Ryanodex (dantrolene) / Eagle Pharma - LARVOL DELTA

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

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

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

PROTEIN MISHANDLING AND MITOCHONDRIAL PATHOPHYSIOLOGY DRIVEN BY CALCIUM DYSHOMEOSTASIS IN ANIMAL AND HUMAN MODELS OF AD (ADPD 2023) - "Normalizing AD-associated aberrant RyR Ca2+ signaling with dantrolene (Ryanodex) restored physiological functioning of these critical organelles. Conclusions These results highlight that aberrant upstream Ca2+ signaling disrupts lysosomal acidification, autophagic processes and mitochondrial functions, and suppressing RyR-Ca2+ release offers a therapeutic intervention that has demonstrated effects in clinically-relevant assays."

Alzheimer's Disease • CNS Disorders • Proteinopathy • Targeted Protein Degradation

Dantrolene sodium fails to reverse robust brain hyperthermia induced by MDMA and methamphetamine in rats. (PubMed, Psychopharmacology (Berl)) - "Our results suggest that dantrolene sodium formulations are not mechanistically suited to treat MDMA- and METH-induced hyperthermia."

Journal • Preclinical • Immunology

Protein mishandling and impaired lysosomal proteolysis generated through calcium dysregulation in Alzheimer's disease. (PubMed, Proc Natl Acad Sci U S A) - "Normalizing AD-associated aberrant RyR-Ca signaling with the negative allosteric modulator, dantrolene (Ryanodex), restored vATPase levels, lysosomal acidification and proteolytic activity, and autophagic clearance of intracellular protein aggregates in AD neurons...Importantly, this is demonstrated in animal models of AD, and in human iPSC-derived neurons from AD patients. Furthermore, pharmacological suppression of RyR-Ca release rescued proteolytic function, revealing a target for therapeutic intervention that has demonstrated effects in clinically-relevant assays."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Proteinopathy • Targeted Protein Degradation

Effects of intranasal dantrolene on cognitive function in P301S (line PS19) tau pathology mice (Neuroscience 2022) - "This study investigates whether intranasal administration of Eagle Research Formulation of Ryanodex (ERFR), a dantrolene formulation, is neuroprotective in tau pathology mice (P301S, Line PS19)...Our results suggest that PS19 mice may not be a reliable AD animal model to test therapeutic efficacy of new or repurposed dantrolene drug products. In the future, intranasal dantrolene drug products will be tested in a suitable animal model with significant sporadic AD (SAD) risk factors."

Preclinical • CNS Disorders

Simulation Training: A Multidisciplinary Approach (ASA 2022) - "We conducted several simulations to prevent OR fires, introduce Ryanodex, and treat local anesthetic toxicity...Through our interdisciplinary sessions, we were able to foster a sense of trust, openness, and excitement among all members. Our debriefing sessions allowed for better communication and teamwork."

Anesthesia

Donating Dantrolene: Development and Implementation of a Malignant Hyperthermia Program in a Scarce Resource Setting. (PubMed, AANA J) - "Facilities in the United States are in a transition period where dantrolene is being replaced with Ryanodex, therefore, there is an opportunity for excess dantrolene to be utilized in LMICs where neither dantrolene nor Ryanodex exist. A designated MH drawer was also created in preparation for an MH event. By procuring dantrolene and implementing an MH program in a facility where no MH protocol, treatment guidelines, supply list, or educational tools existed, LFHC is better equipped to handle a potentially lethal scenario."

Journal • Anesthesia

Lysosome-autophagosome defects mediate proteinopathy in Alzheimer's disease pathogenesis (Neuroscience 2021) - "Protein aggregates, such as β-amyloid and hyperphosphorylated tau, were increased in iNs with V-ATPase inhibition (bafilomycin 125 nM), which was resolved with Ryanodex treatment. Prior to overt histopathology or cognitive deficits, abnormal RyR-mediated Ca 2+ release disrupts lysosomal function leading to altered autophagic-mediated protein clearance that contributes to AD proteinopathy.; Grant Support: NIH R56 AG055497"

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Proteinopathy • LAMP1

An Unusual Case Of Malignant Hyperthermia (ASA 2021) - "Following diagnosis, the patient was treated with Ryanodex 2.5 mg/kg x 2 and other measures, resulting in prompt and dramatic resolution of his hypercarbia (ETCO2 127 to 44) and other vital signs. This case highlights the need for continuous vigilance, early and accurate diagnosis, and expeditious treatment of this rare and potentially fatal anesthesia complication."

Clinical • Anesthesia • Oncology • Squamous Cell Carcinoma