Influenza A viruses; ion channels NMDA, M2; CDK2; Bcl-2; Bax

盐酸金刚烷胺 (0-500 μM，26 小时) 抑制 SARS-CoV-2 复制，IC50 浓度在 83 和 119 μM 之间[4]。 盐酸金刚烷胺 (0-100 μg/mL，24-72 h) 显着抑制 HepG2。盐酸金刚烷胺 (0-75 μg/mL，48 h) 将细胞周期阻滞在 G0/G1 期并诱导细胞的肿胀[6]。 盐酸金刚烷胺 (0-75 μg) 和 SMMC-7721 细胞的肿胀[6]。 /mL，48 h) 可降低细胞周期相关基因和蛋白（cyclin D1、cyclin E 和 CDK2），减少 Bcl-2 并增加 Bax 蛋白和 mRNA 水平[6]。 Cell Viability Assay[4] Cell Line: Vero E6细胞浓度：500 µM、100 µM、20 µM、4 µM 和 8 nM 孵育时间：26 小时 结果：10 ℃感染 26 小时后，导致上清液中病毒核酸浓度依赖性减少（IC50=83 µM） -500 µM。感染后 26 小时，导致细胞质中病毒核酸浓度依赖性减少 (IC50=119 µM)。细胞增殖测定[6] 细胞系：人 HCC 细胞系（HepG2 和 SMMC-7721）和正常肝细胞（L02 细胞） 浓度：0、1、2、5、10、25、50 和 100 µg/mL 孵育时间：24、48 和 72 小时 结果：在 HepG2 和 SMMC-7721 细胞中以时间和剂量依赖性方式抑制细胞增殖。细胞周期分析[6] 细胞系：HepG2 和 SMMC-7721 细胞 浓度：0、10、25、50 和 75 µg/mL 孵育时间：48 小时 结果：G0 期 HepG2 和 SMMC-7721 细胞数量显着增加/G1期呈剂量依赖性，并显着减少S期HepG2细胞的数量。细胞凋亡分析[6] 细胞系：HepG2 和 SMMC-7721 细胞 浓度：0、10、25、50 和 75 µg/mL 孵育时间：48 小时 结果：凋亡 HepG2 和 SMMC-7721 细胞的百分比显着增加（早期-和晚期细胞凋亡）以剂量依赖性方式。 Western Blot 分析[6] 细胞系：HepG2 和 SMMC-7721 细胞 浓度：0、10、25、50 和 75 µg/mL 孵育时间：48 h 结果：显示 cyclin D1、cyclin E 和 CDK2 下调，并显示HepG2 和 SMMC-7721 细胞中 Bcl-2 水平降低，Bax 水平升高。 RT-PCR[6] 细胞系：HepG2 和 SMMC-7721 细胞 浓度：0、10、25、50 和 75 µg/mL 孵育时间：48 小时 结果：显示 Bax 增加，Bcl-2 基因减少。

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金刚烷胺（0-500 µM，26 小时）抑制 SARS-CoV-2 复制的 IC50 值范围为 83 至 119 µM [4]。金刚烷胺（0-100 µg/mL，24-72 小时）强烈抑制 HepG2 和 SMMC-7721 细胞生长 [6]。金刚烷胺（0-75 µg/mL，48 小时）会导致细胞凋亡并使细胞周期停止在 G0/G1 期 [6]。金刚烷胺（0-75 µg/mL，48 小时）可降低 Bcl-2，增加 Bax 蛋白和 mRNA 水平，并降低细胞周期相关基因和蛋白（细胞周期蛋白 D1、细胞周期蛋白 E 和 CDK2）[6]。

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自2019年底严重急性呼吸系统综合征冠状病毒2型疫情开始以来，寻找保护性疫苗和药物治疗已成为应对全球卫生紧急情况的强制性措施。旅行限制、社交距离和口罩是合适的应对措施，但可能无法控制疫情，因为人们会无意中或在一定程度的限制严重程度或持续时间内不遵守规定。即使疫苗获得批准，对抗严重急性呼吸系统综合征冠状病毒2型的抗病毒药物的需求也将持续存在。然而，迄今为止，尚未有明确证据表明任何重新使用的抗病毒药物对严重急性呼吸系统综合征冠状病毒2型有疗效金刚烷胺已被批准为抗甲型流感的抗病毒药物，对严重急性呼吸系统综合征冠状病毒2型的抗病毒活性已通过类比得出，但没有数据。我们在体外测试了金刚烷胺对感染严重急性呼吸系统综合征冠状病毒2型的Vero E6细胞的疗效。事实上，金刚烷胺在两个单独的实验中抑制了严重急性呼吸系统综合征冠状病毒2型的复制，IC50浓度在83至119µM之间。尽管这些IC50浓度在全身给药后高于治疗性金刚烷胺水平，但通过吸入或鼻内滴注局部给药可能会导致气道上皮中金刚烷胺浓度充足，而不会产生高全身暴露。然而，需要在其他模型中进行进一步的研究来证明这一假设。[4]

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肝细胞癌（HCC）是全球最具侵袭性的恶性肿瘤之一，近年来与病毒感染相关的发病率有所增加金刚烷胺是一种三环对称胺，可以有效预防丙型肝炎病毒。然而，其抗肿瘤特性尚不清楚。本研究探讨了金刚烷胺对肿瘤细胞存活率、细胞周期调控和凋亡的影响。MTT法检测HepG2和SMMC-7721细胞（HCC细胞系）的生长情况。流式细胞术用于研究细胞周期调控和凋亡。还进行了逆转录定量聚合酶链式反应和蛋白质印迹分析，以检测细胞周期和凋亡相关基因和蛋白质的表达，包括细胞周期蛋白E、细胞周期蛋白D1、细胞周期素依赖性激酶2（CDK2）、B细胞淋巴瘤2（Bcl-2）和Bax。我们的研究结果表明，金刚烷胺以剂量和时间依赖的方式显著抑制HepG2和SMMC-7721细胞的增殖，并将细胞周期阻滞在G0/G1期。金刚烷胺降低了细胞周期相关基因和蛋白质（细胞周期蛋白D1、细胞周期蛋白E和CDK2）的水平，并显著诱导了细胞凋亡。金刚烷胺治疗还降低了Bcl-2，增加了Bax蛋白和mRNA水平。此外，金刚烷胺治疗后，两种HCC细胞系的Bcl-2/Bax比值较低。总的来说，这些结果强调了金刚烷胺在抑制HCC细胞增殖和诱导凋亡方面的作用，主张将其作为一种新型的肿瘤抑制治疗候选药物[6]。

盐酸金刚烷胺（25 mg/kg，IP，每天一次，持续3天）抑制调节引起的神经调节和学习记忆障碍[5]。 动物模型：Fischer 344大鼠（4月龄，雄性，290-330 g，每组15只大鼠）[5] 剂量：25 mg/kg 给药方式：IP，每日一次，连续3天（手术前15分钟第一次给药） 结果：抑制手术引起的神经炎症和学习记忆障碍，增加GDNF（胶质细胞）线源性神经营养因子）与海马体中的神经胶质原纤维酸性蛋白（星形细胞标记物）共定位。

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金刚烷胺（25 mg/kg，IP，每天一次，持续 3 天）可减少手术引起的神经炎症以及学习和记忆缺陷 [5]。
在训练后1天或8天进行测试时，手术增加了在巴恩斯迷宫中识别目标框的时间[22（中位数）（11-66）（四分位数间距）对照组对158（29-180）手术组，n=15，P=0.022），并减少了恐惧条件测试中与背景相关的冷冻行为。这些影响被金刚烷胺和侧脑室GDNF减弱。金刚烷胺增加了与星形胶质细胞标志物胶质纤维酸性蛋白共定位的GDNF。海马。侧脑室注射抗GDNF抗体而不是变性抗体阻断了金刚烷胺对认知的影响。手术诱导的神经炎症被金刚烷胺抑制。脂多糖增加了C8-B4细胞白细胞介素1β的产生。这种作用被GDNF抑制[5]。

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金刚烷胺减轻了手术引起的学习记忆障碍[5]
随着对照组大鼠、仅接受麻醉的大鼠、只接受Amantadine金刚烷胺的大鼠和接受手术加金刚烷胺的大鼠训练时间的增加，巴恩斯迷宫试验4天训练期间识别目标框的时间缩短了。这四组大鼠在第4天的时间明显短于第1天。这种效果在单独手术后的大鼠身上并不明显。手术对训练课程中识别目标框所需的时间有显著影响[F（1,28）=5.625，P=0.025]。金刚烷胺可消除这种作用[F（1,28）=0.840，P=0.367；与对照组相比]。金刚烷胺或麻醉对训练期间识别目标框的时间没有显著影响[F（1,28）=0.063，P=0.804；F（1,14）=0.074，P+0.790]（图1和图2）。当在训练课程后1天对大鼠进行测试时，接受手术的大鼠识别目标框的时间比对照组大鼠长。金刚烷胺可以减轻这种延长。在训练课程结束8天后进行测试时，也出现了类似的变化模式。然而，无论测试是在训练后1天还是8天进行，单独使用麻醉和金刚烷胺都不会影响识别目标框的时间（图1B和2B）。 与对照组大鼠相比，手术组大鼠（而非仅麻醉组或金刚烷胺组大鼠）在恐惧条件反射测试中的情境相关冷冻行为较少。金刚烷胺消除了这种手术效果（图1C）。对照组、接受金刚烷胺治疗的大鼠、接受手术的大鼠和接受手术加金刚烷胺的大鼠在音调相关的冷冻行为方面没有差异（图1C和2C）。

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金刚烷胺减轻了手术引起的神经炎症[5]
术后6小时和24小时，海马中Iba-1（一种小胶质细胞标志物）、IL-1β和IL-6的表达显著增加。Amantadine金刚烷胺消除了这些增加（图3和图4）。同样，手术后10天，海马齿状回区域的Iba-1表达也增加，这种增加被金刚烷胺阻断（图5）。这些结果表明，手术诱导了金刚烷胺抑制的神经炎症。

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金刚烷胺增加了抑制小胶质细胞活化的GDNF的表达[5]
金刚烷胺/Amantadine显著增加了海马中的GDNF（图7）。GDNF主要与星形胶质细胞标志物GFAP共定位，但与Iba-1不共定位（图7A和7B）。一些GDNF似乎位于神经元标记物NeuN周围（图7C）。手术也增加了GFAP，但这种增加不受海马中金刚烷胺的影响（图7A和7E）。

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抗GDNF抗体可抑制金刚烷胺诱导的术后学习记忆障碍的减弱[5]
与对照组大鼠相似，仅抗体组和手术加金刚烷胺/Amantadine加煮沸抗体组的大鼠找到目标框的时间缩短，训练次数增加。这两组大鼠在训练第4天的时间比训练第1天的时间短。对于手术加金刚烷胺加抗GDNF抗体组的大鼠来说，这种效果并不明显。研究发现，抗GDNF抗体对训练期间识别目标框的时间有显著影响[F（1,14）=19.009，P<0.001；与对照组相比）（图9A）。训练后第1天识别目标框所需的时间在对照组大鼠、接受抗体的大鼠、接受手术加金刚烷胺加抗-GDNF抗体或接受手术加金刚烷基胺加煮沸抗体的大白鼠之间没有差异。然而，接受手术加金刚烷胺加抗-DDNF抗体的大老鼠在训练后第8天需要比对照组大白鼠或接受手术加金刚烷胺加煮沸抗体的老鼠更长的时间来识别目标框（图9B）。 同样，在恐惧条件测试中，接受手术加金刚烷胺加抗GDNF抗体的大鼠也比对照组大鼠或接受手术加金刚烷胺加煮沸抗体的大白鼠有更少的与环境相关的冷冻行为。然而，三组之间与音调相关的冷冻行为没有差异（图9C）。

S-蛋白-ACE2结合试验[4]
使用严重急性呼吸系统综合征冠状病毒2型刺突：ACE2抑制剂筛选试剂盒测试化合物抑制严重急性呼吸系综合征冠状病毒2中刺突蛋白（S蛋白）与ACE2结合的能力。简而言之，将严重急性呼吸系统综合征冠状病毒2型刺突蛋白以1µg/mL的磷酸盐缓冲盐水包被到96微孔板上。去除未结合的蛋白质，并阻断孔中的非特异性结合位点。然后，去除阻断溶液，将稀释的化合物和对照样品加入孔中。将包被的刺突蛋白与化合物预孵育后，加入His标记的ACE2蛋白，并与化合物一起孵育，以允许与刺突蛋白结合。洗涤和阻断后，用与辣根过氧化物酶（HRP）偶联的抗His抗体检测结合的ACE2蛋白。使用化学发光HRP底物进行检测，并在微量滴定板读数器中读取发光强度。将含有稀释化合物的每个样品的发光信号除以不存在任何抑制剂时的发光，并将所得值与化合物浓度绘制成图。

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RT-PCR读数抗病毒活性测定（第一次实验）[4]
将指数增长的Vero E6细胞以每孔8×104个细胞的密度接种到48孔板中，并孵育过夜。取出培养基，用严重急性呼吸系统综合征冠状病毒2型（hCoV-19/意大利/INMI1 isl/2020，MOI为0.01，在含有不同抑制剂浓度的300µL培养基中）感染细胞三次。将Amantadine金刚烷胺溶解在无菌水中，并用培养基进一步稀释至500µM、100µM、20µM、4µM和8 nM的浓度。将雷德西韦溶解在DMSO中，用培养基稀释至50µM、10µM、2µM、0.4µM和80 nM的剂量。雷德西维尔MOCK对照品含有不同量的DMSO。

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用核衣壳蛋白读数进行抗病毒活性测定（第二次实验）[4]
将指数增长的Vero E6细胞在完全培养基中以最佳密度接种到96孔板中；24小时后，细胞以0.01 moi（多重感染）感染严重急性呼吸系统综合征冠状病毒2型（病毒株INMI1），然后暴露于不同浓度的药物（0-0.1-1-10-100-300μM的Amantadine/金刚烷胺）72小时。在培养基中进行药物稀释。检查每个浓度点的复制品。在潜伏期结束时，通过ELISA（定量严重急性呼吸系综合征冠状病毒-2核蛋白）和细胞保护试验（通过倒置显微镜检查毒性效应）检查抗病毒活性。

细胞活力测定[4]
细胞类型： Vero E6 细胞
测试浓度： 500 µM、100 µM、20 µM、4 µM 和 8 nM
孵育持续时间： 26 小时
实验结果：导致病毒浓度依赖性减少 (IC50=83 µM) 26 感染后上清液中的核酸浓度为10-500 µM。导致感染后 26 小时细胞质中病毒核酸浓度依赖性减少 (IC50=119 µM)。

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细胞增殖测定[6]
细胞类型：人 HCC 细胞系（HepG2 和 SMMC-7721）和正常肝细胞（L02 细胞）
测试浓度：0、1、2、5、10、25、50 和 100 µg/mL
孵育时间：24、48 和 72 小时
实验结果：在HepG2和SMMC-7721细胞中以时间和剂量依赖性方式抑制细胞增殖。

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细胞周期分析[6]
细胞类型： HepG2 和 SMMC-7721 细胞
测试浓度： 0、10、25、 50 和 75 µg/mL
孵育持续时间：48 小时
实验结果：HepG2 和 SMMC- 数量显着增加7721细胞以剂量依赖性方式处于G0/G1期，并且数量急剧减少

Fischer 344 rats (Four-month old, male, 290-330 g, 15 rats each group)
25 mg/kg
Administration: IP, once daily for 3 days (the first dose at 15 min before surgery)

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Animal/Disease Models: Fischer 344 rats (4 months old, male, 290-330 g, 15 rats per group) [5]
Doses: 25 mg/kg
Route of Administration: IP, one time/day for 3 days (first dose in 15 minutes before administration)
Experimental Results: Inhibited surgery-induced neuroinflammation and learning and memory impairment, increased GDNF (glial cell line-derived neuronal neuron) co-localized with hippocampal glial fibrillary acidic protein (an astrocyte marker) nutritional factors).

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Four-month old male Fischer 344 rats weighing 290 – 330 g were randomly assigned to: 1) control group (not being exposed to surgery or any drugs), 2) Amantadine group, 3) surgery group (right carotid artery exposure), and 4) surgery plus Amantadine group in the first experiment. Each group had 15 rats. In the second experiment, the rats were assigned to: 5) control group, 6) anti-GDNF antibody group, 7) surgery plus amantadine plus boiled anti-GDNF antibody group, and 8) surgery plus amantadine plus anti-GDNF antibody group. Each group had 8 rats. In the third experiment, the rats were randomly assigned to: 7) control group, 8) anesthesia only group, and 9) surgery plus GDNF group. Each group had 8 rats. GDNF and the anti-GDNF antibody were injected intracerebroventricularly. One week later, these rats were started to be tested in Barnes maze and then fear conditioning. Separate rats were assigned to 1) control group, 2) surgery group, and 3) surgery plus amantadine group (n = 6 per condition) and sacrificed at 6 h, 24 h or 10 days after the surgery for Western blotting and immunohistochemistry.

Amantadine was dissolved in normal saline and injected intraperitoneally at 25 mg/kg/day for three days with the first dose at 15 min before surgery. Similar injections were performed in the amantadine only group except that no surgery and anesthesia were performed. The amantadine dose was chosen based on previous studies.[5]

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Absorption, Distribution and Excretion
Amantadine is well absorbed in the gastrointestinal tract after oral administration. It is primarily excreted unchanged in the urine via glomerular filtration and tubular secretion. 3–8 L/kg [healthy subjects] 0.2–0.3 L/hr/kg 0.10±0.04 L/hr/kg [healthy elderly men] It is rapidly and almost completely absorbed from the gastrointestinal tract. Amantadine can be distributed into breast milk. Excretion: Kidneys; >90% is excreted unchanged in the urine via glomerular filtration and tubular secretion. The excretion rate increases rapidly in acidic urine. Dialysis: Only a small amount (approximately 4%) is removed from the blood via hemodialysis. It is distributed in saliva, tear film, and nasal secretions; in animals, tissue concentrations (especially in the lungs) are higher than serum concentrations. It can cross the placenta and blood-brain barrier; it is distributed in breast milk. One patient's cerebrospinal fluid concentration was 52% of the corresponding plasma concentration. VolD - 4.4 ± 0.2 L/kg (normal renal function). 5.1 ± 0.2 L/kg (renal failure).
For more complete data on the absorption, distribution, and excretion of amantadine (7 metabolites), please visit the HSDB record page.

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Metabolism/Metabolites
No significant metabolism was found, but trace amounts of acetyl metabolites were identified.
Eight amantadine metabolites were identified in human urine. One of these metabolites, the N-acetylated compound, was quantified in human urine at 5-15% of the administered dose. In 5 out of 12 healthy volunteers, the plasma concentration of acetylamantadine was 80% of the corresponding plasma amantadine concentration after administration of 200 mg amantadine. Acetylamantadine was not detected in the plasma of the remaining seven volunteers.
Although trace amounts of acetyl metabolites were detected, no significant metabolism was found. Amantadine is well absorbed from the gastrointestinal tract after oral administration. Its anti-Parkinson's disease mechanism of action is not fully elucidated, but it appears to be achieved by promoting the release of dopamine from nerve endings in brain cells and stimulating a norepinephrine response. Its antiviral mechanism appears to be unrelated to this. The drug interferes with a viral protein, M2 (an ion channel), which is required for viral particles to "uncoat" after entering cells via endocytosis. Metabolites are excreted in the urine (A308). Elimination pathway: Primarily excreted unchanged via glomerular filtration and tubular secretion in the urine. Half-life: The mean half-life is 10 to 14 hours, but renal impairment significantly prolongs it to 7 to 10 days. The pharmacokinetics of amantadine were determined in 24 healthy adult male volunteers after oral administration of a single 100 mg amantadine hydrochloride soft capsule. The half-life is 17 ± 4 hours (range: 10 to 25 hours). In other studies, the mean plasma half-life of amantadine in 19 healthy volunteers was 16 ± 6 hours (range: 9 to 31 hours).
Normal renal function: 11 to 15 hours. Elderly patients: 24 to 29 hours. Severe renal impairment: 7 to 10 days. Hemodialysis: 24 hours.
When creatinine clearance is below 40 mL/min/1.73 m², the elimination half-life increases by 2 to 3 times or more; the mean half-life in patients undergoing long-term maintenance hemodialysis is 8 days.

Toxicity Summary
Its anti-Parkinson's disease mechanism of action is not fully elucidated, but it appears to work by promoting the release of dopamine from nerve endings in brain cells and stimulating a norepinephrine response. It also has NMDA receptor antagonistic activity. Its antiviral mechanism appears to be unrelated to this. The drug interferes with a viral protein, M2 (an ion channel), which is required for viral particles to "uncoat" after entering cells via endocytosis. Hepatotoxicity
Despite its widespread use, there is little evidence that oral amantadine causes liver damage, whether from elevated serum enzymes or clinically apparent liver disease. Likelihood Score: E (Unlikely to cause clinically apparent liver damage). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Because amantadine may have negative effects on lactation, its use is best avoided during lactation. ◉ Effects on Breastfed Infants No relevant published information was found as of the revision date.
◉ Effects on lactation and breast milk
Amantadine is a dopamine agonist. Clinical studies have shown that taking 100 mg of amantadine twice or three times daily can reduce serum prolactin levels and reduce galactorrhea in patients taking dopaminergic antipsychotics such as phenothiazines, haloperidol, and loxapine. [1][2] There are currently no reports on the effects of amantadine on milk production in lactating mothers. For mothers who have established lactation, their prolactin levels may not affect their ability to breastfeed.

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Protein binding
Approximately 67% of the protein is bound to plasma proteins at concentrations ranging from 0.1 to 2.0 μg/mL.

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Toxicity Data
LD50: 800 mg/kg (oral, rat)
LD50: 700 mg/kg (oral, mouse)

Interactions
The anti-influenza A activity of amantadine and ribavirin, as well as the anti-influenza A activity of combined administration, were studied separately. In ferret tracheal ciliated epithelium, the combined use of the drugs synergistically delayed the virus-induced cytopathic effect.
Concomitant use of alcohol and amantadine is not recommended, as this may increase the risk of central nervous system side effects such as dizziness, lightheadedness, orthostatic hypotension, or confusion.
Concomitant use of anticholinergic drugs or other drugs with anticholinergic activity; tricyclic antidepressants; other anti-movement disorder drugs; antihistamines; or phenothiazines may enhance anticholinergic-like side effects, especially confusion, hallucinations, and nightmares; dosage adjustments of these drugs or amantadine may be necessary.
In addition, patients should be advised to report any gastrointestinal problems promptly, as concurrent use of opioids may lead to paralytic ileus. Concomitant use of antidiarrheal medications containing both opioids and anticholinergics may enhance the anticholinergic-like side effects of amantadine; while significant interactions are unlikely with commonly used doses of antidiarrheal medications containing both opioids and anticholinergics, significant interactions may occur if these medications are abused. For more complete data on drug interactions of amantadine (one of 10), please visit the HSDB record page.

[1]. Emergence of amantadine-resistant influenza A viruses: epidemiological study. J Infect Chemother. 2003;9(3):195-200.

[2]. Amantadine: the journey from fighting flu to treating Parkinson disease. Neurology. 2012;78(14):1096-1099.

[3]. A review of compounds exhibiting anti-orthopoxvirus activity in animal models. Antiviral Res. 2003 Jan;57(1-2):41-52.

[4]. Amantadine Inhibits SARS-CoV-2 In Vitro. Viruses. 2021 Mar 24;13(4):539.

[5]. Amantadine alleviates postoperative cognitive dysfunction possibly by increasing glial cell line-derived neurotrophic factor in rats. Anesthesiology. 2014 Oct;121(4):773-85.

[6]. Amantadine inhibits cellular proliferation and induces the apoptosis of hepatocellular cancer cells in vitro. Int J Mol Med. 2015;36(3):904-910.

Amantadine hydrochloride may cause developmental toxicity depending on state or federal labeling requirements. Amantadine hydrochloride is the hydrochloride salt of amantadine, a synthetic tricyclic amine with antiviral, anti-Parkinson's disease, and anti-hyperalgesic activities. Amantadine appears to exert its anti-influenza A virus effect by interfering with the function of the transmembrane domain of the viral M2 protein, thereby preventing the release of infectious viral nucleic acid into host cells; additionally, the drug can also inhibit viral assembly during viral replication. Amantadine exerts its anti-Parkinson's disease effect by stimulating the release of dopamine from striatal dopaminergic nerve endings and inhibiting their presynaptic reuptake. The drug may exert some anticholinergic effects by inhibiting N-methyl-D-aspartate (NMDA) receptor-mediated acetylcholine stimulation, thereby producing an anti-hyperalgesic effect. It is an antiviral drug used for the prevention or treatment of influenza A. It is also used as an anti-Parkinson's disease drug to treat extrapyramidal reactions and postherpetic neuralgia. The mechanism by which it treats movement disorders is not fully understood, but it may reflect an increase in dopamine synthesis and release, and possibly an inhibition of dopamine uptake. See also: Amantadine (with the active moiety). Drug Indications Treatment of Parkinson's disease and Parkinsonian syndromes. Therapeutic Uses Anti-Parkinson's disease drug; antiviral drug; dopamine-like drug. Amantadine is used to treat certain fatigue symptoms associated with multiple sclerosis, including decreased energy, decreased well-being, poor concentration, memory loss, and decreased problem-solving abilities. /Not included in the US or Canadian product label/ Amantadine is indicated for the treatment of idiopathic Parkinson's syndrome (tremor paralysis; tremor paralysis), post-encephalitis Parkinson's syndrome, drug-induced extrapyramidal reactions, symptomatic Parkinson's syndrome following neurological damage caused by carbon monoxide poisoning, and Parkinson's syndrome associated with cerebral arteriosclerosis in the elderly. /US Product Label Includes/
Amantadine is indicated for the prevention and treatment of respiratory infections caused by influenza A virus strains. It is indicated for high-risk groups (including patients with lung or cardiovascular disease, the elderly, and residents of nursing homes and other long-term care facilities with chronic illnesses), close contacts of high-risk patients in hospital wards, immunocompromised patients, personnel in essential public service positions (e.g., police officers, firefighters, medical personnel), high-risk groups for whom influenza vaccination is contraindicated, and patients with severe influenza A virus infection. It is effective against all influenza A virus strains tested to date, including Russian, Brazilian, Texas, and London strains. It can be used concurrently with inactivated influenza A vaccines as a chemopreventive agent until protective antibodies are developed. However, it must be emphasized that annual vaccination of high-risk groups is the most important measure to reduce the impact of influenza. Currently, there are no rigorous controlled studies testing whether amantadine can prevent influenza A complications in high-risk groups. Drug-resistant influenza A virus strains have been reported in patients taking limantanide (amantadine); these resistant strains have apparently also been transmitted through household contact. Rimantadine and amantadine have similar chemical structures, antibacterial spectra, and mechanisms of action, and resistant viral strains exhibit cross-resistance to both amantadine and rimantadine. /US product label contains/
For more complete data on the therapeutic uses of amantadine (6 types), please visit the HSDB record page.

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Drug Warnings
Swine influenza (H1N1) virus contains a unique combination of gene segments that have not been previously reported in swine or human influenza viruses in the United States or other regions. H1N1 virus is resistant to amantadine and ribavirin, but oseltamivir or zanamivir. Rare reports of suicide attempts (some fatal) have been reported in patients taking amantadine, many of whom were receiving short courses of the drug for influenza prevention or treatment. The manufacturer states that the incidence and pathophysiological mechanisms of these suicide attempts are unclear. Suicidal ideation or attempts have been reported in both patients with and without a history of mental illness. Amantadine may exacerbate the mental state of patients with a history of mental illness or substance abuse. Patients with suicidal tendencies may exhibit abnormal mental states, including disorientation, confusion, depression, personality changes, agitation, aggressive behavior, hallucinations, delusions, other psychotic reactions, somnolence, or insomnia. NMS (Neuro-Blocking Malignant Syndrome) has been reported in patients taking amantadine, and this condition is associated with dose reduction or discontinuation of the drug. NMS can be fatal and requires immediate intensive symptomatic and supportive care. Patients should be closely monitored when the amantadine dose is reduced or discontinued; this precaution is especially important for patients concurrently receiving antipsychotic medication. Nausea is one of the most common adverse reactions to amantadine; it has been reported in 5-10% of patients taking the drug at regular doses. Anorexia, constipation, diarrhea, and dry mouth are reported in 1-5% of patients taking amantadine, and vomiting is reported in up to 1%. Abdominal discomfort or dysphagia has also been reported. The incidence of gastrointestinal adverse reactions is comparable between amantadine and limantanide. For more complete data on drug warnings for amantadine (19 in total), please visit the HSDB records page.

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Pharmacodynamics
Amantadine is an antiviral drug with anti-Parkinson's disease effects, often used in combination with levodopa when levodopa efficacy declines (possibly due to tolerance). Like the similar drug lymantadine, it is a derivative of adamantane. The mechanism of action of amantadine in treating Parkinson's disease and drug-induced extrapyramidal reactions is unclear. Studies have shown that amantadine can increase dopamine release in the brain of animals and does not have anticholinergic activity.

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Currently, there are three approved antiviral drugs for influenza in Japan: amantadine, zanamivir, and oseltamivir. These antiviral drugs can be used to control and prevent influenza, but they are not a substitute for vaccination. Amantadine is an antiviral drug effective against influenza A virus but ineffective against influenza B virus. Influenza A virus patients may shed susceptible virus in the early stages of treatment and resistant virus later, especially after 5-7 days of treatment. Even if resistant virus is present, these patients can still benefit from treatment. Amantadine susceptibility screening was performed using enzyme-linked immunosorbent assay, plaque reduction assay and TCID50/0.2 ml titration. The molecular changes associated with resistance have been identified as single nucleotide changes resulting in the substitution of one of the four key sites (amino acids 26, 27, 30 and 31) in the transmembrane region of the M2 protein. Polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis was very effective. Resistant virus has emerged during outbreaks in nursing homes, and amantadine is used not only to treat influenza virus infection but also to treat Parkinson's disease. Measures should be taken to minimize contact between people taking antiviral drugs for treatment or chemoprevention and those not taking antiviral drugs. [1]

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Objective: To investigate how amantadine can be converted from an anti-influenza drug to an anti-Parkinson's disease drug. Methods: A review of historical literature on the use of amantadine from 1966 to the present. Results: Amantadine was initially introduced and used as an antiviral drug. A Parkinson's disease (PD) patient experienced symptom relief after taking amantadine to treat influenza. This discovery aroused interest and led to several important studies that eventually led to the discovery of new indications for amantadine. Conclusion: Amantadine has not been commonly used as a treatment for influenza for many years; however, it has become one of the commonly used drugs for the treatment of early Parkinson's disease symptoms and is also an option for the treatment of movement disorders. [2]

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Various animal models (most commonly mice), rabbits or monkeys have been used to screen compounds effective against orthopox virus infection. Treatment of vaccinia virus infection has been well studied in various models, including skin or eye scratch infection models, and intravenous, peritoneal, intracerebral or intranasal inoculation models. Vaccinia virus has been used in intranasal or aerosol infection studies to evaluate its therapeutic effect on fatal respiratory infections. The use of rabbitpox virus, monkeypox virus and smallpox virus in chemotherapy experiments is not as widespread as other viruses. A review of the literature over the past 50 years has revealed a variety of compounds that are effective in treating one or more of these infections, including thioaminoureas, nucleoside and nucleotide analogs, interferon, interferon inducers, and other unrelated compounds. The most promising anti-poxetine drugs are the acyclic nucleotides (S)-1-(3-hydroxy-2-phosphonomethoxypropyl)cytosine (Cidofovir, HPMPC) and 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphazenecycloheptane-5-yl)methyl]cytosine (cyclic HPMPC), and the acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (S2242). Other classes of compounds that are under-studied in lethal infection models but warrant further attention include thioaminoureas associated with methionine, and analogs of adenosine-N(1)-oxide and 1-(benzyloxy)adenosine. [3]

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Background: Postoperative cognitive impairment is a clinical condition associated with poor prognosis. We investigated the efficacy of amantadine in alleviating surgery-induced cognitive impairment and the role of glial line-derived neurotrophic factor (GDNF) in this effect. Methods: Four-month-old male Fischer 344 rats underwent right carotid artery exposure surgery under intravenous anesthesia. Some rats were intraperitoneally injected with amantadine at 25 mg/kg/day for 3 consecutive days 15 minutes before surgery; or intraventricularly injected with GDNF or anti-GDNF antibody at the end of surgery. One week later, the rats were subjected to Barnes maze and fear conditioning tests. Hippocampal tissue was collected at 6 hours, 24 hours or 10 days after surgery for biochemical analysis. C8-B4 cells (a microglia) were pretreated with 1 ng/ml GDNF for 30 minutes and then treated with 5 ng/ml lipopolysaccharide for 2 hours. [5]

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In summary, amantadine inhibits viral replication in Vero E6 cell systems. In this study, due to the aforementioned limitations, we were unable to confirm that amantadine functionally interferes with the binding of the viral spike protein to ACE2 on target cells. This issue stems from the predicted tight binding of amantadine to Tyr489 and Phe456 in the SARS-CoV-2 receptor-binding domain (RBD); the interaction between the SARS-CoV-2 RBD (Arg319–Phe541 residues) and the N-terminal peptidase domain of ACE2 (Ser19–Asp615 residues) may suggest a potential antiviral mechanism of action for amantadine, but our data do not support this hypothesis from computer simulations. Inhibition of viral porins as another mechanism of action requires further investigation in future studies. In a recently published preprint, amantadine inhibited recombinant SARS-CoV-2 viral porin E and the putative SARS-CoV-2 viral porin Orf10. In an African Xenopus oocyte model, the authors observed that 10 µM amantadine inhibited the protein E ion channel-mediated current by up to 77%, which appears to be a stronger inhibitory effect on overall viral replication than the IC50 values (83–119 µM) observed in more complex eukaryotic cell culture models; these data suggest that viral porin inhibitors warrant further investigation. Finally, amantadine also appears to have an effect on known SARS-CoV-2 mutants to date, as protein E or Orf10 mutations were almost nonexistent or absent in SARS-CoV-2 mutant strains collected from Indian patients. Strain B 1.1.7 had neither protein E nor Orf10 mutations. However, even a single amino acid substitution can reduce the efficacy of small molecule drugs, as was the case with influenza A viruses many years ago.

C10H18CLN

187.7

187.112

C, 63.99; H, 9.67; Cl, 18.89; N, 7.46

665-66-7

Amantadine; 768-94-5; Amantadine sulfate; 31377-23-8

64150

White to off-white solid powder

1.067g/cm3

225.7ºC at 760 mmHg

>300 °C(lit.)

96ºC

1.558

3.416

26.02

2

1

0

12

144

0

Cl[H].N([H])([H])C12C([H])([H])C3([H])C([H])([H])C([H])(C([H])([H])C([H])(C3([H])[H])C1([H])[H])C2([H])[H]

WOLHOYHSEKDWQH-UHFFFAOYSA-N

InChI=1S/C10H17N.ClH/c11-10-4-7-1-8(5-10)3-9(2-7)6-10;/h7-9H,1-6,11H2;1H

adamantan-1-amine;hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: 6.88 mg/mL (36.65 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。 (<60°C).

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
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