5-HT₇ Receptor ( IC50 = 0.495 nM ); 5-HT_1A Receptor ( IC50 = 6.75 nM ); D₂ Receptor ( IC50 = 1.68 nM )

体外活性：Lurasidone 以浓度依赖性方式拮抗多巴胺刺激的 [35S]GTPγS 与人多巴胺 D2L 受体的结合，KB 值为 2.8 nM。 Lurasidone 拮抗 CHO/h5-HT7 细胞中 5-HT 刺激的 cAMP 积累，KB 值为 2.6 nM。 Lurasidone 部分刺激 [35S]GTPγS 与人 5-HT1A 受体膜制剂的结合，最大效果为 33%。 Lurasidone 剂量依赖性地增加大鼠额叶皮层和纹状体中 DOPAC/多巴胺的比率。

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为了研究伊洛哌酮和卢拉西酮是否影响CYP酶的活性，用不同浓度的神经抑制剂进行了探针反应测定。Dixon的CYP特异性底物代谢图，在人类肝微粒体和超体CYP1A2、CYP2D6、CYP2C9、CYP2C19和CYP3A4中进行，在没有或有测试的神经抑制剂的情况下，表明所检查的神经抑制剂对不同的CYP酶具有抑制作用。然而，它们抑制特定CYP酶的效力是不同的。Iloperidone对CYP3A4的活性有很强的抑制作用（Ki = 0.38 肝微粒体和超体分别为0.3µM）和CYP2D6（Ki = 2.9 在肝微粒体和超体中分别为10µM）。此外，伊洛哌酮减弱了CYP2C19的活性（Ki = 6.5 肝微粒体和超体分别为32µM）和CYP1A2（Ki = 45 肝微粒体和超体分别为31µM）。Iloperidone不影响CYP2C9的活性。相比之下，鲁拉西酮适度抑制CYP1A2（Ki = 12.6 肝微粒体和超体分别为15.5µM）、CYP2C9（Ki = 18 肝微粒体和超体分别为3.5µM）、CYP2C19（Ki = 18 肝微粒体和超体分别为18.4µM）和CYP3A4（Ki = 29.4 肝微粒体和超体分别为9.1µM）。鲁拉西酮弱抑制CYP2D6的活性（Ki = 37.5 肝微粒体和超体分别为85µM）。[3]
Lineweaver–Burk的酶抑制动力学图表明，在人肝微粒体和超体中，伊洛哌酮通过非竞争机制抑制CYP3A4的活性，通过竞争机制抑制CY2D6，通过混合机制抑制CYP1A2和CYP2C19的活性（插入图1、3、4、5）。另一方面，鲁拉西酮通过混合机制抑制CYP1A2、CYP2C9和CYP2C19的活性，通过竞争机制抑制CYP3A4和CYP2D6的活性（插入图1、2、3、4、5。表1[1]总结了伊洛哌酮和鲁拉西酮抑制主要人类CYP酶活性的Ki值和机制。

鲁拉西酮对MAP诱发的多动症的抑制作用持续8小时以上，治疗后1小时、2小时、4小时、8小时的ED50值分别为2.3mg/kg、0.87mg/kg 、 1.6 mg/kg 和 5.0 mg/kg 分别。 Lurasidone (1 mg/kg–10 mg/kg) 剂量依赖性地抑制大鼠的条件性回避反应，ED50 为 6.3 mg/kg。 Lurasidone 剂量依赖性地抑制大鼠中 TRY 诱导的前爪阵挛性癫痫发作和 p-CAMP 诱导的高热，ED50 分别为 5.6 mg/kg 和 3.0 mg/kg。 Lurasidone (0.3 mg/kg–30 mg/kg) 具有剂量依赖性，并且在 MED 为 10 mg/kg 的 Vogels 冲突试验中显着增加大鼠受到的电击次数。 Lurasidone（3 mg/kg，2 周）显着抑制嗅球切除模型大鼠的多动行为。 Lurasidone (700 mg/kg–1000 mg/kg) 以剂量依赖性方式稍微延长小鼠由六巴比妥（麻醉）引起的翻正反射丧失的持续时间。 Lurasidone（30 mg/kg，口服）可显着且剂量依赖性地逆转 MK-801 诱导的大鼠被动回避反应损伤。 Lurasidone (3 mg/kg po) 可有效逆转 Morris 水迷宫测试中 MK-801 诱导的大鼠学习障碍。 Lurasidone (3 mg/kg po) 可有效逆转 MK-801 诱导的参考记忆损伤，并在径向臂迷宫测试中适度但不显着减轻 MK-801 诱导的工作记忆损伤。 Lurasidone (10 mg/kg) 治疗会增加大鼠前额皮质中的 BDNF mRNA 总水平，并在较小程度上增加海马中的 BDNF mRNA 水平。 Lurasidone (10 mg/kg) 显着增加大鼠前额皮质中成熟 BDNF 蛋白的水平，而不影响海马提取物中神经营养蛋白（前体和成熟形式）的蛋白水平。[1]

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鲁拉西酮（SM-13496）是一种新型非典型抗精神病药物，对多巴胺D2、血清素5-HT7、5-HT2A、5-HT1A受体和α2C肾上腺素受体具有高度亲和力。本研究评估了鲁拉西酮对大鼠被动回避反应的影响，以及N-甲基-d-天冬氨酸（NMDA）受体拮抗剂MK-801（地佐西平）对其的损伤，并将其与其他抗精神病药物进行了比较。在动物接受足部电击训练后1天，通过测量跨步潜伏期来检查被动回避反应。在训练课前给药时，鲁拉西酮在任何测试剂量（1-30mg/kg，口服）下都不影响被动回避反应。然而，所有其他接受检查的非典型抗精神病药物（即利培酮、奥氮平、喹硫平、氯氮平和阿立哌唑）在相对较高的剂量下显著降低了逐步潜伏期。训练前给予鲁拉西酮可显著且剂量依赖性地逆转MK-801诱导的被动回避反应损伤。在低于影响被动回避反应的剂量下，利培酮、喹硫平和氯氮平部分减轻了MK-801诱导的损伤，而氟哌啶醇、奥氮平和阿立哌唑则没有活性。此外，鲁拉西酮的训练后给药在对抗MK-801效应方面与训练前给药一样有效，这表明鲁拉西酮至少在一定程度上是通过恢复MK-801中断的记忆巩固过程起作用的。这些结果表明，鲁拉西酮在改善MK-801诱导的记忆障碍方面优于其他抗精神病药物，可能在临床上可用于治疗精神分裂症的认知障碍。[2]

体外受体结合谱[1]
如表2所示，体外受体结合实验表明，鲁拉西酮对多巴胺D2和5-HT2A受体的亲和力高于其他测试的抗精神病药物。与其他药物相比，鲁拉西酮对5-HT7、5-HT1A和去甲肾上腺素α2C受体也表现出高亲和力（Ki值分别为0.495、6.75和10.8 nM）。 鲁拉西酮对去甲肾上腺素能α1和α2A受体的亲和力较低（Ki值分别为47.9和40.7 nM），亲和力可以忽略不计。..

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CYP酶活性的测定[3]
为了研究伊洛哌酮和鲁拉西酮对各种CYP亚型活性的抑制作用，使用了混合的人肝微粒体和表达人CYP（超体）的杆状病毒感染昆虫细胞的微粒体。根据之前描述的方法，应用了以下探针反应：CYP1A2的咖啡因3-N-去甲基化（咖啡因200、400和800µM），CYP2C9的双氯芬酸4′-羟基化（双氯芬酸5、10、25µM）；CYP2C19的哌嗪N-去甲基性（哌嗪50、100、200µM）。CYP2C9、2C19和3A4的孵育系统含有：50 mM TRIS/KCL缓冲液（pH = 7.4),NADPH生成系统（1 mM NADP、5 mM葡萄糖6-磷酸、1.7 U/ml葡萄糖6-磷酸脱氢酶、1 mM EDTA和3 mM MgCl2）。CYP1A2的孵育混合物包括：0.15 M磷酸盐缓冲液（pH = 7.4) CYP2D6:0.1 M TRIS/KCL缓冲液（pH = 7.4),NADPH生成系统（1.3 mM NADP、3.3 mM葡萄糖6-磷酸、1 U/ml葡萄糖6-磷酸脱氢酶和3.3 mM MgCl2）。加入适当浓度的人肝微粒体（每次反应0.5 mg/ml）或超体（50 pmol CYP/ml），在有或没有神经抑制剂的情况下加入不同浓度的探针底物（浓度：0.1、0.5、1、5、10µM），反应混合物的最终体积为0.5 ml。超体的孵育时间为30分钟（每次反应），肝微粒体孵育时间：30分钟（双氯芬酸4′-羟基化和丁咯洛尔1′-羟基化成），20分钟（哌嗪N-去甲基化和睾酮6β-羟基化）或50分钟（咖啡因3-N-去甲基化成）。反应停止后，如前所述，通过HPLC法结合紫外检测（或CYP2D6的荧光检测）评估肝微粒体或超体中形成的特定底物及其代谢产物的浓度。

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动力学参数、Ki值和抑制机制的测定[3]
使用Michaelis-Menten方法和非线性回归分析获得了描述肝微粒体或超体中CYP特异性反应过程的动力学参数（Km、Vmax、Ki）。伊洛哌酮和鲁拉西酮对CYP酶的抑制作用如Dixon图（1/V对I）所示，显示Ki值，Lineweaver–Burk图（1/V对1/s）显示了抑制机制（竞争性抑制增加了Km值，不影响Vmax值；非竞争性抑制降低了Vmax值，但不影响Km值；混合抑制导致Km和Vmax值分别发生变化）。

Methamphetamine (MAP) (1 mg/kg i.p.) is injected into each individual SD rat in a clear plastic cage one hour after the drugs or vehicle are administered. One, two, four, and eight hours prior to the MAP injection, luerazone (hydrochloride) (SM-13496 (hydrochloride)) is given as part of the persistence of effect test. Following a 10-minute MAP injection, locomotor activity is monitored for 80 minutes. The ED50 value, which inhibits MAP-induced hyperactivity by 50% of the animals tested, is determined using four or five groups of six to thirteen rats.[1]

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Lurasidone hydrochloride, haloperidol, olanzapine, aripiprazole, risperidone, quetiapine hemifumarate, and clozapine were prepared. The previously reported anti-dopamine ED50 values (mg/kg, p.o.) were used to adjust the test dosage of each antipsychotic drug to a level expected to block dopamine D2 receptors in vivo, i.e., 1–30 mg/kg p.o. for Lurasidone and quetiapine; 0.3 and 1 mg/kg p.o. for haloperidol; 0.3–3 mg/kg for risperidone; 0.3–10 mg/kg for olanzapine and aripiprazole; and 0.3–30 mg/kg p.o. for clozapine (Hirose et al., 2004, Migler et al., 1993, Moore et al., 1992, Sakamoto et al., 1997). All the antipsychotic drugs were dissolved or suspended in 0.5% methylcellulose (MC) as the vehicle, and orally administered at a volume of 5 ml/kg. In the cases in which Lurasidone was injected intravenously, the drug was dissolved in 25% polyethylene glycol, and injected at 1 ml/kg into the tail vein. In this case, anti-dopaminergic doses of 0.1 and 0.3 mg/kg, which effectively antagonize methamphetamine-induced hyperactivity in rats (data not shown), were used. (+)-MK-801 hydrogen maleate was dissolved in saline and injected subcutaneously at a volume of 5 ml/kg. All the test drugs and MK-801 were prepared on the day of the experiment. All other agents were obtained from commercial sources.[2]

We performed 3 sets of studies as described below.
Study 1:
As previously reported for clozapine and olanzapine (Ninan and Kulkarni, 1996, Rasmussen et al., 2001), some antipsychotic drugs may impair passive-avoidance learning when administered alone before the training session. Therefore, we first investigated the effects of Lurasidone and other antipsychotic drugs on the acquisition of the passive-avoidance response, when administered alone without giving MK-801. Antipsychotic drugs or the vehicle MC was administered orally 1 h before the passive-avoidance training. Ten to 15 rats per dose group were used. The data from this study were used to determine dosages of antipsychotic drugs that did not impair the passive-avoidance response.

Study 2:
We next examined the effect of Lurasidone on MK-801-induced deficits in the passive-avoidance response and compared the results with those of the other antipsychotic drugs. A pre-training injection of MK-801 is known to induce state-dependency in some of the context-dependent responses such as the passive avoidance in rats, which apparently impairs the retrieval of acquired response unless a pre-test injection of MK-801 is also given to rats (Harrod et al., 2001, Jackson et al., 1992, Schmidt et al., 1999). In this study, therefore, we gave both pre-training and pre-test injections of MK-801 to avoid the state-dependent influence with MK-801, according to the procedures as previously used in the passive-avoidance test (Harrod et al., 2001, Nakagawa and Iwasaki, 1996). In addition, a relatively low dose of MK-801 (0.05 mg/kg, s.c.) that reportedly does not affect motor functions and the passive-avoidance retrieval with the pre-test injection (Nakagawa and Iwasaki, 1996, Venable and Kelly, 1990) was employed. The antipsychotic drugs were administered 1 h before the training session at doses that did not impair the passive-avoidance response in Study 1. Twenty to 25 rats per dose group were used.

Study 3:
To investigate the interaction of Lurasidone with MK-801 specifically in the memory consolidation process of acquiring the passive-avoidance response (McGaugh, 1973, McGaugh, 2000), lurasidone was injected intravenously, 10 min after the animals received the foot-shock training and were returned to their home cages. MK-801 was given as described for Study 2. Fifteen animals per dose group were used.

Absorption, Distribution and Excretion
Lurasidone is readily absorbed and rapidly reaches its peak concentration (Cmax) within 1–4 hours. When taken with food, drug exposure doubles, and the time to reach peak concentration is prolonged by 0.5–1.5 hours. This is independent of the fat or caloric content of the food. Bioavailability is 9–19%. Urine (approximately 9%) and feces (approximately 80%) 6173 L 3902 mL/min Following a single dose of radiolabeled lurasidone, approximately 80% and 9% of the dose are excreted in feces and urine, respectively. After oral administration, lurasidone is rapidly absorbed and reaches peak serum concentrations within approximately 1–3 hours. The orally absorbed dose is approximately 9–19% of the administered dose. Steady-state drug concentrations are reached within 7 days.

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Metabolisms/Metabolites
Lurasidone is metabolized by CYP3A4, with its major active metabolite being ID-14283 (accounting for 25% of parental exposure). Its two minor metabolites are ID-14326 and ID-11614, accounting for 3% and 1% of parental exposure, respectively. Its two inactive metabolites are ID-20219 and ID-20220.
Lurasidone has a high binding rate (99.8%) to serum proteins (including albumin and α1-acid glycoprotein). The drug is primarily metabolized via CYP3A4. The main biotransformation pathways include oxidative N-dealkylation, hydroxylation of the norbornene ring, and S-oxidation. Lurasidone is metabolized into two active metabolites (ID-14283 and ID-14326) and two major inactive metabolites (ID-20219 and ID-20220).

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Biological half-life
40 mg dose = 18 hours; 120 mg - 160 mg dose = 29-37 hours

Medication Use During Pregnancy and Lactation ◉ Overview of Medication Use During Lactation
Lurasidone binds to plasma proteins at a rate exceeding 99%, making it unlikely that significant amounts will be excreted into breast milk, thus affecting breastfed infants. Data from a mother-infant pair appear to support the view that the amount of drug excreted into breast milk is small and has no effect on breastfed infants. Until more data are available, alternative medications are recommended, especially when breastfeeding newborns or premature infants.
◉ Effects on Breastfed Infants
A woman with depressive schizoaffective disorder took 40 mg of lurasidone nightly and 50 mg of desvenlafaxine daily after delivery. She exclusively breastfed her infant. During a 39-day follow-up period, the infant's growth and development were good.
Patients taking second-generation antipsychotics while breastfeeding (n = 576) registered in the National Atypical Antipsychotics Pregnancy Registry were compared with a breastfeeding control group (n = 818) who did not take second-generation antipsychotics. Among patients taking second-generation antipsychotics, 60.4% were taking more than one psychotropic medication. A review of pediatric medical records showed no adverse reactions regardless of whether the infant had been exposed to second-generation antipsychotic monotherapy or combination therapy. No cases of women taking lurasidone were reported.
◉ Effects on lactation and breast milk
The increase in serum prolactin caused by lurasidone is usually uncommon, minor, and less pronounced than with risperidone. One woman who experienced elevated serum prolactin levels, breast engorgement, and galactorrhea while taking risperidone experienced symptom improvement after switching to lurasidone; these side effects completely disappeared when the dose of lurasidone was increased from 20 mg to 40 mg daily. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.
Patients taking second-generation antipsychotics while breastfeeding (n = 576) registered with the National Atypical Antipsychotic Pregnancy Registry were compared with a control group of breastfeeding patients with a primary diagnosis of major depressive disorder and anxiety disorder (n = 818). The control group of breastfeeding patients typically received selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) as antidepressants, but did not use second-generation antipsychotics. Among women taking second-generation antipsychotics, 60.4% were also taking more than one psychotropic medication, compared to 24.4% in the control group. 59.3% of women taking second-generation antipsychotics reported breastfeeding, compared to 88.2% in the control group. Three months postpartum, 23% of women taking second-generation antipsychotics were still exclusively breastfeeding, compared to 47% in the control group. The number of women taking lurasidone was not reported. A 14-year-old girl with hallucinogenic schizophrenia, who had previously been treated with aripiprazole with poor results, was subsequently switched to paliperidone. At age 16, she transitioned from paliperidone to lurasidone, at which point her serum prolactin level rose to 4240 mIU/L (normal range 60-400 mIU/L). As the lurasidone dose was gradually increased to a maximum daily dose of 111 mg, prolactin levels continued to rise, and the patient experienced breast engorgement and galactorrhea. Six out of seven serum prolactin measurements were in the range of 4240 to 6140 mIU/L. After discontinuing lurasidone, her serum prolactin levels returned to normal. In an Italian study on lurasidone treatment of schizophrenia, 2.4% of patients experienced hyperprolactinemia and galactorrhea. Toxicity Summary: Indications and Uses: Lurasidone is indicated for the treatment of schizophrenia, as a monotherapy for major depressive episodes associated with bipolar I disorder (bipolar depression), and can also be used in combination with lithium or valproate for the treatment of major depressive episodes associated with bipolar I disorder (bipolar depression). Human Exposure and Toxicity: In placebo-controlled studies, an increased incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks), including deaths, was observed in elderly patients with dementia-related psychosis treated with certain atypical antipsychotics (aripiprazole, olanzapine, risperidone). The manufacturer states that lurasidone is not approved for the treatment of dementia-related psychosis. Neuroleptic malignant syndrome (NMS) has been reported in patients treated with antipsychotics, including lurasidone. NMS is a potentially fatal syndrome requiring immediate discontinuation of the drug and intensive symptomatic treatment. Reports of rash and pruritus are common in patients treated with lurasidone, while reports of angioedema are rare. In patients with schizophrenia treated with lurasidone, adverse reactions occurring at a rate ≥5% and at least twice the frequency of the placebo group included somnolence (including narcolepsy, excessive somnolence, and sedation), akathisia, nausea, Parkinson's syndrome, and agitation. Aakathisia and somnolence appear to be dose-related adverse reactions. The effects of lurasidone on childbirth are unclear. It is currently unknown whether lurasidone and/or its metabolites are excreted into human milk. Serum lurasidone concentrations in elderly patients aged 65–85 years with psychosis were similar to those in younger adults. Elderly patients with dementia-related psychosis treated with lurasidone had an increased risk of death compared to those receiving placebo. The safety and efficacy of lurasidone in children and adolescents have not been established. Animal studies: Oral administration of lurasidone (at doses of 12 and 36 mg/kg/day) to female rats increased the incidence of breast cancer; the lowest dose, 3 mg/kg/day, resulted in plasma drug concentrations (AUC) 0.4 times higher than those in humans receiving the maximum recommended human dose (MRHD). No increased tumor incidence was observed in male rats at the highest tested dose, which resulted in plasma drug concentrations (AUC) 6 times higher than those in humans receiving the MRHD. Lurasidone is excreted into rat milk. Rats administered lurasidone orally for 15 consecutive days (at doses of 1.5, 15, and 150 mg/kg/day, respectively) before mating, during mating, and before day 7 of gestation experienced estrous cycle disturbances. The no-effect dose was 0.1 mg/kg, approximately 0.006 times the maximum recommended human dose (MRHD, 160 mg/day) based on body surface area. Decreased fertility was observed only at the highest dose, and fertility returned to normal 14 days after discontinuation. The dose that did not affect fertility was 15 mg/kg, approximately equal to the maximum recommended human dose (MRHD) based on body surface area. No effect on male rat fertility was observed with lurasidone administered orally for 64 consecutive days before and during mating at doses up to 150 mg/kg/day (equivalent to 9 times the MRHD based on mg/m² body surface area). No mutations or chromosomal aberrations were found in either in vitro or in vivo studies. The drug was negative in the Ames gene mutation assay, the Chinese hamster lung (CHL) cell assay, and the in vivo mouse bone marrow micronucleus assay at doses up to 2000 mg/kg (based on mg/m² body surface area, equivalent to 61 times the maximum recommended daily human dose of 160 mg).
Drug Interactions
Lurasidone is not a CYP1A2 substrate in vitro; therefore, smoking should not alter the pharmacokinetics of this drug.
Concomitant administration of the potent CYP3A4 inducer rifampin (600 mg daily for 8 days) and lurasidone (single 40 mg dose) reduced serum peak concentrations and AUCs of lurasidone by approximately 86% and 80%, respectively. Rifampin should not be taken concurrently with lurasidone.
Concomitant administration of lurasidone (steady-state dose of 40 mg daily) with oral contraceptives containing ethinylestradiol and norgestrel resulted in comparable peak plasma concentrations and AUCs compared to oral contraceptives alone. Sex hormone-binding globulin concentrations were not significantly affected by concomitant administration. Patients taking lurasidone concurrently do not require dose adjustment of oral contraceptives. Concomitant administration of lurasidone (steady-state dose 120 mg daily) with a single 5 mg dose of midazolam (CYP3A4 substrate) increased peak plasma concentrations and AUC values of midazolam by approximately 21% and 44%, respectively. Patients taking lurasidone concurrently do not require dose adjustment of midazolam. For more complete data on drug interactions of lurasidone (11 in total), please visit the HSDB record page. Hepatotoxicity: Liver dysfunction occurs in 1% to 3% of patients taking lurasidone long-term, but the incidence is similar in placebo and control groups. ALT elevations are usually mild and transient, and often resolve spontaneously even without dose adjustment or discontinuation. There are currently no published reports of clinically significant liver injury (with symptoms or jaundice) caused by lurasidone treatment. Likelihood Score: E (Unlikely to be the cause of clinically significant liver injury).

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Use during pregnancy and lactation
◉ Overview of use during lactation
Lurasidone binds to plasma proteins at a rate exceeding 99%, making it unlikely to be excreted in breast milk in an amount sufficient to affect a breastfed infant. Data from a mother-infant pair appear to support low excretion of the drug in breast milk and no effect on the breastfed infant. Until more data are available, alternative medications may be preferred, especially in breastfed newborns or preterm infants.
◉ Effects on breastfed infants
A woman with depressive schizoaffective disorder took 40 mg of lurasidone nightly and 50 mg of desvenlafaxine daily after delivery. She exclusively breastfed her infant. During a 39-day follow-up period, the infant's growth and development were good.
Patients taking second-generation antipsychotics while breastfeeding (n = 576) registered with the National Registry for Atypical Antipsychotic Pregnancy were compared with a control group of breastfeeding patients not taking second-generation antipsychotics (n = 818). Among patients taking second-generation antipsychotics, 60.4% were taking more than one psychotropic medication concurrently. A review of pediatric medical records showed no adverse reactions regardless of whether the infant had received second-generation antipsychotic monotherapy or combination therapy. The number of women taking lurasidone was not reported.
◉ Effects on Lactation and Breast Milk
Elevated serum prolactin levels after taking lurasidone are generally uncommon and minor, less so than with risperidone. One woman who experienced elevated serum prolactin levels, breast engorgement, and galactorrhea while taking risperidone experienced improvement after switching to lurasidone; these side effects completely disappeared when the lurasidone dose was increased from 20 mg to 40 mg daily. For established lactating mothers, prolactin levels may not affect their ability to breastfeed. This study compared breastfeeding mothers taking second-generation antipsychotics (n = 576) registered with the National Atypical Antipsychotic Pregnancy Registry with a control group of breastfeeding mothers primarily diagnosed with major depressive disorder and anxiety disorder (n = 818). The control group typically received selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) but not second-generation antipsychotics. Among women taking second-generation antipsychotics, 60.4% were also taking multiple psychotropic medications, compared to 24.4% in the control group. 59.3% of women taking second-generation antipsychotics reported breastfeeding, compared to 88.2% in the control group. At 3 months postpartum, 23% of women taking second-generation antipsychotics were exclusively breastfeeding, compared to 47% in the control group. No reports have been made regarding the number of women taking lurasidone. A 14-year-old girl with hallucinogenic schizophrenia, who had previously been treated with aripiprazole but with poor efficacy, was switched to paliperidone. At age 16, she transitioned from paliperidone to lurasidone, at which point her serum prolactin level rose to 4240 mIU/L (normal range 60-400 mIU/L). As the lurasidone dose was gradually increased to a maximum daily dose of 111 mg, prolactin levels continued to rise, and the patient experienced breast engorgement and galactorrhea. Six out of seven serum prolactin measurements were in the range of 4240 to 6140 mIU/L. After discontinuing lurasidone, her serum prolactin levels returned to normal. An Italian study showed that 2.4% of patients with schizophrenia treated with lurasidone developed hyperprolactinemia and galactorrhea. [LactMed Drug and Lactation Database] ◈ What is lurasidone? Lurasidone is an antipsychotic medication used to treat schizophrenia and bipolar disorder. Its brand name is Latuda®. Sometimes, when people find out they are pregnant, they consider changing their medication regimen or even stopping it entirely. However, it is essential to talk to your healthcare provider before changing your medication regimen. Your healthcare provider can discuss with you the benefits of treating your condition and the risks of not treating the condition during pregnancy. ◈ I am taking lurasidone. Will taking lurasidone affect my pregnancy? There are currently no human studies confirming that lurasidone affects pregnancy. ◈ Does taking lurasidone increase the risk of miscarriage? Miscarriage can occur in any pregnancy. There are currently no studies confirming that lurasidone increases the risk of miscarriage. ◈ Does taking lurasidone increase the risk of birth defects? There is a 3-5% risk of birth defects in every pregnancy; this is called background risk. Information on the use of lurasidone during pregnancy is limited. In animal studies in rats and rabbits, no increased risk of birth defects was found. In one case report of lurasidone use during pregnancy, the infant was born healthy with no birth defects. A study of 134 women who took lurasidone during pregnancy found no specific pattern of birth defects.
◈ Does taking lurasidone during pregnancy increase the risk of other pregnancy-related problems?
Currently, no studies have shown that taking lurasidone during pregnancy increases the risk of pregnancy-related problems such as preterm birth (delivery before 37 weeks of gestation) or low birth weight (birth weight less than 2500 grams).
◈ I need to take lurasidone throughout my pregnancy. Will it cause symptoms after the baby is born?
The FDA product label states that newborns exposed to antipsychotic drugs in late pregnancy may experience symptoms. These symptoms may include involuntary muscle movements, changes in muscle tone, lethargy, difficulty breathing, and/or feeding difficulties. Not all infants exposed to antipsychotic drugs during pregnancy will experience these symptoms. These symptoms may be temporary and resolve on their own. Symptomatic treatment can be started if necessary. There are currently no reports of these symptoms occurring during lurasidone use during pregnancy. Due to very limited information regarding lurasidone use during pregnancy, it is difficult to determine whether these symptoms will occur. If you are taking lurasidone, inform your healthcare provider before delivery. Monitoring of the infant for symptoms may be necessary.
◈ Will taking lurasidone during pregnancy affect the child's future behavior or learning?
There is currently no research indicating whether taking lurasidone during pregnancy will cause behavioral or learning problems in the child.
◈ Breastfeeding while taking lurasidone:
Information regarding taking lurasidone while breastfeeding is limited. One report shows a woman taking lurasidone while breastfeeding, but no adverse effects were reported on the breastfed infant. The benefits of taking lurasidone may outweigh the potential risks. Your healthcare provider can discuss taking lurasidone with you and the best treatment option for you. Be sure to consult your healthcare provider about all breastfeeding-related questions.
◈ If a man takes lurasidone, will it affect fertility (the ability to impregnate a partner) or increase the risk of birth defects?
No human studies have been conducted to determine whether lurasidone affects fertility or increases the risk of birth defects (above background risk). Generally, exposure to this medication by the father or sperm donor is unlikely to increase the risk of pregnancy. For more information, please see the “Father Exposure” information sheet on the MotherToBaby website: https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

[1]. J Pharmacol Exp Ther. 2010 Jul;334(1):171-81

[2]. Eur J Pharmacol. 2007 Oct 31;572(2-3):160-70.

[3]. Pharmacol Rep. 2020 Dec;72(6):1685-1694.

Lurasidone hydrochloride is the hydrochloride salt prepared by reacting lurasidone with an equivalent amount of hydrochloric acid. It is an atypical antipsychotic drug used to treat schizophrenia. It has the effects of a dopaminergic antagonist, a serotonergic antagonist, an adrenergic antagonist, and a second-generation antipsychotic. It contains lurasidone (1+). A thiazole derivative, it is also an atypical antipsychotic drug whose mechanism of action includes: dopamine D2 receptor antagonist, serotonin 5-HT2 receptor antagonist, serotonin 5-HT7 receptor antagonist, adrenergic α2A and α2C receptor antagonist, and a partial serotonin 5-HT1A receptor agonist. It is used to treat schizophrenia and bipolar disorder. See also: lurasidone (with active moiety). Drug Indications For the treatment of schizophrenia in adults aged 18 years and older. Treatment of schizophrenia. Lurasidone [(3aR,4S,7R,7aS)-2-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl]hexahydro-4,7-methylene-2H-isoindole-1,3-dione hydrochloride; SM-13496] is an azapyrone derivative and a novel antipsychotic candidate drug. This study aimed to investigate the in vitro and in vivo pharmacological properties of lurasidone. Under similar detection conditions, the receptor binding affinity of lurasidone to several antipsychotic drugs was tested using cloned human receptors or membrane fractions prepared from animal tissues. The results showed that lurasidone exhibits strong binding affinity to dopamine D₂, serotonin 2A (5-HT₂A), 5-HT₇, 5-HT₁A, and norepinephrine α₂C receptors. It exhibits weak affinity for norepinephrine α₁, α₂A, and 5-HT₂C receptors, while its affinity for histamine H₁ and muscarinic acetylcholine receptors is negligible. In vitro functional studies have shown that lurasidone acts as an antagonist on D₂ and 5-HT₇ receptors and as a partial agonist on the 5-HT₁A receptor subtype. Lurasidone demonstrates potent antipsychotic activity, such as inhibiting methamphetamine-induced ADHD and apomorphine-induced stereotyped behaviors in rats, similar to other antipsychotic drugs. Furthermore, lurasidone exhibits only mild extrapyramidal side effects in rodent models. In animal models of anxiety and depression, lurasidone treatment was associated with significant improvement. Lurasidone preferentially promotes dopamine metabolism in the frontal cortex (but not the striatum). Lurasidone also exhibits very weak anti-α1-norepinephrine, anticholinergic, and central nervous system depressant effects. These results suggest that lurasidone possesses antipsychotic activity and similar antidepressant or anxiolytic effects, with a potentially lower risk of extrapyramidal and central nervous system depressant side effects. [1]

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Background
This study aimed to investigate the inhibitory effects of two atypical antipsychotic drugs, ilopiperidone and lurasidone, on major human cytochrome P450 (CYP) enzymes in CYP enzymes (ultramicrosomes) expressed in mixed human liver microsomes and cDNA.
Methods
The activities of the following CYP-specific reactions were determined by high performance liquid chromatography (HPLC): caffeine 3-N-demethylation/CYP1A2, diclofenac 4′-hydroxylation/CYP2C9, piperazine N-demethylation/CYP2C19, ibuprofen 1′-hydroxylation/CYP2D6, and testosterone 6β-hydroxylation/CYP3A4. Results
Ilopride inhibited CYP3A4 activity via a non-competitive mechanism (Ki = 0.38 and 0.3 µM). Ilopride inhibited CYP1A2 in liver microsomes and ultrasomes (Ki values of 2.9 µM and 10 µM, respectively) and CYP2D6 via a competitive mechanism (Ki values of 2.9 µM and 10 µM, respectively). Furthermore, ilopride attenuated the activity of CYP1A2 (Ki values of 45 µM and 31 µM in microsomes and ultrasomes, respectively) and CYP2C19 (Ki values of 6.5 µM and 32 µM, respectively) via a mixed mechanism, but had no effect on CYP2C9. Lurasidone exhibits moderate inhibitory activity against CYP1A2 (Ki values of 12.6 and 15.5 µM in microsomes and ultrasomes, respectively), CYP2C9 (Ki values of 18 and 3.5 µM in microsomes and ultrasomes, respectively), with a mixed inhibitory mechanism (Ki values of 18 and 18.4 µM in microsomes and ultrasomes, respectively); it also exhibits competitive inhibition against CYP3A4 (Ki values of 29.4 and 9.1 µM in microsomes and ultrasomes, respectively). Furthermore, lurasidone also competitively inhibits CYP2D6 activity, but the inhibitory effect is weak (Ki values of 37.5 and 85 µM in microsomes and ultrasomes, respectively).
Conclusion
The studied antipsychotic drug showed inhibitory activity against different CYP enzymes. The results suggest that metabolic/pharmacokinetic interactions with ilopiperidone (primarily involving CYP3A4 and CYP2D6) and lurasidone (involving CYP1A2, CYP2C9, or CYP2C19) may occur during combination therapy. [3]

C28H37CLN4O2S

529.14

528.23

C, 63.56; H, 7.05; Cl, 6.70; N, 10.59; O, 6.05; S, 6.06

367514-88-3

Lurasidone; 367514-87-2; Lurasidone metabolite 14326 hydrochloride; Lurasidone-d8 hydrochloride; Lurasidone Metabolite 14283-d8; 2070009-43-5; Lurasidone metabolite 14326; 186204-33-1; Lurasidone Metabolite 14326-d8

11237860

White to off-white solid powder

198-205°C

9℃

4.196

84.99

1

6

5

36

804

6

O=C([C@H]([C@H]1CC[C@@H]2C1)[C@H]2C3=O)N3C[C@@H]4CCCC[C@H]4CN(CC5)CCN5C6=NSC7=CC=CC=C76.Cl

NEKCRUIRPWNMLK-SCIYSFAVSA-N

InChI=1S/C28H36N4O2S.ClH/c33-27-24-18-9-10-19(15-18)25(24)28(34)32(27)17-21-6-2-1-5-20(21)16-30-11-13-31(14-12-30)26-22-7-3-4-8-23(22)35-29-26;/h3-4,7-8,18-21,24-25H,1-2,5-6,9-17H2;1H/t18-,19+,20-,21-,24+,25-;/m0./s1

(1S,2R,6S,7R)-4-[[(1R,2R)-2-[[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]methyl]cyclohexyl]methyl]-4-azatricyclo[5.2.1.02,6]decane-3,5-dione;hydrochloride

SM13496; Lurasidone HCl; SM-13496; 367514-88-3; Lurasidone hydrochloride;; UNII-O0P4I5851I; CHEBI:70732; O0P4I5851I; lurasidone monohydrochloride; HCl, Lurasidone; SM 13496; trade name Latuda

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（例如氮气保护），避免吸湿/受潮和光照。

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: ≥ 0.67 mg/mL (1.27 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 6.7 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 0.67 mg/mL (1.27 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 6.7mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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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。