Werling Linda L, Lauterbach Edward C, Calef Ursula
The Institute for Biomedical Sciences, The George Washington University Medical Center, Washington, DC, USA.
Neurologist. 2007 Sep;13(5):272-93. doi: 10.1097/NRL.0b013e3180f60bd8.
Dextromethorphan (DM) is a widely-used antitussive. DM's complex central nervous system (CNS) pharmacology became of interest when it was discovered to be neuroprotective due to its low-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonism.
Mounting preclinical evidence has proven that DM has important neuroprotective properties in various CNS injury models, including focal and global ischemia, seizure, and traumatic brain injury paradigms. Many of these protective actions seem functionally related to its inhibitory effects on glutamate-induced neurotoxicity via NMDA receptor antagonist, sigma-1 receptor agonist, and voltage-gated calcium channel antagonist actions. DM's protection of dopamine neurons in parkinsonian models may be due to inhibition of neurodegenerative inflammatory responses. Clinical findings are limited, with preliminary evidence indicating that DM protects against neuronal damage. Negative findings seem to relate to attainment of inadequate DM brain concentrations. Small studies have shown some promise for treatment of perioperative brain injury, amyotrophic lateral sclerosis, and symptoms of methotrexate neurotoxicity. DM safety/tolerability trials in stroke, neurosurgery, and amyotrophic lateral sclerosis patients demonstrated a favorable safety profile. DM's limited clinical benefit is proposed to be associated with its rapid metabolism to dextrorphan, which restricts its central bioavailability and therapeutic utility. Systemic concentrations of DM can be increased via coadministration of low-dose quinidine (Q), which reversibly inhibits its first-pass elimination. Potential drug interactions with DM/Q are discussed.
Given the compelling preclinical evidence for neuroprotective properties of DM, initial clinical neuroprotective findings, and clinical demonstrations that the DM/Q combination is well tolerated, this strategy may hold promise for the treatment of various acute and degenerative neurologic disorders.
右美沙芬（DM）是一种广泛使用的止咳药。当发现它由于低亲和力、非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗作用而具有神经保护作用时，其复杂的中枢神经系统（CNS）药理学特性引起了人们的兴趣。
越来越多的临床前证据表明，DM在各种中枢神经系统损伤模型中具有重要的神经保护特性，包括局灶性和全脑缺血、癫痫和创伤性脑损伤模型。这些保护作用中的许多似乎在功能上与其通过NMDA受体拮抗剂、σ-1受体激动剂和电压门控钙通道拮抗剂作用对谷氨酸诱导的神经毒性的抑制作用有关。DM在帕金森病模型中对多巴胺神经元的保护作用可能是由于抑制了神经退行性炎症反应。临床研究结果有限，初步证据表明DM可预防神经元损伤。阴性结果似乎与DM在脑内浓度不足有关。小型研究显示，DM在治疗围手术期脑损伤、肌萎缩侧索硬化症和甲氨蝶呤神经毒性症状方面有一定前景。对中风、神经外科手术和肌萎缩侧索硬化症患者进行的DM安全性/耐受性试验显示出良好的安全性。DM有限的临床益处被认为与其快速代谢为右啡烷有关，这限制了其在中枢的生物利用度和治疗效用。通过联合使用低剂量奎尼丁（Q）可以提高DM的全身浓度，奎尼丁可可逆地抑制其首过消除。讨论了与DM/Q潜在的药物相互作用。
鉴于DM神经保护特性的临床前证据令人信服、初步的临床神经保护研究结果以及DM/Q组合耐受性良好的临床证明，该策略可能对治疗各种急性和退行性神经系统疾病具有前景。
