D1/D2 Receptor; PI3Kα (IC50 = 127 nM)

使用氟哌噻吨（2.5-40 μM；72 小时）治疗可剂量依赖性地降低肺癌细胞活力[3]。为了诱导肺癌细胞凋亡，给予氟哌噻吨 (2.5-40 μM) 24 小时 [3]。 Bcl-2 表达水平和 p-AKT 受氟哌噻吨 (2.5–15 μM；24 小时) 抑制 [3]。

鼻内注射氟哌噻吨（40 mg/kg，每天一次，持续 21 天）可防止裸鼠形成 A549 异种移植肿瘤 [3]。

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氟哌噻吨抑制裸鼠A549异种移植物肿瘤生长[3]
最后，我们评估了氟哌噻吨对肺癌体内生长的影响。BALB/C裸鼠皮下注射A549细胞。接种后14天，肿瘤生长到50-80mm3的体积。将小鼠随机分为两组（每组6只），每天灌胃注射PBS（对照组）或氟哌噻吨（40mg/kg），持续21天。我们的结果显示，与赋形剂对照组相比，氟哌噻吨显著减少了肿瘤体积（p<0.05）（图55A）。氟哌噻吨还显著降低了64.1%的肿瘤重量（p<0.05）（图55B-C）。氟哌噻吨治疗对小鼠的平均体重没有实质性影响（图55D）。这些结果表明，氟哌噻吨是一种潜在的安全有效的口服抗癌药物，用于治疗癌症。

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该研究调查了氟哌噻吨在治疗阴性症状方面与利培酮相比的非劣效性。此外，还探讨了氟哌噻吨对情绪和认知症状的影响。在一项随机、双盲、多中心研究中，144名以阴性症状为主的非急性精神分裂症患者接受了灵活剂量的氟哌噻吨（4-12mg/d）或利培酮（2-6mg/d）治疗，治疗时间长达25周。除了非劣效性分析外，还对PANSS进行了事后主成分分析（PCA）。关于阴性症状，氟哌噻吨被证明不亚于利培酮。这两种药物都改善了抑郁情绪，效果大小有利于氟哌噻吨。PCA建议采用五因素结构。认知因素的效应大小，氟哌噻吨高达0.74，利培酮高达0.80。两组的EPS评分均较低，帕金森病均有改善，但氟哌噻吨组的抗胆碱能药物处方频率明显更高，通常显示出明显更多的不良事件。结果表明，与利培酮相比，第一代抗精神病药物氟哌噻吨可改善慢性精神分裂症患者的阴性、情感和认知症状。进一步的研究应使用神经心理学性能测试来证实后者，并应调查耐受性是否会随着剂量范围的显著降低而提高[3]。

无细胞生化激酶抑制试验[2]
通过评估重组激酶PI3Kα对聚EY（4:1 Glu，Tyr）肽底物的磷酸化，在无细胞系统中检测了氟戊四醇对PI3Kα的抑制作用。根据制造商的说明，使用ADP-Glo激酶检测试剂盒评估重组激酶的抑制作用。简而言之，将不同浓度范围（1 nM-1µM）的氟戊四醇与4 ng重组激酶和0.2µg/mL聚EY底物在室温下孵育60分钟。然后，加入5µL ADP-Glo试剂，在室温下继续孵育40分钟。最后，加入10µL激酶检测试剂，使混合物在室温下温育30分钟，然后用GloMax 20/20光度计测量发光。

细胞活力测定[3]
细胞类型： A549、H661、SK-SEM-1 和 NCAL-H520 细胞
测试浓度： 2.5、5、 10、20 或 40 μM
孵育时间：72 小时
实验结果：显示 IC50 为 5.708 μM A549 和 H661 细胞分别为 6.374 μM 和 6.374 μM。

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细胞凋亡分析[3]
细胞类型： A549 和 H661 细胞
测试浓度： 5、10、20 和 40 μM
孵育时间：24小时
实验结果：与阴性对照相比，A549和H661中早期凋亡细胞的百分比有所增加（ p < 0.05）。以剂量依赖性方式诱导 PARP 和 caspase-3 裂解。

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蛋白质印迹分析 [3]
细胞类型： H661 和 A549 细胞
测试浓度： 2.5、5、10 和 15 μM
孵育持续时间：24 小时
实验结果：以剂量依赖性方式降低 AKT 磷酸化水平和 Bcl-2 表达水平方式。

Animal/Disease Models: BALB/C nude mice injected with A549 cells [3]
Doses: 40 mg/kg
Route of Administration: gavage; 40 mg/kg; one time/day; 21 days
Experimental Results: Compared with the vehicle control, the tumor volume diminished ( p<0.05), tumor weight diminished by 64.1% (p<0.05).

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A549 growth in nude mice[2]
Male BALB/C nude mice of 5-6 weeks old were used. A549 cells (1×106/0.2 ml PBS per mice) were injected subcutaneously into the right flank of the mice. Seven days after inoculation, tumors grew to a volume of 80-100 mm3. The mice were randomly divided into two groups (six mice per group) and injected by intragastric injection administration (i.g.) every day for 21 days with either PBS (control group) or flupentixol (40 mg/kg in PBS). Tumor volumes were measured every 3-4 days after tumor appearance and calculated by the equation V=ab2/2 (a=longest axis; b=shortest axis). The mice were sacrificed on day 21 after treatment, and tumors were isolated and weighed.

Absorption, Distribution and Excretion
Following oral administration, flupentixol is readily absorbed from the gastrointestinal tract, with oral bioavailability of about 40%. Tmax ranges from three to eight hours. Steady-state plasma levels are achieved in about seven days and following once-daily oral administration of 5 mg flupentixol, the mean minimum steady-state level was about 1.7 ng/mL (3.9 nmol/L). From the site of intramuscular injection, esterified flupentixol diffuses slowly from the oil solution and is slowly released into the extracellular fluid and the circulation to be distributed to different tissues. Peak drug concentrations are reached between four and seven days following intramuscular injection. Intramuscularly administered flupentixol is detectable in the blood three weeks after injection and reaches steady-state concentrations after about three months of repeated administration.
Fecal excretion is more predominant than renal excretion. In the feces, flupentixol is recovered in the feces mainly as the unchanged form, as well as its lipophilic metabolites, such as dealkyl-flupentixol. Flupentixol is recovered in the urine as the unchanged form as well as its hydrophilic sulfoxide and glucuronide metabolites.
The apparent volume of distribution is about 14.1 L/kg. Following administration, the highest levels of flupentixol are found in the lungs, liver, and spleen. Lower concentrations of the drug are found in the blood and brain.
Following oral administration, the mean systemic clearance is about 0.29 L/min.

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Metabolism / Metabolites
Flupentixol is metabolized in the liver via sulfoxidation, dealkylation, and glucuronidation to form pharmacologically inactive metabolites. Flupentixol decanoate, the active ingredient in the intramuscular formulation, is hydrolyzed to flupentixol.

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Biological Half-Life
The elimination half-life is about 35 hours following oral administration and three weeks following intramuscular administration.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Flupenthixol is not approved for marketing in the United States by the U.S. Food and Drug Administration, but is available in other countries. Limited information indicates that maternal oral doses of up to 4 mg daily or depot injections of 40 mg every 2 weeks produced low levels in milk and breastfed infants' serum, and caused no adverse developmental consequences. A safety scoring system finds flupenthixol possible to use cautiously during breastfeeding. Until more data are available, flupenthixol should be used with careful infant monitoring during breastfeeding.
◉ Effects in Breastfed Infants
A woman took flupenthixol 1 mg and nortriptyline 100 mg daily during pregnancy and flupenthixol 4 mg and nortriptyline 125 mg daily immediately postpartum. She exclusively breastfed her infant. Over a 4-month period, the infant showed no signs of adverse drug effects and had normal motor development with a maternal dosage of flupenthixol 2 mg daily and nortriptyline 75 mg daily.
◉ Effects on Lactation and Breastmilk
Flupenthixol can increase serum prolactin and has caused galactorrhea. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Protein Binding
Flupentixol is 99% bound to plasma proteins.

[1]. Effect of cis-(Z)-flupentixol on DPPC membranes in the presence and absence of cholesterol. Chem Phys Lipids. 2016 Jun;198:61-71.

[2]. Efficacy of flupentixol and risperidone in chronic schizophrenia with predominantly negative symptoms. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Jun 30;31(5):1012-22.

[3]. The antipsychotic agent flupentixol is a new PI3K inhibitor and potential anticancer drug for lung cancer. Int J Biol Sci. 2019 Jun 2;15(7):1523-1532.

Cis-flupenthixol is a flupenthixol in which the double bond adopts a cis-configuration. It has a role as a dopaminergic antagonist. It is a conjugate base of a cis-flupenthixol(2+).
Flupentixol is an antipsychotic drug of the thioxanthene group. It exists in two geometric isomers, the trans(E) and pharmacologically active cis(Z) forms. Flupentixol decanoate is one of the active ingredients found in injectable drug formulations: it is produced by esterification of cis(Z)‐flupentixol with decanoic acid. Flupentixol is an antagonist of both D1 and D2 dopamine receptors. Available as oral tablets or long-acting intramuscular injections, flupentixol is marketed under brand names such as Depixol and Fluanxol. It is approved for use in Canada and other countries around the world, but not in the US. It is used for the management of chronic schizophrenia in patients whose main manifestations do not include excitement, agitation or hyperactivity. It has been marketed to manage symptoms of depression in patients who may or may not exhibit signs of anxiety. In combination with [melitracen], flupentixol is used to manage symptoms of anxiety, depression, and asthenia.
A thioxanthene neuroleptic that, unlike CHLORPROMAZINE, is claimed to have CNS-activating properties. It is used in the treatment of psychoses although not in excited or manic patients. (From Martindale, The Extra Pharmacopoeia, 30th ed, p595)

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Drug Indication
Flupentixol is indicated for maintenance therapy of chronic schizophrenic patients whose main manifestations do not include excitement, agitation or hyperactivity. It is indicated for the management of depression in adult patients who may, or may not, also be showing signs of anxiety. Flupentixol in combination with [melitracen] is indicated to manage symptoms of anxiety, depression, and asthenia in adults.

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Mechanism of Action
The mechanism of action of flupentixol is not completely understood. The antipsychotic actions are mainly thought to arise from cis(Z)-flupentixol, the active stereoisomer, acting as an antagonist at both dopamine D₁ and D₂ receptors with equal affinities. Schizophrenia is a mental illness characterized by positive (such as hallucinations and delusions) and negative (such as affect flattening and apathy) symptoms. While several neurotransmitter systems are implicated in the pathophysiologic processes leading to the development of symptoms, the dopamine and glutamate systems have been extensively studied. It is generally understood that positive symptoms of schizophrenia arise from a dysregulated striatal dopamine pathway, leading to hyperstimulation of D₂ receptors. Many antipsychotic agents work by blocking D₂ receptors as antagonists; similarly, cis(Z)-flupentixol, the active stereoisomer, is an antagonist at D₂ receptors. However, there is now evidence that antipsychotic agents can work by blocking other dopamine receptor subtypes, such as D₁, D₃, or D₄ receptors. One study showed that cis(Z)-flupentixol is an antagonist at both dopamine D₁ and D₂ receptors with equal affinities, and binds to D3 and D4 receptors with lower affinities. It also binds to alpha-1 adrenoceptors. Antidepressant effects of flupentixol are understood to be mediated by antagonism at 5-HT_2A receptors, which are commonly downregulated following repeated antidepressant treatment. Flupentixol also binds to 5-HT_2C receptors.

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Pharmacodynamics
Flupentixol is an antipsychotic agent with anxiolytic and mild sedative actions. It exerts weak anticholinergic and adrenergic effects. It possesses antiemetic actions. As flupentixol works by antagonizing dopamine actions, it can cause extrapyramidal effects, mostly at doses greater than 10 mg. In clinical trials, flupentixol-induced extrapyramidal effects have been managed with anti-Parkinsonian drugs. Drug esterification in the intramuscular formulation of the drug results in slow release of the drug from the injection site and a prolonged duration of action. Flupentixol has been investigated for use in mild to moderate depression: compared to other antidepressant agents, flupentixol has a rapid onset of action, where antidepressive effects were observed within the first two to three days after administration. As with other antipsychotic agents, flupentixol can cause QTc prolongation and increase the risk of arrhythmias. In clinical trials, flupentixol was associated with the risk of cardiovascular disease, cerebrovascular adverse events, stroke, and venous thromboembolism. Flupentixol can elevate the levels of prolactin; however, the clinical significance of hyperprolactinemia caused by neuroleptic drugs is unclear. Long-term hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone mineral density in both female and male subjects. Interestingly, recent studies show that flupentixol exhibits anti-tumour properties alone or synergistically with other anticancer drugs like gefitinib. One study demonstrated that _in vitro_, flupentixol docks to the ATP binding pocket of phosphatidylinositol 3-kinase (PI3K), a lipid kinase that activates signalling pathways that are often hyperactivated in some cancers. Flupentixol inhibited the PI3K/AKT pathway and survival of lung cancer cells _in vitro_ and _in vivo_.

C23H25N2OF3S

434.5176

434.164

C, 63.58; H, 5.80; F, 13.12; N, 6.45; O, 3.68; S, 7.38

2709-56-0

Flupentixol dihydrochloride;2413-38-9;cis-(Z)-Flupentixol dihydrochloride;51529-01-2; 51529-02-3 [(E)-Flupentixol]

5281881

Typically exists as solid at room temperature

1.306g/cm3

554.7ºC at 760mmHg

233-234

289.3ºC

1.607

4.477

52.01

1

7

5

30

592

0

OCCN1CCN(CC/C=C2\C3=CC=CC=C3SC3C=CC(=CC\2=3)C(F)(F)F)CC1

NJMYODHXAKYRHW-DVZOWYKESA-N

InChI=1S/C23H25F3N2OS/c24-23(25,26)17-7-8-22-20(16-17)18(19-4-1-2-6-21(19)30-22)5-3-9-27-10-12-28(13-11-27)14-15-29/h1-2,4-8,16,29H,3,9-15H2/b18-5-

2-[4-[(3Z)-3-[2-(trifluoromethyl)thioxanthen-9-ylidene]propyl]piperazin-1-yl]ethanol

FLUPENTHIXOL; Flupentixol; trans-flupenthixol; trans-Flupentixol; (E)-Flupenthixol; 53772-85-3; beta-Flupenthixol; ...; 2709-56-0;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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。