Dantrolene and coenzyme Q10 as a suggested combination therapy to statin-induced myopathy in high fat diet rats: A possible interference with ROS/ TGF-ß / Smad4 signaling pathway.

One of the major hitches for statins' utilization is the development of myotoxicity. Versatile studies reported that the underlining molecular mechanisms including coenzyme Q10 (CoQ10)/ubiquinone depletion, as well as the disturbance in the cytoplasmic Ca2+ homeostasis. Therefore, we investigated the consequences of supplementing CoQ10 and dantrolene, a cytoplasmic Ca2+ reducing agent, in combination with simvastatin. This adjuvant therapy normalized the simvastatin-mediated elevation in serum ALT, AST, CK-MM, as well as tissue Ca2+ content, in addition to suppressing the simvastatin-mediated oxidative stress in simvastatin-treated rats, while having no effect upon statin-induced antihyperlipidemic effect. Additionally, the combination inhibited the simvastatin-induced TGF-ß/ Smad4 pathway activation. Collectively, the current study emphasizes on the potential utilization of dantrolene and CoQ10 as an adjuvant therapy to statins treatment for improving their side effect profile.

Malignant hyperthermia in maxillofacial surgery: Literature review supported by case presentation.

OBJECTIVE: Malignant hyperthermia (MH) is characterized by a state of hypermetabolism after exposure to halogenated inhalational anesthetics or succinylcholine. The aims of this study were to carry out an updated review on the subject and report an illustrative case of MH in urgent maxillofacial surgery. MATERIAL AND METHODS: A search of the PubMed/MEDLINE database using the keyword "malignant hyperthermia" was performed including articles published over the last 11 years in English, Spanish or Portuguese. Exclusion criteria were similar presentations but not associated with MH and cases not related to the use of anesthetic drugs as a trigger of the condition. CASE REPORT: A 45-year-old man (75 kg, ASA status IE) with a negative family history for neuromuscular diseases, victim of a car accident with a facial fracture, underwent surgery under balanced general anesthesia and developed signs of MH 4 h after anesthesia induction. In our patient, the causative agent was sevoflurane and the diagnosis of MH was confirmed, subsequently, by muscle biopsy. RESULTS/DISCUSSION: Overall, 44 cases of MH were found. According to the recent literature, MH shows a male predilection (3:1) and the mean age of patients is 32.2 ± 22.2 years. The most frequently cited causative agents were sevoflurane (30.5%), isoflurane (22.2%), and sevoflurane + succinylcholine (13.8%). The most common clinical indicators included hypercarbia (88.8%), hyperthermia (86.1%), and tachycardia (63.8%). Dantrolene was administered in 24 cases. The outcome was favorable in 31 cases (86.1%). The in vitro muscle contracture test (IVCT) was performed in only 15 patients and all of them tested positive. In our patient, the causative agent was sevoflurane and the diagnosis of MH was confirmed by muscle biopsy. CONCLUSION: The mortality from MH is still high and an early clinical diagnosis and specific treatment with dantrolene are necessary for a favorable outcome. A complete understanding will allow better management of patients with MH. At present, the best management is to identify susceptible patients and to avoid triggering agents, combined with vigilant monitoring.

Should rocuronium and sugammadex replace succinylcholine for airway emergencies in class B ambulatory anesthesia settings?

INTRODUCTION: In class B surgical facilities, where only oral or intravenous (IV) sedation is employed without the administration of volatile anesthetics, laryngospasm is among the most common airway complications. However, these facilities generally do not stock succinylcholine to avoid the cost of storing dantrolene for the treatment of malignant hyperthermia (MH). High dose IV rocuronium with sugammadex reversal has been suggested as an alternative to succinylcholine for airway emergencies. The aim of this paper was to evaluate the clinical utility, patient safety, and financial implications of replacing succinylcholine with rocuronium and sugammadex in lieu of stocking dantrolene in class B facilities. EVIDENCE ACQUISITION: A systematic review of the literature concerning neuromuscular blockade for airway emergencies in class B settings in adult patients was conducted. The MEDLINE and EMBASE databases were searched for published studies from January 1, 1990, to October 1, 2021. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system was used to assess the certainty of evidence. EVIDENCE SYNTHESIS: The search strategy yielded 1124 articles. After review, 107 articles were included, with 49 graded as "strong" evidence to provide recommendations for the posed questions. CONCLUSIONS: The use of succinylcholine in isolation without volatile agents has a low incidence of triggering MH. Laryngospasm is a common airway emergency that requires immediate treatment to avoid morbidity and mortality. Both succinylcholine and rocuronium-sugammadex provide adequate treatment of airway emergencies and rapid return of spontaneous ventilation, but succinylcholine has a superior economic and clinical profile.

Dantrolene, a stabilizer of the ryanodine receptor, prevents collagen-induced arthritis.

Dantrolene inhibits Ca2+ leakage from destabilized ryanodine receptors and therefore may serve as a therapeutic agent against endoplasmic reticulum stress-associated diseases. However, its effectiveness in treating autoimmune diseases remains unclear. Here, we investigated the effect of dantrolene on collagen-induced arthritis (CIA) in mice. Oral administration of dantrolene resulted in significantly lower arthritic scores in both male and female CIA mice than in the control mice. Micro-computed tomographic and histological analyses showed that dantrolene suppressed bone and chondral destruction. The serum levels of anti-type II collagen (CII) IgG were positively correlated with the arthritic scores (r = 0.704, p < 0.01). In addition, the serum levels of anti-CII IgG were significantly lower in the dantrolene group than in the control group (p < 0.05). These results demonstrate that oral administration of dantrolene to CIA mice inhibits the production of serum anti-CII IgG and consequently prevents arthritis. Therefore, dantrolene may be a potential anti-rheumatic drug.

Catatonia.

Catatonia is associated with psychomotor symptoms and severe disturbances of executive functioning. While the prognosis is good in most cases, malignant catatonia still continues to occur. The first-line choice for drug therapy is lorazepam, which usually results in a good response. In catatonic stupor, i.e. immobility and stupor, the first-line therapy is electrotherapy, preferably at an earliest possible stage. In mania, catatonia may become manifest also as psychomotor excitement. Electrotherapy can be used primarily in malignant catatonia, with dantrolene and bromocriptin also finding use in a critical situation.

Antispasmodic effect of shakuyakukanzoto extract on experimental muscle cramps in vivo: role of the active constituents of Glycyrrhizae radix.

ETHNOPHARMACOLOGICAL RELEVANCE: Shakuyakukanzoto (SKT) composed of Glycyrrhizae radix (G. radix) and Paeoniae radix (P. radix) has been traditionally used in Japan, Korea and China as an antispasmodic drug for the treatment of skeletal muscle cramps and intestinal cramps. AIM OF THIS STUDY: To evaluate the antispasmodic activity of SKT and its two components, as well as to identify the key constituents of the components which mediate this effect in skeletal muscles in vivo. MATERIALS AND METHODS: An experimental cramp model was constructed to evaluate the effects of peripherally-acting muscle relaxants on electrically-induced cramps under physiological conditions. This was accomplished by surgically isolating the motor supply to the gastrocnemius muscle in an anesthetized rat and delivering electrical stimuli to an isolated tibial nerve to induce tetanic contractions. We first tested dantrolene, a well-known peripherally-acting relaxant, to determine the sensitivity and reliability of our experimental model. We then evaluated the effects of SKT, P. radix, G. radix, and the eight active constituents of G. radix against tetanic contractions. RESULTS: We found that dantrolene (10 and 30 mg/kg, i.d.) rapidly and significantly inhibited tetanic contractions (P<0.01) irrespective of dose. SKT (0.5, 1.0, and 2.0 g/kg, i.d.) and G. radix (0.5 and 1.0 g/kg, i.d.) also significantly inhibited tetanic contractions (P<0.01) but in a dose-dependent manner owing to the actions of six of the eight active constituents in G. radix (liquiritin apioside, liquiritigenin, isoliquiritin apioside, isoliquiritigenin, glycycoumarin, and glycyrrhetinic acid, 20 µmol/kg, i.v.). These constituents, which include flavonoids, a triterpenoid, and a courmarin derivative, demonstrated temporal variations in their inhibitory activity. In contrast, P. radix (0.5 and 1.0 g/kg, i.d.) did not show a statistically significant antispasmodic effect in our study; however, we previously found that it had a significant antinociceptive effect. CONCLUSIONS: Our findings show that SKT inhibits tetanic contractions in vivo and that G. radix is the main antispasmodic component due to the actions of its active constituents, thus supporting the traditional use of SKT. We further propose that SKT containing the antispasmodic G. radix and antinociceptive P. radix is a pharmaceutically elegant option for muscle cramps as treatment requires a two-pronged approach, i.e., inhibition of hyperexcitable skeletal tissues and modulation of the pain accompanying cramps.

[Case of suspected malignant hyperthermia following local infiltration anesthesia].

A 49-year-old man with no past history of malignant hyperthermia (MH) and scheduled for hernia repair was suspected of MH after local infiltration anesthesia at other hospital. Although intravenous diazepam was not effective for increased body temperature, tachycardia, and convulsion, dantrolene was effective for these signs. However, blood test showed no abnormal finding. At our hospital, he was scheduled for hernia repair and muscle biopsy under total intravenous anesthesia. No event occurred intra- and postoperatively. The examination for muscle biopsy revealed that the function of his ryanodine receptor 1 is abnormal. The events which had occurred at other hospital were uncertain of being associated with MH.

Spasticity: revisiting the role and the individual value of several pharmacological treatments.

Though in the last few decades only a few new drugs have come available for the treatment of spasticity, new insights may revise the role and individual value of several pharmacological treatments. Diazepam, baclofen and tizanidine are the most prescribed drugs for the treatment of spasticity. Intrathecal baclofen and local infiltration of botulin toxin are added values in selective patients. Gabapentin is a novelty, and the working mechanism of cannabis has been elucidated. Dantrolene sodium appears to owe its selectivity from the recently discovered ryanodine receptor, with a peripheral effect in muscles. In this review the pathophysiology and epidemiology of spasticity, pharmacology, clinical efficacy and unwanted effects of the different drugs for spasticity are updated.

GIF-0173 protects against cerebral infarction through DP1 receptor activation.

The neuroprotective effects and mechanism of action of GIF-0173, a Delta12-prostaglandin J analogue, were investigated in the early phase of cerebral ischemia. GIF-0173 was administered intravenously immediately following middle cerebral artery occlusion (MCAO) in photochemically induced thrombosis model of rat. Neurological scores and infarct sizes were examined at 24 h after MCAO. Cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry for 1 h after MCAO. In cultured cortical neurons obtained from 1-day-old rats, the effects of GIF-0173 on the excitotoxicity induced by glutamate were examined. Morphological changes, neuronal death, and changes in intracellular calcium concentration ([Ca(2+)](i)) were also examined. GIF-0173 improved neurological scores and reduced the infarct size in a dose-dependent manner following MCAO. But GIF-0173 did not improve CBF after MCAO. GIF-0173 also prevented glutamate-induced neuronal death and acute cellular swelling in primary cultures in a dose-dependent manner, indicating that it inhibited neuronal necrosis. GIF-0173 dose-dependently suppressed the glutamate-induced increase in [Ca(2+)](i), but could not inhibit NMDA-induced calcium influx. The effects of GIF-0173 against glutamate-induced [Ca(2+)](i) increase were reversed by addition of non-specific prostaglandin D (PGD(2)) receptor antagonist and were comparable to the effects of PGD(2) DP1 receptor agonist, which prevented [Ca(2+)](i) increase and neuronal death. We conclude that GIF-0173 reduces cerebral infarction and protects cultured neurons against glutamate-induced excitotoxicity by inhibiting [Ca(2+)](i) increase through DP1 receptor activation.

Cooling and hemodynamic management in heatstroke: practical recommendations.

INTRODUCTION: Although rapid cooling and management of circulatory failure are crucial to the prevention of irreversible tissue damage and death in heatstroke, the evidence supporting the optimal cooling method and hemodynamic management has yet to be established. METHODS: A systematic review of all clinical studies published in Medline (1966 to 2006), CINAHL (Cumulative Index to Nursing & Allied Health Literature) (1982 to 2006), and Cochrane Database was performed using the OVID interface without language restriction. Search terms included heatstroke, sunstroke, and heat stress disorders. RESULTS: Fourteen articles reported populations subjected to cooling treatment for classic or exertional heatstroke and included data on cooling time, neurologic morbidity, or mortality. Five additional articles described invasive monitoring with central venous or pulmonary artery catheters. The four clinical trials and 15 observational studies covered a total of 556 patients. A careful analysis of the results obtained indicated that the cooling method based on conduction, namely immersion in iced water, was effective among young people, military personnel, and athletes with exertional heatstroke. There was no evidence to support the superiority of any one cooling technique in classic heatstroke. The effects of non-invasive, evaporative, or conductive-based cooling techniques, singly or combined, appeared to be comparable. No evidence of a specific endpoint temperature for safe cessation of cooling was found. The circulatory alterations in heatstroke were due mostly to a form of distributive shock associated with relative or absolute hypovolemia. Myocardial failure was found to be rare. CONCLUSION: A systematic review of the literature failed to identify reliable clinical data on the optimum treatment of heatstroke. Nonetheless, the findings of this study could serve as a framework for preliminary recommendations in cooling and hemodynamic management of heatstroke until more evidence-based data are generated.

Cooling methods used in the treatment of exertional heat illness.

OBJECTIVE: To review the different methods of reducing body core temperature in patients with exertional heatstroke. METHODS: The search strategy included articles from 1966 to July 2003 using the databases Medline and Premedline, Embase, Evidence Based Medicine (EBM) reviews, SPORTDiscus, and cross referencing the bibliographies of relevant papers. Studies were included if they contained original data on cooling times or cooling rates in patients with heat illness or normal subjects who were subjected to heat stress. RESULTS: In total, 17 papers were included in the analysis. From the evidence currently available, the most effective method of reducing body core temperature appears to be immersion in iced water, although the practicalities of this treatment may limit its use. Other methods include both evaporative and invasive techniques, and the use of chemical agents such as dantrolene. CONCLUSIONS: The main predictor of outcome in exertional heatstroke is the duration and degree of hyperthermia. Where possible, patients should be cooled using iced water immersion, but, if this is not possible, a combination of other techniques may be used to facilitate rapid cooling. There is no evidence to support the use of dantrolene in these patients. Further work should include a randomised trial comparing immersion and evaporative therapy in heatstroke patients.

Heat stroke : a review of cooling methods.

The prognosis of heat stroke in patients is directly related to the degree of hyperthermia and its duration. Therefore, the most important feature in the treatment of heat stroke is rapid cooling. Several cooling methods have been presented in the literature including immersion in water at different temperatures, evaporative cooling, ice pack application, pharmacological treatment and invasive techniques. This article describes the various cooling techniques in terms of efficacy, availability, adverse effects and mortality rate. Data suggest that cooling should be initiated immediately at time of collapse and should be based on feasible field measures including ice or tepid water (1-16 degrees C), which are readily available. In the emergency department, management should be matched to the patient's age and medical background and include immersion in ice water (1-5 degrees C) or evaporative cooling.

Calcium antagonists in N-methyl d-aspartate-induced retinal injury.

PURPOSE: To detect the neuroprotective role of nimodipine and dantrolene in N-methyl- d-aspartate (NMDA)-induced retinal injury. METHODS: In this study we used two calcium antagonists which have two different modes of action, nimodipine and dantrolene, to prevent NMDA-induced retinal ischemia in guinea pigs. In 40 animals we injected nimodipine (n=10), dantrolene (n=10), a combination of both (n=10) or sterile 0.9% NaCl solution as a placebo (n=10) before intravitreal injection of NMDA. We enucleated one eye of each animal after 48 hours and performed histopathologic examination. We also measured malondialdehyde (MDA) levels in retinal homogenates as a marker of ischemic injury. RESULTS: Our results indicate that ganglion cells of the retina were preserved mostly by nimodipine, followed by combined nimodipine-dantrolene, and dantrolene respectively. The ganglion cell count was statistically significantly higher in cases where we used calcium antagonists than in the control group (p<0.05). We also found that MDA was significantly reduced by calcium antagonists compared to the control group (p<0.05). CONCLUSION: Our data show that nimodipine and dantrolene both have potential neuroprotective effects; nimodipine preserved retinal ganglion cells to a greater extent than dantrolene from NMDA-induced retinal injury.

Síndrome neuroléptico maligno / Neuroleptic malignant syndrome

El Síndrome Neuroléptico Maligno es una enfermedad rara pero con alta mortalidad, por lo cual es conveniente tenerla presente ante la aparición de un cuadro de hipertermia inducido por drogas. En ocasiones la presentación clínica suele ser indistinguible de una Hipertermia Maligna, si bien su mecanismo fisiopatológico es completamente diferente. Sus características clínicas comprenden hipertermia, rigidez muscular, elevación de la creatininfosfoquinasa (C.P.K.) además de mioglobinemia y mioglobinuria, como consecuencia de la rabdomiólisis. En esta recopilación mencionaremos su fisiopatología, etiología, criterios clínicos, su relación con Hipertermia maligna y los detalles de su tratamiento.

Síndrome neuroléptico maligno / Neuroleptic malignant syndrome

El Síndrome Neuroléptico Maligno es una enfermedad rara pero con alta mortalidad, por lo cual es conveniente tenerla presente ante la aparición de un cuadro de hipertermia inducido por drogas. En ocasiones la presentación clínica suele ser indistinguible de una Hipertermia Maligna, si bien su mecanismo fisiopatológico es completamente diferente. Sus características clínicas comprenden hipertermia, rigidez muscular, elevación de la creatininfosfoquinasa (C.P.K.) además de mioglobinemia y mioglobinuria, como consecuencia de la rabdomiólisis. En esta recopilación mencionaremos su fisiopatología, etiología, criterios clínicos, su relación con Hipertermia maligna y los detalles de su tratamiento. (AU)

Management of spasticity, pain, and paroxysmal phenomena in multiple sclerosis.

Multiple sclerosis (MS) is a disease with tremendous variability and innumerable symptoms. Among the more common symptoms is spasticity. Despite a lack of full knowledge of the physiology causing this phenomenon, successful treatments have been developed. Many of these have had a recent introduction. Pain and paroxysmal phenomena are surprisingly common in MS, but have not had the recognition their frequency deserves. It is not unusual to hear that they are rare in MS, but surprisingly they are all too common. Their management is changing as newer treatments are developed.

Presentación de un caso de hipertermia maligna con diagnóstico ratificado por el puntaje de NAMHR (North American Malignant Hyperthermia Registry) / Presentation of a case of malignant hyperthermia ratified by NAMHR's (North American Malignant Hyperthermia Registry) score

Introducción: Desarrollo de cuadro clínico de hipertermia maligna en un paciente anestesiado con anestesia endovenosa total. Diagnóstico a través del puntaje del North American Malignant Hyperthermia Registry. Caso clínico: Se presenta un caso clínico de hipertermia maligna acontecido en nuestro servicio, con la particularidad de haberse desencadenado durante el intraoperatorio de una cirugía bajo anestesia intravenosa total. Paciente de 30 años, con diagnóstico de hidronefrosis; se anestesió con midazolam, remifentanilo y mivacurio. Luego de 1 hora de cirugia y sin causa clínica aparente, comenzó con hipotensión. Simultánea y progresivamente, se taquicardizó alcanzando valores de 155'. Se tomó 37.8 §C de temperatura axilar. La ETCO2 era de 75 mmHg. Luego, la temperatura se elevó a 43 §C y se decidió tratar con dantrolene. Discusión: La carencia de un método precoz de diagnóstico de HM, sumada a cambios metabólicos rápidos, hipermetabolismo marcado y excesiva producción de calor, nos enfrenta al dilema de iniciar el tratamiento específico -dantrolene-, que evite secuelas irreversibles o la muerte. Conclusiones: Creemos que la clasificación con el puntaje del North American Malignant Hyperthermia Registry, por la simplicidad de su diseño y facilidad de aplicación, puede ser un método útil e indispensable como método de screening en aquellos pacientes en que por alguna causa se sospecha una susceptibilidad o un cuadro de HM.

Presentación de un caso de hipertermia maligna con diagnóstico ratificado por el puntaje de NAMHR (North American Malignant Hyperthermia Registry) / Presentation of a case of malignant hyperthermia ratified by NAMHRs (North American Malignant Hyperthermia Registry) score

Introducción: Desarrollo de cuadro clínico de hipertermia maligna en un paciente anestesiado con anestesia endovenosa total. Diagnóstico a través del puntaje del North American Malignant Hyperthermia Registry. Caso clínico: Se presenta un caso clínico de hipertermia maligna acontecido en nuestro servicio, con la particularidad de haberse desencadenado durante el intraoperatorio de una cirugía bajo anestesia intravenosa total. Paciente de 30 años, con diagnóstico de hidronefrosis; se anestesió con midazolam, remifentanilo y mivacurio. Luego de 1 hora de cirugia y sin causa clínica aparente, comenzó con hipotensión. Simultánea y progresivamente, se taquicardizó alcanzando valores de 155. Se tomó 37.8 ºC de temperatura axilar. La ETCO2 era de 75 mmHg. Luego, la temperatura se elevó a 43 ºC y se decidió tratar con dantrolene. Discusión: La carencia de un método precoz de diagnóstico de HM, sumada a cambios metabólicos rápidos, hipermetabolismo marcado y

Dantrolene and recovery from heat stroke.

Several authors have shown that dantrolene may be effective in the treatment of heat stroke patients. However, the scant data available are still controversial. The aim of this investigation was to establish an animal experimental model for studying the efficacy of this drug both as a prophylactic agent and as a means of hastening the cooling process after heat stroke. Male albino rats were divided into five groups: Sedentary controls (SC), Sedentary+dantrolene (S+D), Exercise controls (EC), and Exercise+dantrolene (E+D, E+D1). The drug (140 mg x kg(-1) body weight) was administered i.v. either prior to subjection to heat stress (40 degrees C) (S+D, E+D) or upon development of heat stroke syndrome (E+D1). In the S+D group, dantrolene administered prior to heat stress (HS) delayed the development of heat stroke by 70%, although colonic temperature (Tc) at the onset of heat stroke was similar to that in group SC (43.0 +/- 0.1 degrees C and 43.2 +/- 0.4 degrees C for S+D and SC, respectively). In E+D animals, dantrolene shortened exercise endurance in the heat by 17.5%, but concomitantly hindered severe Tc rise (40.9 +/- 0.2 degrees C and 40.0 +/- 0.2 degrees C for EC and E+D, respectively). Administration of dantrolene on the development of heat stroke appeared to improve cooling in the exercise group (0.25 degrees C x min(-1) and 0.18 degrees C x min(-1), for the first 1 5 min of cooling, for E+D1 and EC, respectively). The results suggest that dantrolene is effective as a prophylactic agent in sedentary animals only. It also might have application on development of heat stroke. It is hypothesized that the observed rapid cooling is associated with dantrolene's effect on muscle contraction, thus leading to attenuated heat production and peripheral vascular relaxation.