Human D1 Receptor; human 5-HT2; Human D4 Receptor; Human D2Receptor

在洛沙平存在的情况下，[3H]酮色林附着在人和牛大脑额叶皮质中的 5-HT2 受体上，Ki 值分别为 6.2 nM 和 6.6 nM。在使用人膜的竞争测定中，洛沙平对不同受体的效力分级如下：5-HT2≥D4>>>>>D1>D2[1]。在 LPS 激活的混合神经胶质细胞培养物中，洛沙平 (0–20 μM) 会降低 IL-1β 的分泌；在混合神经胶质细胞培养物中，它会减少 IL-2 的分泌；在小胶质细胞中，它会减少 LPS 诱导的 IL-1β 和 IL-2 分泌 [2]。

在大鼠大脑中，洛沙平（5 mg/kg；腹腔注射；每日一次，持续 4 或 10 周）会减少血清素 (S2)，但不会增加多巴胺 (D2) 受体的数量 [3]。

受体结合测定-多巴胺、5-HT2、NMDA受体[1]
为了进行受体结合测定，将0.8 nM的[3H]SCH23390（Di受体拮抗剂）、0.5 nM的[3H]螺环哌啶醇（D2和D4受体拮抗剂”）、0.5 nM的[3H]酮色林（5-HT2受体拮抗剂“）和2.0 nM的[3H]MK801（NMDA受体拮抗剂，）与150μg的膜蛋白一起孵育，最终体积为1 ml。在1μM（+）丁咯酚（D2和D4-测定）、10μM顺式氟戊噻醇（Di测定）、2μM甲氧基嘧啶（5-HT2测定）和50μM MK801（NMDA测定）存在的情况下，在平行测定中测定非特异性结合。使用[3H]螺环哌啶醇的检测还包括50 nM酮色林，以阻断血清素能位点的存在。对于竞争实验，在测定管中加入了不同浓度的洛沙平。Di、D2、5-HT2和NMDA受体分别在25°C下孵育90分钟、25°C孵育60分钟、37°C孵孵育15分钟和25°C孵化120分钟。使用膜制备部分所述的细胞结合缓冲液，在22°C下孵育COS细胞的D4受体结合试验120分钟。在孵育结束时，通过在Whatman GF/B过滤器上快速过滤来分离结合和游离配体，用5 ml冷过滤缓冲液洗涤3次：（50 mM Tris-HCL，1.0 mM EDTA，pH 7.4）用于[3H]螺哌啶醇和[3H]SCH23390测定，（50 mM Tr-HCL，pH 7.4。使用贝克曼闪烁计数器（型号LS 5000TA）测量结合放射性。

细胞因子IL-1β和IL-2由中枢神经系统中活化的神经胶质细胞释放，能够增强儿茶酚胺能神经传递。目前尚无关于抗精神病药物对神经胶质细胞活性影响的数据。到达大脑的抗精神病药物不仅作用于神经元，还可能作用于神经胶质细胞。本研究旨在评估氯丙嗪和洛沙平对混合胶质细胞和小胶质细胞培养中IL-1β和IL-2释放的影响。浓度为2和20μM的氯丙嗪以及0.2、2和20微M的洛沙平在暴露1天和3天后减少了LPS激活的混合胶质细胞培养物的IL-1β分泌。0.2、2和20微M浓度的氯丙嗪在接触3天后降低了混合神经胶质培养物中IL-2的分泌。0.2、2和20μM浓度的洛沙平在暴露1和3天后降低了混合胶质细胞培养物中IL-2的分泌，此外，洛沙平还降低了2、10和20μm浓度的LPS诱导的小胶质细胞培养中IL-1β和IL-2的分泌。Quinpirole是一种D2多巴胺能激动剂，仅在20微M的最高剂量下增加了LPS诱导的混合胶质细胞培养中IL-1β和IL-2的分泌。这些发现表明皮质小胶质细胞上缺乏功能性多巴胺受体。去除小胶质细胞的混合胶质细胞培养物（通过摇晃和用L-亮氨酸甲酯孵育）不释放IL-1β和IL-2。这一观察表明，小胶质细胞可能是评估细胞因子的来源。本研究的结果支持了抗精神病药物不仅作用于神经元，而且作用于神经胶质细胞的观点。然而，这些观察结果的临床意义尚不清楚[2]。

Animal/Disease Models: Adult male Wistar rat (150-175 g) [3]
Doses: 5 mg/kg
Route of Administration: intraperitoneal (ip) injection, one time/day for 4 or 10 weeks
Experimental Results: Induced significant reduction in serotonin (S2) (more than 50%)) daily injections increased receptor density after 4 or 10 weeks, but did not produce any significant increase in dopamine receptor density.

Absorption, Distribution and Excretion
Systemic bioavailability of the parent drug was only about one third that after an equivalent intramuscular dose (25 mg base) in male volunteers
Metabolites are excreted in the urine in the form of conjugates and in the feces unconjugated.
Animal studies with radioactive drug indicate that loxapine and/or its metabolites are widely distributed in body tissues with highest concentrations in brain, lungs, heart, liver, and pancreas. The drug appears in the CSF.
Loxapine is rapidly and almost completely absorbed from the GI tract. The drug is also almost completely absorbed following IM administration.
RAPIDLY & ALMOST COMPLETELY ABSORBED FROM GI TRACT. PEAK LOXAPINE SERUM LEVELS /WITHIN 2 HR, RANGE FROM 0.006 TO 0.013 MCG/ML AFTER/ 25 MG ORAL DOSE...MAJOR /ACTIVE/ METABOLITE IN SERUM IS 8-HYDROXYLOXAPINE /MAX CONCN 0.012-0.038 MCG/ML WITHIN 2-4 HR AFTER ORAL LOXAPINE. HUMAN/
LOXAPINE AND/OR METABOLITES...WIDELY DISTRIBUTED IN BODY TISSUES...HIGHEST CONCN IN BRAIN, LUNGS, HEART, LIVER, & PANCREAS...APPEARS IN CSF...CROSSES PLACENTA...IN MILK OF NURSING MOTHERS /ANIMALS, RADIOACTIVE DRUG/
METABOLITES /7- & 8-HYDROXY-, 7- & 8-HYDROXYDESMETHYLLOXAPINE; N-OXIDES OF LOXAPINE, 7- & 8-HYDROXYLOXAPINE/ EXCRETED IN URINE & FECES. LITTLE OR NO UNMETABOLIZED DRUG...FOUND...METABOLITES /PRIMARILY GLUCURONIDE OR SULFATE CONJUGATES IN URINE, PRIMARILY UNCONJUGATED IN FECES. HUMAN, ORAL/

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Metabolism / Metabolites
Hepatic
RAPIDLY & EXTENSIVELY METABOLIZED IN LIVER BY AROMATIC HYDROXYLATION, N-DEMETHYLATION & N-OXIDATION. MAJOR METABOLITES...8-HYDROXYLOXAPINE, & 7-HYDROXYLOXAPINE WHICH ARE ACTIVE...8-HYDROXYDESMETHYLLOXAPINE, 7-HYDROXYDESMETHYLLOXAPINE & LOXAPINE-N-OXIDE WHICH ARE INACTIVE /HUMAN, ORAL/
SIGNIFICANT AMT OF N-OXIDES OF /7-HYDROXY- & 8-HYDROXYLOXAPINES, METABOLITES FORMED BY HYDROXYLATION & N-OXIDATION/, PRESENT...LOXAPINE METABOLITES ARE EXCRETED IN URINE PRIMARILY AS GLUCURONIDE OR SULFATE CONJUGATES /HUMAN, ORAL/
2 METABOLITES: 8-HYDROXYLOXAPINE & 8-HYDROXYAMOXAPINE, INCR ON ORAL MEDICATION.
Loxapine is rapidly and extensively metabolized in the liver by aromatic hydroxylation, N-oxidation. The major metabolites of loxapine are 8-hydroxyloxapine and 7-hydroxyloxapine which are active and 8-hydroxydesmethylloxapine, 7-hydroxydesmethylloxapine, and loxapine N-oxide which are inactive. Significant amounts of the N-oxides of the hydroxyloxapines are also present.
Loxepine has known human metabolites that include Loxepine N-glucuronide.
Hepatic
Route of Elimination: Metabolites are excreted in the urine in the form of conjugates and in the feces unconjugated.
Half Life: Oral-4 hours

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Biological Half-Life
Oral-4 hours
SERUM LEVELS OF LOXAPINE & METABOLITES DECLINE IN BIPHASIC MANNER. HALF-LIFE DURING 1ST PHASE...5 HR...DURING 2ND PHASE...19 HR. /AFTER SINGLE 25 MG ORAL DOSE, SEDATIVE EFFECT BEGINS IN 20-30 MIN; PEAK EFFECT WITHIN 1.5-3 HR; DURATION APPROX 12 HR. HUMAN/

Toxicity Summary
Loxapine is a dopamine antagonist, and also a serotonin 5-HT2 blocker. The exact mode of action of Loxapine has not been established, however changes in the level of excitability of subcortical inhibitory areas have been observed in several animal species in association with such manifestations of tranquilization as calming effects and suppression of aggressive behavior.

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Toxicity Data
LD₅₀=65 mg/kg (Orally in mice)

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Interactions
LOXAPINE MAY BE ADDITIVE WITH OR MAY POTENTIATE ACTION OF OTHER CNS DEPRESSANTS (INCLUDING BARBITURATES & ALCOHOL) OR ANTICHOLINERGIC AGENTS...INHIBITS VASOPRESSOR EFFECT OF EPINEPHRINE
Concurrent use /with alcohol or other central nervous system (CNS) depression-producing medications, especially anesthetics, barbiturates, and opiod (narcotic) analgesics/ may potentiate and prolong the CNS depressant effects of either these medications or loxapine; dosage adjustments to approximately 1/2 to 1/4 of the ususal dose may be necessary.
Concurrent use /with amphetamines/ may decrease the effects of amphetamines since loxapine produces alpha-adrenergic blockade.
Concurrent use /with antacids or adsorbent antidiarrheals/ may inhibit the absorption of orally administered loxapine.
For more Interactions (Complete) data for LOXAPINE (18 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 151 mg/kg
LD50 Rat ip 35 mg/kg
LD50 Rat sc 350 mg/kg
LD50 Rat iv 18 mg/kg
For more Non-Human Toxicity Values (Complete) data for LOXAPINE (8 total), please visit the HSDB record page.

[1]. A neurochemical basis for the antipsychotic activity of loxapine: interactions with dopamine D1, D2, D4 and serotonin 5-HT2 receptor subtypes. J Psychiatry Neurosci. 1996 Jan;21(1):29-35.

[2]. Chlorpromazine and loxapine reduce interleukin-1beta and interleukin-2 release by rat mixed glial and microglial cell cultures. Eur Neuropsychopharmacol. 2005 Jan;15(1):23-30.

[3]. Loxapine and clozapine decrease serotonin (S2) but do not elevate dopamine (D2) receptor numbers in the rat brain. Psychiatry Res. 1984 Aug;12(4):277-85.

[4]. Clozapine inhibits catalepsy induced by olanzapine and loxapine, but prolongs catalepsy induced by SCH 23390 in rats. Naunyn Schmiedebergs Arch Pharmacol. 1997 Mar;355(3):361-4.

[5]. Keating GM. Loxapine inhalation powder: a review of its use in the acute treatment of agitation in patients with bipolar disorder or schizophrenia. CNS Drugs. 2013 Jun;27(6):479-89.

[6]. Loxapine, an antipsychotic drug, suppresses intracellular multiple-antibiotic-resistant Salmonella enterica serovar Typhimurium in macrophages. J Microbiol Immunol Infect. 2019 Aug;52(4):638-647.

Loxapine is a dibenzooxazepine. It has a role as an antipsychotic agent and a dopaminergic antagonist.
Loxapine is a conventional antipsychotic used in the therapy of schizophrenia. Loxapine therapy is commonly associated with minor serum aminotransferase elevations and in very rare instances has been linked to clinically apparent acute liver injury.
Loxapine is only found in individuals that have used or taken this drug. It is an antipsychotic agent used in schizophrenia. Loxapine is a dopamine antagonist, and also a serotonin 5-HT2 blocker. The exact mode of action of Loxapine has not been established, however changes in the level of excitability of subcortical inhibitory areas have been observed in several animal species in association with such manifestations of tranquilization as calming effects and suppression of aggressive behavior.
An antipsychotic agent used in schizophrenia.
See also: Loxapine Succinate (has salt form); Loxapine Hydrochloride (has salt form).

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Drug Indication
For the management of the manifestations of psychotic disorders such as schizophrenia
Adasuve is indicated for the rapid control of mild-to-moderate agitation in adult patients with schizophrenia or bipolar disorder. Patients should receive regular treatment immediately after control of acute agitation symptoms.
Treatment of bipolar disorder, Treatment of schizophrenia

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Mechanism of Action
Loxapine is a dopamine antagonist, and also a serotonin 5-HT2 blocker. The exact mode of action of Loxapine has not been established, however changes in the level of excitability of subcortical inhibitory areas have been observed in several animal species in association with such manifestations of tranquilization as calming effects and suppression of aggressive behavior.
STUDIES HAVE SHOWN THAT LOXAPINE PRODUCES SEDATION & PRONOUNCED EXTRAPYRAMIDAL REACTIONS, DECR CONVULSIVE THRESHOLD, & HAS ANTIADRENERGIC & ANTICHOLINERGIC EFFECTS. /SUCCINATE/

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Therapeutic Uses
Antipsychotic Agents; Dopamine Antagonists
THIS DIBENZOXAZEPINE DERIVATIVE IS EFFECTIVE IN TREATMENT OF SCHIZOPHRENIA BUT IT IS NOT CLEAR WHETHER IT HAS ANY ADVANTAGE OVER OTHER ANTIPSYCHOTIC AGENTS. /SUCCINATE/
Loxapine is indicated for the management of symptoms and characteristics of psychotic conditions. /Included in US product labeling/
Loxapine has been used to treat anxiety neurosis with depression. /NOT included in US product labeling/

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Drug Warnings
...LOXAPINE SHOULD BE RESERVED FOR USE IN PT WHO ARE REFRACTORY TO ESTABLISHED ANTIPSYCHOTIC AGENTS. /SUCCINATE/
Safe use of loxapine during pregnancy has not been established; therefore, the drug should not be used in pregnant women or women who might become pregnant unless the potential benefits outweigh the possible risk to the woman or fetus.
Pending accumulation of clinical data on the use of the drug in children, loxapine is not recommended for use in children younger than 16 years of age.
Loxapine should be used with caution, particularly in conjunction with anticholinergic antiparkinsonian agents and in patients with glaucoma or a tendency toward urinary retention because of possible anticholinergic activity. Since loxapine may have an aniemetic effect, it is possible that the drug could mask the sign of overdosage of toxic agents or interfere with the diagnosis of such conditions as intestinal obstruction or brain tumor. Loxapine is contraindicated in comatose patients, patients who have severe CNS depression from any cause, or known hypersensitivity to the drug.
For more Drug Warnings (Complete) data for LOXAPINE (13 total), please visit the HSDB record page.

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Pharmacodynamics
Loxapine, a dibenzoxazepine compound, represents a subclass of tricyclic antipsychotic agents, chemically distinct from the thioxanthenes, butyrophenones, and phenothiazines. Pharmacologically, Loxapine is a tranquilizer for which the exact mode of action has not been established, however, it is believed that by antagonising dopamine and serotonin receptors, there is a marked cortical inhibition which can manifest as tranquilization and suppression of aggression.

C18H18CLN3O

327.812

327.114

C, 65.95; H, 5.53; Cl, 10.81; N, 12.82; O, 4.88

1977-10-2

Loxapine succinate;27833-64-3;Loxapine hydrochloride;54810-23-0;Loxapine-d8 hydrochloride;1246820-19-8;Loxapine-d8;1189455-63-7

3964

Light yellow to yellow solid powder

1.2299 (rough estimate)

109-110°

1.36E-08mmHg at 25°C

1.5800 (estimate)

3.082

28.07

0

3

1

23

450

0

XJGVXQDUIWGIRW-UHFFFAOYSA-N

InChI=1S/C18H18ClN3O/c1-21-8-10-22(11-9-21)18-14-12-13(19)6-7-16(14)23-17-5-3-2-4-15(17)20-18/h2-7,12H,8-11H2,1H3

8-chloro-6-(4-methylpiperazin-1-yl)benzo[b][1,4]benzoxazepine

CL 62,362; AZ-004; Cloxazepine; Oxilapine; Loxitane; Loxapin; Dibenzacepin; Dibenzoazepine;Adasuve

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)

DMSO : ≥ 33.33 mg/mL (~101.67 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (7.63 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 25.0 mg/mL澄清DMSO储备液加入到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: ≥ 2.5 mg/mL (7.63 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 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，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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配方 3 中的溶解度: ≥ 2.5 mg/mL (7.63 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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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。