This multiple‐ascending‐dose study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P₁ receptor modulator and a potential new treatment for autoimmune diseases. In part A, 10 healthy male and female subjects received once daily oral doses of ponesimod (5, 10, or 20 mg) or placebo for 7 days. Sinus bradycardia and, in some subjects, atrioventricular (AV) block occurred primarily on the first day of dosing, as desensitization developed to ponesimod‐induced heart rate (HR) reduction and PR‐prolongation. This elicited the design of an up‐titration schedule in 17 subjects to a dose of 40 mg in part B. The up‐titration regimen reduced HR and PQ/PR effects. Reported adverse events were mainly related to the cardiac and respiratory systems. Respiratory effects increased with higher doses. Ponesimod multiple‐dose pharmacokinetics were slightly more than dose‐proportional and characterized by a time to maximum concentration and an elimination half‐life varying from 2.5 to 4.0 hours and 30.9 to 33.5 hours, respectively, and an accumulation of about 2.3‐fold. Ponesimod caused a dose‐dependent sustained decrease in total lymphocyte count, reversible within 7 days of discontinuation. A pharmacokinetic–pharmacodynamic model enabled comparing day 1 and steady‐state conditions. These results warrant further investigation of ponesimod in patients.

Background: Subarachnoid hemorrhage (SAH) is a severe neurological condition with high mortality and morbidity rates, often exacerbated by secondary complications such as inflammation, cerebral vasospasm, and apoptosis. Proinflammatory cytokines, including interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), play critical roles in these pathological processes. Anakinra, an IL-1 receptor antagonist, has demonstrated significant anti-inflammatory effects in various disease models. This study aimed to evaluate the efficacy of anakinra in mitigating inflammation, vasospasm, and apoptosis in an experimental rat model of SAH. Methods: Thirty-two male Sprague Dawley rats were divided into four groups: Control (healthy), SAH (no treatment), Saline (0.2 mL saline subcutaneously), and Anakinra (50 mg/kg subcutaneously, twice daily). Proinflammatory markers (CRP, TNF-α, IL-1, IL-6, and fibrinogen) were measured in serum and cerebrospinal fluid (CSF) at 3, 7, and 10 days post-SAH. Basilar artery diameter was evaluated histopathologically, and Caspase-3 expression was assessed immunohistochemically to determine apoptotic activity. Results: SAH significantly increased levels of CRP, TNF-α, IL-1, IL-6, and fibrinogen in both serum and CSF, reduced basilar artery diameter, and elevated Caspase-3 expression compared to the Control group. Saline treatment provided limited improvements, with inflammatory markers and histopathological parameters remaining elevated. Anakinra treatment significantly reduced inflammatory markers, restored basilar artery diameter, and lowered Caspase-3 expression, highlighting its efficacy in mitigating inflammation, vasospasm, and apoptosis. Conclusions: Anakinra effectively suppresses inflammation, alleviates cerebral vasospasm, and inhibits apoptosis in an experimental model of SAH. These findings suggest its potential as a therapeutic agent for managing SAH and its complications. Further research is needed to explore its clinical applicability and long-term effects.

Objective: Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular condition that triggers a robust inflammatory response and cerebral vasospasm. This study aimed to evaluate the effects of anakinra, an interleukin-1 receptor antagonist, and tocilizumab, an interleukin-6 receptor antagonist, on inflammation and vasospasm in an experimental rat SAH model. Methods: Forty male Sprague Dawley rats (200–250 g) were randomly assigned to five groups: control, SAH, SAH + anakinra (ANA), SAH + tocilizumab (TCZ), and SAH + anakinra + tocilizumab (ANA+TCZ). SAH was induced by injecting non-heparinized arterial blood into the cisterna magna. Treatment groups received anakinra (50 mg/kg twice daily), tocilizumab (8 mg/kg once daily), or their combination for three days. Blood and cerebrospinal fluid (CSF) samples were analyzed for inflammatory markers (IL-1, IL-6, TNF-α, CRP), and histopathological evaluations were conducted to assess vasospasm and apoptosis. Results: SAH significantly increased pro-inflammatory cytokines (IL-1, IL-6, TNF-α, CRP) and fibrinogen levels in serum and CSF while reducing the basilar artery lumen diameter (p < 0.001). Anakinra and tocilizumab treatments significantly reduced inflammatory markers and vasospasm severity compared to the SAH group (p < 0.05). Combination therapy was more effective in reducing inflammation and vasospasm than either treatment alone (p < 0.05). Anakinra showed a stronger effect on IL-1 reduction, while tocilizumab was more effective in lowering IL-6 levels. The ANA+TCZ group exhibited a significant decrease in caspase activity, indicating reduced apoptosis (p < 0.05). Conclusions: Anakinra and tocilizumab effectively mitigated inflammation and vasospasm in an experimental SAH model, with combination therapy showing superior efficacy. These findings suggest that targeting both IL-1 and IL-6 pathways may be a promising therapeutic strategy for managing SAH complications. Further studies are warranted to evaluate long-term outcomes and clinical implications.

Türkiye genelindeki cerrahlar tarafından gerçekleştirilen karmaşık spinal cerrahi operasyonlarının vaka bazlı sunumlarını ve deneyimli hocaların bu vakalara yönelik analizlerini içermektedir. Servikal, torakal ve lomber bölgelerdeki tümörler, travmalar, anomaliler ve dejeneratif hastalıklar gibi zorlayıcı klinik durumlar; tanı, cerrahi teknik ve postoperatif takip süreçleriyle birlikte detaylandırılmıştır. Eser, cerrahların kendi bakış açılarının yanı sıra kıdemli bir hakem yorumcu desteğiyle vaka tecrübesini zenginleştirmeyi ve eğitim süreçlerine pratik katkı sağlamayı hedeflemektedir. Presents case-based reports of complex spinal surgeries performed by surgeons across Turkey, accompanied by analytical reviews from senior experts. It details diagnostic processes, surgical techniques, and postoperative follow-ups for challenging conditions such as tumors, traumas, anomalies, and degenerative diseases in the cervical, thoracic, and lumbar regions. The work aims to enrich clinical experience and contribute to neurosurgical education by combining individual surgical perspectives with senior peer reviews.

14 yaşındaki bir kadın hasta, yürüme bozukluğu ve spastik tetraparazi şikayetleriyle başvurmuş; yapılan incelemelerde C2-C3 instabilitesi, Klippel-Feil sendromu ve tip B baziler invajinasyon tespit edilmiştir. Daha önce geçirdiği başarısız operasyon sonrası semptomları artan hastaya, mevcut anatomik anomaliler ve instabilite göz önünde bulundurularak atlas, C2 ve C5 seviyelerini kapsayan geniş bir enstrümantasyon ve füzyon cerrahisi uygulanmıştır. Postoperatif dönemde herhangi bir komplikasyon gelişmemiş olup, cerrahi müdahale ile kranioservikal bileşkedeki patolojilerin stabilizasyonu hedeflenmiştir. A 14-year-old female patient presented with gait disturbance and spastic quadriparesis, leading to the diagnosis of C2-C3 instability, Klippel-Feil syndrome, and type B basilar invagination. Following a previously unsuccessful operation that resulted in worsening symptoms, the patient underwent an extensive instrumentation and fusion surgery spanning from the assimilated atlas to the C5 level. The procedure was completed without postoperative complications, effectively addressing the complex craniovertebral junction pathologies through stabilization.