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Neuroleptic malignant syndrome is a rare medical emergency associated with the use of antipsychotics and other antidopaminergic drugs. There is no specific test, and diagnosis is based on high clinical suspicion and good differential diagnosis. A clinical picture consistent with hyperthermia, muscle rigidity, altered level of consciousness, together with signs of rhabdomyolysis in analytical studies and a history of taking neuroleptic drugs are the key elements in the detection of this entity. Due to its low incidence and potential mortality, it is essential to publish case reports of neuroleptic malignant syndrome in order to raise awareness of this entity and facilitate diagnostic suspicion when encountering a patient with compatible symptoms. The following is the case of a 79 year old patient with chronic alcohol consumption as the only history of interest, who was given a single dose of haloperidol after an episode of delirium in the postoperative period of conventional trauma surgery. She subsequently developed a picture of progressive deterioration of the level of consciousness, diaphoresis, generalized muscle rigidity, hyperthermia, together with severe metabolic acidosis, hyperlacticaemia, rhabdomyolysis, hypertransaminasemia and hypocalcemia. After ruling out other entities compatible with the clinical picture, neuroleptic malignant syndrome was given as the main diagnostic hypothesis. Diagnosis was confirmed after clinical and analytical improvement following treatment with dantrolene. The patient was discharged from hospital with no sequelae a few days after onset of the condition.

The impairment of intracellular calcium homeostasis plays an essential role during ischemia-reperfusion injury. Calcium release from sarcoplasmic reticulum which is triggered by myocardial ischemia is mainly mediated by ryanodine receptors. Dantrolene sodium is a ryanodine receptor antagonist. The objective of the present study was to evaluate the in-vivo impact of dantrolene sodium on myocardial ischemia-reperfusion injury in swine models. An in vivo, experimental trial comparing 10 experimental animals which received dantrolene sodium with 9 control swine models was conducted. Their left anterior descending coronary artery was temporarily occluded for 75 minutes via a vessel tourniquet, which was then released. Myocardial reperfusion was allowed for 24 hours. Dantrolene was administered at the onset of the reperfusion period and levels of troponin, creatine phosphokinase and creatine kinase myocardial band between the two groups were compared. Additionally, various other hemodynamic parameters and left ventricular morphology and function were examined. There were significantly lower values of troponin, creatine phosphokinase and creatine kinase myocardial band in the dantrolene group indicating less ischemia-reperfusion injury. Moreover, the postischemic cardiac index was also greater in the dantrolene group, whereas viable myocardium was also better preserved. In conclusion, the in vivo cardioprotective role of dantrolene sodium against ischemia-reperfusion injury in swine models was indicated in this study. Therefore, dantrolene sodium administration could be a promising treatment against ischemia-reperfusion injury in humans. However, large randomized clinical studies should be firstly carried out to prove this hypothesis.

Background: Hepatocellular carcinoma (HCC) is the 6th prevalent cancer and the 4th leading cause of cancer-related deaths all over the world. A major challenge for sorafenib, the standard chemotherapeutic agent in HCC treatment, is the chemo-resistance. Objective: This study was conducted to evaluate the role of dantrolene as a possible antineoplastic agent in HCC, and in chemo-sensitization of sorafenib via targeting Ca+2/PI3K pathway. Methods: HCC was induced in rats using a single dose of diethylnitrosamine (DENA) (200 mg/kg, ip), followed by phenobarbital sodium (0.05%) in drinking water for 18 weeks. At the end of the 18th week, rats were allocated into 4 groups (10 rats/each), one group was left without treatment (DENA group) and the other three groups were treated with either sorafenib, dantrolene, or their combination for further 4 weeks. One day after the last injection, serum and liver tissues were collected. Liver tissue p53, VEGF, MMP-9, Cyclin D1, PI3K, and, serum AFP were assessed using immunoassay. Hepatic and serum Ca+2 were also computed. Furthermore, Ki-67 was assessed immunohistochemically. Results: Dantrolene exhibited synergistic effect when used in combination with sorafenib compared to either drug alone (p Conclusion: Dantrolene exerted antineoplastic effect as well as augmented sorafenib antineoplastic activity via the intervention of Ca+2/PI3K pathway, manifested by ameliorating angiogenesis, apoptosis, proliferation and metastasis.

Background Malignant hyperthermia (MH) is a rare and potentially life-threatening pharmacogenetic disorder encountered during general anesthesia, with the incidence higher in children than in adults. Dantrolene is the specific antagonist of MH, but it is not readily available in China, thus developing alternative treatment protocols is of great practical importance. Case Presentation Herein, the authors report a two-month-old infant who underwent holmium laser epiglottis retrofitting through a bronchoscope, but developed limb muscular stiffness, tachypnea, tachycardia, and hyperthermia after sevoflurane exposure. After the diagnosis of MH, corresponding supportive treatment was implemented. Because there was no dantrolene available, continuous blood purification and mechanical ventilation were performed. A few days later, the boy recovered without any complications. Conclusion Based on the authors’ successful clinical practice, the authors consider continuous blood purification as a reliable treatment for MH. But its feasibility still needs to be clarified after multicenter clinical observations.

Mutations in the type 1 ryanodine receptor (RyR1), a Ca2+ release channel in skeletal muscle, hyperactivate the channel to cause malignant hyperthermia (MH) and are implicated in severe heat stroke. Dantrolene, the only approved drug for MH, has the disadvantages of having very poor water solubility and long plasma half-life. We show here that an oxolinic acid-derivative RyR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (Compound 1, Cpd1), effectively prevents and treats MH and heat stroke in several mouse models relevant to MH. Cpd1 reduces resting intracellular Ca2+, inhibits halothane- and isoflurane-induced Ca2+ release, suppresses caffeine-induced contracture in skeletal muscle, reduces sarcolemmal cation influx, and prevents or reverses the fulminant MH crisis induced by isoflurane anesthesia and rescues animals from heat stroke caused by environmental heat stress. Notably, Cpd1 has great advantages of better water solubility and rapid clearance in vivo over dantrolene. Cpd1 has the potential to be a promising candidate for effective treatment of patients carrying RyR1 mutations., Mutations in ryanodine receptor 1 (RyR1), a Ca2+ release channel in skeletal muscle, cause malignant hyperthermia (MH) and are involved in heat stroke. Here, the authors show that an oxolinic acid-derivative RyR1 inhibitor effectively prevents and treats MH and heat stroke in various MH mouse models.

Diabetics have a higher risk of developing cerebral vasospasms (CVSP) after subarachnoid hemorrhagic stroke than non-diabetics. Serotonin (5-HT) is one of the key vasoconstrictors released in the hemorrhagic blood and an important contributor to the etiology of CVSP. The combination of the ryanodine receptor blocker dantrolene and the Ca2+ channel blocker nimodipine significantly reduces phenylephrine (PHE)-induced vascular contraction in both diabetic and nondiabetic rats, but the effectiveness of this drug combination in reducing 5-HT-induced contraction is unknown. Dose–response curves for the 5-HT-induced contraction (from 0.1 nM to 100 µM) were performed on aortic rings from diabetic and non-diabetic rats after a 30-min incubation period with dantrolene, nimodipine, and both drugs in combination. In diabetic rats, 10 μM of dantrolene alone failed to reduce 5-HT-induced maximal contraction (Emax), but 50 μM reduced this parameter by 34% (n = 7, p 50 values for the 5-HT-induced contraction curves in both diabetics (from 10.31 ± 1.17 µM to 19.26 ± 2.82; n = 10, p

Malignant hyperthermia (MH) is caused by a genetic disorder of the skeletal muscle that induces a hypermetabolic response when patients are exposed to a triggering agent such as volatile inhaled anesthetics or depolarizing neuromuscular blockers. Symptoms of MH include increased carbon dioxide production, hyperthermia, muscle rigidity, tachypnea, tachycardia, acidosis, hyperkalemia, and rhabdomyolysis. Common scenarios for triggering agents are those used are during surgery and rapid sequence intubation. Hypermetabolic symptoms have a rapid onset; hence, prompt recognition and treatment are vital to prevent morbidity and mortality. The first-line treatment agent for an MH response is dantrolene. Further treatment includes managing complications related to a hypermetabolic response such as hyperkalemia and arrhythmias. This review is focused on the recognition and treatment considerations of MH in the emergency department to optimize therapy and improve patient morbidity and mortality.

Background Malignant hyperthermia (MH) is a rare genetic disease characterized by the development of very serious symptoms, and hence prompt and appropriate treatment is required. However, postoperative MH is very rare, representing only 1.9% of cases as reported in the North American Malignant Hyperthermia Registry (NAMHR). We report a rare case of a patient who developed sudden postoperative hyperthermia after mastectomy, which was definitively diagnosed as MH by the calcium-induced calcium release rate (CICR) measurement test. Case presentation A 61-year-old Japanese woman with a history of stroke was hospitalized for breast cancer surgery. General anesthesia was introduced by propofol, remifentanil, and rocuronium. After intubation, anesthesia was maintained using propofol and remifentanil, and mastectomy and muscle flap reconstruction surgery was performed and completed without any major problems. After confirming her spontaneous breathing, sugammadex was administered and she was extubated. Thereafter, systemic shivering and masseter spasm appeared, and a rapid increase in body temperature (maximum: 38.9 °C) and end-tidal carbon dioxide (ETCO2) (maximum: 59 mmHg) was noted. We suspected MH and started cooling the body surface of the axilla, cervix, and body trunk, and administered chilled potassium-free fluid and dantrolene. After her body temperature dropped and her shivering improved, dantrolene administration was ended, and finally she was taken to the intensive care unit (ICU). Body cooling was continued within the target range of 36–37 °C in the ICU. No consciousness disorder, hypotension, increased serum potassium level, metabolic acidosis, or cola-colored urine was observed during her ICU stay. Subsequently, her general condition improved and she was discharged on day 12. Muscle biopsy after discharge was performed and provided a definitive diagnosis of MH. Conclusions The occurrence of MH can be life-threatening, but its frequency is very low, and genetic testing and muscle biopsy are required to confirm the diagnosis. On retrospective evaluation using the malignant hyperthermia scale, the present case was almost certainly that of a patient with MH. Prompt recognition and immediate treatment with dantrolene administration and body cooling effectively reversed a potentially fatal syndrome. This was hence a valuable case of a patient with postoperative MH that led to a confirmed diagnosis by CICR.

Background Neuroblastoma is the most common malignant extracranial solid tumor in pediatrics patients. Intraoperative hyperthermia is extremely rare in patients with neuroblastoma and can cause a series of complications. Here, we represent a case of neuroblastoma accompanied by hyperthermia during anesthesia, and propose a rational explanation and management options. Case presentation The patient had gait disturbance and sitting-related pain without fever. Magnetic resonance imaging revealed a soft tissue mass located in the right posterior mediastinum, paravertebral space and canalis vertebralis. Serum tumor marker screening showed that the patient had increased epinephrine, norepinephrine and neuron specific enolase levels, with an increased 24 hour urine vanillylmandelic acid level. Intraspinal tumor resection was conducted. The temperature of the patient rapidly arose to 40.1 °C over 10 minutes when waiting for tracheal extubation. The arterial gas analysis results indicated malignant hyperthermia was less likely, and dantrolene was not administered. Physical cooling methods were used, and the temperature dropped to 38.6 ℃. The trachea was successfully extubated. Histological results confirmed the diagnosis of neuroblastoma. Conclusions Hyperthermia during anesthesia is a serious adverse event. Catecholamines secreted from neuroblatoma cells can lead to hypermetabolism and hyperthermia. Surgeons and anesthesiologists should be aware of the possibility of hyperthermia in patients with neuroblastoma.

Malignant hyperthermia (MH) is a severe hypermetabolic disorder associated with dysregulation of calcium homeostasis and is triggered by inhalational anesthetics (isoflurane, sevoflurane, desflurane) and a depolarizing muscle relaxant (succinylcholine). We report the case of a 16-day-old infant undergoing laparoscopic surgery. The patient developed hyperthermia and hypercarbia with muscle rigidity. After the diagnosis of MH, dantrolene was administered with sufficient hydration. The patient was transferred to the pediatric intensive care unit for monitoring and treatment of acute renal injury due to myoglobinuria. Subsequently, two variants of the ryanodine receptor 1 (RYR1) gene were identified in the patient as the mutation point at c.1589G > A p.Arg530His and c.1841G > T p.Arg614Leu, which are known to be associated with MH. This was a rare case of MH in a 16-day-old infant that might be related to two RYR1 mutations inherited from the parents.

Dantrolene represents yet another interesting example of abundant molecular crystal polymorphism existing in at least six different neat polymorphs, three of which can be obtained via crystallizati...

Malignant hyperthermia is defined in the International Classification of Diseases as a progressive life-threatening hyperthermic reaction occurring during general anaesthesia. Malignant hyperthermia has an underlying genetic basis, and genetically susceptible individuals are at risk of developing malignant hyperthermia if they are exposed to any of the potent inhalational anaesthetics or suxamethonium. It can also be described as a malignant hypermetabolic syndrome. There are no specific clinical features of malignant hyperthermia and the condition may prove fatal unless it is recognised in its early stages and treatment is promptly and aggressively implemented. The Association of Anaesthetists has previously produced crisis management guidelines intended to be displayed in all anaesthetic rooms as an aide memoire should a malignant hyperthermia reaction occur. The last iteration was produced in 2011 and since then there have been some developments requiring an update. In these guidelines we will provide background information that has been used in updating the crisis management recommendations but will also provide more detailed guidance on the clinical diagnosis of malignant hyperthermia. The scope of these guidelines is extended to include practical guidance for anaesthetists dealing with a case of suspected malignant hyperthermia once the acute reaction has been reversed. This includes information on care and monitoring during and after the event; appropriate equipment and resuscitative measures within the operating theatre and ICU; the importance of communication and teamwork; guidance on counselling of the patient and their family; and how to make a referral of the patient for confirmation of the diagnosis. We also review which patients presenting for surgery may be at increased risk of developing malignant hyperthermia under anaesthesia and what precautions should be taken during the peri-operative management of the patients.

Right ventricular (RV) failure is a major cause of death in patients with pulmonary arterial hypertension, and the mechanism of RV failure remains unclear. While the malfunction of RyR2 (ryanodine receptor type 2) on sarcoplasmic reticulum (SR) and aberrant Ca 2+ cycling in cardiomyocytes have been recognized in some cardiovascular diseases, their roles in RV failure secondary to pulmonary arterial hypertension require further investigation. In a monocrotaline-induced rat model of pulmonary arterial hypertension, the RV remodeling process was divided into normal, compensated, and decompensated stages according to the hemodynamic and morphological parameters. In both compensated and decompensated stages, significant diastolic SR Ca 2+ leakage was detected along with reduced intracellular Ca 2+ transient amplitude and SR Ca 2+ contents in RV myocytes. RyR2 protein levels decreased progressively during the process, and the thiol oxidation proportions of RyR2 were higher in compensated and decompensated stages than in normal stage. Inhibition of RyR2 oxidation by dithiothreitol or repairing RyR2 directly by dantrolene could restore Ca 2+ homeostasis in RV myocytes. Daily intraperitoneal injection of dantrolene delayed decompensation progression and significantly improved the survival rate of pulmonary hypertension rats in decompensated stage (79.3% versus 55.9%; P =0.026). Our findings suggest that diastolic SR Ca 2+ leakage via oxidized RyR2 facilitates the development of RV failure. Dantrolene can inhibit diastolic SR Ca 2+ leakage in RV cardiomyocytes, delay right cardiac dysfunction, and improve the survival of rats with pulmonary arterial hypertension.

Malignant hyperthermia is a potentially fatal condition, in which genetically predisposed individuals develop a hypermetabolic reaction to potent inhalation anaesthetics or succinylcholine. Because of the rarity of malignant hyperthermia and ethical limitations, there is no evidence from interventional trials to inform the optimal perioperative management of patients known or suspected with malignant hyperthermia who present for surgery. Furthermore, as the concentrations of residual volatile anaesthetics that might trigger a malignant hyperthermia crisis are unknown and manufacturers' instructions differ considerably, there are uncertainties about how individual anaesthetic machines or workstations need to be prepared to avoid inadvertent exposure of susceptible patients to trigger anaesthetic drugs. The present guidelines are intended to bundle the available knowledge about perioperative management of malignant hyperthermia-susceptible patients and the preparation of anaesthesia workstations. The latter aspect includes guidance on the use of activated charcoal filters. The guidelines were developed by members of the European Malignant Hyperthermia Group, and they are based on evaluation of the available literature and a formal consensus process. The most crucial recommendation is that malignant hyperthermia-susceptible patients should receive anaesthesia that is free of triggering agents. Providing that this can be achieved, other key recommendations include avoidance of prophylactic administration of dantrolene; that preoperative management, intraoperative monitoring, and care in the PACU are unaltered by malignant hyperthermia susceptibility; and that malignant hyperthermia patients may be anaesthetised in an outpatient setting.

Background: Bidirectional ventricular tachycardia (BD-VT) is an intriguing arrhythmia, characterized by a beat-to-beat alternation of the QRS polarity on electrocardiogram. Currently there is no simple BD-VT animal model. Objective: We report a simple animal model of BD-VT induced by caffeine and dobutamine (C+D) challenge in normal rats in which the arrhythmia can be attenuated by dantrolene (a ryanodine receptor stabilizer) treatment, but not by the pacemaker channel blocker ivabradine treatment. Methods: Adult (4–5 months old) Sprague-Dawley rats (both sexes) were randomized into C+D (n = 8, received caffeine 120 mg/kg intraperitoneally [IP] and dobutamine 60 μg/kg IP, sequentially) and control (n = 8) groups. In addition, a group of 7 rats were pretreated with dantrolene (10 mg/kg, IP) 30 minutes before the C+D challenge and another group of 8 rats were pretreated with ivabradine (5 mg/kg, IP) 30 minutes before the C+D challenge. Results: C+D challenge induced spontaneous premature ventricular contractions (PVCs) in 7 of 8 rats and BD-VT (lasted 4.3 ± 2.9 minutes, terminated spontaneously) in 6 of 8 (75%) rats. No ventricular arrhythmia was induced in the control group (P < .05 vs C+D group). Dantrolene treatment significantly decreased BD-VT (1 of 7 rats in the Dantrolene+C+D group vs 6 of 8 rats in C+D group, P < .05). Ivabradine treatment did not affect C+D-induced BD-VT (7 of 8 rats in the Ivabradine+C+D group vs 6 of 8 in the C+D group, P > .05). Conclusion: Caffeine and dobutamine challenge induces BD-VT in a majority of normal rats. Stabilizing cardiac ryanodine receptors with dantrolene treatment can significantly decrease the occurrence of BD-VT, but pacemaker channel blocker ivabradine treatment does not have effect in this animal model.

Biomass-derived commodity chemical 5-hydroxymethyl furfural is an underutilized C6-platform chemical derived from cellulose that is ideal to prepare next-generation value-added products. We have developed an efficient synthetic strategy to access 2,5-diaryl nonsymmetric furans from 5-hydroxymethyl furfural utilizing decarboxylative cross-couplings. A key finding was that the presence of the hydroxymethyl handle enhances the yields of the palladium-catalyzed decarboxylative cross-coupling reaction. The method provides access to a broad-range nonsymmetric 2,5-diaryl furans where each arene can be systematically introduced as required. Additionally, this green synthetic strategy was employed for a formal synthesis of the muscle relaxant Dantrolene in excellent yields.

This study demonstrated that an enteric polymer can mitigate the effects of gastric pH on the oral absorption of a poorly water-soluble weak acid drug, dantrolene (DNT). An amorphous solid dispersion (ASD) of DNT with hydroxypropyl methylcellulose (HPMC) acetate succinate (ASD-HPMCAS) was prepared as the enteric released ASD (ER-SF). ASD with HPMC (ASD-HPMC) and DNT sodium salt were also used as immediate-release supersaturable formulations (IR-SFs) with and without water-soluble polymer, respectively. In vivo study with rats and in vitro study with a dissolution/permeation (D/P) system were performed to evaluate oral DNT absorption from each formulation under normal and high gastric pH conditions in rats and humans, respectively. The oral absorption of DNT from both IR-SFs in rats with a high gastric pH was significantly higher than that in rats with a normal gastric pH. In contrast, ASD-HPMCAS attenuated the difference in oral absorption between normal and high gastric pH conditions with significant improvement of DNT absorption. In vivo results implied that an enteric polymer delayed the onset of dissolution until after gastric emptying. ASD-HPMCAS generated supersaturation in the small intestine irrespective of gastric conditions, which was supported bythe in vitrostudy using the D/P system. This study suggested that an enteric polymer is useful to mitigate the inter- and intra-individual differences in oral absorption of poorly water-soluble weak acid drugs.

Activities of the somatomotor (MA), cardiovascular and respiratory systems were investigated in conditions of activation and blockade of ryanodine receptors (RyR) impaired cholinergic regulation in rat pups aged 3, 16 and 30 days. It was found that blockage of RyR by dantrolene has a negative chronotropic effect, the severity of which decreases with age, reduces the respiratory rate in rats on P3 and practically does not change in older animals. The amplitude of EMG and the power of motor bursts decreases in rats on P3-P16 and increases on P30. The duration of MA in the activity- rest cycle remains unchanged at P3 and decreases at P16-P30, which indicates a different change in the pattern of MA in rats of different ages after the blockade of RyR. Caffeine-induced activation of RyR is accompanied by an increase in heart rate and respiratory rate in rats on P30 and does not cause significant changes in these parameters on P3-P16. There has been an increase in all MA indices, especially in P3. Certain age-related regularities were revealed in the conditions of acetylcholinesterase inhibition by physostigmine, carried out against the background of RyR inhibition or activation. Maximum sensitivity to such effects was found in rats on P3. It was shown that in early postnatal ontogenesis of rats the sensitivity of RyR, including RyR2, to dantrolene is higher than in adult animals. Changes in RyR activity level do not prevent the development of pathological forms of heart rhythm that developing in rats after the physostigmine injection.

Summary Faced with a malignant hyperthermia crisis, the immediate access to sufficient dantrolene is essential to achieve the best possible outcome for the patient. However, malignant hyperthermia crises are rare, and there may be administrative pressures to limit the amount of dantrolene stocked or, in some countries, not to stock dantrolene at all. There are no published guidelines to support anaesthetic departments in their effort to ensure availability of sufficient dantrolene for the management of malignant hyperthermia crises. After a literature review that confirmed a lack of clinical trials to inform this guideline, we undertook a formal consensus development process, in which 25 members of the European Malignant Hyperthermia Group participated. The consensus process used a modified web-based Delphi exercise, in which participants rated the appropriateness of statements that covered the dosing regimen for dantrolene in a malignant hyperthermia crisis, the types of facility that should stock dantrolene, and the amount of dantrolene that should be stocked. The resulting guidelines are based on available evidence and the opinions of international malignant hyperthermia experts representing a large group of malignant hyperthermia laboratories from around the world. Key recommendations include: the dosing regimen of dantrolene should be based on actual body weight, dantrolene should be available wherever volatile anaesthetics or succinylcholine are used, and 36 vials of dantrolene should be immediately available with a further 24 vials available within 1 h.

Background/objective This study compares the effectiveness and safety of intranasal versus subcutaneous administration of dantrolene in 5XFAD Alzheimer's disease (AD) mice. Methods 5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal or subcutaneous dantrolene (5 mg/kg, 3×/wk), or vehicle. The early (ETG) and late (LTG) treatment groups began treatment at 2 or 6 months of age, respectively, and both treatment groups finished at12 months of age. Behavior was assessed for olfaction (buried food test), motor function (rotarod), and cognition (fear conditioning, Morris water maze). Liver histology (H & E staining) and function, synaptic proteins, and brain amyloid immunohistochemistry were examined. Plasma and brain dantrolene concentrations were determined in a separate cohort after intranasal or subcutaneous administration. Results Intranasal dantrolene achieved higher brain and lower plasma concentrations than subcutaneous administration. Dantrolene administration at both approaches significantly improved hippocampal-dependent and -independent memory in the ETG, whereas only intranasal dantrolene improved cognition in the LTG. Dantrolene treatment had no significant change in the amyloid burden or synaptic proteins and no significant side effects on mortality, olfaction, motor, or liver functions in 5XFAD mice. Intranasal dantrolene treatment significantly ameliorated memory loss when it was started either before or after the onset of AD symptoms in 5XFAD mice. Conclusions The long-term intranasal administration of dantrolene had therapeutic effects on memory compared to the subcutaneous approach even started after onset of AD symptoms, suggesting use as a disease-modifying drug, without significant effects on amyloid plaques, side effects, or mortality.

Context Neuroleptic malignant syndrome (NMS) is an uncommon but serious adverse event to antipsychotic medications. Case details A 14-year-old Ugandan lady presented with high grade fevers, multiple convulsions, altered mentation and lead-pipe rigidity following an intramuscular injection of zuclopenthixol acetate (as Clopixol-Acuphase®). Her labs were significant for elevated aminotransferases and leucocytosis. She had a normal brain CT scan, renal function and cerebrospinal fluid analysis. Discontinuation of Clopixol, administration of bromocriptine 5mg once daily and dantrolene 25mg three times a day and supportive treatment resulted in a complete neurological recovery within 4 weeks of the onset of symptoms. Discussion Early diagnosis and prompt supportive therapy are required to reduce mortality and morbidity. Early recognition of symptoms and discontinuation of offending agent by health care providers are needed to have recovery even in settings with limited resources.

Codonopsis lanceolata has been widely used as an anti-inflammatory and anti-lipogenic agent in traditional medicine. Recently, C. lanceolata was reported to prevent hypertension by improving vascular function. This study evaluated the effects of C. lanceolata and its major component lancemaside A on cytosolic calcium concentration in vascular endothelial cells and vascular smooth muscle cells. Cytosolic calcium concentration was measured using fura-2 AM fluorescence. C. lanceolata or lancemaside A increased the cytosolic calcium concentration by releasing Ca2+ from the endoplasmic reticulum and sarcoplasmic reticulum and by Ca2+ entry into endothelial cells and vascular smooth muscle cells from extracellular sources. The C. lanceolata- and lancemaside A-induced cytosolic calcium concentration increases were significantly inhibited by lanthanum, an inhibitor of non-selective cation channels, in both endothelial cells and vascular smooth muscle cells. Moreover, C. lanceolata and lancemaside A significantly inhibited store-operated Ca2+ entry under pathological extracellular Ca2+ levels. In Ca2+-free extracellular fluid, increases in the cytosolic calcium concentration induced by C. lanceolata or lancemaside A were significantly inhibited by U73122, an inhibitor of phospholipase C, and 2-APB, an inositol 1,4,5-trisphosphate receptor antagonist. In addition, dantrolene treatment, which inhibits Ca2+ release through ryanodine receptor channels, also inhibited C. lanceolata- or lancemaside A-induced increases in the cytosolic calcium concentration through the phospholipase C/inositol 1,4,5-trisphosphate pathway. These results suggest that C. lanceolata and lancemaside A increase the cytosolic calcium concentration through the non-selective cation channels and phospholipase C/inositol 1,4,5-trisphosphate pathways under physiological conditions and inhibit store-operated Ca2+ entry under pathological conditions in endothelial cells and vascular smooth muscle cells. C. lanceolata or lancemaside A can protect endothelial cells and vascular smooth muscle cells by maintaining cytosolic calcium concentration homeostasis, suggesting possible applications for these materials in diets for preventing vascular damage.

Exertional heat stroke (EHS) and malignant hyperthermia (MH) are life-threatening conditions, triggered by different environmental stimuli that share several clinical symptoms and pathophysiological features. EHS manifests during physical activity normally, but not always, in hot and humid environments. MH manifests during exposure to haloalkane anesthetics or succinylcholine, which leads to a rapid, unregulated release of calcium (Ca2+) within the skeletal muscles inducing a positive-feedback loop within the excitation-contraction coupling mechanism that culminates in heat stroke-like symptoms, if not rapidly recognized and treated. Rare cases of awake MH, independent of anesthesia exposure, occur during exercise and heat stress. It has been suggested that EHS and MH are mediated by similar mechanisms, including mutations in Ca2+ regulatory channels within the skeletal muscle. Rapid cooling, which is the most effective treatment for EHS, is ineffective as an MH treatment; rather, a ryanodine receptor antagonist drug, dantrolene sodium (DS), is administered to the victim to prevent further muscle contractions and hyperthermia. Whether DS can be an effective treatment for EHS victims remains uncertain. In the last decade, multiple reports have suggested a number of mechanistic links between EHS and MH. Here, we discuss aspects related to the pathophysiology, incidence, diagnosis and treatment. Furthermore, we present evidence regarding potential overlapping mechanisms between EHS and MH and explore current knowledge to establish what is supported by evidence or a lack thereof (i.e. conjecture).

Introduction A review of the literature has shown that there are many similarities in the presentation of neuroleptic malignant syndrome (NMS) and catatonia. Attempts to reconcile the differences have been made by suggesting that NMS and catatonia may represent different presentations of the same illness or that they lie within the same spectrum of a poorly understood clinical syndrome. The described case is of a patient who presented with NMS and catatonia which was difficult to diagnose, but which responded to treatment with intravenous diazepam. Case presentation The case concerns a 22-year-old male admitted for pulmonary hypertension to an intensive care unit (ICU). Three days following admission, he developed a high fever that did not respond to antibiotics. The patient then developed rigidity, nocturnal agitation, decreased responsiveness, and somnolence. Without the use of bromocriptine (Novartis, Basel, Switzerland) or dantrolene (Par Pharmaceuticals, Chestnut Ridge, USA) discontinuation of neuroleptics combined with intravenous diazepam (Pfizer, NY, USA) led to a very rapid response and marked improvement in the case. Conclusions Early recognition and management of NMS and MC in a complex, gravely ill patient, may be accomplished in the ICU despite obfuscation of traditional signs and symptoms of the NMS and MC syndrome. Such interventions can have life-saving effects on patients in danger of fatal autonomic instability.

Alzheimer’s Disease (AD), a neurodegenerative disorder with high incidence and mortality, is leading its way to the top of the list of the deadliest diseases without an effective disease-modifying drug. Ca2+ dysregulation, specifically abnormal release of Ca2+ via over activated ryanodine receptor (RyR), has been increasingly considered as an alternative upstream mechanism in AD pathology. Consequently, dantrolene, a RyR antagonist and FDA approved drug to treat malignant hyperthermia and chronic muscle spasms, has been shown to ameliorate memory loss in AD transgenic mice. However, the inefficiency of dantrolene to pass the Blood Brain Barrier (BBB) and penetrate the Central Nervous System needs to be resolved, considering its dose-dependent neuroprotection in AD and other neurodegenerative diseases. In this mini-review, we will discuss the current status of dantrolene neuroprotection in AD treatment and a strategy to maximize its beneficial effects, such as intranasal administration of dantrolene.

Patients with multiple sclerosis (MS) may suffer from spasticity and pain during their disease course. Baclofen, dantrolene, diazepam and gabapentin have been used as first-line options to treat these conditions, with modest results. Medical use of marijuana smoking has bypassed traditional clinical trials and has been legalized as a therapeutic option for MS-related spasticity and pain in some countries. Cannabis-derived drugs have been tested and approved for medical use.With the development of nabiximols by the pharmaceutical industry, more countries have made it possible for patients with MS to have legal access to cannabis-related therapies. The evidence-based data on nabiximols and MS-related spasticity, pain, and urinary symptoms is consistent. There are over 7,500 patients reported in 33 studies (12 from the United Kingdom and 11 from Italy).Nabiximols is safe and effective for patients with MS whose spasticity could not be treated with the first-line oral drugs. At present, legislation, bureaucracy and costs involved in prescribing this drug limit the experience of neurologists from many countries. There is no scientific evidence that smoking marijuana can be beneficial to patients with MS.

Background: Cardiac ryanodine receptor 2 (RyR2) dysfunction and elevated diastolic Ca2+ leak have been linked to arrhythmogenesis not only in inherited arrhythmia syndromes but also in acquired forms of heart disease including heart failure (HF) and atrial fibrillation (AF). Thus, stabilizing RyR2 may exert therapeutic effects in these conditions. Objective: The purpose of this study was to investigate the effects of stabilizing RyR2 with chronic dantrolene treatment on HF development and AF inducibility in a myocardial infarction (MI)–induced HF model in rats. Methods: MI was induced in adult Sprague-Dawley rats by ligation of the left anterior descending coronary artery. Two weeks after MI surgery, rats with large MI (≥40%) were randomly assigned to MI-vehicle (n = 14) or MI-dantrolene (10 mg/kg/d; n = 13) groups. Sham-surgery rats (n = 7) served as controls. Results: Compared to the MI-vehicle group, 4-week dantrolene treatment significantly improved cardiac function, with increased left ventricular (LV) fractional shortening (19.48% ± 3.61% vs 15.43% ± 2.65%; P

Aims In atrial fibrillation (AF), an increased diastolic Ca2+ leak from the sarcoplasmic reticulum (SR) mediated by calcium/calmodulin-dependent-protein-kinaseIIδC (CaMKII) can serve as a substrate for arrhythmia induction and persistence. Dantrolene has been shown to stabilize the cardiac ryanodine-receptor. This study investigated the effects of dantrolene on arrhythmogenesis in human and mouse atria with enhanced CaMKII activity. Methods and results Human atrial cardiomyocytes (CMs) were isolated from patients with AF. To investigate CaMKII-mediated arrhythmogenesis, atrial CMs from mice overexpressing CaMKIIδC (TG) and the respective wildtype (WT) were studied using confocal microscopy (Fluo-4), patch-clamp technique, and in vivo atrial catheter-based burst stimulations. Dantrolene potently reduced Ca2+ spark frequency (CaSpF) and diastolic SR Ca2+ leak in AF CMs. Additional CaMKII inhibition did not further reduce CaSpF or leak compared to dantrolene alone. While the increased SR CaSpF and leak in TG mice were reduced by dantrolene, no effects could be detected in WT. Dantrolene also potently reduced the pathologically enhanced frequency of diastolic SR Ca2+ waves in TG without having effects in WT. As an increased diastolic SR Ca2+ release can induce a depolarizing transient inward current, we could demonstrate that the incidence of afterdepolarizations in TG, but not in WT, mice was significantly diminished in the presence of dantrolene. To translate these findings into an in vivo situation we could show that dantrolene strongly suppressed the inducibility of AF in vivo in TG mice. Conclusion Dantrolene reduces CaMKII-mediated atrial arrhythmogenesis and may therefore constitute an interesting antiarrhythmic drug for treating patients with atrial arrhythmias driven by an enhanced CaMKII activity, such as AF.

Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer an attractive experimental platform to investigate cardiac diseases and therapeutic outcome. In this study, iPSC-CMs were utilized to study their calcium transient signals and drug effects by means of machine learning, a central part of artificial intelligence. Drug effects were assessed in six iPSC-lines carrying different mutations causing catecholaminergic polymorphic ventricular tachycardia (CPVT), a highly malignant inherited arrhythmogenic disorder. The antiarrhythmic effect of dantrolene, an inhibitor of sarcoplasmic calcium release, was studied in iPSC-CMs after adrenaline, an adrenergic agonist, stimulation by machine learning analysis of calcium transient signals. First, beats of transient signals were identified with our peak recognition algorithm previously developed. Then 12 peak variables were computed for every identified peak of a signal and by means of this data signals were classified into different classes corresponding to those affected by adrenaline or, thereafter, affected by a drug, dantrolene. The best classification accuracy was approximately 79% indicating that machine learning methods can be utilized in analysis of iPSC-CM drug effects. In the future, data analysis of iPSC-CM drug effects together with machine learning methods can create a very valuable and efficient platform to individualize medication in addition to drug screening and cardiotoxicity studies.

Background 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. Methods Patients with chronic heart failure who had functional status of New York Heart Association class II and III and a left ventricular ejection fraction Results This paper presents the rationale and trial design of the study. Recruitment for the study started on 8 December 2017. Conclusions 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.

Aims Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been shown to induce aberrant Ca2+ release from the cardiac ryanodine receptor (RyR2) in various diseased hearts. However, the precise pathogenic mechanism remains to be elucidated. Here, we investigated the effect of dantrolene (DAN): a RyR2 stabilizer on local Ca2+ release, cardiac function, and lethal arrhythmia in CaMKIIδc transgenic (TG) mice. Methods and results The TG mice showed an increase in left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) with a reduction in LV fractional shortening (LVFS). The phosphorylation levels of Ser2814 in RyR2 and Thr287 in CaMKII increased in TG mice. In TG cardiomyocytes, peak cell shortening (CS) decreased, and the frequency of spontaneous Ca2+ transients (sCaTs) increased. Endogenous RyR2-associated calmodulin (CaM) markedly decreased in TG cardiomyocytes. After chronic DAN treatment for 1 month, LVESD (but not LVEDD) decreased with an increase in LVFS. In the chronic DAN-treated cardiomyocytes, CS increased, sCaTs decreased, and the endogenous CaM binding to RyR2 normally restored. The phosphorylation levels of Ser2814 in RyR2 and Thr287 in CaMKII remained elevated even after DAN treatment. Moreover, in TG mice, chronic DAN treatment prevented sustained ventricular tachycardia induced by epinephrine. Conclusions Defective association of CaM with RyR2 is most likely to be involved in the pathogenesis of CaMKII-mediated cardiac dysfunction and lethal arrhythmia.

Introduction: Malignant hyperthermia (MH) is an acute syndrome triggered by certain anesthetic medications. Dantrolene is the only specific treatment for MH crises. Without treatment, lethality may be as high as 80%. In Colombia, it is not mandatory to keep dantrolene supplies in stock. Objective: To establish the cost-benefit ratio, from the perspective of healthcare institutions, of keeping dantrolene supplies in stock in the operating theater. Methods: Using a decision tree, a Monte Carlo simulation was run with 10,000 scenarios to determine the median annual cost of keeping full or partial stocks (36 or 12 vials x 20 mg, respectively) of dantrolene. For the option of not keeping supplies in stock, the cost threshold was calculated where the expected value of both alternatives of the decision tree is equalized. Indifference curves were constructed for complete and partial supplies. Results: The median annual cost was estimated at 6.6 million Colombian pesos (COP) for full dantrolene supplies, and at COP 2.2 million for partial supplies. The median economic consequence threshold for 1 death due to the unavailability of dantrolene was estimated at COP 18.5 million for full supplies, and at COP 57.0 million for partial supplies. Conclusion: If, as a result of the unavailability of dantrolene, the economic consequences of a death due to MH exceed the threshold of COP 57.0 or COP 18.5 million, the purchase of full or partial stocks, respectively, is justified. Resumen Introducción: La hipertermnia maligna (HM) es un síndrome agudo desencadenado por algunos medicamentos anestésicos. El dantroleno es el único tratamiento específico para las crisis de HM. Sin tratamiento puede tener una letalidad cercana al 80%. En Colombia, el abastecimiento de dantroleno no es obligatorio. Objetivo: Establecer la relación costo-efectividad, desde el punto de vista de las instituciones prestadoras de servicios de salud, de mantener un abastecimiento de dantroleno en quirófanos. Métodos: Mediante un árbol de decisiones se realizó una simulación Monte Carlo con 10 mil escenarios para determinar la mediana del costo anual de un abastecimiento completo o parcial (36 o 12 viales de 20 mg, respectivamente) de dantroleno. Para la alternativa de no tener abastecimiento, se calculó el umbral de costo, donde se iguala el valor esperado de ambas alternativas del árbol de decisiones. Se construyeron curvas de indiferencia para el abastecimiento completo y parcial. Resultados: La mediana del costo anual del abastecimiento completo de dantroleno se estimó en $6.6 millones de pesos colombianos (COP), y el del abastecimiento parcial en $2.2 millones COP. La mediana del umbral de consecuencias económicas por una muerte sin disponibilidad de dantroleno se estimó en 18.5 millones COP para el abastecimiento completo, y en 57.0 millones COP para el abastecimiento parcial. Conclusión: Si por no disponer de dantroleno las consecuencias económicas de una muerte por HM superan el umbral de $57.0 o $18.5 millones COP, se justifica la compra de un abastecimiento completo o parcial, respectivamente.

Phenytoin is a hydantoin derivative that is used clinically for the treatment of epilepsy and has been reported to have antiarrhythmic actions on the heart. In a failing heart, the elevated diastolic Ca2+ leak from the sarcoplasmic reticulum can be normalized by the cardiac ryanodine receptor 2 (RyR2) inhibitor, dantrolene, without inhibiting Ca2+ release during systole or affecting Ca2+ release in normal healthy hearts. Unfortunately, dantrolene is hepatotoxic and unsuitable for chronic long-term administration. Because phenytoin and dantrolene belong to the hydantoin class of compounds, we test the hypothesis that dantrolene and phenytoin have similar inhibitory effects on RyR2 using a single-channel recording of RyR2 activity in artificial lipid bilayers. Phenytoin produced a reversible inhibition of RyR2 channels from sheep and human failing hearts. It followed a hyperbolic dose response with maximal inhibition of ∼50%, Hill coefficient ∼1, and IC50 ranging from 10 to 20 µM. It caused inhibition at diastolic cytoplasmic [Ca2+] but not at Ca2+ levels in the dyadic cleft during systole. Notably, phenytoin inhibits RyR2 from failing human heart but not from healthy heart, indicating that phenytoin may selectively target defective RyR2 channels in humans. We conclude that phenytoin could effectively inhibit RyR2-mediated release of Ca2+ in a manner paralleling that of dantrolene. Moreover, the IC50 of phenytoin in RyR2 is at least threefold lower than for other ion channels and clinically used serum levels, pointing to phenytoin as a more human-safe alternative to dantrolene for therapies against heart failure and cardiac arrythmias. SIGNIFICANCE STATEMENT: We show that phenytoin, a Na channel blocker used clinically for treatment of epilepsy, is a diastolic inhibitor of cardiac calcium release channels [cardiac ryanodine receptor 2 (RyR2)] at doses threefold lower than its current therapeutic levels. Phenytoin inhibits RyR2 from failing human heart and not from healthy heart, indicating that phenytoin may selectively target defective RyR2 channels in humans and pointing to phenytoin as a more human-safe alternative to dantrolene for therapies against heart failure and cardiac arrhythmias.

Dysregulation of calcium homeostasis is a major mechanism of doxorubicin (DOX)-induced cardiotoxicity. Treatment with DOX causes activation of sarcoplasmic reticulum (SR) ryanodine receptor (RYR) and rapid release of Ca2+ in the cytoplasm resulting in depression of myocardial function. The aim of this study was to examine the effect of dantrolene (DNT) a RYR blocker on both the cardiotoxicity and antitumor activity of DOX in a rat model of breast cancer. Female F344 rats with implanted MAT B III breast cancer cells were randomized to receive intraperitoneal DOX twice per week (12 mg/kg total dose), 5 mg/kg/day oral DNT or a combination of DOX + DNT for 3 weeks. Echocardiography and blood troponin I levels were used to measure myocardial injury. Hearts and tumors were evaluated for histopathological alterations. Blood glutathione was assessed as a measure of oxidative stress. The results showed that DNT improved DOX-induced alterations in the echocardiographic parameters by 50%. Histopathologic analysis of hearts showed reduced DOX induced cardiotoxicity in the group treated with DOX + DNT as shown by reduced interstitial edema, cytoplasmic vacuolization, and myofibrillar disruption, compared with DOX-only–treated hearts. Rats treated with DNT lost less body weight, had higher blood GSH levels and lower troponin I levels than DOX-treated rats. These data indicate that DNT is able to provide protection against DOX cardiotoxicity without reducing its antitumor activity. Further studies are needed to determine the optimal dosing of DNT and DOX in a tumor-bearing host.

Background: 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. Objective: 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. Case report: 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. Conclusions: 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. Resumo: Justificativa: A sepse é uma disfunção orgânica fatal com características clínicas inespecíficas que podem imitar outras condições clínicas com quadro hipermetabólico, como a hipertermia maligna. Esses cenários são extremamente desafiadores para a anestesia perioperatória e requerem intervenção urgente. Objetivo: 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. Relato de caso: 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. Conclusões: 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. Keywords: Sepsis, Malignant hyperthermia, Dantrolene, Malignant hyperthermia association hotline, Transrectal ultrasound, Palavras-chave: Sepse, Hipertermia maligna, Dantrolene, Linha direta da associação de hipertermia maligna, Ultrassonografia transretal

Dantrolene, a ryanodine receptor antagonist, is primarily known as the only clinically acceptable and effective treatment for Malignant Hyperthermia (MH). Inhibition of Ryanodine Receptor (RyR) by dantrolene decreases the abnormal calcium release from the Sarcoplasmic Reticulum (SR) or Endoplasmic Reticulum (ER), where RyR is located. Recently, emerging researches on dissociated cells, brains slices, live animal models and patients have demonstrated that altered RyR expression and function can also play a vital role in the pathogenesis of Alzheimer’s Disease (AD). Therefore, dantrolene is now widely studied as a novel treatment for AD, targeting the blockade of RyR channels or another alternative pathway, such as the inhibitory effects of NMDA glutamate receptors and the effects of ER-mitochondria connection. However, the therapeutic effects are not consistent. In this review, we focus on the relationship between the altered RyR expression and function and the pathogenesis of AD, and the potential application of dantrolene as a novel treatment for the disease.

Malignant hyperthermia (MH) is an acute pharmacogenetic disorder, which while uncommon is potentially fatal. MH is a calcium channelopathy of skeletal muscle in which a constant increase of intracytoplasmic Ca2+ concentration occurs causing a change in cellular metabolism. A hypermetabolic state develops when susceptible patients are exposed to halogenated volatile inhalational anesthetic agents and depolarizing muscle relaxants and/or extreme physical activity in hot environments. MH presents variable clinical expression. During an episode of MH, the patient may present clinical signs and laboratory findings including masseter muscle spasm, tachycardia, rise in end-tidal CO2 (EtCO2), tachypnea, hyperthermia, cyanosis, metabolic acidosis, rhabdomyolysis, hyperkalemia, myoglobinuria, hyperlactacidemia, and acute renal failure. The aim of this case report is to describe an episode of MH associated with the use of halogenated anesthetic during bariatric surgery. A 29-year-old Brazilian man was admitted to the hospital to undergo a bariatric surgery. The patient’s relevant medical history included morbid obesity grade III, allergy to sulfa-based drugs and severe obstructive sleep apnea. Preoperative evaluations with cardiopulmonary exercise testing, echocardiogram and electrocardiogram showed no anatomical and functional changes of the patient’s heart. Surgical procedures lasted for 4 h, without complications, but the evolution of the patient’s condition indicated oliguria and acute breathing insufficiency. Five hours after the patient was placed under mechanical ventilation in the intensive care unit, he started to present clinical signs of hypermetabolic state, with tremors, excessive sweating, and rapid body temperature increases. In the postoperative period, the patient had hyperglycemia, hypocalcemia, hypernatremia, hyperkalemia, changes in creatine phosphokinase (CPK), aspartate transaminase (AST), alanine aminotransferase (ALT), urea and creatine concentrations, and metabolic and respiratory acidosis. Urinalysis showed traces of proteinuria, presence of ketones, leukocytes, red blood cells, and urobilinogen. In our case report, MH crisis was diagnosed late; the dantrolene was not administrated because it was not available and the patient died. This detailed case report of MH episode triggered by isoflurane anesthetic during bariatric surgery allowed us to describe the severity and lethality of this hypermetabolic syndrome. Dantrolene should be mandatory in all operating rooms. Knowledge of the symptoms, an early diagnosis and an adequate treatment can prevent the death of patients in MH crisis.

Background Intrathecal baclofen (ITB) is a mainstay of treatment for patients with chronic spasticity. Up to 40% of all patients receiving ITB experience overdose or withdrawal symptoms, which in the most severe cases can lead to multisystem organ failure and death. There is currently no well-established treatment for ITB withdrawal. One previous case report details an intubated pediatric patient who underwent baclofen pump removal in which dexmedetomidine was used in combination with other medications to prevent baclofen withdrawal. Case Report We report a case of baclofen withdrawal where the decision was made to initiate a dexmedetomidine infusion, with subsequent improvement of the patient's hypertension and tachycardia. At no point during her stay did the patient require intubation for airway protection, and the patient was ultimately discharged to her previous nursing facility on hospital day 9 with no new neurologic deficits. Why Should an Emergency Physician Be Aware of This? Emergency physicians should be aware of dexmedetomidine as a promising option for the treatment of ITB withdrawal in the acute setting. Although little evidence is currently present, dexmedetomidine was used successfully in this case, and should be considered as a temporizing treatment for ITB withdrawal. Dexmedetomidine holds promise in the management of ITB withdrawal compared to other previously described treatments, including oral baclofen, cyproheptadine, and dantrolene. In addition, dexmedetomidine has a superior safety profile compared to propofol or large doses of benzodiazepines. Further research will be useful in supporting the use of dexmedetomidine for this purpose.

Variants in the ryanodine receptor-1 gene (RYR1) have been associated with a wide range of neuromuscular conditions, including various congenital myopathies and malignant hyperthermia (MH). More recently, a number of RYR1 variants, mostly MH-associated, have been demonstrated to contribute to rhabdomyolysis events not directly related to anesthesia in otherwise healthy individuals. This review focuses on RYR1-related rhabdomyolysis in the context of several clinical presentations (i.e., exertional rhabdomyolysis, exertional heat illnesses and MH), and conditions involving a similar hypermetabolic state, in which RYR1 variants may be present (i.e., neuroleptic malignant syndrome and serotonin syndrome). The variety of triggers that can evoke rhabdomyolysis, on their own or in combination, as well as the number of potentially associated complications, illustrates that this is a condition relevant to several medical disciplines. External triggers include but are not limited to strenuous physical exercise, especially if unaccustomed or performed under challenging environmental conditions (e.g., high ambient temperature or humidity), alcohol/illicit drugs, prescription medication (in particular statins, other anti-lipid agents, antipsychotics and antidepressants) infection, or heat. Amongst all patients presenting with rhabdomyolysis, genetic susceptibility is present in a proportion, with RYR1 being one of the most common genetic causes. Clinical clues for a genetic susceptibility include recurrent rhabdomyolysis, creatine kinase (CK) levels above 50 times the upper limit of normal, hyperCKemia lasting for 8 weeks or longer, drug/medication doses insufficient to explain the rhabdomyolysis event, and positive family history. For the treatment or prevention of RYR1-related rhabdomyolysis, the RYR1 antagonist dantrolene can be administered, both in the acute phase or prophylactically in patients with a history of muscle cramps and/or recurrent rhabdomyolysis events. Aside from dantrolene, several other drugs are being investigated for their potential therapeutic use in RYR1-related disorders. These findings offer further therapeutic perspectives for humans, suggesting an important area for future research.

Oxidative stress plays an important role in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The oxindole compound GIF-2165X-G1 is a hybrid molecule composed of the oxindole skeleton of the neuroprotective compound GIF-0726-r and the polyphenolic skeleton of the antioxidant curcumin. We previously reported that novel oxindole derivatives such as GIF-0726-r and GIF-2165X-G1 prevent endogenous oxidative stress-induced cell death in mouse hippocampal HT22 cells. In this study, we present a detailed investigation of the effect of GIF-2165X-G1 on endogenous oxidative stress in HT22 cells in comparison with GIF-0726-r and curcumin. GIF-2165X-G1 exhibited more potent neuroprotective activity than GIF-0726-r or curcumin and had less cytotoxicity than that observed with curcumin. Both GIF-0726-r and GIF-2165X-G1 were found to have ferrous ion chelating activity similar to that exhibited by curcumin. GIF-2165 X-G1 and curcumin induced comparable antioxidant response element transcriptional activity. Although the induction of heme oxygenase-1, an antioxidant response element-regulated gene product, was much stronger in curcumin-treated cells than in GIF-2165X-G1-treated cells, it turned out that the induction of heme oxygenase-1 is dispensable for neuroprotection. These results demonstrate that the introduction of the polyphenol skeleton of curcumin to the oxindole GIF-0726-r improves neuroprotective features. Furthermore, intrastriatal injection of GIF-2165X-G1 alleviated apomorphine-induced rotation and prevented dopaminergic neuronal loss in a 6-hydroxydopamine mouse model of Parkinson's diseases. Collectively, our novel findings indicate that the novel oxindole compound GIF-2165X-G1 serves to delay the progression of Parkinson's disease by suppressing oxidative stress.

Systemic delivery of antisense oligonucleotides (AO) for DMD exon skipping has proven effective for reframing DMD mRNA, rescuing dystrophin expression, and slowing disease progression in animal models. In humans with Duchenne muscular dystrophy treated with AOs, low levels of dystrophin have been induced, and modest slowing of disease progression has been observed, highlighting the need for improved efficiency of human skipping drugs. Here, we demonstrate that dantrolene and Rycals S107 and ARM210 potentiate AO-mediated exon skipping of exon 44 or exon 45 in patient-derived myotube cultures with appropriate mutations. Further, dantrolene is shown to boost AO-mediated exon skipping in patient-derived, induced cardiomyocyte cultures. Our findings further validate the ryanodine receptors (RyR) as the likely target responsible for exon skip boosting and demonstrate potential applicability beyond exon 51 skipping. These data provide preclinical support of dantrolene trial as an adjuvant to AO-mediated exon-skipping therapy in humans and identify a novel Rycal, ARM210, for development as a potential exon-skipping booster. Further, they highlight the value of mutation-specific DMD culture models for basic discovery, preclinical drug screening and translation of personalized genetic medicines. Keywords: Duchenne muscular dystrophy, combination therapy, dantrolene, dystrophin, exon skipping, armgo, ARM210, muscle, therapy

Malignant hyperthermia (MH) is a life-threatening hypermetabolic disorder triggered by volatile anesthetics and/or succinylcholine. We report a case of a 58-year-old patient with a type-A aortic dissection. After induction of general anesthesia, a hypermetabolic reaction was successfully treated by deep hypothermia using cardiopulmonary bypass. Dantrolene became available in theater after the hypermetabolism was already treated successfully by hypothermia. Because of a low suspicion of MH, dantrolene was not administered when it became available. The patient fully recovered, and MH susceptibility was confirmed. Cardiopulmonary bypass should be considered to treat MH in case dantrolene and conservative therapy are unavailable or insufficient.

Ca2+-induced Ca2+ release (CICR) is mediated by ryanodine receptors, a Ca2+ release channel in the sarcoplasmic/endoplasmic reticulum (SR/ER), and plays an important role in various tissues. Type 1 ryanodine receptor (RYR1) plays a key role during excitation–contraction coupling of skeletal muscle. Mutations in RYR1 overactivate the channel to cause malignant hyperthermia (MH). MH is a serious complication characterized by skeletal muscle rigidity and elevated body temperature in response to commonly used inhalational anesthetics. Thus far, >300 mutations in the RYR1 gene have been reported in patients with MH. Some heat stroke triggered by exercise or environmental heat stress is also related to MH mutations in the RYR1 gene. The only drug approved for ameliorating the symptoms of MH is dantrolene, which has been first developed in the 1960s as a muscle relaxant. However, dantrolene has several disadvantages for clinical use: poor water solubility, which makes rapid preparation difficult in emergency situations, and long plasma half-life, which causes long-lasting side effects such as muscle weakness. Here, we show that a novel RYR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (compound 1 [Cpd1]), effectively rescues MH and heat stroke in new mouse model (RYR1-p.R2509C) relevant to MH. Cpd1 has great advantages of higher water solubility and shorter plasma half-life compared with dantrolene. Our data suggest that Cpd1 has the potential to be a promising new candidate for effective treatment of patients carrying RYR1 mutations. Finally, we have recently identified that heat directly activates RYR1, which induces Ca2+ release from intracellular stores. Our results provide direct evidence that heat induces Ca2+ release (HICR) from the SR through the mutants rather than wild type RYR1, causing an immediate rise in the cytosolic Ca2+ concentration.