Stability Characterization, Kinetics and Mechanism of Degradation of Dantrolene in Aqueous Solution: Effect of pH and Temperature

The mechanism of degradation of dantrolene in aqueous buffer solutions was studied at various pH values in the range of pH 1.2-9.5 and at temperatures ranging from 25℃ to 75℃ to determine the optimum pH and temperature requirements for its stability and eventual product performance over the human gastrointestinal pH range. Dantrolene was analyzed by reversed phase ultra-performance liquid chromatographic (UPLC). Chromatographic separation was achieved on a Waters Acquity UPLC system using a Waters BEH C18 analytical column and Waters BEH C18 guard column. The compounds were eluted with a linear acetonitrile gradient (25%-75%) over three minutes with a buffer composition of 2.0 mM of sodium acetate at pH 4.5 for degradation studies. The flow rate was maintained at 0.5 mL/min. Column temperature was maintained at 35℃. Injection volume was 4 μL and the degradation products were detected by a photodiode array (PDA) detector at 375 nm. Degradation products, including compound B and C were analyzed by mass spectroscopy (MS) and nuclear magnetic resonance spectroscopy (NMR) and the degradation pathways were proposed. Degradation of dantrolene followed pseudo first–order kinetics and a V-shaped pH-rate profile over the pH range 1.2-9.5. The maximum stability was observed at pH 7.4 and 37℃. Although the focus of this paper was on the mechanism of hydrolysis of dantrolene, the poor aqueous solubility of dantrolene, the developed understanding can be utilized to improve the quality of the formulation and the risk associated with the extravasation of dantrolene sodium solution in its current form.

Dantrolene in the Treatment of Refractory Hyperthermic Conditions in Critical Care: A Multicenter Retrospective Study

Purpose: To examine the use of intravenous dantrolene in hospitalized patients. Materials and Methods: Medical Records of patients treated with intravenous dantrolene between 2007 and 2012 at 6 teaching hospitals were reviewed. Temperature, muscle rigidity, creatine kinase levels, and mortality were assessed in association with dantrolene use. Results: Twenty-five patients received intravenous dantrolene, 9 patients with neuroleptic malignant syndrome (NMS), 8 with hyperthermia due to sepsis, 4 with NMS and sepsis, 2 for malignant hyperthermia (MH), and 2 with hypermetabolic syndrome associated with juvenile diabetic ketoacidosis. Dantrolene was administered as a bolus of 1 - 3 mg/kg. Core temperature decreased after dantrolene administration in all groups but significant only for MH, NMS cases (Pre 102.3 ± 0.9&degF vs. Post 99.5 ± 0.9&degF;p Conclusion: Dantrolene was associated with reductions in temperature and rigidity in hyperthermia of diverse origins in patients admitted to Intensive care settings.

Malignant hyperthermia as a rare complication of local lidocaine injection:A case report

BACKGROUND Malignant hyperthermia(MH)is a hypermetabolic disorder of skeletal muscles triggered by exposure to volatile anesthetics and depolarizing muscular relaxants.It manifests with clinical presentations such as tachycardia,muscle rigidity,hyperpyrexia,and rhabdomyolysis in genetically predisposed individuals with ryanodine receptor or calcium voltage-gated channel subunit alpha1 S mutations.Local anesthetics,such as lidocaine,are generally considered safe;however,complications can arise,albeit rarely.Lidocaine administration has been reported to induce hypermetabolic reactions resembling MH in susceptible individuals.The exact mechanism by which lidocaine might trigger MH is not fully understood.Although some mechanisms are postulated,further research is needed for a better understanding of this.CASE SUMMARY We present the case of MH in a 43-year-old male patient with an unknown genetic predisposition following a lidocaine injection during a dental procedure.This case serves as a reminder that while the occurrence of lidocaine-induced MH is rare,lidocaine can still trigger this life-threatening condition.Therefore,caution should be exercised when administering lidocaine to individuals who may be susceptible to MH.It is important to note that prompt intervention played a crucial role in managing the patient’s symptoms.Upon recognizing the early signs of MH,aggressive measures were initiated,including vigorous intravenous normal saline administration and lorazepam.Due to the effectiveness of these interventions,the administration of dantrolene sodium,a specific antidote for MH,was deferred.CONCLUSION This case highlighted the significance of vigilant monitoring and swift action in mitigating the detrimental effects of lidocaine-induced MH.Caution should be exercised when administering lidocaine to individuals who may be predisposed to MH.It is very important to be aware and vigilant of the signs and symptoms of MH as early recognition and treatment intervention are important to prevent serious complications to decrease mortality.

The current status of malignant hyperthermia

Malignant hyperthermia(MH) is a rare and life-threatening pharmacogenetic disorder triggered by volatile anesthetics, the depolarizing muscle relaxant succinylcholine, and rarely by strenuous exercise or environmental heat. The exact prevalence of MH is unknown, and it varies from 1:16 000 in Denmark to 1:100 000 in New York State. The underlying mechanism of MH is excessive calcium release from the sarcoplasmic reticulum(SR),leading to uncontrolled skeletal muscle hyper-metabolism. Genetic mutations in ryanodine receptor type 1(RYR1)and CACNA1 S have been identified in approximately 50% to 86% and 1% of MH-susceptible(MHS) individuals,respectively. Classic clinical symptoms of MH include hypercarbia, sinus tachycardia, masseter spasm,hyperthermia, acidosis, muscle rigidity, hyperkalemia, myoglobinuria, and etc. There are two types of testing for MH: a genetic test and a contracture test. Contracture testing is still being considered as the gold standard for MH diagnosis. Dantrolene is the only available drug approved for the treatment of MH through suppressing the calcium release from SR. Since clinical symptoms of MH are highly variable, it can be difficult to establish a diagnosis of MH. Nevertheless, prompt diagnosis and treatments are crucial to avoid a fatal outcome. Therefore, it is very important for anesthesiologists to raise awareness and understand the characteristics of MH. This review summarizes epidemiology, clinical symptoms, diagnosis and treatments of MH and any new developments.

Atypical Neuroleptic Malignant Syndrome: Pitfalls and Challenges in the Delirious Substance Abuser

Introduction: A rare and atypical form of Neuroleptic Malignant Syndrome (NMS) can be a deceptive and life threatening condition if not diagnosed properly in acute and critical care settings. Methods: The management of a patient presenting with atypical NMS without prominent rigidity, but with extensive rhabdomyolysis after the administration of haloperidol and ziprasidone is described in this report. Results: Prompt recognition of atypical features of NMS was managed by intensive care unit admission, supportive care and pharmacotherapy, leading to a complete resolution of the syndrome and a favorable outcome verified by laboratory findings. Conclusion: Early stages and atypical features of NMS may be variable in presentation and clinical course. The absence of muscle rigidity may not rule out NMS. A strong clinical suspicion based on clinical history is crucial for early diagnosis and treatment. Termination of dantrolene therapy may not be necessary during rhabdomyolysis and elevated aminotransferase levels.

Glutamate-induced swelling of cultured astrocytes is mediated by metabotropic glutamate receptor

The effects of glutamate and its agonists and antagonists on the swelling of cultured astrocytes were studied. Swelling of astrocytes was measured by [3H]-O-methyl-D-glucose uptake. Glutamate at 0.5, 1 and 10mmol/L and irons-l-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD), a metabotropic glutamate receptor (mGluR) agonist, at 1 mmol/L caused a significant increase in astrocytic volume, whereas alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) was not effective. L-2-amino-3-phosphonopropionic acid (L-AP3), an antagonist of mGluR, blocked the astrocytic swelling induced by trans-ACPD or glutamate. In Ca2+-free condition, glutamate was no longer effective. Swelling of astrocytes induced by glutamate was not blocked by CdCl2 at 20 μmol/L, but significantly reduced by CdCl2 at 300 μmol/L and dantrolene at 30 μmol/L. These findings indicate that mGluR activation results in astrocytic swelling and both extracellular calcium and internal calcium stores play important roles in the genesis of astrocytic swelling induced by glutamate.