Kemoterapiye Bağlı Nöropatik Ağrı: Mekanizmalar ve Yeni Farmakolojik Yaklaşımlar
Özet
Kemoterapiye bağlı periferik nöropati (KBPN), çeşitli nörotoksik antineoplastik ajanların sıklıkla görülen ve doz sınırlayıcı bir yan etkisi olup, hastaların yaşam kalitesini ciddi şekilde düşüren kronik ve debilitan bir tabloya evrilebilmektedir. KBPN’nin patofizyolojisi; aksonal dejenerasyon, mikrotübül bozulması, mitokondriyal disfonksiyon, oksidatif stres, nöroenflamasyon, iyon kanalı disregülasyonu ve inhibitör nörotransmisyon kaybı gibi kompleks ve çok faktörlü mekanizmalarla ilerlemektedir. Mevcut tedavi stratejileri büyük ölçüde semptomatiktir ve genel nöropatik ağrı kılavuzlarından uyarlanan ilaçlar (ör. duloksetin, gabapentinoidler) yetersiz veya tutarsız etkinlik göstermektedir; onaylanmış etkili bir koruyucu veya hastalık modifiye edici ajan bulunmamaktadır. Bu bölümde, KBPN’nin klinik özellikleri ve altında yatan moleküler mekanizmalar güncel literatür ışığında gözden geçirilmiştir. Ayrıca, semptomatik palyasyonun ötesine geçerek nöroproteksiyon, hastalık modifikasyonu ve rejenerasyonu hedefleyen yeni farmakolojik yaklaşımlar değerlendirilmiştir. Yeniden konumlandırılan tedaviler (özellikle yeni nesil antiepileptik senobamat, NMDA antagonistleri ve antidiyabetikler), seçici iyon kanalı modülatörleri, antioksidanlar, kannabinoidler, kök hücre kaynaklı egzosomlar, gen tedavisi ve epigenetik/immünomodülatör ajanlar gibi mekanizma temelli yeni nesil stratejilerin KBPN yönetimindeki potansiyel rolleri ve klinik öncesi/klinik veriler tartışılmıştır.
Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent, dose-limiting adverse effect of various neurotoxic antineoplastic agents that can evolve into a chronic, debilitating condition severely impairing patients' quality of life. The pathophysiology of CIPN progresses through complex, multifactorial mechanisms, including axonal degeneration, microtubule disruption, mitochondrial dysfunction, oxidative stress, neuroinflammation, ion channel dysregulation, and loss of inhibitory neurotransmission. Current management strategies are largely symptomatic, and drugs adapted from general neuropathic pain guidelines (e.g., duloxetine, gabapentinoids) demonstrate limited or inconsistent efficacy; furthermore, there are no approved prophylactic or disease-modifying agents. This chapter reviews the clinical features and underlying molecular mechanisms of CIPN in light of current literature. Additionally, novel pharmacological approaches targeting neuroprotection, disease modification, and regeneration beyond symptomatic palliation are evaluated. The potential roles and preclinical/clinical data of mechanism-based next-generation strategies—such as repurposed therapies (particularly the novel antiepileptic cenobamate, NMDA antagonists, and antidiabetics), selective ion channel modulators, antioxidants, cannabinoids, stem cell-derived exosomes, gene therapy, and epigenetic/immunomodulatory agents—in CIPN management are discussed.
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