We read with interest the papers by Brenner1 and Cimolai2 regarding the therapeutic potential of memantine for coronavirus disease 2019 (COVID‐19). Memantine, an adamantane derivative and an N‐methyl‐D‐aspartate (NMDA) receptor antagonist that reduces glutamate toxicity by decreasing the prolonged Ca²⁺ influx in neurons, is used for treating Alzheimer's disease.

Angiotensin‐converting enzyme 2 (ACE2), a cell surface receptor for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), is widely distributed in multiple organs, including the nose, lungs, kidneys, liver, blood vessels, immune system, and brain. Memantine may be a candidate drug for COVID‐19 treatment as it interferes with NMDA activity and inhibits excess glutamate release in the medulla, which is a potential neurotoxic effect resulting from ACE2 depletion and which contributes to the development of acute respiratory distress syndrome via activating the sympathetic nervous system, thereby leading to increased blood pressure, systemic vasoconstriction, and pulmonary capillary leakage.1, 2 Memantine also directly inhibits viral replication through potential interaction with viral E protein and lysosomal function.3

A recent study reported that 22 patients with the neurologic disorder who were diagnosed with polymerase chain reaction‐confirmed SARS‐CoV‐2 infection and treated with memantine or related adamantanes did not develop clinical symptoms of COVID‐19.4 Brenner1 introduced this study and commented that memantine and related adamantanes might exert an antiviral effect on COVID‐19. However, 80% of patients with COVID‐19 experience only mild or no symptoms at all, and only 15% have severe infection requiring oxygen.5 Moreover, the abovementioned study had a small sample size, which affects the reliability of the results.

Thus, we evaluated the national COVID‐19 claim database of South Korea6 and identified 5726 patients with confirmed COVID‐19, of whom 140 had died. The relationship between treatment with memantine and COVID‐19‐associated mortality was investigated.

Our observations revealed no statistically significant relationship between COVID‐19‐associated mortality and ongoing treatment with memantine after adjustment for clinically relevant potential confounders of age, sex, and/or comorbidities. This result was consistently observed both in the overall analysis of all patients with COVID‐19 and in the subgroup analysis that was limited to patients with dementia (Figure 1).

Our results should be interpreted with caution given the disadvantage associated with retrospective analyses and reliability of data. However, memantine is typically prescribed to older patients, who are at higher risk of COVID‐19, and, therefore, ideal candidates for retrospective investigations aimed at determining whether memantine has therapeutic effects on COVID‐19.

In conclusion, our analysis revealed no association between memantine treatment and mortality in patients with COVID‐19. However, we must explore all feasible options for preventing and treating COVID‐19 due to the current lack of licensed vaccines or therapeutics for the disease. A low‐risk and cost‐effective strategy could be trial repurposing of medications that are inexpensive and readily available. Future studies should analyze whether memantine can shorten the clinical course and/or improve patient outcomes according to disease severity as well as overall mortality of COVID‐19.

我们感兴趣地阅读了 Brenner 1和 Cimolai 2关于美金刚对 2019 年冠状病毒病 (COVID-19) 的治疗潜力的论文。美金刚是一种金刚烷衍生物和N-甲基-D-天冬氨酸 (NMDA) 受体拮抗剂，可通过减少神经元中延长的 Ca ²⁺内流来降低谷氨酸毒性，用于治疗阿尔茨海默病。

血管紧张素转换酶 2 (ACE2) 是严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的细胞表面受体，广泛分布于多个器官，包括鼻、肺、肾、肝、血管、免疫系统，和大脑。美金刚可能是 COVID-19 治疗的候选药物，因为它会干扰 NMDA 活性并抑制髓质中过量谷氨酸的释放，这是由 ACE2 耗竭引起的潜在神经毒性作用，并通过激活交感神经系统，从而导致血压升高、全身血管收缩和肺毛细血管渗漏。1, 2美金刚还通过与病毒 E 蛋白和溶酶体功能的潜在相互作用直接抑制病毒复制。3

最近的一项研究报告称，22 名被诊断为聚合酶链反应确诊的 SARS-CoV-2 感染并接受美金刚或相关金刚烷治疗的神经系统疾病患者没有出现 COVID-19 的临床症状。4 Brenner 1介绍了这项研究并评论说美金刚和相关的金刚烷可能对 COVID-19 发挥抗病毒作用。然而，80% 的 COVID-19 患者仅出现轻微症状或根本没有症状，只有 15% 的患者出现需要吸氧的严重感染。5此外，上述研究的样本量较小，影响了结果的可靠性。

因此，我们评估了韩国6的国家 COVID-19 索赔数据库，并确定了 5726 名确诊的 COVID-19 患者，其中 140 人死亡。研究了美金刚治疗与 COVID-19 相关死亡率之间的关系。

我们的观察结果显示，在调整了年龄、性别和/或合并症的临床相关潜在混杂因素后，COVID-19 相关死亡率与持续使用美金刚治疗之间没有统计学上的显着关系。这一结果在所有 COVID-19 患者的总体分析和仅限于痴呆患者的亚组分析中都得到了一致的观察（图 1）。

鉴于与回顾性分析和数据可靠性相关的缺点，我们的结果应谨慎解释。然而，美金刚通常开给老年患者，他们患 COVID-19 的风险较高，因此是回顾性研究的理想候选者，旨在确定美金刚是否对 COVID-19 有治疗作用。

总之，我们的分析显示美金刚治疗与 COVID-19 患者的死亡率之间没有关联。但是，由于目前缺乏针对该疾病的许可疫苗或疗法，我们必须探索预防和治疗 COVID-19 的所有可行方案。一种低风险且具有成本效益的策略可能是尝试重新利用廉价且易于获得的药物。未来的研究应根据疾病严重程度以及 COVID-19 的总体死亡率分析美金刚是否可以缩短临床病程和/或改善患者预后。