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Anaesthesiology Intensive Therapy 2022Malignant hyperthermia (MH) is a life-threatening syndrome caused by sudden skeletal muscle hypermetabolism in response to inhalation anaesthetics and depolarising...
INTRODUCTION
Malignant hyperthermia (MH) is a life-threatening syndrome caused by sudden skeletal muscle hypermetabolism in response to inhalation anaesthetics and depolarising relaxants. The estimated incidence of MH is between 1 : 10,000 and 1 : 250,000 anaesthetic procedures. In Poland the incidence of MH is unknown. Dantrolene is imported as a life-saving drug and temporally authorised for sale. The aim of the study is to assess the incidence of MH and access to dantrolene in the Mazovia Province.
METHODS
Anonymous questionnaires were sent to anaesthesia departments in the Mazovia Province after prior contact by phone and e-mail. The survey was approved by the local ethical review board.
RESULTS
Completed surveys were received from 60 respondents which represents 72% of anaesthesiology departments in Mazovia. In the last 5 years there have been 4 episodes of MH in the Mazovia Province. Three patients survived the MH crisis. In a centre that did not have access to dantrolene, the patient died. Dantrolene is found only in 11 (18.3%) anaesthesiology departments in Mazovia. Only 6 (10%) hospitals are able to administer dantrolene within 5 minutes of suspecting MH crisis, while 5 centres may receive it after a few days. Only 38% of units have an algorithm for dealing with MH crisis in the operating theatres.
CONCLUSIONS
MH is rare, but if untreated, it can be fatal. Therefore prompt diagnosis and treatment are crucial to avoid fatal outcome. Every centre using inhalational anaesthetics and/or succinylcholine should have dantrolene. To ensure the safety of our patients, we must be better prepared.
Topics: Anesthetics, Inhalation; Dantrolene; Humans; Malignant Hyperthermia; Operating Rooms; Succinylcholine
PubMed: 35579281
DOI: 10.5114/ait.2022.115348 -
Psychiatry and Clinical Neurosciences Oct 1999Prolonged neuroleptic exposure is often associated with several forms of tardive movement disorders, conditions adversely affecting the patient's quality of life. Risk... (Review)
Review
Prolonged neuroleptic exposure is often associated with several forms of tardive movement disorders, conditions adversely affecting the patient's quality of life. Risk factors for individual tardive movement disorders is noted. Once they develop, one should modify neuroleptic regimen with preferential replacement of conventional neuroleptics with lower potency ones. The subsequent algorithm is difficult to formulate, and its success is sometimes hampered by coexisting psychiatric disease. Several suggestions to be tried are as follows: high doses of anticholinergics and/or dantrolene sodium against tardive dystonia, and reduction of anticholinergic dose and/or clonidine, a alpha2 agonist, against tardive dyskinesia and tardive akathisia.
Topics: Algorithms; Antipsychotic Agents; Cholinergic Antagonists; Dantrolene; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Humans; Muscle Relaxants, Central; Neurologic Examination
PubMed: 10560894
DOI: No ID Found -
Scientific Reports Sep 2023Physiological muscle contraction requires an intact ligand gating mechanism of the ryanodine receptor 1 (RyR1), the Ca-release channel of the sarcoplasmic reticulum....
Physiological muscle contraction requires an intact ligand gating mechanism of the ryanodine receptor 1 (RyR1), the Ca-release channel of the sarcoplasmic reticulum. Some mutations impair the gating and thus cause muscle disease. The RyR1 mutation T4706M is linked to a myopathy characterized by muscle weakness. Although, low expression of the T4706M RyR1 protein can explain in part the symptoms, little is known about the function RyR1 channels with this mutation. In order to learn whether this mutation alters channel function in a manner that can account for the observed symptoms, we examined RyR1 channels isolated from mice homozygous for the T4709M (TM) mutation at the single channel level. Ligands, including Ca, ATP, Mg and the RyR inhibitor dantrolene were tested. The full conductance of the TM channel was the same as that of wild type (wt) channels and a population of partial open (subconductive) states were not observed. However, two unique sub-populations of TM RyRs were identified. One half of the TM channels exhibited high open probability at low (100 nM) and high (50 μM) cytoplasmic [Ca], resulting in Ca-insensitive, constitutively high P channels. The rest of the TM channels exhibited significantly lower activity within the physiologically relevant range of cytoplasmic [Ca], compared to wt. TM channels retained normal Mg block, modulation by ATP, and inhibition by dantrolene. Together, these results suggest that the TM mutation results in a combination of primary and secondary RyR1 dysfunctions that contribute to disease pathogenesis.
Topics: Animals; Mice; Ryanodine Receptor Calcium Release Channel; Dantrolene; Muscular Diseases; Cytoplasm; Myotonia Congenita; Adenosine Triphosphate
PubMed: 37670077
DOI: 10.1038/s41598-023-41801-2 -
Neurocritical Care 2009Calcium plays a central role in neuronal function and injury. Dantrolene, an inhibitor of the ryanodine receptor, inhibits intracellular calcium release from the... (Review)
Review
Calcium plays a central role in neuronal function and injury. Dantrolene, an inhibitor of the ryanodine receptor, inhibits intracellular calcium release from the sarco-endoplasmic reticulum. We review the available data of dantrolene as a potential neuroprotective agent and briefly summarize its other pharmacologic effects that may have potential applications for patients in the neurointensive care unit (NICU). Areas with the need for continued research are identified.
Topics: Brain Diseases; Calcium; Critical Care; Dantrolene; Humans; Muscle Relaxants, Central; Ryanodine Receptor Calcium Release Channel
PubMed: 18696266
DOI: 10.1007/s12028-008-9133-4 -
Scientific Reports Jan 2017Dantrolene was introduced for treatment of malignant hyperthermia. It also has antiarrhythmic properties and may thus be an alternative to amiodarone for the treatment... (Randomized Controlled Trial)
Randomized Controlled Trial
Dantrolene was introduced for treatment of malignant hyperthermia. It also has antiarrhythmic properties and may thus be an alternative to amiodarone for the treatment of ventricular fibrillation (VF). Aim of this study was to compare the return of spontaneous circulation (ROSC) with dantrolene and amiodarone in a pig model of cardiac arrest. VF was induced in anesthetized pigs. After 8 min of untreated VF, chest compressions and ventilation were started and one of the drugs (amiodarone 5 mg kg, dantrolene 2.5 mg kg or saline) was applied. After 4 min of initial CPR, defibrillation was attempted. ROSC rates, hemodynamics and cerebral perfusion measurements were measured. Initial ROSC rates were 7 of 14 animals in the dantrolene group vs. 5 of 14 for amiodarone, and 3 of 10 for saline). ROSC persisted for the 120 min follow-up in 6 animals in the dantrolene group, 4 after amiodarone and 2 in the saline group (n.s.). Hemodynamics were comparable in both dantrolene group amiodarone group after obtaining ROSC. Dantrolene and amiodarone had similar outcomes in our model of prolonged cardiac arrest, However, hemodynamic stability was not significantly improved using dantrolene. Dantrolene might be an alternative drug for resuscitation and should be further investigated.
Topics: Amiodarone; Animals; Blood Gas Analysis; Brain; Cardiopulmonary Resuscitation; Dantrolene; Disease Models, Animal; Double-Blind Method; Electric Countershock; Hemodynamics; Muscle Relaxants, Central; Swine; Ventricular Fibrillation
PubMed: 28098197
DOI: 10.1038/srep40875 -
Anesthesiology Oct 2019
Topics: Anesthesia; Dantrolene; Succinylcholine
PubMed: 31453814
DOI: 10.1097/ALN.0000000000002949 -
Biochemical Pharmacology May 2017The inositol 1,4,5-trisphosphate receptors (IPRs) and intracellular Ca signaling are critically involved in regulating different steps of autophagy, a lysosomal...
The inositol 1,4,5-trisphosphate receptors (IPRs) and intracellular Ca signaling are critically involved in regulating different steps of autophagy, a lysosomal degradation pathway. The ryanodine receptors (RyR), intracellular Ca-release channels mainly expressed in excitable cell types including muscle and neurons, have however not yet been extensively studied in relation to autophagy. Yet, aberrant expression and excessive activity of RyRs in these tissues has been implicated in the onset of several diseases including Alzheimer's disease, where impaired autophagy regulation contributes to the pathology. In this study, we determined whether pharmacological RyR inhibition could modulate autophagic flux in ectopic RyR-expressing models, like HEK293 cells and in cell types that endogenously express RyRs, like C2C12 myoblasts and primary hippocampal neurons. Importantly, RyR3 overexpression in HEK293 cells impaired the autophagic flux. Conversely, in all cell models tested, pharmacological inhibition of endogenous or ectopically expressed RyRs, using dantrolene or ryanodine, augmented autophagic flux by increasing lysosomal turn-over (number of autophagosomes and autolysosomes measured as mCherry-LC3 punctae/cell increased from 70.37±7.81 in control HEK RyR3 cells to 111.18±7.72 and 98.14±7.31 after dantrolene and ryanodine treatments, respectively). Moreover, in differentiated C2C12 cells, transmission electron microscopy demonstrated that dantrolene treatment decreased the number of early autophagic vacuoles from 5.9±2.97 to 1.8±1.03 per cellular cross section. The modulation of the autophagic flux could be linked to the functional inhibition of RyR channels as both RyR inhibitors efficiently diminished the number of cells showing spontaneous RyR3 activity in the HEK293 cell model (from 41.14%±2.12 in control cells to 18.70%±2.25 and 9.74%±2.67 after dantrolene and ryanodine treatments, respectively). In conclusion, basal RyR-mediated Ca-release events suppress autophagic flux at the level of the lysosomes.
Topics: Animals; Autophagy; Cells, Cultured; Dantrolene; HEK293 Cells; Humans; Rats; Ryanodine Receptor Calcium Release Channel
PubMed: 28322744
DOI: 10.1016/j.bcp.2017.03.011 -
Anesthesiology May 2020Overactivation of ryanodine receptors and the resulting impaired calcium homeostasis contribute to Alzheimer's disease-related pathophysiology. This study hypothesized...
BACKGROUND
Overactivation of ryanodine receptors and the resulting impaired calcium homeostasis contribute to Alzheimer's disease-related pathophysiology. This study hypothesized that exposing neuronal progenitors derived from induced pluripotent stems cells of patients with Alzheimer's disease to dantrolene will increase survival, proliferation, neurogenesis, and synaptogenesis.
METHODS
Induced pluripotent stem cells obtained from skin fibroblast of healthy subjects and patients with familial and sporadic Alzheimer's disease were used. Biochemical and immunohistochemical methods were applied to determine the effects of dantrolene on the viability, proliferation, differentiation, and calcium dynamics of these cells.
RESULTS
Dantrolene promoted cell viability and proliferation in these two cell lines. Compared with the control, differentiation into basal forebrain cholinergic neurons significantly decreased by 10.7% (32.9 ± 3.6% vs. 22.2 ± 2.6%, N = 5, P = 0.004) and 9.2% (32.9 ± 3.6% vs. 23.7 ± 3.1%, N = 5, P = 0.017) in cell lines from sporadic and familial Alzheimer's patients, respectively, which were abolished by dantrolene. Synapse density was significantly decreased in cortical neurons generated from stem cells of sporadic Alzheimer's disease by 58.2% (237.0 ± 28.4 vs. 99.0 ± 16.6 arbitrary units, N = 4, P = 0.001) or familial Alzheimer's disease by 52.3% (237.0 ± 28.4 vs.113.0 ± 34.9 vs. arbitrary units, N = 5, P = 0.001), which was inhibited by dantrolene in the familial cell line. Compared with the control, adenosine triphosphate (30 µM) significantly increased higher peak elevation of cytosolic calcium concentrations in the cell line from sporadic Alzheimer's patients (84.1 ± 27.0% vs. 140.4 ± 40.2%, N = 5, P = 0.049), which was abolished by the pretreatment of dantrolene. Dantrolene inhibited the decrease of lysosomal vacuolar-type H-ATPase and the impairment of autophagy activity in these two cell lines from Alzheimer's disease patients.
CONCLUSIONS
Dantrolene ameliorated the impairment of neurogenesis and synaptogenesis, in association with restoring intracellular Ca homeostasis and physiologic autophagy, cell survival, and proliferation in induced pluripotent stem cells and their derived neurons from sporadic and familial Alzheimer's disease patients.
Topics: Adult; Alzheimer Disease; Cells, Cultured; Dantrolene; Humans; Induced Pluripotent Stem Cells; Male; Middle Aged; Muscle Relaxants, Central; Neurogenesis; Random Allocation; Synapses
PubMed: 32149777
DOI: 10.1097/ALN.0000000000003224 -
American Journal of Veterinary Research Apr 2015To determine the effect of dantrolene premedication on various cardiovascular and biochemical variables and recovery in isoflurane-anesthetized horses. (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Administration, Oral; Anesthesia Recovery Period; Anesthesia, Inhalation; Anesthetics, Combined; Anesthetics, Inhalation; Animals; Blood Gas Analysis; Cross-Over Studies; Dantrolene; Female; Horses; Isoflurane; Male; Muscle Relaxants, Central; Premedication
PubMed: 25815570
DOI: 10.2460/ajvr.76.4.293 -
JCI Insight Aug 2021BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although...
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.
Topics: Adolescent; Adult; Biological Availability; Calcium Signaling; Child; Dantrolene; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Insulin-Secreting Cells; Interleukin-18; Interleukin-1beta; Molecular Targeted Therapy; Muscle Relaxants, Central; Neurologic Examination; Quality of Life; Treatment Outcome; Visual Acuity; Wolfram Syndrome
PubMed: 34185708
DOI: 10.1172/jci.insight.145188