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Contact in Context 2023Dantrolene sodium is a direct-acting skeletal muscle relaxant. Dantrolene sodium for injection is indicated, along with suitable supportive measures, for the management...
Dantrolene sodium is a direct-acting skeletal muscle relaxant. Dantrolene sodium for injection is indicated, along with suitable supportive measures, for the management of sudden, severe hypermetabolism of skeletal muscle typical of malignant hyperthermia crises in patients of any age. The formulation scanned in this work was designed to be injected intravenously. Intra-lot and inter-lot variability in the spectra of REVONTO (dantrolene sodium) was measured in the Drug Quality Study (DQS) using Fourier transform near-infrared spectrometry (FTNIR). Spectra of 69 vials from lot 20REV01A contained two groups (n=56 vials, n=13 vials) when scanned with an FTNIR. The two groups of spectra in lot 20REV01A were found to be 66.7 SDs apart using a subcluster detection test, suggesting that the two groups were manufactured differently. As a result, all available samples of dantrolene were examined. A library of spectra of 141 vials of dantrolene from 4 lots were found to contain 3 separate groups, also suggesting that different vials contain different materials.
PubMed: 37424832
DOI: 10.6084/m9.figshare.23317136 -
Anesthesia and Analgesia Dec 2010Calcium, as a second messenger, has an important role in a variety of cellular functions. However, disruption of intracellular calcium homeostasis leads to cytotoxicity... (Review)
Review
Calcium, as a second messenger, has an important role in a variety of cellular functions. However, disruption of intracellular calcium homeostasis leads to cytotoxicity and cell death. Excessive calcium release from intracellular stores, via the calcium channel ryanodine receptor, contributes to cell damage. Dysfunction of calcium homeostasis is established in tissue culture and animal models of ischemia, hypoxia, seizure, trauma, anesthesia, and neurodegenerative diseases. Dantrolene, the primary drug to treat malignant hyperthermia, is a ryanodine receptor antagonist. Dantrolene inhibits abnormal calcium release from the sarco-endoplasmic reticulum, which is the primary intracellular calcium store. Dantrolene has been investigated widely for its possible cytoprotective effects against cell damage in different tissue culture or animal models of diseases involving cytotoxicity induced by disruption of intracellular calcium homeostasis in pathogenesis. In this review, we summarize the role of the disruption of intracellular calcium homeostasis on cell death, the pharmacologic and pharmacokinetic features of dantrolene, and the cytoprotective effects and potential application of dantrolene for the inhibition of cell damage in a wide variety of models of stress and disease.
Topics: Animals; Calcium; Calcium Channel Blockers; Calcium Signaling; Cytoprotection; Dantrolene; Homeostasis; Humans; Nerve Degeneration; Neurons; Ryanodine Receptor Calcium Release Channel
PubMed: 20861418
DOI: 10.1213/ANE.0b013e3181f7181c -
British Journal of Anaesthesia Feb 1988
Review
Topics: Calcium; Child; Dantrolene; Drug Interactions; Female; Humans; Malignant Hyperthermia; Muscles
PubMed: 3279988
DOI: 10.1093/bja/60.3.279 -
Neurocritical Care 2009Cerebral vasoconstriction is associated with increased cytosolic Ca(2+) concentration in vascular smooth muscle, presumably due to Ca(2+) influx and Ca(2+) release from...
INTRODUCTION
Cerebral vasoconstriction is associated with increased cytosolic Ca(2+) concentration in vascular smooth muscle, presumably due to Ca(2+) influx and Ca(2+) release from intracellular stores. We tested the hypothesis that dantrolene (a blocker of Ca(2+)-induced Ca(2+) release from the ryanodine receptor channel on the sarco-endoplasmic reticulum) would potentiate the action of nimodipine (a voltage-dependent L-type Ca(2+) channel blocker, considered standard therapy for SAH) in inhibiting the vasoconstriction of isolated cerebral arteries.
METHOD
Sprague-Dawley rat basilar and femoral arteries were analyzed for ryanodine receptor expression by immunofluorescence and PCR. Vasoconstriction of basilar artery ex vivo was measured in a wire myograph while exposed to serotonin (5-HT) or endothelin-1 (ET-1) in the presence or absence of dantrolene (10-100 muM) and/or nimodipine (30 nM). Femoral artery was examined for comparison.
RESULTS
Basilar and femoral arteries express only the ryanodine receptor 3 (RyR3) isoform. In both basilar and femoral arteries, dantrolene significantly inhibited the constriction to 5-HT, whereas it poorly affected the constriction to ET-1. The inhibitory effect of dantrolene on 5-HT was substantially increased by nimodipine, inducing a 10-fold increase in the 50% effective concentration of 5-HT and a 46% reduction in maximum basilar constriction. In femoral artery, dantrolene modestly affected constriction to phenylephrine and there was no interaction with nimodipine.
CONCLUSION
Dantrolene has synergistic effects with nimodipine against 5-HT-induced vasoconstriction in isolated cerebral arteries. Dantrolene-nimodipine interaction will require testing in a pathophysiological model but might provide treatment for reducing SAH-related vasospasm or other 5-HT-related vasospastic syndromes, such as Call-Fleming syndrome.
Topics: Animals; Basilar Artery; Dantrolene; Femoral Artery; Male; Muscle Relaxants, Central; Muscle, Smooth, Vascular; Nimodipine; Rats; Rats, Sprague-Dawley; Ryanodine Receptor Calcium Release Channel; Tissue Culture Techniques; Vasoconstriction; Vasodilator Agents
PubMed: 18923817
DOI: 10.1007/s12028-008-9153-0 -
Journal of Alzheimer's Disease : JAD 2020This study compares the effectiveness and safety of intranasal versus subcutaneous administration of dantrolene in 5XFAD Alzheimer's disease (AD) mice.
BACKGROUND/OBJECTIVE
This study compares the effectiveness and safety of intranasal versus subcutaneous administration of dantrolene in 5XFAD Alzheimer's disease (AD) mice.
METHODS
5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal or subcutaneous dantrolene (5 mg/kg, 3×/wk), or vehicle. The early (ETG) and late (LTG) treatment groups began treatment at 2 or 6 months of age, respectively, and both treatment groups finished at12 months of age. Behavior was assessed for olfaction (buried food test), motor function (rotarod), and cognition (fear conditioning, Morris water maze). Liver histology (H & E staining) and function, synaptic proteins, and brain amyloid immunohistochemistry were examined. Plasma and brain dantrolene concentrations were determined in a separate cohort after intranasal or subcutaneous administration.
RESULTS
Intranasal dantrolene achieved higher brain and lower plasma concentrations than subcutaneous administration. Dantrolene administration at both approaches significantly improved hippocampal-dependent and -independent memory in the ETG, whereas only intranasal dantrolene improved cognition in the LTG. Dantrolene treatment had no significant change in the amyloid burden or synaptic proteins and no significant side effects on mortality, olfaction, motor, or liver functions in 5XFAD mice. Intranasal dantrolene treatment significantly ameliorated memory loss when it was started either before or after the onset of AD symptoms in 5XFAD mice.
CONCLUSIONS
The long-term intranasal administration of dantrolene had therapeutic effects on memory compared to the subcutaneous approach even started after onset of AD symptoms, suggesting use as a disease-modifying drug, without significant effects on amyloid plaques, side effects, or mortality.
Topics: Administration, Intranasal; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Dantrolene; Disease Models, Animal; Memory; Memory Disorders; Mice; Neuroprotective Agents
PubMed: 32623395
DOI: 10.3233/JAD-200227 -
Heart Rhythm O2 Sep 2023Alcohol and caffeine are the 2 frequently consumed substances in the general population, and the 2 substances are frequently co-consumed. Both substances may increase...
BACKGROUND
Alcohol and caffeine are the 2 frequently consumed substances in the general population, and the 2 substances are frequently co-consumed. Both substances may increase cardiac arrhythmia risk. However, it is unknown whether alcohol and caffeine co-consumption can synergistically enhance cardiac arrhythmogenesis.
OBJECTIVE
The study sought to investigate whether caffeine and binge drinking synergistically affect cardiac arrhythmogenesis.
METHODS
A binge drinking rat model (alcohol 2 g/kg, intraperitoneal, every other day for 3 times) was used. Rats (4 months old, both sexes) were randomized into the following 4 groups: binge alcohol-only group (A) (n = 8), nonalcohol, caffeine-only (60 mg/kg, intraperitoneal) group (C) (n = 8), binge alcohol plus caffeine group (A+C) (n = 8), and binge alcohol + caffeine + dantrolene group (A+D) (n = 7, treated with dantrolene 10 mg/kg before each alcohol injection). We also investigated whether alcohol induces Ca sparks and dantrolene treatment attenuates alcohol-induced Ca leak in ventricular myocytes.
RESULTS
No arrhythmia was induced with caffeine alone (group C, n = 0 of 8) or alcohol alone (group A, n = 0 of 8). However, alcohol + caffeine induced spontaneous ventricular tachyarrhythmias in all rats (group A+C, n = 8 of 8; < .001 vs group C or A). Dantrolene prevented ventricular tachyarrhythmia induction in all 7 rats (group A+D, n = 0 of 7; < .001 vs group A+C). In isolated ventricular myocytes, alcohol significantly increased Ca sparks and dantrolene treatment reduced alcohol-induced Ca sparks.
CONCLUSION
Co-consumption of caffeine and binge drinking synergistically promote spontaneous ventricular tachyarrhythmias in rats. Dantrolene treatment can decrease alcohol-enhanced Ca sparks in vitro and prevented alcohol and caffeine induced ventricular tachyarrhythmias in vivo.
PubMed: 37744935
DOI: 10.1016/j.hroo.2023.07.005 -
Archives of Disease in Childhood Nov 1984
Topics: Adult; Anesthesia, General; Animals; Calcium; Child; Dantrolene; Heat Exhaustion; Humans; Malignant Hyperthermia; Muscular Diseases; Neuroleptic Malignant Syndrome; Sudden Infant Death; Swine
PubMed: 6508337
DOI: 10.1136/adc.59.11.1013 -
BMC Anesthesiology Sep 2022Intravenous dantrolene is often prescribed for hypermetabolic syndromes other than the approved indication of malignant hyperthermia (MH). To clarify the extent of and...
BACKGROUND
Intravenous dantrolene is often prescribed for hypermetabolic syndromes other than the approved indication of malignant hyperthermia (MH). To clarify the extent of and indications for dantrolene use in conditions other than MH, we sought to document current practices in the frequency, diagnoses, clinical characteristics and outcomes associated with dantrolene treatment in critical care settings.
METHODS
Inpatients receiving intravenous dantrolene from October 1, 2004 to September 30, 2014 were identified retrospectively in the U.S. Veterans Health Administration national database. Extracted data included; diagnoses of hypermetabolic syndromes; triggering drugs; dantrolene dosages; demographics; vital signs; laboratory values; in-hospital mortality; complications; and lengths of stay. Frequency and mortality of patients who did not receive dantrolene were obtained in selected diagnoses for exploratory comparisons.
RESULTS
Dantrolene was administered to 304 inpatients. The most frequent diagnoses associated with dantrolene treatment were neuroleptic malignant syndrome (NMS; N = 108, 35.53%) and sepsis (N = 47, 15.46%), with MH accounting for only 13 (4.28%) cases. Over half the patients had psychiatric comorbidities and received psychotropic drugs before dantrolene treatment. Common clinical findings in patients receiving dantrolene included elevated temperature (mean ± SD; 38.7 ± 1.3 °C), pulse (116.33 ± 22.80/bpm), respirations (27.75 ± 9.58/min), creatine kinase levels (2,859.37 ± 6,646.88 IU/L) and low pO (74.93 ± 40.16 mmHg). Respiratory, renal or cardiac failure were common complications. Mortality rates in-hospital were 24.01% overall, 7.69% in MH, 20.37% in NMS and 42.55% in sepsis, compared with mortality rates in larger and possibly less severe groups of unmatched patients with MH (5.26%), NMS (6.66%), or sepsis (41.91%) who did not receive dantrolene.
CONCLUSIONS
In over 95% of cases, dantrolene administration was associated with diagnoses other than MH in critically-ill patients with hypermetabolic symptoms and medical and psychiatric comorbidities. Exploratory survey data suggested that the efficacy and safety of dantrolene in preventing mortality in hypermetabolic syndromes other than MH remain uncertain. However, randomized and controlled studies using standardized criteria between groups matched for severity are essential to guide practice in using dantrolene.
Topics: Creatine Kinase; Dantrolene; Humans; Malignant Hyperthermia; Retrospective Studies; Sepsis; Veterans Health
PubMed: 36123618
DOI: 10.1186/s12871-022-01841-z -
Turkish Neurosurgery 2020To evaluate the possible neuroprotective effects of ketamine and dantrolene on the hippocampal apoptosis and spatial learning in rats exposed to repeated...
Investigation of the Possible Protective Effects of Ketamine and Dantrolene on the Hippocampal Apoptosis and Spatial Learning in Rats Exposed to Repeated Electroconvulsive Seizures as a Model of Status Epilepticus.
AIM
To evaluate the possible neuroprotective effects of ketamine and dantrolene on the hippocampal apoptosis and spatial learning in rats exposed to repeated electroconvulsive seizures (ECS) as a model of status epilepticus (SE).
MATERIAL AND METHODS
Twenty-four rats were assigned to 4 groups. 1st Group was Sham. 2nd Group was ECS: ECS was induced by ear electrodes via electrical stimulation. The same ECS protocol was applied to the 3th and 4th Groups which received ketamine (40 mg/kg s.c.) or dantrolene (5 mg/kg i.p.) 1 h before each ECS, respectively. Following 30 days of recovery, the cognitive status of the animals was evaluated via Morris Water Maze (MWM). The same experimental protocol was repeated 14 days afterward to evaluate the retention of the memory. Hippocampal apoptosis was examined in corresponding experimental groups.
RESULTS
All the animals in four groups learned the task with no significant difference between groups in MWM. The ECS+ketamine group showed memory impairment 14 days afterward. ECS+dantrolene group was not different from controls. ECS caused long term apoptotic processes in dentate gyrus (DG) and non-apoptotic neuronal injury in CA1 and CA2.
CONCLUSION
Dantrolene and ketamine inhibited apoptosis and showed neuroprotective effects. Although ketamine and dantrolene inhibited ECS-induced apoptosis and non-apoptotic injury, they did not produce similar effects on memory retention. It will be warranted to evaluate cognitive dysfunction by taking into consideration the other factors in addition to apoptosis and neurodegenerative changes.
Topics: Animals; Apoptosis; Dantrolene; Disease Models, Animal; Electroshock; Hippocampus; Ketamine; Male; Maze Learning; Neuroprotective Agents; Rats; Status Epilepticus
PubMed: 32705669
DOI: 10.5137/1019-5149.JTN.27023-19.3 -
Journal of Cardiology Apr 2020Leakage of Ca from the sarcoplasmic reticulum (SR) is a critical contributing factor to heart failure pathophysiology. Therefore, reducing SR Ca leaks may provide... (Randomized Controlled Trial)
Randomized Controlled Trial
A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design.
BACKGROUND
Leakage of Ca from the sarcoplasmic reticulum (SR) is a critical contributing factor to heart failure pathophysiology. Therefore, reducing SR Ca leaks may provide significant additive benefits when used in combination with conventional therapies. Dantrolene, a drug routinely used to treat malignant hyperthermia, also stabilizes the cardiac isoform of the release channel (RyR2), thus decreasing SR Ca leaks. The purpose of this study is to evaluate the effect of chronic administration of dantrolene on heart failure and lethal arrhythmia in patients with chronic heart failure and reduced ejection fraction in a multicenter, randomized, double-blind, controlled study.
METHODS
Patients with chronic heart failure who had functional status of New York Heart Association class II and III and a left ventricular ejection fraction <40% were treated according to the Japanese Circulation Society, the European Society of Cardiology, and the American Heart Association/the American College of Cardiology guidelines for diagnosis and treatment of acute and chronic heart failure. Patients were randomized and divided into two groups in a double-blind fashion: dantrolene group and placebo group (target sample size: 300 cases). These drugs were administered for 96 weeks. The primary endpoint is cardiovascular death, first hospitalization for exacerbation of heart failure, or lethal arrhythmia [ventricular tachycardia (VT) storm, sustained VT, ventricular fibrillation] for 2 years after starting administration of dantrolene 1 cap (25mg) three times daily (if not tolerable, two times daily) or matching placebo.
RESULTS
This paper presents the rationale and trial design of the study. Recruitment for the study started on 8 December 2017.
CONCLUSIONS
The results of this trial will clarify the efficacy and safety of dantrolene for ventricular arrhythmia, as well as mortality and morbidity in patients with chronic heart failure and reduced ejection fraction during guideline-directed medical treatment.
Topics: Chronic Disease; Dantrolene; Double-Blind Method; Female; Heart Failure; Humans; Male; Morbidity; Research Design; Stroke Volume; Tachycardia, Ventricular; Treatment Outcome
PubMed: 31866190
DOI: 10.1016/j.jjcc.2019.08.020