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Tetanus is a life-threatening, vaccine-preventable disease caused by an endotoxin produced by Clostridium tetani . We report a case of severe tetanus in an adult male with a history of intravenous drug use. The patient presented with a 1-day history of inability to open his jaw and a right lower extremity necrotic wound. Initial management consisted of tetanus toxoid, human tetanus immunoglobulin, antimicrobials and intermittent lorazepam. Due to progressive symptoms, wound debridement and placement of an advanced airway in the operating room ensued. Episodes of tetany were associated with fever, autonomic instability, acute desaturations and preemptive ventilator triggering despite maximum doses of continuous propofol and midazolam. Neuromuscular blockade with cisatracurium was added, resulting in control of tetany. Despite initial control, NMB could not be weaned due to recurrent spasms. Intravenous dantrolene was therefore sought as an alternative antispasmodic. Following an initial load, patient was successfully liberated from cisatracurium. Dantrolene was therefore converted to enteral to facilitate gradual down-titration of intravenous sedatives with subsequent conversion to oral benzodiazepines. After a prolonged hospital course, the patient was able to be discharged home. Dantrolene was thus effectively utilized as an adjunctive antispasmodic agent to facilitate liberation from cisatracurium and continuous sedation., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Progressive neuronal demise is a key contributor to the key pathogenic event implicated in many different neurodegenerative disorders (NDDs). There are several therapeutic strategies available; however, none of them are particularly effective. Targeted neuroprotective therapy is one such therapy, which seems a compelling option, yet remains challenging due to the internal heterogeneity of the mechanisms underlying various NDDs. An alternative method to treat NDDs is to exploit common modalities involving molecularly distinct subtypes and thus develop specialized drugs with broad-spectrum characteristics. There is mounting evidence which supports for the theory that dysfunctional ryanodine receptors (RyRs) disrupt intracellular Ca 2+ homeostasis, contributing to NDDs significantly. This review aims to provide direct and indirect evidence on the intersection of NDDs and RyRs malfunction, and to shed light on novel strategies to treat RyRs-mediated disease, modifying pharmacological therapies such as the potential therapeutic role of dantrolene, a RyRs antagonist., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.

Rationale: Several hereditary myopathies that can predispose to malignant hyperthermia (MH) are reported. However, the risk of MH in myotonic dystrophy type I (DM1) has been suggested equal to general population, although the evidence is limited to only a few case reports., Patient Concerns: We encountered a rare case of MH during anesthesia induction with sevoflurane in a male adolescent with previously undiagnosed DM1., Diagnoses: After the event, genetic testing revealed the presence of a previously unknown heterozygous missense mutation in ryanodine receptor 1 (RYR1) associated with MH (c.6898T > C; p.ser2300Pro). Concomitantly, the patient was diagnosed with DM1 with abnormal cytosine-thymine-guanine triplet expansion in the DMPK gene., Interventions: Dantrolene was administered to treat the hypermetabolic manifestations in 20 minutes after the identification of MH., Outcomes: The patient was successfully treated and discharged without any complications. Laboratory abnormalities were recovered to baseline at postoperative 4 days., Lessons: The authors suggest that possible MH susceptibility in DM1 patients may be refocused. Genetic testing can be a screening tool for MH susceptibility in these population, prior to receiving general anesthesia., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

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 (E max ), but 50 μM reduced this parameter by 34% (n = 7, p < 0.05). In non-diabetic rats, by contrast, dantrolene did not modify the vascular response to 5-HT. 50 nM of nimodipine alone, however, reduced this parameter by 57% in diabetic rats (n = 10, p < 0.05), and by 34% in non-diabetic rats (n = 10, p < 0.05). In addition, concomitant administration of dantrolene and nimodipine reduced vascular reactivity to a similar extent in both diabetic (~ 60% reduction, n = 10, p < 0.05) and non-diabetic rats (~ 70% reduction, n = 10, p < 0.05). Moreover, the combination of nimodipine with the higher concentration of dantrolene significantly increased the EC 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 < 0.05) and non-diabetic rats (5.93 ± 0.54 µM to 15.80 ± 3.24; n = 10, p < 0.05). These results suggest that simultaneous administration of dantrolene and nimodipine has a synergistic effect in reducing 5-HT-induced vascular contraction under both diabetic and non-diabetic conditions. If our findings with rats are applicable to humans, concomitant administration of these drugs may represent a promising alternative for the management of CVSP in both diabetics and non-diabetics.

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 (ETCO 2 ) (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.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ryanodine receptor ( RYR ) mutations confer stress-triggered malignant hyperthermia (MH) susceptibility. Dietary caffeine (CAF) is the most commonly consumed psychoactive compound by humans. CAF-triggered Ca 2+ release and its influences on skeletal muscle contractility are widely used as experimental tools to study RYR function/dysfunction and diagnose MH susceptibility. We hypothesize that dietary CAF achieving blood levels measured in human plasma exacerbates the penetrance of RYR1 MH susceptibility mutations triggered by gaseous anesthetic, affecting both central and peripheral adverse responses. Heterozygous R163C-RYR1 (HET) MH susceptible mice are used to investigate the influences of dietary CAF on both peripheral and central responses before and after induction of halothane (HAL) maintenance anesthesia under experimental conditions that maintain normal core body temperature. HET mice receiving CAF (plasma CAF 893 ng/ml) have significantly shorter times to respiratory arrest compared with wild type, without altering blood chemistry or displaying hyperthermia or muscle rigor. Intraperitoneal bolus dantrolene before HAL prolongs time to respiratory arrest. A pilot electrographic study using subcutaneous electrodes reveals that dietary CAF does not alter baseline electroencephalogram (EEG) total power, but significantly shortens delay to isoelectric EEG, which precedes respiratory and cardiac arrest. CAF ± HAL are studied on RYR1 single-channel currents and HET myotubes to define molecular mechanisms of gene-by-environment synergism. Strong pharmacological synergism between CAF and HAL is demonstrated in both single-channel and myotube preparations. Central and peripheral nervous systems mediate adverse responses to HAL in a HET model of MH susceptibility exposed to dietary CAF, a modifiable lifestyle factor that may mitigate risks of acute and chronic diseases associated with RYR1 mutations. SIGNIFICANCE STATEMENT: Dietary caffeine at a human-relevant dose synergizes adverse peripheral and central responses to anesthesia in malignant hyperthermia susceptible mice. Synergism of these drugs can be attributed to their actions at ryanodine receptors., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, autosomal recessive inborn error of metabolism in which several neurotransmitters including serotonin, dopamine, norepinephrine and epinephrine are deficient. Symptoms typically appear in the first year of life and include oculogyric crises and dystonia, hypotonia, and global developmental delay. Dystonia is of particular concern as a dystonic storm can ensue leading to rhabdomyolysis. Rhabdomyolysis can become life-threating and therefore its recognition and prompt management is of significant importance. Here we present two cases of patients with AADC deficiency and a history of dystonic crisis causing rhabdomyolysis. We hypothesize that in addition to the hypodopaminergic, a hypercholinergic state is contributing to the pathophysiology of dystonia in AADC deficiency, as well as to the associated rhabdomyolysis. We were able to prevent rhabdomyolysis in both patients with using Dantrolene and we suggest using a trial of this medication in cases of sustained dystonic crisis in AADC deficiency patients., Competing Interests: None declared, (Georg Thieme Verlag KG Stuttgart · New York.)

Dantrolene has been demonstrated to be neuroprotective for multiple neurodegenerative diseases. However, dantrolene's limited penetration into the CNS hampers its effectiveness as a neuroprotective agent. Here, we studied whether the intranasal administration of dantrolene provided better penetration into the brain than the commonly used oral approach. C57BL/6 mice, aged 2-4 months, received a single dose of either intranasal or oral dantrolene (5mg/kg). Inhibition of dantrolene clearance from the brain was examined by co-administration with P-gp/BCRP inhibitors, nimodipine or elacridar. The concentration of dantrolene in the brain and plasma was measured at 10, 20, 30, 50, 70, 120, 150 and 180 minutes after administration. Separate cohorts of mice were given intranasal dantrolene (5mg/kg) or vehicle, 3 times/ week, for either 3 weeks or 4 months, to examine potential adverse side effects on olfaction and motor coordination, respectively. We found that Dantrolene concentrations were sustained in the brain after intranasal administration for 180 min, while concentrations fell to zero at 120 min for oral administration. Chronic use of intranasal dantrolene did not impair olfaction or motor function in these mice. Blood brain barrier pump inhibitors did not further increase dantrolene peak concentrations in the brain. Our results suggested that Intranasal administration of dantrolene is an effective route to increase its concentration and duration in the brain compared to the oral approach, without any obvious side effects on olfaction or motor function., Competing Interests: This study was supported by research grant from National Institute of General Medical Science (NIGMS R01GM084979) and National Institute of Aging (NIA R01AG061447). The results of this manuscript have been included in a US provisional patent application titled “Intranasal Administration of Dantrolene for Treatment of Alzheimer’s Disease” filed on June 28, 2019 (Serial number 62/868,820) by the University of Pennsylvania Trustee. Four of the co-authors, all employees of the University of Pennsylvania, Drs. Huafeng Wei, Qingcheng Meng, Ge Liang and Maryellen Eckenhoff, are listed as inventors of the provisional patent application. The patent application is also part of the research collaboration agreement between the University of Pennsylvania and Eagle Pharmaceutical Company, which produces and sells a formulation of dantrolene (Ryanodex) for the treatment of malignant hyperthermia. The dantrolene used in this study was purchased from Sigma Company. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Diabetics have a higher risk of developing cerebral vasospasms (CVSPs) than non-diabetics. Current therapies are ineffective in reducing CVSPs, but a a combination of dantrolene and nimodipine may be a viable treatment. Considering the potentially harmful secondary effects of dantrolene, however, we evaluated the efficacy of 10 μM dantrolene compared to 50 μM dantrolene alone or in combination with 50 nM nimodipine., Methods: Dose-response curves for the phenylephrine (PHE)-induced contraction and acetylcholine (ACh)-induced relaxation were performed on aortic rings from diabetic and non-diabetic rats, before and after a 30-min incubation period with dantrolene (50 μM and 10 μM), alone or in combination with 50 nM nimodipine., Results: Whereas 50 μM dantrolene reduced PHE-induced contraction by 47% in diabetic rats and 29% in controls, 10 μM dantrolene failed to reduce this parameter in either group. Furthermore, 50 μM dantrolene reduced PHE-induced contraction by about 80% in both diabetic and controls when combined with nimodipine (N = 9, P < 0.05). The combination of 10 μM dantrolene and 50 nM nimodipine, however, was ineffective. Only 50 μM dantrolene improved endothelial dysfunction., Conclusions: Improved endothelial-dependent relaxation and reduced vascular contractility with dantrolene are dose dependent. Thus, although dantrolene appears to be a promising alternative for the treatment of CVSPs when added to conventional therapies, careful titration should be performed to achieve a significant reduction in vascular hyperreactivity. Moreover, if our findings with rats are applicable to humans, the combined use of dantrolene and nimodipine at optimal doses may reduce CVSPs, especially in the diabetic population.

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., (Copyright © 2019 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.)

Malignant hyperthermia is a well-known but potentially lethal disorder which is triggered by volatile anesthetics and depolarizing muscle relaxants. Early diagnosis and treatment could save lives. However, during cardiac surgery, hypothermia and cardiopulmonary bypass make the diagnosis of malignant hyperthermia extremely difficult than other surgeries. We report a case of almost-certain malignant hyperthermia, according to the clinical grading scale, in a patient undergoing on-pump coronary artery bypass grafting surgery. The patient underwent difficult weaning from cardiopulmonary bypass until intra-aortic balloon pump and temporary cardiac pacemaker had been implanted. Although dantrolene and corresponding treatments were administered recently, the patient died 12 days after surgery because of acute kidney failure and cardiac arrest. Therefore, it is important for us to previously recognize some specific signs of malignant hyperthermia during cardiopulmonary bypass to avoid severe outcomes.

This document represents a joint effort of the Society for Ambulatory Anesthesia (SAMBA) and the Ambulatory Surgical Care Committee of the American Society of Anesthesiologists (ASA) concerning the safe anesthetic care of adult malignant hyperthermia (MH)-susceptible patients in a free-standing ambulatory surgery center (ASC). Adult MH-susceptible patients can safely undergo a procedure in a free-standing ASC assuming that proper precautions for preventing, identifying, and managing MH are taken. The administration of preoperative prophylaxis with dantrolene is not indicated in MH-susceptible patients scheduled for elective surgery. There is no evidence to recommend an extended stay in the ASC, and the patient may be discharged when the usual discharge criteria for outpatient surgery are met. Survival from an MH crisis in an ASC setting requires early recognition, prompt treatment, and timely transfer to a center with critical care capabilities.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Dantrolene has a safe side-effect profile and a mechanism of action that makes it attractive as an option for treatment of cerebral vasospasm. The authors report 2 cases of refractory cerebral vasospasm secondary to aneurysmal subarachnoid hemorrhage that were successfully treated with intra-arterial (IA) dantrolene., Case Description: Two patients, a 63-year-old woman and 36-year-old woman, developed severe vasospasm refractory to IA vasodilators after rupture of anterior communicating artery aneurysms. IA dantrolene was injected in doses of 15-30 mg in the affected distributions and mean arterial pressure, intracranial pressure, and heart rate were monitored. There was immediate improvement in lumen diameter of the affected vessels following dantrolene injection. No significant differences in mean arterial pressure or intracranial pressure before and after IA dantrolene were observed. Both patients demonstrated clinical improvement within 24 hours without any further deterioration during the rest of their admission. Follow-up angiography 48 hours after IA dantrolene treatment demonstrated continued resolution of cerebral vasospasm., Conclusions: This evidence suggests IA dantrolene as a safe and effective novel alternative for the treatment of cerebral vasospasm., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Malignant Hyperthermia (MH) is a life-threatening pharmacogenetic disorder which results from exposure to volatile anesthetic agents and depolarizing muscle relaxants. It manifests as a hypermetabolic response resulting in tachycardia, tachypnea, hyperthermia, hypercapnia, acidosis, muscle rigidity and rhabdomyolysis. An increase in the end-tidal carbon dioxide is one of the earliest diagnostic signs. Dantrolene sodium is effective in the management of MH, and should be available whenever general anesthesia is administered. This review also aims to highlight the genetics and pathology of MH, along with its association with various inherited myopathy syndromes like central core disease, multi-mini core disease, Native-American myopathy, and King-Denborough syndrome.

Dantrolene sodium (DS) is the only drug specifically used for the treatment of malignant hyperthermia. Nevertheless, its clinical application is significantly restricted due to its aqueous insolubility and the limited formulations available in clinical practice. In order to solve these problems, a novel mixed micelle composed of phospholipid and Cremophor EL was designed and evaluated. The mixed micelle was prepared using a stirring- ultrasonic method. The Dynamic Light Scattering (DLS) results showed that the micelle was small in size (12.14 nm) and narrowly distributed (PdI = 0.073). Transmission Electron Microscopy (TEM) images showed that the micelle was homogeneous and spherical. The stability study indicated that the system was stable for storage and dilution with distilled water, while the safety testing showed that the micelle was safe for intravenous administration with low hemolysis rates and low allergic reaction rates. In the pharmaceutics study, the C max and AUC 0-t of the DS-loaded micelle were 4- and 4.5- folds higher than that of the DS. Therefore, the constructed phospholipid-Cremophor EL mixed micelle is a promising drug delivery system for DS.

Aim: Differential pulse polarography was used for the concurrent analysis of the coadministered dantrolene (DAN) and indomethacin (IND) in plasma., Materials & Methods: DAN and IND, Hanging mercury drop electrode and Britton-Robinson buffer at pH 5 were used. In plasma, cathodic reduction of DAN nitro group and its active metabolite at -0.2 V was done. IND was analyzed after carbonyl group reduction at -1.1 V., Results: Drugs determination in rat plasma with good recoveries and low limit of quantitation was done. Application to trace analysis of drugs in rat plasma was done with C max and T max determination., Conclusion: This technique shows high sensitivity, simplicity and low cost. The method is US FDA validated and it is applicable to human level.

There has been a resurgence in the use of 2,4-dinitrophenol, C 6 H 4 N 2 O 5 (DNP) recently as an illegal weight loss drug. We present a case of a healthy 25-year-old girl who took two tablets of DNP, purchased from an overseas online retailer. She was managed with aggressive, invasive cooling measures and 2.5 mg kg -1 dantrolene. Despite this, her temperature continued to rise exponentially to 41.5°C. Cardiac arrest occurred and resuscitation was unsuccessful. To our knowledge, this is the first reported case of the ineffective use of dantrolene in acute DNP poisoning. We review the pathophysiology of DNP toxicity and argue that the use of dantrolene therapy is biochemically implausible, based on poor evidence and likely to be futile. We have contacted the UK National Poisons Information Service (NPIS/TOXBASE) to propose changes to the management of acute DNP toxicity., Competing Interests: Competing interests: JVS is a ST4 Registrar in Anaesthetics and Intensive Care Medicine, North Central School of Anaesthetics, London and an Anaesthetic Academic Clinical Fellow who holds an Honorary Research Assistant post in the Division of Surgery and Interventional Science University College London. EK is a CT2 in General Surgery in the North West Thames Deanery. She has undertaken a rotation in Intensive Care Medicine as part of her surgical training. AT is a consultant in Anaesthetics and Intensive Care Medicine at The Hillingdon Hospitals NHS Trust., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: The Malignant Hyperthermia Association of the United States recommends that dantrolene be available for administration within 10 min. One approach to dantrolene availability is a malignant hyperthermia cart, stocked with dantrolene, other drugs, and supplies. However, this may not be of cost benefit for maternity units, where triggering agents are rarely used., Methods: The authors performed a cost-benefit analysis of maintaining a malignant hyperthermia cart versus a malignant hyperthermia cart readily available within the hospital versus an initial dantrolene dose of 250 mg, on every maternity unit in the United States. A decision-tree model was used to estimate the expected number of lives saved, and this benefit was compared against the expected costs of the policy., Results: We found that maintaining a malignant hyperthermia cart in every maternity unit in the United States would reduce morbidity and mortality costs by $3,304,641 per year nationally but would cost $5,927,040 annually. Sensitivity analyses showed that our results were largely driven by the extremely low incidence of general anesthesia. If cesarean delivery rates in the United States remained at 32% of all births, the general anesthetic rate would have to be greater than 11% to achieve cost benefit. The only cost-effective strategy is to keep a 250-mg dose of dantrolene on the unit for starting therapy., Conclusions: It is not of cost benefit to maintain a fully stocked malignant hyperthermia cart with a full supply of dantrolene within 10 min of maternity units. We recommend that hospitals institute alternative strategies (e.g., maintain a small supply of dantrolene on the maternity unit for starting treatment).

Acute RyR2 activation by exchange protein directly activated by cAMP (Epac) reversibly perturbs myocyte Ca 2+ homeostasis, slows myocardial action potential conduction, and exerts pro-arrhythmic effects. Loose patch-clamp studies, preserving in vivo extracellular and intracellular conditions, investigated Na + current in intact cardiomyocytes in murine atrial and ventricular preparations following Epac activation. Depolarising steps to varying test voltages activated typical voltage-dependent Na + currents. Plots of peak current against depolarisation from resting potential gave pretreatment maximum atrial and ventricular currents of -20.23 ± 1.48 (17) and -29.8 ± 2.4 (10) pA/μm 2 (mean ± SEM [n]). Challenge by 8-CPT (1 μmol/L) reduced these currents to -11.21 ± 0.91 (12) (P < .004) and -19.3 ± 1.6 (11) pA/μm 2 (P < .04) respectively. Currents following further addition of the RyR2 inhibitor dantrolene (10 μmol/L) (-19.91 ± 2.84 (13) and -26.6 ± 1.7 (17)), and dantrolene whether alone (-19.53 ± 1.97 (8) and -27.6 ± 1.9 (14)) or combined with 8-CPT (-19.93 ± 2.59 (12) and -29.9 ± 2.5(11)), were indistinguishable from pretreatment values (all P >> .05). Assessment of the inactivation that followed by applying subsequent steps to a fixed voltage 100 mV positive to resting potential gave concordant results. Half-maximal inactivation voltages and steepness factors, and time constants for Na + current recovery from inactivation in double-pulse experiments, were similar through all the pharmacological conditions. Intracellular sharp microelectrode membrane potential recordings in intact Langendorff-perfused preparations demonstrated concordant variations in maximum rates of atrial and ventricular action potential upstroke, (dV/dt) max . We thus demonstrate an acute, reversible, Na + channel inhibition offering a possible mechanism for previously reported pro-arrhythmic slowing of AP propagation following modifications of Ca 2+ homeostasis, complementing earlier findings from chronic alterations in Ca 2+ homeostasis in genetically-modified RyR2-P2328S hearts., (© 2017 The Authors. Clinical and Experimental Pharmacology and Physiology Published by John Wiley & Sons Australia, Ltd.)

Background Context: Damage to the spinal cord can result in irreversible impairment or complete loss of motor, sensory, and autonomic functions. Riluzole and dantrolene have been shown to provide neuroprotection by reducing neuronal apoptosis after brain and spinal cord injury (SCI) in several animal models of neurologic disorders. As these drugs protect the injured spinal cord through different mechanisms, we investigated the cumulative effects of riluzole and dantrolene., Purpose: This study aimed to investigate the neuroprotective efficacy of the combined administration of riluzole and dantrolene in experimental thoracic SCI., Study Design: Twenty-nine Wistar rats were laminectomized at T12 and divided in five groups. Rats in GI (n=6) underwent laminectomy alone and were treated with placebo. Rats in GII (n=6) underwent laminectomy followed by SCI and were treated with placebo. Rats in GIII (n=5) underwent laminectomy followed by SCI and were treated with riluzole and placebo 15 minutes and 1 hour after laminectomy, respectively. Rats in GIV (n=6) underwent laminectomy followed by SCI and were treated with placebo and dantrolene 15 minutes and 1 hour after laminectomy, respectively. Rats in GV (n=6) underwent laminectomy followed by SCI and were treated with riluzole and dantrolene 15 minutes and 1 hour after laminectomy, respectively. A compressive trauma was performed to induce SCI., Methods: Behavioral testing of hind limb function was performed using the Basso Beattie Bresnahan locomotor rating scale, which revealed significant recovery in the group treated with the association of riluzole and dantrolene compared with other groups. After euthanasia, the spinal cord was evaluated using light microscopy and immunochemistry with anti-NeuN and transferase dUTP nick-end-labeling (TUNEL) staining., Results: Animals treated with the association of riluzole and dantrolene showed a larger number of NeuN-positive neurons adjacent to the epicenter of injury (p≤.05). Furthermore, the TUNEL staining was similar between animals treated with riluzole and dantrolene and those that did not receive spinal cord trauma (p>.05)., Conclusions: These results showed that riluzole and dantrolene have a synergistic effect in neuroprotection after traumatic SCI by decreasing apoptotic cell death., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Although "teeth clenching" induces pressor response, the reflex tracts of the response are unknown. In this study, dantrolene administration inhibited teeth clenching generated by electrical stimulation of the masseter muscles and completely abolished the pressor response. In addition, trigeminal ganglion block or hexamethonium administration completely abolished the pressor response. Local anesthesia of molar regions significantly reduced the pressor response to 27 ± 10%. Gadolinium (mechanoreceptor blocker of group III muscle afferents) entrapment in masticatory muscles also significantly reduced the pressor response to 62 ± 7%. Although atropine methyl nitrate administration did not change the pressor response, a significant dose-dependent augmentation of heart rate was observed. These results indicate that both periodontal membrane and mechanoreceptors in masticatory muscles are the receptors for the pressor response, and that the afferent and efferent pathways of the pressor response pass through the trigeminal afferent nerves and sympathetic nerves, respectively.

Introduction: Sporadic clinical episodes of malignant hyperthermia (MH) that develop during general anaesthesia (GA) have been reported in Singapore. However, there is no published local report of a confirmed case of MH susceptibility (MHS) by skeletal muscle contracture tests and/or molecular tests., Materials and Methods: We report 2 patients from an extended family who developed signs of clinical MH while under GA. The MH episodes were successfully treated with intravenous dantrolene sodium. Sequence analysis of the entire Ryanodine Receptor Type 1 (RyR1) coding gene was carried out in an index patient., Results: The index patient was found to carry a c.7373G>A (p.Arg2458His) mutation in exon 46. This particular mutation satisfies the criteria for a MHS causative mutation. Hence, the index patient was considered to be MHS and did not need to undergo further muscle contracture testing. The same mutation was also found in 3 other members of his extended family., Conclusion: This is the first report of a Singaporean family with at least 4 members carrying a MH-causative mutation in RyR1 gene. This report serves to highlight the existence of the putative gene for MH in Singapore, and the need for clinical vigilance during anaesthesia involving the use of triggering agents.

During resection of a duodenal carcinoid tumor, a 28-year-old morbidly obese woman developed suspected malignant hyperthermia. This hypermetabolic state posed a diagnostic challenge given the similar intraoperative presentation of carcinoid crisis and malignant hyperthermia. The patient's weight posed therapeutic challenges as massive doses and prolonged administration of dantrolene were required that quickly depleted the available supply. Current dantrolene dosing recommendations are based on actual body weight despite a paucity of literature in obese patients. We speculate that the prolonged need for dantrolene redosing was from the continuous release of the volatile anesthetic from the patient's adipose tissue.

The aim of the current research was to determine the precipitation kinetics of dantrolene sodium using canine biorelevant in vitro testing and to model the precipitation kinetics by appropriately coupling the data with an in silico tool adapted for dogs. The precipitation profiles of dantrolene sodium solutions were obtained with the in vitro paddle apparatus at a revolution rate of 50rpm. The in silico prediction tool was designed using STELLA software and the predicted plasma concentration profiles of dantrolene using the in vitro precipitation data were compared with the observed in vivo pharmacokinetics in beagle dogs. The plasma profiles of dantrolene, which served as a model weakly acidic drug which precipitates in the upper gastrointestinal tract, was successfully predicted using the in vitro precipitation testing coupled with the in silico modeling and simulation approach. The approach was subsequently used to forecast the effect of pharmaceutical excipients (HPMC/PG) on the ability of the drug to supersaturate in the gut and the resulting pharmacokinetics. The agreement of the simulated pharmacokinetics with the observed values confirms the ability of canine biorelevant media to predict oral performance of enhanced dosage forms in dogs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Malignant hyperthermia (MH) can be fatal if the crisis is not appropriately treated. It is an inherited disease usually triggered by the administration of volatile inhalational anesthetics and/or succinylcholine, a muscle relaxant. In a patient with suspected MH, the mechanism of calcium release from storage in the sarcoplasmic reticulum in the skeletal muscle is abnormally accelerated. Unexplained hypercarbia representing >55 mmHg of end-tidal carbon dioxide, tachycardia, and muscle rigidity (including masseter muscle rigidity) are early signs of the initiation of MH, because the metabolism is accelerated. The body temperature can rise by >0.5 °C/15 min and may reach ≥40 °C. Respiratory and metabolic acidosis, arrhythmia, cola-colored urine, increased levels of serum potassium, and tented T-waves on electrocardiogram are common and can lead to cardiac arrest. MH should be treated by discontinuation of the triggering agents, administration of intravenous dantrolene (initially 1 mg/kg), and reduction of the body temperature. Early diagnosis and sufficient dantrolene with body temperature reduction are essential to relieve the patient's MH crisis. This guideline in Japanese translation has been posted on the website: http://www.anesth.or.jp/guide/pdf/guideline&#95;akuseikounetsu.pdf .

Dantrolene sodium (Da) is an effective skeletal muscle relaxant. However, its pharmacological effects are severely limited owing to its poor solubility and low oral bioavailability. In order to solve these problems, an inclusion complex using hydroxypropyl-β-cyclodextrin (HP-β-CD) to improve the oral bioavailability of Da was prepared successfully by freeze-drying. The prepared complex was characterized by Powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy (FTIR) and evaluated by a dissolution test and a pharmacokinetic study. The results of PXRD and FTIR proved the formation of a complex between Da and HP-β-CD. The dissolution rate of Da was markedly improved from inclusion complex with more than 90% being released within 5min. The in vivo pharmacokinetics of Da and dantrolene sodium-hydroxypropyl-β-cyclodextrin (Da-HP-β-CD) inclusion complex were investigated in rats using a UPLC/MS/MS method. The C max and AUC 0-t of the Da-HP-β-CD inclusion complex were 5- and 3-fold higher than that of the Da. These results suggested that the Da-HP-β-CD inclusion complex markedly improved the dissolution rate and bioavailability of Da., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Neuronopathic Gaucher disease (nGD) manifests as severe neurological symptoms in patients with no effective treatment available. Ryanodine receptors (Ryrs) are a family of calcium release channels on intracellular stores. The goal of this study is to determine if Ryrs are potential targets for nGD treatment. A nGD cell model (CBE-N2a) was created by inhibiting acid β-glucosidase (GCase) in N2a cells with conduritol B epoxide (CBE). Enhanced cytosolic calcium in CBE-N2a cells was blocked by either ryanodine or dantrolene, antagonists of Ryrs and by Genz-161, a glucosylceramide synthase inhibitor, suggesting substrate-mediated ER-calcium efflux occurs through ryanodine receptors. In the brain of a nGD (4L;C*) mouse model, expression of Ryrs was normal at 13 days of age, but significantly decreased below the wild type level in end-stage 4L;C* brains at 40 days. Treatment with dantrolene in 4L;C* mice starting at postnatal day 5 delayed neurological pathology and prolonged survival. Compared to untreated 4L;C* mice, dantrolene treatment significantly improved gait, reduced LC3-II levels, improved mitochondrial ATP production and reduced inflammation in the brain. Dantrolene treatment partially normalized Ryr expression and its potential regulators, CAMK IV and calmodulin. Furthermore, dantrolene treatment increased residual mutant GCase activity in 4L;C* brains. These data demonstrate that modulating Ryrs has neuroprotective effects in nGD through mechanisms that protect the mitochondria, autophagy, Ryr expression and enhance GCase activity. This study suggests that calcium signalling stabilization, e.g. with dantrolene, could be a potential disease modifying therapy for nGD., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Organophosphate (OP) compounds which include nerve agents and pesticides are considered chemical threat agents. Currently approved antidotes are crucial in limiting OP mediated acute mortality. However, survivors of lethal OP exposure exhibit delayed neuronal injury and chronic behavioral morbidities. In this study, we investigated neuroprotective capabilities of dantrolene and carisbamate in a rat survival model of paraoxon (POX) induced status epilepticus (SE). Significant elevations in hippocampal calcium levels were observed 48-h post POX SE survival, and treatment with dantrolene (10mg/kg, i.m.) and carisbamate (90mg/kg, i.m.) lowered these protracted calcium elevations. POX SE induced delayed neuronal injury as characterized by Fluoro Jade C labeling was observed in critical brain areas including the dentate gyrus, parietal cortex, amygdala, and thalamus. Dantrolene and carisbamate treatment provided significant neuroprotection against delayed neuronal damage in these brain regions when administered one-hour after POX-SE. These results indicate that dantrolene or carisbamate could be effective adjuvant therapies to the existing countermeasures to reduce neuronal injury and behavioral morbidities post OP SE survival., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: An initiative to optimize the treatment of malignant hyperthermia in surgical patients through a dantrolene product conversion program is described., Summary: A large health system's formulary evaluation of a new dantrolene sodium product indicated that despite a higher cost per treatment course, the product could offer key advantages over older formulations of dantrolene in terms of preparation and administration time, product content, and storage requirements. A work group, consisting of pharmacy personnel, an anesthesiologist, a nurse anesthetist, and a representative of the health system's group purchasing organization, determined that a switch to the new dantrolene product would offer both patient care benefits and process benefits. With the approval of the health system's pharmacy and therapeutics committee, the new product was added to the formulary as the preferred dosage form of dantrolene, and existing dantrolene product stock was converted to the new formulation. Key implementation steps included (1) concurrent replacement of dantrolene stock on all "malignant hyperthermia carts" across the 15-hospital health system, (2) development of educational materials to raise awareness of the conversion and revised product preparation procedures, (3) anesthesiology provider and pharmacy staff education, (4) revision of dantrolene listings in each hospital's computerized prescriber-order-entry system, and (5) redistribution of returned dantrolene product stock. The dantrolene product conversion occurred over a four-month period., Conclusion: A multifacility health system was successful in converting an existing stock of dantrolene to a newly available formulation., (Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

This case report describes a female with p.Lys4876Arg amino acid change in the ryanodine receptor type 1 (RYR1) and a sibling who died of malignant hyperthermia (MH) during anesthesia. After her diagnosis as MH susceptible, this patient was administered low-dose dantrolene daily for greater than 25 years for treatment of chronic muscle spasm and pain in her lower extremities and back limiting sleep. Her creatine phosphokinase (CPK) was as high as 2390 IU/L during labor and 900 IU at rest. With 25 mg dantrolene daily, muscle cramps were eliminated, and sleep was improved. Gait instability was noted with dantrolene in the morning, but not when taken at bedtime. There was no evidence of liver injury. This case suggests that low dose dantrolene by mouth could be considered for the treatment of chronic muscle pain in individuals with MH susceptibility.

Since 2012, Matsudo City Hospital has increased the number of pharmacists stationed in the ward on weekday mornings at the emergency care center, the intensive care unit (ICU) and the high care unit (HCU). Multidisciplinary joint meetings and joint conferences are conducted in the emergency care center, and patient and drug information is shared. A 20-year-old man was transferred to our hospital after a traffic accident. He was diagnosed with subarachnoid hemorrhage and brain contusion. He exhibited violent movement and intense restlessness. He was sedated with a continuous intravenous infusion of 5 mg/h midazolam and 20 μg/h fentanyl, with intubation. Propofol was also used intermittently. The midazolam infusion was concluded on day 5 of hospitalization. However, his restlessness recurred so an intravenous drip infusion of 150 mg/h haloperidol was administered. On the 7th day, he developed a high-grade fever, muscle rigidity, perspiration, and leukocytosis, and malignant syndrome or malignant hyperthermia was suspected. For malignant syndrome treatment, he received an intravenous drip infusion of 60 mg dantrolene, followed by the combined oral administration of 100 mg/d dantrolene and 7.5 mg/d bromocriptine. Considering various pharmacological effects, we selected an intravenous drip infusion of 25 mg hydroxyzine hydrochloride as the drug to alleviate restlessness. The patient's course continued without recurrence of malignant syndrome; his symptoms improved because of pharmaceutical care with an awareness of patient benefits through clinical and laboratory findings, consultation with the attending physician, presentation of information on causative and therapeutic drugs, and coordinated planning of a prescription design.

Dantrolene is the first line therapy of malignant hyperthermia. Animal studies suggest that dantrolene also protects against heart failure and arrhythmias caused by spontaneous Ca(2+) release. Although dantrolene inhibits Ca(2+) release from the sarcoplasmic reticulum of skeletal and cardiac muscle preparations, its mechanism of action has remained controversial, because dantrolene does not inhibit single ryanodine receptor (RyR) Ca(2+) release channels in lipid bilayers. Here we test the hypothesis that calmodulin (CaM), a physiologic RyR binding partner that is lost during incorporation into lipid bilayers, is required for dantrolene inhibition of RyR channels. In single channel recordings (100 nM cytoplasmic [Ca(2+)] + 2 mM ATP), dantrolene caused inhibition of RyR1 (rabbit skeletal muscle) and RyR2 (sheep) with a maximal inhibition of Po (Emax) to 52 ± 4% of control only after adding physiologic [CaM] = 100 nM. Dantrolene inhibited RyR2 with an IC50 of 0.16 ± 0.03 µM. Mutant N98S-CaM facilitated dantrolene inhibition with an IC50 = 5.9 ± 0.3 nM. In mouse cardiomyocytes, dantrolene had no effect on cardiac Ca(2+) release in the absence of CaM, but reduced Ca(2+) wave frequency (IC50 = 0.42 ± 0.18 µM, Emax = 47 ± 4%) and amplitude (IC50 = 0.19 ± 0.04 µM, Emax = 66 ± 4%) in the presence of 100 nM CaM. We conclude that CaM is essential for dantrolene inhibition of RyR1 and RyR2. Its absence explains why dantrolene inhibition of single RyR channels has not been previously observed., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly malignant inherited arrhythmogenic disorder. Type 1 CPVT (CPVT1) is caused by cardiac ryanodine receptor (RyR2) gene mutations resulting in abnormal calcium release from sarcoplasmic reticulum. Dantrolene, an inhibitor of sarcoplasmic Ca(2+) release, has been shown to rescue this abnormal Ca(2+) release in vitro. We assessed the antiarrhythmic efficacy of dantrolene in six patients carrying various RyR2 mutations causing CPVT. The patients underwent exercise stress test before and after dantrolene infusion. Dantrolene reduced the number of premature ventricular complexes (PVCs) on average by 74% (range 33-97) in four patients with N-terminal or central mutations in the cytosolic region of the RyR2 protein, while dantrolene had no effect in two patients with mutations in or near the transmembrane domain. Induced pluripotent stem cells (iPSCs) were generated from all the patients and differentiated into spontaneously beating cardiomyocytes (CMs). The antiarrhythmic effect of dantrolene was studied in CMs after adrenaline stimulation by Ca(2+) imaging. In iPSC derived CMs with RyR2 mutations in the N-terminal or central region, dantrolene suppressed the Ca(2+) cycling abnormalities in 80% (range 65-97) of cells while with mutations in or near the transmembrane domain only in 23 or 32% of cells. In conclusion, we demonstrate that dantrolene given intravenously shows antiarrhythmic effects in a portion of CPVT1 patients and that iPSC derived CM models replicate these individual drug responses. These findings illustrate the potential of iPSC models to individualize drug therapy of inherited diseases.Trial Registration: EudraCT Clinical Trial Registry 2012-005292-14.

Objective: To determine the effect of dantrolene premedication on various cardiovascular and biochemical variables and recovery in isoflurane-anesthetized horses., Animals: 6 healthy horses., Procedures: Each horse was anesthetized twice with a 21- to 28-day washout period between anesthetic sessions. Food was not withheld from horses before either session. During each session, dantrolene (6 mg/kg in 2 L of water) or water (2 L) was administered via a nasogastric tube 1 hour before anesthesia was induced. Anesthesia was maintained with isoflurane for 90 minutes, during which blood gas analyses and lithium-dilution cardiac output (CO) measurements were obtained every 10 minutes. Serum creatine kinase activity was measured before and at 4, 8, and 12 hours after anesthesia., Results: When horses were premedicated with dantrolene, CO at 25, 35, and 45 minutes after induction of anesthesia was significantly lower than that when horses were premedicated with water after which time difficulty in obtaining valid measurements suggested a continued decrease in CO; plasma potassium concentration progressively increased during anesthesia, whereas serum creatine kinase activity remained fairly stable and within reference limits through 12 hours after anesthesia; and 2 of 6 horses developed cardiac arrhythmias that required medical intervention. The quality of anesthetic recovery was slightly better when horses were premedicated with dantrolene versus water, although the time required for recovery did not differ significantly between treatments., Conclusions and Clinical Relevance: Results suggested that dantrolene premedication prevented muscle damage without affecting anesthetic recovery but impaired CO and precipitated hyperkalemia and cardiac arrhythmias in healthy isoflurane-anesthetized horses.

Background: In 1997, the International Classification of Diseases (ICD), 9th Revision Clinical Modification (ICD-9) coding system introduced the code for malignant hyperthermia (MH) (995.86). The aim of this study was to estimate the accuracy of coding for MH in hospital discharge records., Methods: An expert panel of anesthesiologists reviewed medical records for patients with a discharge diagnosis of MH based on ICD-9 or ICD-10 codes from January 1, 2006 to December 31, 2008 at six tertiary care medical centers in North America. All cases were categorized as possible, probable, or fulminant MH, history of MH (family or personal) or other., Results: A total of 47 medical records with MH diagnoses were reviewed; 68.1% had a documented surgical procedure and general anesthesia, and 23.4% (95% CI, 12.3-38.0%) had a possible, probable, or fulminant MH event. Dantrolene was given in 81% of the MH events. All patients judged to have an incident MH event survived to discharge. Family and personal history of MH accounted for 46.8% of cases. High fever without evidence of MH during admission accounted for 23.4%, and the reason for MH coding was unclear in 6.4% of cases., Conclusions: Approximately one quarter of ICD-9 or ICD-10 coded MH diagnoses in hospital discharge records refer to incident MH episodes and an additional 47% to MH susceptibility (including personal history or family history). Information such as surgical procedure, anesthesia billing data, and dantrolene administration may aid in identifying incident MH cases among those with an ICD-9 or ICD-10 coded MH diagnosis in their hospital discharge records.

Purpose: A virtual screening study has suggested that the skeletal muscle relaxant, dantrolene, and the antiemetic drug, ondansetron, may act as inhibitors of the enzyme acetylcholinesterase (AChE). Based on this proposal, the current study examines the AChE inhibitory properties of these drugs., Methods and Findings: Using AChE from human erythrocytes as enzyme source, it is shown that dantrolene and ondansetron inhibit AChE with IC(50) values of 12.8 µM and 37.1 µM, respectively. For comparison, the reference AChE inhibitors, tacrine and ranitidine, exhibit IC(50) values of 0.144 µM and 3.37 µM, respectively. By measuring the recoveries of enzyme activities after dilution of enzyme-inhibitor mixtures, it is further shown that dantrolene and ondansetron act as reversible AChE inhibitors., Conclusions: By considering the typical plasma concentrations of dantrolene and ondansetron in humans at therapeutic doses, the pharmacological relevance of the AChE inhibitory potencies of these drugs is discussed. At typical plasma concentrations, ondansetron is unlikely to inhibit AChE under physiological conditions. The inhibition of AChE by ondansetron is therefore not of clinical relevance in humans. In contrast, after intravenous administration of dantrolene to humans, the typical plasma concentrations reached are similar to the recorded IC(50) value for the inhibition of AChE, and dantrolene may thus produce pharmacological significant inhibition of AChE. Further investigation is necessary to clarify the pharmacological relevance of the AChE inhibitory effect of dantrolene., (© Georg Thieme Verlag KG Stuttgart · New York.)

We report the case of a 16-year-old man who presented with hyperthermia (>40°C), an elevated creatine kinase level (>64,000 IU · l-1), and myoglobinuria one week after undergoing two successive neurosurgeries for a brain hemorrhage under sevoflurane anesthesia. After having been diagnosed with suspicious atypical postoperative malignant hyperthermia, he was treated with dantrolene and his symptoms disappeared on the day of dantrolene administration. Central hyperthermia is defined as hyperthermia associated with thermoregulatory dysfunction after brainstem injury. Postoperative malignant hyperthermia can sometimes be difficult to distinguish from central hyperthermia, especially after neurosurgery. We could not eliminate the possibility of central hyperthermia as a cause of hyperthermia in the present patient If marked postoperative hyperthermia must be addressed immediately and managed appropriately in neurosurgical patients and dantrolene having few serious side effects, we were able to control his symptoms immediately after the infusion of dantrolene. Therefore, the administration of dantrolene should be considered when treating unidentified postoperative hyperthermia after a neurosurgical procedure.

What Is Known and Objective: Dantrolene can be combined with baclofen to better treat spasticity, but may cause muscular weakness and dysphagia. We instead describe a pharyngeal spasm due to dantrolene., Case Summary: A 12-year-old male received dantrolene 3 mg/kg/day in adjunct to baclofen 2 mg/kg/day, to improve spasticity. After 5 days of full-dose dantrolene, his dysphagia worsened and he developed pharyngeal spasm. Dantrolene was suspected for an adverse reaction and removed. The patient subsequently improved., What Is New and Conclusion: Causality analysis determined a probable relationship between dantrolene and pharyngeal spasm. This may be due to direct muscle contraction by dantrolene, an effect seen previously in vitro., (© 2014 John Wiley & Sons Ltd.)

Background: Malignant hyperthermia (MH) is a rare hypermetabolic syndrome of the skeletal muscle and a potentially fatal complication of general anesthesia. Dantrolene is currently the only specific treatment for MH. The Malignant Hyperthermia Association of the United States has issued guidelines recommending that 36 vials (20 mg per vial) of dantrolene remain in stock at every surgery center. However, the cost of stocking dantrolene in ambulatory surgery centers has been a concern. The purpose of this analysis is to assess the cost-effectiveness of stocking dantrolene in ambulatory surgery centers as recommended by the Malignant Hyperthermia Association of the United States., Methods: A decision tree model was used to compare treatment with dantrolene to a supportive care-only strategy. Model assumptions include the incidence of MH, MH case fatality with dantrolene treatment and with supportive care-only. Sensitivity analyses were performed to assess the robustness of the estimated cost-effectiveness., Results: The estimated annual number of MH events in ambulatory surgery centers in the United States was 47. The incremental effectiveness of dantrolene compared with supportive care was 33 more lives saved per year. The incremental cost-effectiveness ratio was $196,320 (in 2010 dollars) per life saved compared with a supportive care strategy. Sensitivity analysis showed that the results were robust for the plausible range of all variables and assumptions tested., Conclusion: The results of this analysis suggest that stocking dantrolene for the treatment of MH in ambulatory surgery centers as recommended by the Malignant Hyperthermia Association of the United States is cost-effective when compared with the estimated values of statistical life used by U.S. regulatory agencies.

The pharmacokinetics of dantrolene and its active metabolite, 5-hydroxydantrolene, after a single oral dose of either 5 or 10 mg/kg of dantrolene was determined. The effects of exposure to dantrolene and 5-hydroxydantrolene on activated whole-blood gene expression of the cytokines interleukin-2 (IL-2) and interferon-γ (IFN-γ) were also investigated. When dantrolene was administered at a 5 mg/kg dose, peak plasma concentration (Cmax ) was 0.43 μg/mL, terminal half-life (t1/2 ) was 1.26 h, and area under the time-concentration curve (AUC) was 3.87 μg·h/mL. For the 10 mg/kg dose, Cmax was 0.65 μg/mL, t1/2 was 1.21 h, and AUC was 5.94 μg·h/mL. For all calculated parameters, however, there were large standard deviations and wide ranges noted between and within individual dogs: t1/2 , for example, ranged from 0.43 to 6.93 h, Cmax ratios ranged from 1.05 to 3.39, and relative bioavailability (rF) values ranged from 0.02 to 1.56. While activated whole-blood expression of IL-2 and IFN-γ as measured by qRT-PCR was markedly suppressed following exposure to very high concentrations (30 and 50 μg/mL, respectively) of both dantrolene and 5-hydroxydantrolene, biologically and therapeutically relevant suppression of cytokine expression did not occur at the much lower drug concentrations achieved with oral dantrolene dosing., (© 2013 John Wiley & Sons Ltd.)