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Advanced Science (Weinheim,... May 2024Nanomedicine has reshaped the landscape of cancer treatment. However, its efficacy is still hampered by innate tumor defense systems that rely on adenosine triphosphate...
Nanomedicine has reshaped the landscape of cancer treatment. However, its efficacy is still hampered by innate tumor defense systems that rely on adenosine triphosphate (ATP) for fuel, including damage repair, apoptosis resistance, and immune evasion. Inspired by the naturally enzymatic reaction of glucose oxidase (GOx) with glucose, here a novel "two birds with one stone" technique for amplifying enzyme-mediated tumor apoptosis and enzyme-promoted metabolic clearance is proposed and achieved using GOx-functionalized rhenium nanoclusters-doped polypyrrole (Re@ReP-G). Re@ReP-G reduces ATP production while increasing HO concentrations in the tumor microenvironment through GOx-induced enzymatic oxidation, which in turn results in the downregulation of defense (HSP70 and HSP90) and anti-apoptotic Bcl-2 proteins, the upregulation of pro-apoptotic Bax, and the release of cytochrome c. These processes are further facilitated by laser-induced hyperthermia effect, ultimately leading to severe tumor apoptosis. As an enzymatic byproduct, HO catalyzes the conversion of rhenium nanoclusters in Re@ReP-G nanostructures into rhenate from the outside in, which accelerates their metabolic clearance in vivo. This Re@ReP-G-based "two birds with one stone" therapeutic strategy provides an effective tool for amplifying tumor apoptosis and safe metabolic mechanisms.
Topics: Animals; Apoptosis; Mice; Glucose Oxidase; Neoplasms; Humans; Disease Models, Animal; Cell Line, Tumor; Nanomedicine; Tumor Microenvironment; Hydrogen Peroxide; Polymers
PubMed: 38447152
DOI: 10.1002/advs.202308251 -
European Journal of Anaesthesiology May 2024Delays in treating anaesthesia-induced malignant hyperthermia increase risks of complications and death. NPJ5008 is a novel formulation of the indicated treatment,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Delays in treating anaesthesia-induced malignant hyperthermia increase risks of complications and death. NPJ5008 is a novel formulation of the indicated treatment, dantrolene sodium, developed to shorten preparation and administration times compared with the reference formulation Dantrium®. The two formulations have been compared preclinically.
OBJECTIVES
Assess bioequivalence of overall dantrolene (free acid) exposure of NPJ5008 versus Dantrium® and ascertain similarities in their pharmacokinetics and safety/tolerability profiles. Evaluate preparation/administration time savings for the new formulation.
DESIGN
Part 1 of this open-label trial in humans was a 1 : 1 randomised crossover study; part 2 was a single-arm study. Trial pharmacy data and laboratory simulations assessed preparation/administration step timings.
SETTING
Single clinical centre in the UK, April to July 2021.
PARTICIPANTS
Twenty-one healthy male and female individuals.
INTERVENTIONS
Part 1: single intravenous 60 mg dose of NPJ5008 or Dantrium®, sequentially. Part 2: single intravenous 120 mg dose of NPJ5008. Simulation: five vials per formulation using paediatric and adult cannulas.
MAIN OUTCOME MEASURES
Overall drug exposure to last measurable concentration (AUC 0 to last ) and extrapolated to infinity (AUC 0 to ∞ ) were primary endpoints. Other pharmacokinetic, clinical and muscle-function parameters, and adverse events, were monitored.
RESULTS
Adjusted geometric mean ratios of NPJ5008 versus Dantrium® were 90.24 and 90.44% for AUC 0 to last and AUC 0 to ∞ , respectively, with the 90% confidence intervals (CI) within the 80 to 125% acceptance interval, establishing bioequivalence. No new safety issues emerged: any adverse events were of a similar magnitude across treatments and related to pharmacological properties of dantrolene. Pharmacy and simulation data revealed that every step in preparation and administration was 26 to 69% faster for NPJ5008 than Dantrium®.
CONCLUSION
NPJ5008 showed comparable pharmacokinetic and safety profiles to Dantrium®, while reducing dantrolene dose preparation/administration times, potentially reducing patient complications/healthcare resourcing in malignant hyperthermia.
TRIAL REGISTRATION
EudraCT Number: 2020-005719-35, MHRA approval.
Topics: Adult; Humans; Male; Female; Child; Dantrolene; Biological Availability; Malignant Hyperthermia; Healthy Volunteers; Therapeutic Equivalency; Cross-Over Studies; Area Under Curve; Administration, Oral
PubMed: 38445365
DOI: 10.1097/EJA.0000000000001966 -
Cureus Jan 2024Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common X-linked recessive red blood cell disease in humans. The highest prevalence of G6PD deficiency is...
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common X-linked recessive red blood cell disease in humans. The highest prevalence of G6PD deficiency is reported to be in Africa, Southern Europe, the Middle East, Southeast Asia, and the islands of the Central and South Pacific. G6PD deficiency causes acute hemolysis upon exposure to oxidative stress. Various stress factors that can cause hemolysis include infections, fever, sepsis, various foods such as fava beans, and various medications. In this report, we describe the case of a 13-year-old child who was diagnosed with G6PD deficiency in childhood but did not experience typical complications, such as hemolysis or jaundice. This child underwent Mathieu's flip-flap surgery for the treatment of distal penile hypospadias under spinal anesthesia and underwent the procedure uneventfully, with no hemolytic complications, malignant hyperthermia, or methemoglobinemia. Therefore, the main goals of our anesthesia management are to avoid various agents that cause hemolysis, use agents with antioxidant properties, reduce the stress of surgery through appropriate pain management, and monitor for signs of hemolysis. Therefore, in our case, subarachnoid blockade was found to be a safe and effective anesthetic technique compared with general anesthesia in the treatment of children with G6PD deficiency. Dexmedetomidine has antioxidant properties, maintains upper respiratory tract patency, and has sedative effect. Therefore, in our case, it was administered intravenously for perioperative management.
PubMed: 38406051
DOI: 10.7759/cureus.52998 -
Anesthesiology May 2024
Evaluation of Malignant Hyperthermia Features in Patients with Pathogenic or Likely Pathogenic RYR1 Variants Disclosed through a Population Genomic Screening Program: Erratum.
PubMed: 38376144
DOI: 10.1097/ALN.0000000000004928 -
BJA Education Mar 2024
Review
PubMed: 38375493
DOI: 10.1016/j.bjae.2023.12.003 -
Cureus Jan 2024Central core disease is a rare muscular disorder in which anesthetic considerations for the prevention of malignant hyperthermia and for avoidance of residual...
Central core disease is a rare muscular disorder in which anesthetic considerations for the prevention of malignant hyperthermia and for avoidance of residual neuromuscular block are required. A 63-year-old woman with central core disease underwent thoracoscopic sublobar lung resection under total IV anesthesia with a prepared anesthetic workstation. The rocuronium-induced neuromuscular block was monitored by using acceleromyography at the left adductor pollicis muscle and the right masseter muscle. The recovery of neuromuscular block at the masseter was slower than that at the adductor pollicis. The patient showed no symptoms of malignant hyperthermia and residual neuromuscular block and had an uneventful postoperative course. In the present case, malignant hyperthermia was successfully prevented with general anesthesia that is free of triggering agents using a prepared anesthetic machine. The authors speculate that the masseter may be an auxiliary site for neuromuscular monitoring to ensure recovery from neuromuscular block in patients with central core disease.
PubMed: 38371001
DOI: 10.7759/cureus.52456 -
Brazilian Journal of Anesthesiology... 2024
Topics: Humans; Malignant Hyperthermia; Hotlines; Retrospective Studies; Brazil
PubMed: 38341140
DOI: 10.1016/j.bjane.2024.844482 -
Cureus Jan 2024Neuroleptic malignant syndrome (NMS) is characterized by hyperthermia, severe rigidity, and autonomic instability that is life-threatening if not treated promptly by...
Neuroleptic malignant syndrome (NMS) is characterized by hyperthermia, severe rigidity, and autonomic instability that is life-threatening if not treated promptly by intensive supportive care. However, there have been numerous reports of "atypical NMS" where the diagnostic criteria of NMS are only partially satisfied. We present a case of an elderly male who presented with atypical NMS secondary to antidopaminergic drug administration which precipitated acute respiratory failure. Our patient exhibited features of severe rigidity and autonomic instability, without hyperthermia. He developed tachypneic hypoventilation with type 2 hypercapneic respiratory failure which was treated with non-invasive ventilation (NIV). The patient recovered after three days with resolution of rigidity and was transferred to a normal medical ward on oxygen via a facemask, where he gradually improved. This study highlights that non-invasive ventilation may have a role in treating respiratory failure in mild to moderate cases of atypical NMS, avoiding the need for intubation.
PubMed: 38327911
DOI: 10.7759/cureus.51878 -
Alternative Therapies in Health and... Jan 2024Deep hyperthermia combined with platinum-based chemotherapy (DHCT) might lead to the development of better therapeutic strategy for patients with malignant tumor. This...
OBJECTIVE
Deep hyperthermia combined with platinum-based chemotherapy (DHCT) might lead to the development of better therapeutic strategy for patients with malignant tumor. This study aimed to analyze the computational medical differences in ovarian cancer patients treated with DHCT compared with platinum-based chemotherapy alone.
METHODS
78 patients with advanced ovarian cancer admitted from November 2017 to November 2021 were randomly selected as subjects. Overall survival analysis and CA125 clinical efficiency evaluation were performed to explore the effect of DHCT on cis-platinum therapy. All patients were informed and consented, and approved by the hospital committee. The data were systematically analyzed by chi-squared test to analyze clinical effect and safety observation, and the Kaplan-Meier method and log-rank test were used for survival analysis.
RESULTS
Survival analysis showed that DHCT was strongly associated with improved overall survival (OS) in the platinum treatment of ovarian cancer patients (Hazard Ratio = 1.57, 95% CI: 0.93-2.44, P = .017). For ovarian cancer patients receiving lobaplatin treatment, DHCT could also elevate their survival (Hazard Ratio = 1.52, 95% CI :1.02-2.25, P = .013). The study also showed a statistically significant difference in clinical outcomes between the two groups (P < .001), and the opposite is true for adverse reactions.
CONCLUSION
Our results suggest that DHCT is expected to be combined with platinum chemotherapy, which is helpful for the molecular classification of ovarian cancer patients. More studies are needed to further verified the clinical significance.
PubMed: 38290437
DOI: No ID Found -
Pharmaceuticals (Basel, Switzerland) Jan 2024Despite efforts in osteosarcoma (OS) research, the role of inductive moderate hyperthermia (IMH) in delivering and enhancing the antitumor effect of liposomal...
Despite efforts in osteosarcoma (OS) research, the role of inductive moderate hyperthermia (IMH) in delivering and enhancing the antitumor effect of liposomal doxorubicin formulations (LDOX) remains unresolved. This study investigated the effect of a combination treatment with LDOX and IMH on Saos-2 human OS cells. We compared cell viability using a trypan blue assay, apoptosis and reactive oxygen species (ROS) measured by flow cytometry and pro-apoptotic Bax protein expression examined by immunocytochemistry in response to IMH (42 MHz frequency, 15 W power for 30 min), LDOX (0.4 μg/mL), and LDOX plus IMH. The lower IC value of LDOX at 72 h indicated increased accumulation of the drug in the OS cells. LDOX plus IMH resulted in a 61% lower cell viability compared to no treatment. Moreover, IMH potentiated the LDOX action on the Saos-2 cells by promoting ROS production at temperatures of <42 °C. There was a 12% increase in cell populations undergoing early apoptosis with a less heterogeneous distribution of Bax after combination treatment compared to those treated with LDOX ( < 0.05). Therefore, we determined that IMH could enhance LDOX delivery and its antitumor effect via altered membrane permeabilization, ROS generation, and a lower level of visualized Bax heterogeneity in the Saos-2 cells, suggesting the potential translation of these findings into in vivo studies.
PubMed: 38276006
DOI: 10.3390/ph17010133