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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 -
Journal of the Formosan Medical... Apr 2011Spasticity is a common disability in children with cerebral palsy. Pharmacological and non-pharmacological treatments, including physical therapy, occupational therapy,... (Review)
Review
Spasticity is a common disability in children with cerebral palsy. Pharmacological and non-pharmacological treatments, including physical therapy, occupational therapy, orthotics, rhizotomy, and orthopedic surgery, all play important roles in the management of spasticity. The purpose of this article is to provide an overview of available medications for treatment of spasticity in children with cerebral palsy. Common medications include benzodiazepines, dantrolene sodium, baclofen, tizanidine, botulinum toxins, phenol, alcohol and intrathecal baclofen. In general, oral medications and intrathecal baclofen are used for treating generalized spasticity, whilst chemodenervation agents (botulinum toxins, phenol, and alcohol) are used to treat localized spasticity. There is more sufficient evidence for the recommendation of botulinum toxin A as an effective anti-spasticity treatment in children with cerebral palsy. However, more data concerning safety and long-term effects of botulinum toxin A is needed. Further study is needed to determine which kinds of medications can cause substantial improvement in daily activity, participation level, self-competence, or quality of life in children with cerebral palsy.
Topics: Baclofen; Benzodiazepines; Cerebral Palsy; Child; Clonidine; Dantrolene; Humans; Muscle Spasticity; Neuromuscular Blocking Agents
PubMed: 21540003
DOI: 10.1016/S0929-6646(11)60033-8 -
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 -
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 -
Proceedings of the National Academy of... May 2017Malignant hyperthermia (MH) is a clinical syndrome of skeletal muscle that presents as a hypermetabolic response to volatile anesthetic gases, where susceptible persons...
Malignant hyperthermia (MH) is a clinical syndrome of skeletal muscle that presents as a hypermetabolic response to volatile anesthetic gases, where susceptible persons may develop lethally high body temperatures. Genetic predisposition mainly arises from mutations on the skeletal muscle ryanodine receptor (RyR). Dantrolene is administered to alleviate MH symptoms, but its mechanism of action and its influence on the Ca transients elicited by MH triggers are unknown. Here, we show that Ca release in the absence of Mg is unaffected by the presence of dantrolene but that dantrolene becomes increasingly effective as cytoplasmic-free [Mg] (free [Mg]) passes mM levels. Furthermore, we found in human muscle susceptible to MH that dantrolene was ineffective at reducing halothane-induced repetitive Ca waves in the presence of resting levels of free [Mg] (1 mM). However, an increase of free [Mg] to 1.5 mM could increase the period between Ca waves. These results reconcile previous contradictory reports in muscle fibers and isolated RyRs, where Mg is present or absent, respectively, and define the mechanism of action of dantrolene is to increase the Mg affinity of the RyR (or "stabilize" the resting state of the channel) and suggest that the accumulation of the metabolite Mg from MgATP hydrolysis is required to make dantrolene administration effective in arresting an MH episode.
Topics: Adult; Animals; Calcium Signaling; Dantrolene; Female; Halothane; Humans; Magnesium; Male; Malignant Hyperthermia; Muscle, Skeletal; Rats; Rats, Wistar; Ryanodine Receptor Calcium Release Channel
PubMed: 28373535
DOI: 10.1073/pnas.1619835114 -
The Cochrane Database of Systematic... 2000Spasticity is a major health problem for patients with a spinal cord injury (SCI) that limits patients' mobility and affects independence in activities of daily living... (Review)
Review
BACKGROUND
Spasticity is a major health problem for patients with a spinal cord injury (SCI) that limits patients' mobility and affects independence in activities of daily living and work. Spasticity may also cause pain, loss of range of motion, contractures, sleep disorders and impair ambulation in patients with an incomplete lesion. The effectiveness of available drugs is still uncertain and they may cause adverse effects. Assessing what works in this area is complicated by the lack of valid and reliable measurement tools. The aim of this systematic review is to critically appraise and summarise existing information of the effectiveness of available treatments and to identify areas where further research is needed.
OBJECTIVES
To assess the effectiveness and safety of Baclofen, Dantrolene, Tizanidine and any other drugs for the treatment of long term spasticity in SCI patients as well as the effectiveness and safety of different routes of administration of Baclofen.
SEARCH STRATEGY
We searched the Injuries Group specialised register, the Cochrane Controlled Trials Register, MEDLINE, EMBASE and CINHALH up to 1998. Drug companies and experts active in the area were also contacted.
SELECTION CRITERIA
All parallel and crossover RCTs including spinal cord injury patients complaining of "severe spasticity". Studies where less than 50% of patients had a spinal cord injury were excluded.
DATA COLLECTION AND ANALYSIS
Methodological quality of studies (allocation concealment, blinding, patients characteristics, inclusion and exclusion criteria; interventions; outcomes; lost to follow up) was independently assessed by two investigators. The heterogeneity among studies did not allow quantitative combination of results.
MAIN RESULTS
Nine out of 53 studies met the inclusion criteria. Study design was: 8 cross over, 1 parallel-group trial. Two studies (14 SCI patients), showed a significant effect of intrathecal baclofen in reducing spasticity (Ashworth Score and ADL performances), compared to placebo, without any side effect. The study comparing tizanidine to placebo (118 SCI patients) showed a significant effect of tizanidine in improving Ashworth Score but not in ADL performances. Tizanidine group reported significant rates of adverse effects (drowsiness, xerostomia). For the other drugs (Gabapentine, Clonidine, Diazepam, Amytal and oral Baclofen ) the results do not provide evidence for a clinical significant effectiveness.
REVIEWER'S CONCLUSIONS
There is insufficient evidence to assist clinicians in a rational approach to antispastic treatment for SCI. Further research is urgently needed to improve the scientific basis of patient care.
Topics: Baclofen; Clonidine; Dantrolene; Humans; Muscle Relaxants, Central; Parasympatholytics; Spasm; Spinal Cord Injuries
PubMed: 10796750
DOI: 10.1002/14651858.CD001131 -
The Biochemical Journal Sep 1997Dantrolene inhibits and ryanodine stimulates calcium release from skeletal-muscle sarcoplasmic reticulum (SR), the former by an unknown mechanism, and the latter by...
Dantrolene inhibits and ryanodine stimulates calcium release from skeletal-muscle sarcoplasmic reticulum (SR), the former by an unknown mechanism, and the latter by activating the ryanodine receptor (RyR), the primary Ca2+-release channel of SR. Dantrolene is used to treat malignant hyperthermia (MH), a genetic predisposition to excessive intracellular Ca2+ release upon exposure to volatile anaesthetics. Porcine MH results from a point mutation in the SR RyR that alters the open probability of the channel, and is reflected in altered [3H]ryanodine binding parameters. Specific binding sites for [3H]dantrolene and [3H]ryanodine co-distribute on SR that has been isolated by discontinuous sucrose gradient centrifugation. If the two drug-binding sites are functionally linked, [3H]dantrolene binding might be affected both by pharmacological and by genetic modulators of the functional state of the RyR. Accordingly, we compared the characteristics of [3H]dantrolene binding to porcine malignant-hyperthermia-susceptible and normal-skeletal-muscle SR, and examined the effects of RyR modulators on [3H]dantrolene binding to these membranes. Additionally, the feasibility of separating the SR binding sites for [3H]dantrolene and [3H]ryanodine was investigated. No significant differences in [3H]dantrolene binding characteristics to SR membranes from the two muscle types were detected, and the Bmax ratio for [3H]dantrolene/[3H]ryanodine was 1.4(+/-0.1):1 in both muscle types. [3H]Dantrolene binding is unaffected by the RyR modulators caffeine, ryanodine, Ruthenium Red and calmodulin, and neither dantrolene nor azumolene have any effect on [3H]ryanodine binding. Additionally, distinct peaks of [3H]dantrolene and [3H]ryanodine binding are detected in SR membranes fractionated by linear sucrose centrifugation, although no differences in protein patterns are detected by SDS/PAGE or Western-blot analysis. We suggest that the binding sites for these two drugs are pharmacologically distinct, and may exist on separate molecules.
Topics: Animals; Binding Sites; Cell Membrane; Dantrolene; Malignant Hyperthermia; Muscle Relaxants, Central; Muscle, Skeletal; Osmolar Concentration; Radioligand Assay; Ryanodine; Swine
PubMed: 9307036
DOI: 10.1042/bj3260847 -
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 -
BioMed Research International 2023Malignant hyperthermia (MH) is a rare genetic disorder but one of the most severe complications of general anesthesia. The mortality rate of MH has dropped from 70% in...
PURPOSE
Malignant hyperthermia (MH) is a rare genetic disorder but one of the most severe complications of general anesthesia. The mortality rate of MH has dropped from 70% in the 1960s to 15% because of dantrolene, the only currently accepted specific treatment for MH. In this study, we retrospectively identified the optimal dantrolene administration conditions to reduce MH mortality further.
METHODS
Our database performed a retrospective analysis of patients with MH clinical grading scale (CGS) grade 5 (very likely) or 6 (almost certain) between 1995 and 2020. We examined whether dantrolene administration affected mortality and compared the clinical variables associated with improved prognosis. Furthermore, a multivariable logistic regression analysis was used to identify specific variables associated with improved prognosis.
RESULTS
128 patients met the inclusion criteria. 115 patients were administered dantrolene; 104 survived, and 11 died. The mortality rate of patients who were not administered dantrolene was 30.8%, which was significantly higher than those of patients who were administered dantrolene ( = 0.047). Among patients administered dantrolene, the interval from the first sign of MH to the start of dantrolene administration was significantly longer in the deceased than in the survivors (100 min vs. 45.0 min, < 0.001), and the temperature at the start of dantrolene administration was also significantly higher in the deceased (41.6°C vs. 39.1°C, < 0.001). There was no significant difference in the rate of increase in temperature between the two, but there was a substantial difference in the maximum temperature ( < 0.001). The multivariable analysis also showed that the patient's temperature at dantrolene administration and interval from the first MH sign to dantrolene administration was significantly associated with improved prognosis.
CONCLUSIONS
Dantrolene should be given as rapidly as possible once MH has been diagnosed. Beginning treatment at a more normal body temperature can prevent critical elevations associated with a worse prognosis.
Topics: Humans; Dantrolene; Malignant Hyperthermia; Retrospective Studies; Body Temperature; East Asian People; Rare Diseases
PubMed: 36874927
DOI: 10.1155/2023/8340209 -
Anesthesiology Oct 2019
Topics: Anesthesia; Dantrolene; Succinylcholine
PubMed: 31453814
DOI: 10.1097/ALN.0000000000002949