Agilus®, a novel formulation of intravenous dantrolene as an alternative to Dantrium® for the treatment of a malignant hyperthermia crisis
Year: 2025
Type: article
Abstract: Promising outcomes have emerged from the European Medicines Agency's decision to approve the novel formulation of dantrolene as an effective treatment for perioperative malignant hyperthermia crises.This formulation has never been marketed in Europe.Malignant hyperthermia (MH) is an inherited, multifactorial channelopathy marked by uncontrolled release of calcium ions (Ca 2+ ) from the sarcoplasmic reticulum of skeletal muscle that results in sustained muscle contraction following exposure to volatile anesthetics and succinylcholine 1 .The pathophysiology of MH is widely understood to entail the sustained activation of the ryanodine receptor (RyR1) 2 .The energy expenditure required to restore cellular calcium homeostasis generates a demand for adenosine triphosphate (ATP), subsequently resulting in heat production.The integrity of the muscle membrane becomes compromised, culminating in rhabdomyolysis and life-threatening ion disturbances.If not addressed swiftly through the cessation of anesthetic use and the administration of dantrolene, the mortality rate may exceed 70%.Until the 1970's, no pathogenetic pharmacological intervention existed for this particular pathology, resulting in a notably high mortality rate.In 1975, Dr. Harrison and his colleagues suggested that dantrolene be used as an effective remedy for the swift management of MH crises 3 .Dantrolene operates by obstructing the release of Ca 2+ from the sarcoplasmic reticulum.Its mechanism of action involves the antagonism of RyR1, thereby diminishing the excitation-contraction coupling in muscle cells.The advent of the intravenous formulation of dantrolene in 1979, in conjunction with other measures, led to a dramatic reduction in the mortality rate associated with MH crises, which plummeted from 84% to 9% 4 .Nowadays, dantrolene represents the most important component in the causal treatment of MH crises, serving as the sole agent capable of rapidly alleviating MH symptoms by diminishing the release of Ca 2+ from the endoplasmic reticulum 5 .Dantrolene sodium is currently the only available medication for targeted and effective management of MH crises in humans.According to the current guidelines of the European Malignant Hyperthermia Group (www.emhg.org):"An early and appropriate dose of IV dantrolene is essential in the treatment of fulminant MH… An initial dose of dantrolene 2-2.5 mg kg -1 IV should be used in the treatment of an MH reaction" 6 .Any delay to the intravenous administration of dantrolene is associated with an increased rate of complications 6 .In Europe, the sole form of dantrolene for intravenous use has been Dantrium ® , which is supplied in packs of 12 vials.Each vial contains 20 mg of dantrolene sodium powder, that requires reconstitution with 60 mLs of sterile water.In the USA a nanoparticle suspension formulation of dantrolene (RYANODEX ® ) is available and contains 250 mg per vial.Notwithstanding the life-saving benefits of Dantrium ® in Europe, its usage presents several challenges.A notable drawback is that the powder is prepared with mannitol and sodium hydroxide as excipients.This limits the water solubility of the formulation, thus limiting the swift preparation of intravenous solutions during emergency situations 7 .Agilus ® , a novel formulation of intravenous dantrolene as an alternative to Dantrium ® for the treatment of a malignant hyperthermia crisis
Source: Acta Anaesthesiologica Belgica
DOI: 10.56126/76.2.12
Author: S Temurziev
Language: English
Subfield: Anesthesiology and Pain Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: Norgine
OpenAlex ID: W4410755248