Progressive multiple sclerosis is associated with metabolic failure of the axon and excitotoxicity that leads to chronic neurodegeneration. Global sodium-channel blockade causes side effects that can limit its use for neuroprotection in multiple sclerosis. Through selective targeting of drugs to lesions we aimed to improve the potential therapeutic window for treatment. This was assessed in the relapsing-progressive experimental autoimmune encephalomyelitis ABH mouse model of multiple sclerosis using conventional sodium channel blockers and a novel central nervous system-excluded sodium channel blocker (CFM6104) that was synthesized with properties that selectively target the inflammatory penumbra in experimental autoimmune encephalomyelitis lesions. Carbamazepine and oxcarbazepine were not immunosuppressive in lymphocyte-driven autoimmunity, but slowed the accumulation of disability in experimental autoimmune encephalomyelitis when administered during periods of the inflammatory penumbra after active lesion formation, and was shown to limit the development of neurodegeneration during optic neuritis in myelin-specific T cell receptor transgenic mice. CFM6104 was shown to be a state-selective, sodium channel blocker and a fluorescent p-glycoprotein substrate that was traceable. This compound was >90% excluded from the central nervous system in normal mice, but entered the central nervous system during the inflammatory phase in experimental autoimmune encephalomyelitis mice. This occurs after the focal and selective downregulation of endothelial p-glycoprotein at the blood-brain barrier that occurs in both experimental autoimmune encephalomyelitis and multiple sclerosis lesions. CFM6104 significantly slowed down the accumulation of disability and nerve loss in experimental autoimmune encephalomyelitis. Therapeutic-targeting of drugs to lesions may reduce the potential side effect profile of neuroprotective agents that can influence neurotransmission. This class of agents inhibit microglial activity and neural sodium loading, which are both thought to contribute to progressive neurodegeneration in multiple sclerosis and possibly other neurodegenerative diseases.
The conventional treatment for patients with acute upper airway obstruction is tracheostomy, which is a safe, definitive procedure in most hands. Alternatively, a debulking procedure can be considered but this requires both surgical and anaesthetic skill and expertise. However, where possible, it provides a good alternative with the advantages of removing the cause of obstruction and yielding tissue for histopathological analysis, and avoiding the need for a tracheostomy, with its associated morbidity. We evaluated all patients who presented with acute upper airway obstruction and underwent endoscopic laser debulking surgery performed by the senior author, over a three and a half year period. We recorded patient demographic data, their underlying pathologies, complication rates associated with laser debulking surgery and the conversion to tracheostomy. Thirty patients were identified, including 19 males and 11 females, with a mean age of 57.10 ± 17.20 years (19-93 years). All patients underwent debulking procedures with carbon dioxide laser under general anaesthetic. All patients had their underlying diagnosis confirmed from their debulking surgery. Twelve patients were found to have benign pathology and 18 had malignant airway obstruction. There were no laser-associated complications. One patient required conversion to emergency tracheostomy, during their debulking surgery. Endoscopic laser assisted debulking surgery has successfully been used to establish a safe airway. It allows obtaining tissue specimens, to confirm the underlying diagnosis, thus avoiding the need for further biopsies under anaesthetic. For all malignant cases, patients were subsequently able to proceed to definitive treatment. It has obviated the need for emergency tracheostomy in almost all of the cases in our patient cohort.
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