5-HT3 Receptor

在任何评估的细胞类型中，顺铂的细胞毒性都不受SENS-401（高达10μM）添加的影响。体外数据支持SENS-401的耳保护潜力和耐受性，而不影响化疗潜力[2]。

所有SENS-401剂量均改善了ABR阈值偏移和恢复，治疗28天后ABR阈值恢复达到统计学意义（p<0.05）。13.2mg/kg BID SENS-401的DPOAE振幅损失和恢复明显改善，14天后达到显著性水平（p<0.05）。启动SENS-401延迟96小时后，ABR阈值偏移/恢复和DPOAE振幅损失显著改善（p<0.05），延迟72小时后，DPOAE的振幅恢复显著改善（p>0.05）。在创伤后延迟24至96小时后，与安慰剂相比，SENS-401治疗后存活的OHC明显更多，基底耳蜗转向中的细胞多5.3倍。 结论：体内数据支持每天两次口服SENS-401的耳保护潜力。听力损失恢复的改善使SENS-401成为治疗声创伤引起的听力损失的有前景的临床候选者，包括在不立即开始治疗的情况下。[1]

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在体内，与安慰剂相比，所有SENS-401剂量均显著改善了听觉脑干反应阈值偏移（高达30 dB）和畸变产物耳声发射振幅损失（高达19 dB）。接受安慰剂和接受26.4 mg/kg SENS-401的大鼠的体重和存活率没有显著差异。与安慰剂相比，SENS-401治疗后存活的外毛细胞明显更多（p<0.001），耳蜗基底匝的存活率高达11倍[2]。

The dose-response relationship of SENS-401 (6.6 mg/kg BID, 13.2 mg/kg BID, 26.4 mg/kg QD) and treatment time-window (13.2 mg/kg BID starting 24, 72, and 96 h posttrauma) versus placebo for 28 days were evaluated in a male rat model of severe acoustic trauma-induced hearing loss (120 dB SPL, 2 h) using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) measures followed by cochlear outer hair cell (OHC) counting with myosin-VIIa immunolabeling.[1]

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For audiometry experiments, female 5-week-old Wistar rats ∼150 g were housed for 2 weeks before experimentation in a temperature-controlled environment with a 12-hours light/dark cycle and free access to water and food. They were randomly divided into groups of 8 to 13 animals. All rats received cisplatin (8 mg/kg in saline) on day 1 as a 30-minute intravenous injection under isoflurane anesthesia. (R)-Azasetron besylate (SENS-401) (6.6, 13.2, 26.4 mg/kg/d, 0.9% NaCl) or placebo (0.9% NaCl) were given orally for 14 days using a gavage needle dipped in sucrose (14), initiated 15 minutes before cisplatin. Animals were weighed from Day 1 to 14, before the daily treatment. Two successive series of ABR and DPOAE experiments were performed, the first comparing placebo with 26.4 mg/kg/d SENS-401 and the second comparing placebo with 6.6 and 13.2 mg/kg/d SENS-401. Evaluations were performed at baseline (pre-exposure) 2 days before treatment initiation, and after 14 days of SENS-401/placebo. Animals were deeply anesthetized throughout the audiometry experiments using 80 mg/kg ketamine, 8 mg/kg xylazine, and 1 mg/kg acepromazine inside a sound-proof chamber. After audiometry tests on day 14, four to five animals per treatment group were sacrificed for immunolabeling.[2]

For pharmacokinetics experiments, male 7-week-old Wistar rats aged ∼325 g were maintained as described above. They were randomly divided into groups of 24 animals (four rats sacrificed per time point), each receiving a single dose of oral SENS-401 (6.6, 13.2, 26.4 mg/kg/d, 0.9% NaCl) using a gavage needle.[2]

[1]. SENS-401 Effectively Reduces Severe Acoustic Trauma-Induced Hearing Loss in Male Rats With Twice Daily Administration Delayed up to 96 hours. Otol Neurotol. 2019 Feb;40(2):254-263.

[2]. Oral Administration of Clinical Stage Drug Candidate SENS-401 Effectively Reduces Cisplatin-induced Hearing Loss in Rats. Otol Neurotol. 2017 Oct;38(9):1355-1361.

Arazasetron Besylate is the besylate salt form of the R-enantiomer of azasetron, a benzamide derivative and selective serotonin (5-hydroxytryptamine; 5-HT) receptor and calcineurin antagonist, with potential antinauseant and antiemetic, and otoprotective activities. Upon administration, arazasetron selectively binds to and inhibits 5-HT subtype 3 receptors (5-HT3R) located peripherally on vagus nerve terminals and centrally in the chemoreceptor trigger zone (CTZ) of the area postrema, which may result in suppression of nausea and vomiting. R-azasetron also targets and inhibits the activation of calcineurin, thereby preventing inner ear lesions, nerve degeneration, induction of apoptosis and sensory hair loss. This may prevent hearing loss. Calcineurin activation plays a key role in structural degeneration, swelling, synaptic uncoupling and the induction of apoptosis in the inner ear leading to hair cell loss and hearing loss.

C23H26CLN3O6S

507.987043857574

507.123

C, 54.38; H, 5.16; Cl, 6.98; N, 8.27; O, 18.90; S, 6.31

2025360-91-0

123040-69-7; 2025360-91-0 (besylate); 123040-16-4 (HCl)

131801108

White to off-white solid powder

125Ų

2

7

3

34

707

1

CN1C(=O)COC2=C(C=C(C=C21)Cl)C(=O)N[C@H]3CN4CCC3CC4.C1=CC=C(C=C1)S(=O)(=O)O

GFVBDLIBPSGFDL-ZOWNYOTGSA-N

InChI=1S/C17H20ClN3O3.C6H6O3S/c1-20-14-7-11(18)6-12(16(14)24-9-15(20)22)17(23)19-13-8-21-4-2-10(13)3-5-21;7-10(8,9)6-4-2-1-3-5-6/h6-7,10,13H,2-5,8-9H2,1H3,(H,19,23);1-5H,(H,7,8,9)/t13-;/m0./s1

N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-6-chloro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide;benzenesulfonic acid

(R)-Azasetron besylate; R-Azasetron besylate; 2025360-91-0; UXP39EQ477; (R)-Azasetron (besylate); ARAZASETRON BESYLATE; UNII-UXP39EQ477; ARAZASETRON;

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。