Ryanodex (dantrolene) / Eagle Pharma - LARVOL DELTA

Ryanodex Reduces Persistent Hippocampal Effects of Single Mild Traumatic Brain Injury in Rats. (PubMed, Neurotrauma Rep) - "However, mild TBI (mTBI) significantly enhanced synaptic transmission at hippocampal CA3-CA1 synapses and increased CA1 pyramidal cell excitability for at least 30 days-effects that were significantly attenuated by acute and subacute injection of Ryanodex, a concentrated nanocrystalline formulation of the ryanodine receptor allosteric modulator dantrolene. Ryanodex may, therefore, offer a promising intervention to reduce persistent hippocampal dysfunction following mTBI, with potential clinical applications for acute TBI treatment."

Journal • Preclinical • CNS Disorders • Vascular Neurology • CA3 • GFAP

Investigating the interplay between calcium dysregulation and insulin signaling dysfunction in Alzheimer's disease using ROSMAP iPSCs-derived human neurons (Neuroscience 2025) - "Calcium imaging demonstrated that AD neurons exhibit significantly increased ER-calcium release, which was normalized by Ryanodex, a negative regulator of the ryanodine receptor (RyR)...These findings support a bidirectional pathogenic feedback loop in which excessive calcium influx impairs insulin signaling, and insulin resistance further disrupts calcium homeostasis, thereby exacerbating mitochondrial dysfunction in AD. Leveraging ROSMAP's rich clinical and neuropathological data, this human iPSC derived neuronal model offers a unique platform to understand disease-relevant cellular mechanisms and opens avenues for identifying novel therapeutic targets aimed at restoring calcium homeostasis and insulin signaling in AD brain."

Alzheimer's Disease • CNS Disorders • AKT1 • IR • PTEN

A Clinical Trial Utilizing Dantrolene in Patients With Ventricular Arrhythmias. (clinicaltrials.gov) - P2/3 | N=68 | Completed | Sponsor: Vanderbilt University Medical Center | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Heart Failure • Ventricular Tachycardia

Impact of Dantrolene on Strength and Respiratory Mechanics - A Clinical Trial (ASA 2025) - "Following ablation but prior to and 10, 20, and 120 minutes after study drug (intravenous dantrolene [Ryanodex] 1mg/kg vs. placebo), we assessed respiratory support, respiratory parameters, arterial blood gas, and electrolytes. Dantrolene reduced skeletal muscle strength and ventilation up to two hours after administration. Escalation of respiratory support was not significantly higher in subjects treated with dantrolene, although a deleterious effect cannot be excluded. Careful monitoring of respiratory function should be undertaken in non-intubated patients treated with dantrolene."

Clinical • Anesthesia • Cardiovascular

Atypical Presentation of Malignant Hyperthermia in a Pediatric Patient (ASA 2025) - "We present an 18-month-old male who underwent a circumcision with an LMA placement maintained on sevoflurane. Transferred to PICU, he remained intubated on 24-hour Ryanodex until an uncomplicated discharge three days later."

Clinical • Anesthesia • Cardiovascular • Metabolic Disorders • Pediatrics

A Clinical Trial Utilizing Dantrolene in Patients With Ventricular Arrhythmias. (clinicaltrials.gov) - P2/3 | N=68 | Active, not recruiting | Sponsor: Vanderbilt University Medical Center | Trial completion date: Jan 2026 ➔ Aug 2025

Trial completion date • Cardiovascular • Heart Failure • Ventricular Tachycardia

Mitochondrial dysfunction mediated by ER-calcium dysregulation in neurons derived from Alzheimer's disease patients. (PubMed, Acta Neuropathol Commun) - "Notably, impairments to mitochondria in AD neurons were largely prevented with the RyR negative allosteric modulator, Ryanodex. These findings highlight how excess RyR-Ca2+ release broadly contributes to early cellular pathology in AD which includes a cascade of ER, lysosomal, and mitochondrial deficits culminating in neuronal decline and degeneration. Additionally, pharmacological suppression of RyR-Ca2+ release preserves mitochondrial, ER and lysosomal function, thus providing a novel and effective therapeutic strategy."

Journal • Alzheimer's Disease • CNS Disorders • Metabolic Disorders • CASP3 • RYR2

Intranasal Dantrolene Nanoparticles for Treatment of Amyotrophic Lateral Sclerosis as a Disease-Modifying Drug. (PubMed, bioRxiv) - "Male and female C57BL/6SJLF1 non-transgenic control and SOD1-G93A ALS transgenic mice were assigned to one of three experimental groups: 1) NO TX: No treatment control; 2) IN-DAN: Intranasal administration of dantrolene in the Ryanodex formulation vehicle (RFV), at a dosage of 5mg/kg, administered daily from ages 90-120 days; 3) IN-VEH: Intranasal administration of RFV alone (as a vehicle control), following the same dosing schedule as the IN-DAN condition. These improvements were associated with a marked inhibition of spinal cord weight loss. Additionally, dantrolene treatment reversed body weight loss and significantly improved survival probability in ALS mice."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • NEFL

Dantrolene in Statin-induced Myopathy (clinicaltrials.gov) - P2/3 | N=23 | Not yet recruiting | Sponsor: Tanta University

New P2/3 trial • Myositis

Intranasal Delivery of Lithium Salt Suppresses Inflammatory Pyroptosis in the Brain and Ameliorates Memory Loss and Depression-like Behavior in 5XFAD Mice. (PubMed, J Neuroimmune Pharmacol) - "Intranasal administration of LiCl in RFV significantly decreased lithium blood concentrations and increased brain/blood lithium concentration ratio, in comparison to its oral administration. Intranasal administration of LiCl in RFV robustly protected against both memory loss and depressive-like behavior, while had no side effects concerning thyroid and kidney toxicity in 5XFAD mice. These lithium-induced beneficial effects were strongly associated with lithium's suppression of InsP3R-1 Ca2+ channel receptor increase, pathological neuroinflammation and activation of the pyroptosis pathway, as well as the loss of the synaptic protein PSD-95. Intranasal delivery of lithium salt in RFV could become an effective and potent inhibitor of pathological inflammation/pyroptosis in the CNS and serve as a new treatment for both AD-associated dementia and depression with minimal unwanted side effects including peripheral organ toxicity."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Depression • Inflammation • Mood Disorders • Psychiatry • IL10 • IL18 • IL1B • IL6 • Napsin A • NLRP3 • TNFA

Drug Development. (PubMed, Alzheimers Dement) - "IDNs robustly protect both depression behavior and memory loss in young and aged 5XFAD mice, with no adverse effects with chronic use. This was associated with its potent inhibition of inflammation, pyroptosis, and associated synapse protein loss. IDNs emerge as a promising therapeutic intervention for both depression and dementia, particularly in AD."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Depression • Inflammation • Psychiatry • CASP1 • IL10 • IL18 • IL1B • IL6 • Napsin A • NLRP3 • TNFA

Drug Development. (PubMed, Alzheimers Dement) - "Intranasal LiCl in RFV ameliorates memory loss and depressive behavior in 5XFAD mice without side effects or organ toxicity, with chronic use. Intranasal LiCl in RFV effectively inhibited, oxidative stress, inflammation and pyroptosis in aged 5XFAD brains."

Journal • CNS Disorders • Cognitive Disorders • Depression • Inflammation • Psychiatry • IL10 • IL18 • IL1B • IL6 • NLRP3 • TNFA

A Clinical Trial Utilizing Dantrolene in Patients with Ventricular Arrhythmias. (clinicaltrials.gov) - P2/3 | N=84 | Active, not recruiting | Sponsor: Vanderbilt University Medical Center | Trial completion date: Nov 2024 ➔ Jan 2026 | Trial primary completion date: Nov 2024 ➔ Mar 2025

Trial completion date • Trial primary completion date • Cardiovascular • Heart Failure • Ventricular Tachycardia

Dysregulated RyR-Ca2+signaling drives mitochondrial dysfunction in AD neurons (Neuroscience 2024) - "The attenuation of RyR-Ca2+ signaling with Ryanodex reduced observed mitochondrial defects, decreased superoxide production, and restored mitophagy in AD HiNs. Additionally, increased susceptibility to apoptosis was observed in AD HiNs with increased caspase 3 activity and an increased pool of readily releasable cytochrome c.Our data demonstrate that dysregulated RyR-Ca2+ signaling can act as an upstream mechanism of mitochondrial dysfunction. The complete or partial rescuing of mitochondrial functions through pharmacological interventions emphasizes the importance of dysfunctional RyR-Ca2+ signaling as a driving factor for mitochondrial dysfunction and provides a potential therapeutic target for combating cellular dysfunction in early AD."

Alzheimer's Disease • CNS Disorders • CASP3

Intranasal Lithium Chloride Nanoparticles Inhibit Inflammatory Pyroptosis in Brains and Ameliorate Memory Loss and Depression Behavior in 5xFAD mice. (PubMed, bioRxiv) - "This study compares the changes in lithium concentrations in the brain and blood following the administration of intranasal or oral lithium chloride (LiCl) dissolved in either Ryanodex Formulation Vehicle (RFV) or water, as well as the therapeutic effectiveness and side effects of intranasal versus oral lithium chloride (LiCl) in RFV, and their mechanisms for inhibiting inflammation and pyroptosis in 5xFAD Alzheimer's Disease (AD) mice brains...This lithium mediated neuroprotection was associated with its potent effects on the inhibition of InsP3R-1 Ca 2+ channel receptor increase, ameliorating pathological inflammation and activation of the pyroptosis pathway, and the associated loss of synapse proteins. Intranasal LiCl in RFV could become an effective and potent inhibitor of pathological inflammation/pyroptosis in the CNS and treat both dementia and depression with no or minimal side effects/organ toxicity, particular in AD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Dementia • Depression • Inflammation • Mood Disorders • Psychiatry

Intranasal dantrolene nanoparticles inhibit lipopolysaccharide-induced depression and anxiety behavior in mice. (PubMed, bioRxiv) - "This study investigates the therapeutic effectiveness of intranasal dantrolene nanoparticles in the Ryanodex formulation (DNRF) pretreatment to inhibit lipopolysaccharide (LPS)-induced depressive and anxiety behavior in mice. In both types of mice, intranasal DNRF significantly inhibited LPS-induced pathological elevation of IL-1β and IL-18 in the blood. Intranasal DNRF abolished LPS-induced depression and anxiety behaviors behavior in both WT and 5XFAD mice, without obvious side effects, which was associated with its significant inhibition of pathological elevation of pyroptosis related cytokines in blood."

Journal • Preclinical • CNS Disorders • Depression • Inflammation • Mood Disorders • Psychiatry • IL18 • IL1B

A Clinical Trial Utilizing Dantrolene in Patients With Ventricular Arrhythmias. (clinicaltrials.gov) - P2/3 | N=84 | Active, not recruiting | Sponsor: Vanderbilt University Medical Center | Trial completion date: Jun 2024 ➔ Nov 2024 | Trial primary completion date: Jun 2024 ➔ Nov 2024

Trial completion date • Trial primary completion date • Atrial Fibrillation • Cardiovascular • Heart Failure • Ventricular Tachycardia

Intranasal lithium in Ryanodex formulation vehicle inhibits inflammation and pyroptosis in aged 5XFAD mice brains. (AAIC 2024) - "Intranasal LiCl in RFV ameliorates memory loss and depressive behavior in 5XFAD mice without side effects or organ toxicity, with chronic use. Intranasal LiCl in RFV effectively inhibited, oxidative stress, inflammation and pyroptosis in aged 5XFAD brains."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Inflammation • Psychiatry • IL10 • IL18 • IL1B • IL6 • NLRP3 • TNFA

Intranasal dantrolene nanoparticles abolished depression behavior and memory loss as a disease-modifying drug in 5XFAD mice (AAIC 2024) - " 5XFAD and wild-type B6SJLF1/J mice were treated with IDNs (IDN, 5 mg/kg) in Ryanodex formulation for a duration of 12 weeks. IDNs robustly protect both depression behavior and memory loss in young and aged 5XFAD mice, with no adverse effects with chronic use. This was associated with its potent inhibition of inflammation, pyroptosis, and associated synapse protein loss. IDNs emerge as a promising therapeutic intervention for both depression and dementia, particularly in AD."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Depression • Inflammation • Mood Disorders • Psychiatry • CASP1 • IL10 • IL18 • IL1B • IL6 • Napsin A • NLRP3 • TNFA

Effects of Intranasal Dantrolene Nanoparticles on Brain Concentration and Behavior in PS19 Tau Transgenic Mice. (PubMed, J Alzheimers Dis) - "The effects of a nanoparticle intranasal formulation, the Eagle Research Formulation of Ryanodex (ERFR), in young adult and aged wild type and PS19 tau transgenic mice was investigated. The behavioral assays showed no significant changes in cognition, olfaction, or motor function in the PS19 mice compared to controls after chronic treatment with intranasal ERFR, even with acrolein. Our studies suggest the intranasal administration of ERFR has higher concentrations in the brain than the blood in aged mice and has no serious systemic side effects with chronic use in PS19 mice."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

A Clinical Trial Utilizing Dantrolene in Patients With Ventricular Arrhythmias. (clinicaltrials.gov) - P2/3 | N=84 | Active, not recruiting | Sponsor: Vanderbilt University Medical Center | Recruiting ➔ Active, not recruiting

Enrollment closed • Atrial Fibrillation • Cardiovascular • Heart Failure • Ventricular Tachycardia

Fever Fiasco! Malignant Hyperthermia Complicated by Gemella morbillorum Septic Shock (SCCM 2024) - "Initially, he was admitted with the presumed diagnosis of CAP and started on ceftriaxone and azithromycin after appropriate cultures were obtained...MH was suspected and he was rapidly stabilized using Ryanodex and supportive care with a prompt reduction in his temperature and hypercapnia...Our patient developed MH due to succinylcholine and despite early recognition and rapid treatment of his malignant hyperthermia, he developed multi-organ failure due to septic shock from a rare pathogen. This case highlights the importance of maintaining a high degree of suspicion for MH, especially in the critical care setting where succinylcholine is used frequently, and sepsis induced fever can lead to a delay in recognition and management."

Anesthesia • Critical care • Genetic Disorders • Metabolic Disorders • Rare Diseases • Septic Shock

Elevated ER-Ca2+signaling in human AD neurons drives disruptions in mitochondrial functions (Neuroscience 2023) - "In neurons from AD patients, resting mitochondrial Ca2+ levels, membrane potential, and superoxide production were significantly higher than in non-AD neurons and was normalized by the RyR negative allosteric modulator, Ryanodex (10uM)...The data demonstrate that elevated RyR-Ca2+ signaling elicits a maladaptive response within the mitochondria that links with AD features such as impaired cellular metabolism and increased free radical production. Thus, identifying the pathogenic cascades within the mitochondria that result from elevated ER-Ca2+ release is essential for elucidating cellular disease mechanisms in early AD."

CNS Disorders • RYR2

A cascade of intracellular organelle defects drives cellular pathophysiology in Alzheimer’s disease and Down syndrome neurons (Neuroscience 2023) - "Normalizing aberrant RyR-Ca2+ signaling with dantrolene (Ryanodex) restored physiological functioning of these critical organelles in both conditions. These results highlight that aberrant ER Ca2+ signaling disrupts a series of key organelle interactions that collectively drive a neuronal AD phenotype, and point to shared pathogenic mechanisms between AD and DS. Furthermore, pharmacological suppression of RyR-Ca2+ release rescues organelle function, revealing a target for therapeutic intervention that has demonstrated effects in clinically-relevant assays."

Alzheimer's Disease • CNS Disorders • Proteinopathy

A Clinical Trial Utilizing Dantrolene in Patients With Ventricular Arrhythmias. (clinicaltrials.gov) - P2/3 | N=84 | Recruiting | Sponsor: Vanderbilt University Medical Center | Trial primary completion date: Jun 2023 ➔ Jun 2024

Trial primary completion date • Atrial Fibrillation • Cardiovascular • Heart Failure • Ventricular Tachycardia