The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis.

Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl-) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise. Here, we show that partial inhibition of ClC-1 with an orally bioavailable small molecule (NMD670) can restore muscle function in rat models of MG and in patients with MG. In severely affected MG rats, ClC-1 inhibition enhanced neuromuscular transmission, restored muscle function, and improved mobility after both single and prolonged administrations of NMD670. On this basis, NMD670 was progressed through nonclinical safety pharmacology and toxicology studies, leading to approval for testing in clinical studies. After successfully completing phase 1 single ascending dose in healthy volunteers, NMD670 was tested in patients with MG in a randomized, placebo-controlled, single-dose, three-way crossover clinical trial. The clinical trial evaluated safety, pharmacokinetics, and pharmacodynamics of NMD670 in 12 patients with mild MG. NMD670 had a favorable safety profile and led to clinically relevant improvements in the quantitative myasthenia gravis (QMG) total score. This translational study spanning from single muscle fiber recordings to patients provides proof of mechanism for ClC-1 inhibition as a potential therapeutic approach in MG and supports further development of NMD670.

Idiopathic delayed-onset edema surrounding deep brain stimulation leads: Insights from a case series and systematic literature review.

INTRODUCTION: Deep brain stimulation (DBS) is effective for some neurological and psychiatric conditions. Idiopathic delayed-onset edema (IDE) surrounding the leads has been anecdotally reported. The etiology, predisposing factors and prognosis of this complication are unknown. We present a multicenter case series of patients with IDE, and a systematic literature review, aimed at defining the pathophysiology and identifying appropriate treatment strategies. METHODS: IDE was defined as edema along the DBS lead, occurring ≥72 h postoperatively, in absence of trauma, vascular events or infection. Information on patients with IDE was collected in a standardized way. A systematic search was performed in Pubmed. RESULTS: Twelve new patients presenting with 14 episodes of IDE are described. From the literature, 38 patients were identified. No common surgical aspects or patient-related factors were identified as risk predictors for the onset of IDE. Symptoms included deterioration of the stimulation effect, seizures and focal neurological signs. Although the condition is self-limiting, with symptoms resolution in 28.5 days on average, three patients underwent surgical revision and seven received antibiotics. CONCLUSIONS: IDE is a rare complication of DBS procedures, presenting from few days to months after surgery. Symptoms can be mild and not-specific, and the condition is self-limiting. The diagnosis of IDE is made after exclusion of vascular events or infections. The pathophysiology is still unexplained. The recognition of this complication can help avoiding unnecessary surgical procedures (system explantation) and antibiotic treatment.