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Orphanet Journal of Rare Diseases Jun 2019Satoyoshi syndrome is a multisystemic rare disease of unknown etiology, although an autoimmune basis is presumed. Its main symptoms are: painful muscle spasms, diarrhea,... (Review)
Review
BACKGROUND
Satoyoshi syndrome is a multisystemic rare disease of unknown etiology, although an autoimmune basis is presumed. Its main symptoms are: painful muscle spasms, diarrhea, alopecia and skeletal abnormalities. Clinical course without treatment may result in serious disability or death. A review of treatment and its response is still pending.
RESULTS
Sixty-four cases of Satoyoshi syndrome were published between 1967 and 2018. 47 cases described the treatment administered. Drugs used can be divided into two main groups of treatment: muscle relaxants/anticonvulsants, and corticosteroids/immunosuppressants. Dantrolene improved muscle symptoms in 13 out of 15 cases, but not any other symptoms of the disease. Other muscle relaxants or anticonvulsant drugs showed little or no effect. 28 out of 30 cases responded to a regimen that included costicosteroids. Other immunosuppressive drugs including cyclosporine, mycophenolate mofetil, azathioprine, methotrexate, tacrolimus and cyclophosphamide were used to decrease corticosteroid dose or improve efficacy. Immunoglobulin therapy was used in nine patients and four of them obtained a favorable response.
CONCLUSION
Corticosteroids was the most widely treatment employed with the best results in Satoyoshi syndrome. Further studies are needed to determine optimal dose and duration of corticosteroids as well as the role of other immunosuppressants and immunoglobulin therapy. Genetic or autoimmune markers will be useful to guide future therapies.
Topics: Adrenal Cortex Hormones; Alopecia; Animals; Anticonvulsants; Bone and Bones; Dantrolene; Diarrhea; Female; Humans; Immunization, Passive; Immunosuppressive Agents; Male; Rare Diseases; Spasm
PubMed: 31217029
DOI: 10.1186/s13023-019-1120-7 -
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 -
CNS & Neurological Disorders Drug... 2019Dantrolene, a ryanodine receptor antagonist, is primarily known as the only clinically acceptable and effective treatment for Malignant Hyperthermia (MH). Inhibition of... (Review)
Review
Dantrolene, a ryanodine receptor antagonist, is primarily known as the only clinically acceptable and effective treatment for Malignant Hyperthermia (MH). Inhibition of Ryanodine Receptor (RyR) by dantrolene decreases the abnormal calcium release from the Sarcoplasmic Reticulum (SR) or Endoplasmic Reticulum (ER), where RyR is located. Recently, emerging researches on dissociated cells, brains slices, live animal models and patients have demonstrated that altered RyR expression and function can also play a vital role in the pathogenesis of Alzheimer's Disease (AD). Therefore, dantrolene is now widely studied as a novel treatment for AD, targeting the blockade of RyR channels or another alternative pathway, such as the inhibitory effects of NMDA glutamate receptors and the effects of ER-mitochondria connection. However, the therapeutic effects are not consistent. In this review, we focus on the relationship between the altered RyR expression and function and the pathogenesis of AD, and the potential application of dantrolene as a novel treatment for the disease.
Topics: Alzheimer Disease; Animals; Calcium; Dantrolene; Humans; Malignant Hyperthermia; Muscle, Skeletal; Ryanodine Receptor Calcium Release Channel
PubMed: 29921212
DOI: 10.2174/1871527317666180619162649 -
Anesthesiology Jan 2019Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia...
BACKGROUND
Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10 min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality.
METHODS
The authors performed focused analyses of the Multicenter Perioperative Outcomes Group (2005 through 2016), North American MH Registry (2013 through 2016), and Anesthesia Closed Claims Project (1970 through 2014) databases, as well as a systematic literature review (1987 through 2017). The authors used difficult mask ventilation (grades III and IV) as a surrogate for airway rescue. MH experts judged dantrolene treatment. For MH morbidity/mortality analyses, the authors included U.S. and Canadian cases that were fulminant or scored 20 or higher on the clinical grading scale and in which volatile anesthetics or succinylcholine were given.
RESULTS
Among 6,368,356 queried outcomes cases, 246,904 (3.9%) received succinylcholine without volatile agents. Succinylcholine was used in 46% (n = 710) of grade IV mask ventilation cases (median dose, 100 mg, 1.2 mg/kg). Succinylcholine without volatile anesthetics triggered 24 MH cases, 13 requiring dantrolene. Among 310 anesthetic-triggered MH cases, morbidity was 20 to 37%. Treatment delay increased complications every 10 min, reaching 100% with a 50-min delay. Overall mortality was 1 to 10%; 15 U.S. patients died, including 4 after anesthetics in freestanding facilities.
CONCLUSIONS
Providers use succinylcholine commonly, including during difficult mask ventilation. Succinylcholine administered without volatile anesthetics may trigger MH events requiring dantrolene. Delayed dantrolene treatment increases the likelihood of MH complications. The data reported herein support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used.
Topics: Humans; Dantrolene; Databases, Factual; Malignant Hyperthermia; Muscle Relaxants, Central; Neuromuscular Depolarizing Agents; Succinylcholine
PubMed: 30550426
DOI: 10.1097/ALN.0000000000002490 -
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 -
Anesthesiology Oct 2019
Topics: Anesthesia; Dantrolene; Humans; Malignant Hyperthermia; Neuromuscular Depolarizing Agents; Succinylcholine
PubMed: 31469670
DOI: 10.1097/ALN.0000000000002950 -
Current Alzheimer Research 2020Alzheimer's Disease (AD), a neurodegenerative disorder with high incidence and mortality, is leading its way to the top of the list of the deadliest diseases without an... (Review)
Review
Alzheimer's Disease (AD), a neurodegenerative disorder with high incidence and mortality, is leading its way to the top of the list of the deadliest diseases without an effective disease-modifying drug. Ca2+ dysregulation, specifically abnormal release of Ca2+ via over activated ryanodine receptor (RyR), has been increasingly considered as an alternative upstream mechanism in AD pathology. Consequently, dantrolene, a RyR antagonist and FDA approved drug to treat malignant hyperthermia and chronic muscle spasms, has been shown to ameliorate memory loss in AD transgenic mice. However, the inefficiency of dantrolene to pass the Blood Brain Barrier (BBB) and penetrate the Central Nervous System needs to be resolved, considering its dose-dependent neuroprotection in AD and other neurodegenerative diseases. In this mini-review, we will discuss the current status of dantrolene neuroprotection in AD treatment and a strategy to maximize its beneficial effects, such as intranasal administration of dantrolene.
Topics: Alzheimer Disease; Animals; Calcium Channel Blockers; Calcium Signaling; Dantrolene; Humans; Neuroprotective Agents; Ryanodine Receptor Calcium Release Channel; Treatment Outcome
PubMed: 32442084
DOI: 10.2174/1567205017666200522204722 -
British Journal of Pharmacology Jun 2022QT prolongation and intracellular Ca loading with diastolic Ca release via ryanodine receptors (RyR2) are the predominant mechanisms underlying hypokalaemia-induced...
BACKGROUND AND PURPOSE
QT prolongation and intracellular Ca loading with diastolic Ca release via ryanodine receptors (RyR2) are the predominant mechanisms underlying hypokalaemia-induced ventricular arrhythmia. We investigated the antiarrhythmic actions of two RyR2 inhibitors: dantrolene and VK-II-86, a carvedilol analogue lacking antagonist activity at β-adrenoceptors, in hypokalaemia.
EXPERIMENTAL APPROACH
Surface ECG and ventricular action potentials (APs) were recorded from whole-heart murine Langendorff preparations. Ventricular arrhythmia incidence was compared in hearts perfused with low [K ], and those pretreated with dantrolene or VK-II-86. Whole-cell patch clamping was used in murine and canine ventricular cardiomyocytes to study effects of dantrolene and VK-II-86 on AP parameters in low [K ] and effects of VK-II-86 on the inward rectifier current (I ), late sodium current (I ) and the L-type Ca current (I ). Effects of VK-II-86 on I were investigated in transfected HEK-293 cells. A fluorogenic probe quantified the effects of VK-II-86 on oxidative stress in hypokalaemia.
KEY RESULTS
Dantrolene reduced the incidence of ventricular arrhythmias induced by low [K ] in explanted murine hearts by 94%, whereas VK-II-86 prevented all arrhythmias. VK-II-86 prevented hypokalaemia-induced AP prolongation and depolarization but did not alter AP parameters in normokalaemia. Hypokalaemia was associated with decreased I and I , and increased I , and I . VK-II-86 prevented all hypokalaemia-induced changes in ion channel activity and oxidative stress.
CONCLUSIONS AND IMPLICATIONS
VK-II-86 prevents hypokalaemia-induced arrhythmogenesis by normalizing calcium homeostasis and repolarization reserve. VK-II-86 may provide an effective treatment in hypokalaemia and other arrhythmias caused by delayed repolarization or Ca overload.
Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Calcium; Carvedilol; Dantrolene; Dogs; HEK293 Cells; Humans; Hypokalemia; Mice; Myocytes, Cardiac; Ryanodine Receptor Calcium Release Channel; Sodium
PubMed: 34877651
DOI: 10.1111/bph.15775 -
Scientific Reports May 2021Diabetics have a higher risk of developing cerebral vasospasms (CVSP) after subarachnoid hemorrhagic stroke than non-diabetics. Serotonin (5-HT) is one of the key...
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), 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 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.
Topics: Animals; Calcium Channel Blockers; Dantrolene; Diabetes Mellitus, Experimental; Drug Therapy, Combination; Humans; Male; Muscle Contraction; Muscle Relaxants, Central; Muscle, Smooth, Vascular; Nimodipine; Rats; Serotonin; Streptozocin; Subarachnoid Hemorrhage; Vasospasm, Intracranial
PubMed: 33972638
DOI: 10.1038/s41598-021-89338-6 -
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