dantrolene. In cases of treatment cessation, the reason was investigated. Significantly elevated LFT levels were defined as ≥ to 2 times the upper limit of the normal range. Results: Treatment duration was 268.0±428.5 days with a daily dose of 65.2±44.7mg. At the end of the investigation, 95 patients (39.1%) had been lost to follow-up, and 105 (43.2%) had stopped treatment. The reasons for cessation were improved spasticity (42.9%), no effect of the medication (27.6%), weakness (6.7%), and other medical problems (5.7%). Patients with weaknesses did not have elevated LFT values. A 32-year-old man with head injuries and multiple trauma developed hepatic dysfunction 82 days after the initial dose and 43 days after a dose increment to 400mg/d. Other patients did not experience significant LFT abnormalities. Conclusions: One case of hepatic dysfunction was recorded in 243 cases after at least 4 weeks of low-dose oral dantrolene administration. Low-dose dantrolene can be used safely with meticulous clinical and laboratory monitoring. [Copyright &y& Elsevier]

Copyright of Revista Médica Clínica Las Condes is the property of Editorial Sanchez y Barcelo and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Spasticity is a common disability in children with cerebral palsy. Pharmacological and non-pharmacological treatments, including physical therapy, occupational therapy, orthotics, rhizotomy, and orthopedic surgery, all play important roles in the management of spasticity. The purpose of this article is to provide an overview of available medications for treatment of spasticity in children with cerebral palsy. Common medications include benzodiazepines, dantrolene sodium, baclofen, tizanidine, botulinum toxins, phenol, alcohol and intrathecal baclofen. In general, oral medications and intrathecal baclofen are used for treating generalized spasticity, whilst chemodenervation agents (botulinum toxins, phenol, and alcohol) are used to treat localized spasticity. There is more sufficient evidence for the recommendation of botulinum toxin A as an effective anti-spasticity treatment in children with cerebral palsy. However, more data concerning safety and long-term effects of botulinum toxin A is needed. Further study is needed to determine which kinds of medications can cause substantial improvement in daily activity, participation level, self-competence, or quality of life in children with cerebral palsy. [Copyright &y& Elsevier]

Dantrolene sodium is an inhibitor of a skeletal muscle subtype of ryanodine receptors that stabilizes intracellular calcium concentrations and exerts neuroprotective effects in neurons submitted to excitotoxic challenges. Propofol is a short-acting intravenous anaesthetic. It has widely been used clinically as an intravenous general anaesthetic and as a sedative for critically ill patients. 6-Phosphogluconate dehydrogenase (6PGD) constitutes the pentose phosphate pathway and produces NADPH. It is also considered as a lipogenic gene since NADPH is a pivotal cofactor for lipogenesis. In this study, in vivo inhibition effects of dantrolene sodium and propofol on 6PGD were studied. The 6PGD activity was inhibited in vivo by both dantrolene sodium and propofol. Dantrolene at pharmacological dosage (10 mg/ kg) inhibited the significantly (p<0.05) 3 h after dosing. However, the enzyme activity has been raised to the normal level at 5 h. On the other hand, at the pharmacological dosage (5 mg/kg), propofol also inhibited the significantly 1 h (p<0.05) and 3 h (p.< 0.05) after dosing. However, the enzyme activity has been raised to the normal level at 5 h. [ABSTRACT FROM AUTHOR]

Summary: Malignant hyperthermia (MH) was first recognised as a potentially fatal pharmacogenetic disorder nearly 50 years ago. The abnormality has been localised to skeletal muscle, specifically the mechanisms regulating myoplasmic calcium ion homeostasis. The gene principally implicated is RYR1, which encodes the skeletal muscle sarcoplasmic reticulum calcium release channel, but the genetics of MH are relatively complex, with more than 100 mutations described in RYR1 and with a significant minority of cases not involving this gene. This review describes how the pathophysiology of MH relates to the clinical features, which follow a logical pattern. Reasons for the reaction reaching an untreatable stage are proposed, emphasising the importance of early diagnosis and aggressive treatment using the latest guidelines. Early intervention in suspected cases, and the lack of specificity of any single clinical feature for MH, necessitates laboratory confirmation of the diagnosis using muscle biopsy specimens. These relatively invasive tests can also be used to screen family members of known cases, although the limited introduction of DNA testing has obviated the need for some individuals to have a muscle biopsy. Patients at risk of developing MH can receive general anaesthesia and guidelines for this are described. [Copyright &y& Elsevier]

Abstract: Mechanical loads can profoundly alter cell growth and cell proliferation. The dinoflagellates are especially sensitive to mechanical stimulation. Many species will be arrested in cell cycle in response to turbulence or shear stress. We demonstrate here that mechanical shaking and caffeine, the ryanodine-receptor agonist, induced an elevation of cytosolic calcium in the dinoflagellate Crypthecodinium cohnii. Dantrolene, a ryanodine-receptor antagonist, dose-dependently inhibited both shaking-induced and caffeine-induced calcium release. Similar to the effect of mechanical shaking, caffeine alone dose-dependently and reversibly induced cell cycle arrest in dinoflagellates. Prolonged shaking substantially abolished the magnitude of caffeine-induced calcium release and vice-versa, suggesting that both agents released calcium from similar stores through ryanodine receptors. Fluorescence-conjugated ryanodine gave positive labeling, which could be blocked by ryanodine, in the cortice of C. cohnii cells. In addition, caffeine or shaking mobilized intracellular chlortetracycline (CTC)-positive membrane-bound calcium, which could be similarly depleted by t-BuBHQ, a SERCA pump inhibitor. Prior treatment with shaking or caffeine also inhibited the ability of the other agent in mobilizing CTC-positive calcium. CTC-positive microsomal fractions could also be induced to release calcium by caffeine and cADPR, the ryanodinee receptor modulator. t-BuBHQ, but not calcium ionophores, induced cell cycle arrest, and the calcium chelator BAPTA-AM was unable to rescue caffeine-induced cell cycle arrest. These data culminate to suggest that mobilization or depletion of caffeine-sensitive calcium stores, but not calcium elevation per se, is involved in the induction of cell cycle arrest by mechanical stimulation. The present study establishes the role of caffeine-sensitive calcium stores in the regulation of cell cycle progression. [Copyright &y& Elsevier]

Malignant hyperthermia (MH) is a rare genetic condition which may manifest for the first time during anaesthesia associated with a routine surgical procedure. Characterised initially by muscle rigidity, increased body temperature and metabolic acidosis, the syndrome may prove fatal unless prompt, effective treatment is administered. The sudden development of MH constitutes a medical emergency; hence it is essential that theatre practitioners are knowledgeable about the presenting symptoms and management of the condition. [ABSTRACT FROM AUTHOR]

Copyright of EMC-Anesthesie--Reanimation is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Malignant hyperthermia (MH) is a rare genetic disorder that develops following exposure to volatile anaesthetic agents and depolarizing muscle relaxants. In this case report, a 10-year-old boy with cleft lip and palate underwent alveolar bone grafting for right cleft alveolus. In this surgery, the MH episode occurred approximately 2 h following induction of anaesthesia when the patient was noted to develop hypercapnia, tachycardia and hyperthermia. An MH crisis was declared. Immediate management included active cooling and intravenous dantrolene, to which the patient responded. In conclusion, early diagnosis and prompt action are very important in the successful management of MH. [ABSTRACT FROM AUTHOR]

A 33 year old lady with no obvious reason to suspect susceptibility to malignant hyperpyrexia (MH) succumbed to this unexpected complication in spite of attempts to save her life with aggressive supportive measures. We are reporting this case of possible malignant hyperthermia probably the seventh reported case in India and second from Kerala in the last decade (Saxena and Dua, 2007; Punj et al., 2001; Gopalakrishnan et al., 2010; Jain, 2010; Ramakant and Singh, 2012; Sharma et al., 2012). This was the first ever case of MH in our institution in 25 years This emphasises the need to ensure availability of Dantrolene and MH kits, diagnostic centres with appropriate lab controls and above all high index of suspicion and heightened awareness among the anaesthesiologists of this potential albeit rare risk of MH in Indian population. [ABSTRACT FROM AUTHOR]

Abstract: Malignant hyperthermia (MH) is a pharmacogenetic disorder. Indeed, it was among the first group of pharmacogenetic conditions reviewed in the anaesthetic literature. Most patients who are susceptible to MH have no overt manifestations of the condition until they are exposed to the triggering drugs, which comprise the potent inhalational anaesthetics and suxamethonium. There is currently no valid population screening test for MH and the key to avoiding mortality or chronic morbidity rests with anaesthetists recognizing the early features of a developing MH reaction and then intervening appropriately. There are no clinical pathognomonic features of MH but an understanding of the cellular and systemic events underlying the reaction is most useful in making the provisional diagnosis. This article will focus on these pathophysiological mechanisms and the rationale for published management guidelines. As MH is fundamentally a disorder of skeletal muscle calcium regulation it is necessary first to summarize the physiology of skeletal muscle calcium release and reuptake. [Copyright &y& Elsevier]

The article presents a case study of a36-year-old woman with a history bipolar affective disorder who was presented to an emergency department with fever, headache, diarrhea, nausea, and vomiting. The patient was diagnosed with neuroleptic malignant syndrome (NMS) and was started on bromocriptine. The study suggests that the interesting aspect about the atypical case of NMS was the absence of muscle rigidity on clinical examination.

Abstract: Malignant hyperthermia (MH) is a pharmacogenetic disorder. Indeed, it was among the first group of pharmacogenetic conditions reviewed in the anaesthetic literature. Most patients who are susceptible to MH have no overt manifestations of the condition until they are exposed to the triggering drugs, which comprise the potent inhalational anaesthetics and suxamethonium. There is currently no valid population screening test for MH and the key to avoiding mortality or chronic morbidity rests with anaesthetists recognizing the early features of a developing MH reaction and then intervening appropriately. There are no clinical pathognomonic features of MH but an understanding of the cellular and systemic events underlying the reaction is most useful in making the provisional diagnosis. This article will focus on these pathophysiological mechanisms and the rationale for published management guidelines. As MH is fundamentally a disorder of skeletal muscle calcium regulation it is necessary first to summarize the physiology of skeletal muscle calcium release and reuptake. [Copyright &y& Elsevier]

Abstract: Malignant hyperthermia (MH) is a pharmacogenetic disorder. Indeed, it was among the first group of pharmacogenetic conditions reviewed in the anaesthetic literature. Most patients who are susceptible to MH have no overt manifestations of the condition until they are exposed to the triggering drugs, which comprise the potent inhalational anaesthetics and suxamethonium. There is currently no valid population screening test for MH and the key to avoiding mortality or chronic morbidity rests with anaesthetists recognizing the early features of a developing MH reaction and then intervening appropriately. There are no clinical pathognomonic features of MH but an understanding of the cellular and systemic events underlying the reaction is most useful in making the provisional diagnosis. This article will focus on these pathophysiological mechanisms and the rationale for published management guidelines. As MH is fundamentally a disorder of skeletal muscle calcium regulation it is necessary first to summarize the physiology of skeletal muscle calcium release and reuptake. [Copyright &y& Elsevier]

Malignant hyperthermia is a rare and sometimes deadly disease that is difficult to diagnose and treat unless surgery centers have undergone proper training and prepared the right way. [ABSTRACT FROM AUTHOR]

Background: 2,4-Dinitrophenol (DNP) is a known uncoupler of oxidative phosphorylation that clinically results in hyperthermia, tachycardia, tachypnea, and metabolic acidosis. Overdoses of DNP are often fatal and there is no specific reversal therapy. Dantrolene interferes with calcium release in skeletal muscle and is traditionally used to treat malignant hyperthermia. There has been limited published data on its use in DNP toxicity. We present two cases of DNP toxicity that were treated with dantrolene. CASE 1: A 22-year-old male presented following an overdose of his bodybuilding supplements including DNP. He became altered, tachycardic, and hyperthermic to 40.0C. He required intubation and aggressive cooling. He received multiple doses of dantrolene over the initial 36 h with resolution of his hyperthermia. He was extubated and discharged home on hospital day 6. CASE 2: A 20-year-old male presented following a staggered ingestion of DNP. He was tachypneic and tachycardic on arrival. He became hyperthermic to 40.2C and required intubation. He underwent aggressive cooling and received 200 mg of IV dantrolene. His temperature normalized, however, he expired 4 h after ED arrival.Conclusion: DNP toxicity has limited treatment options. Dantrolene may ameliorate the hypermetabolic state in DNP toxicity by lessening excitation-contraction coupling in muscle cells and improving the associated hyperthermia. Our cases demonstrate the hyperthermia reducing effects of dantrolene in DNP toxicity and contribute to the existing literature on this topic. Being aware of the possible use of dantrolene to treat the associated hyperthermia could assist emergency physicians in the treatment of DNP toxicity. [ABSTRACT FROM AUTHOR]

The thermal reaction of (4-nitrophenyl) nitrene with oxygen in low-temperature matrices produced a new molecular species, which was identified as 4-nitrophenylnitroso oxide on the basis of its IR spectrum in combination with isotopic labeling with 18O2 and vibration analyses by the DFT method. This is the first report for the infrared detection of an aryl nitroso oxide. We could monitor also the wavelength-dependent N--O and O--O bond cleavage of the nitroso oxide. [ABSTRACT FROM AUTHOR]