| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
Human D1 Receptor; human 5-HT2; Human D4 Receptor; Human D2Receptor
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|---|---|
| ln Vitro |
[3H]ketanserin attaches to 5-HT2 receptors in the frontal cortex of human and bovine brains in the presence of loxapine, with Ki values of 6.2 nM and 6.6 nM, respectively. The potency of loxapine at different receptors was graded as follows in competition assays employing human membranes: 5-HT2≥D4>>>>>D1>D2[1]. In LPS-activated mixed glial cell cultures, loxapine (0–20 μM) decreases IL-1β secretion; in mixed glial cell cultures, it decreases IL-2 secretion; and in microglia cells, it decreases LPS-induced IL-1β and IL-2 secretion [2].
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| ln Vivo |
In the rat brain, loxapine (5 mg/kg; i.p.; daily for 4 or 10 weeks) reduces serotonin (S2) but does not raise the number of dopamine (D2) receptors [3].
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| Enzyme Assay |
Receptor binding assays - dopamine, 5-HT2, NMDA receptors [1]
To perform the receptor binding assays, 0.8 nM of [3H] SCH23390 (Di receptor antagonist), 0.5 nM [3H] spiroperidol (D2 and D4 receptor antagonist), 0.5 nM of [3H] ketanserin (5-HT2 receptor antagonist), and 2.0 nM [3H] MK801 (NMDA receptor antagonist) were incubated with 150 )ig of membrane proteins in a final volume of 1 ml. Nonspecific binding was determined in parallel assays in the presence of 1 jM (+) butaclamol (D2 and D4 assays), 10 jM cis-flupenthixol (Di assays), 2 ,uM methysergide (5-HT2 assays) and 50 jM MK801 (NMDA assays). Assays using [3H] spiroperidol also included 50 nM ketanserin to occlude the presence ofserotonergic sites. For the competition experiments, varying concentrations of loxapine were included in the assay tubes. Incubations forthe Di, D2, 5-HT2 andNMDA receptors were performed at 25°C for 90 min, 25°C for 60 min, 37°C for 15 min and 25°C for 120 min, respectively. D4 receptor binding assays with COS cells were incubated at 22°C for 120 min using the cell binding buffer described in the membrane preparation section. At the end ofthe incubation, the bound and free ligands were separated by rapid filtration on Whatman GF/B filters, which were washed 3 times with 5 ml ofcold filtration buffer: (50 mM Tris-HCL, 1.0 mM EDTA, pH 7.4) for the [3H] spiroperidol and [3H] SCH23390 assays, (50 mM Tris-HCL, pH 7.4) for [3H] ketanserin assays, and (10 mM HEPES, 1 mM EDTA, pH 7.4) for [3H] MK80 1 assays. Bound radioactivity was measured using a Beckman Scintillation Counter (model LS 5000TA).[1]
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| Cell Assay |
The cytokines IL-1beta and IL-2 are released from activated glial cells in the central nervous system and they are able to enhance catecholaminergic neurotransmission. There is no data concerning influence of antipsychotics on glial cell activity. Antipsychotics reaching the brain act not only on neurons but probably also on glial cells. The aim of this study was to evaluate the effect of chlorpromazine and loxapine on release of IL-1beta and IL-2 by mixed glial and microglial cell cultures. Chlorpromazine in concentrations 2 and 20 muM, and loxapine 0.2, 2 and 20 microM reduced IL-1beta secretion by LPS-activated mixed glia cultures after 1 and 3 days of exposure. Chlorpromazine in concentrations of 0.2, 2 and 20 microM reduced the IL-2 secretion in mixed glial cultures after 3 days of exposure. Loxapine in concentrations of 0.2, 2 and 20 microM reduced IL-2 secretion in mixed glia cultures after 1 and 3 days of exposure, and additionally loxapine decreased IL-1beta and IL-2 secretion in LPS-induced microglia cultures in concentrations of 2, 10 and 20 muM. Quinpirole-a D2 dopaminergic agonist increased LPS-induced IL-1beta and IL-2 secretion in mixed glia cultures only in the highest dose of 20 microM. These findings suggest the absence of functional dopamine receptors on cortical microglial cells. Mixed glia cultures deprived of microglia (by shaking and incubating with L-leucine methyl ester) did not release IL-1beta and IL-2. This observation suggests that microglia can be a source of assessed cytokines. Results of the present study support the view that antipsychotics act not only on neurons but also on glial cells. However, the clinical significance of these observations still remains unclear[2].
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| Animal Protocol |
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. |
| ADME/Pharmacokinetics |
Absorption
In male volunteers, the systemic bioavailability of the parent drug after intramuscular injection of an equivalent dose (25 mg base) was only about one-third that of the intramuscular injection. Excretion Metabolites are excreted in urine as conjugates and in feces as unconjugates. Animal studies of radiopharmaceuticals have shown that loxapine and its metabolites are widely distributed throughout the body, with the highest concentrations in the brain, lungs, heart, liver, and pancreas. The drug is also found in cerebrospinal fluid. Loxapine is rapidly and almost completely absorbed from the gastrointestinal tract. Following intramuscular injection, the drug is also almost completely absorbed. It is rapidly and almost completely absorbed from the gastrointestinal tract. After oral administration of 25 mg loxapine, peak serum loxapine concentrations reached 0.006 to 0.013 μg/mL within 2 hours. The main active metabolite in serum is 8-hydroxyloxapine, with a maximum concentration of 0.012-0.038 μg/mL within 2-4 hours after oral administration. Humans/ Loxapine and its metabolites…are widely distributed in human tissues…with the highest concentrations in the brain, lungs, heart, liver, and pancreas…found in cerebrospinal fluid…can cross the placenta…present in the breast milk of lactating mothers/animals, radiopharmaceuticals/ Metabolites/7- and 8-hydroxy-, 7- and 8-hydroxydesmethylloxapine; N-oxides of loxapine, 7- and 8-hydroxyloxapine/excreted in urine and feces. Almost no unmetabolized drug is detected…metabolites are mainly present in urine as glucuronide or sulfate conjugates, and mainly in feces as unconjugates. Human, Oral / View MoreMetabolism/Metabolites Biological half-life: Oral administration - 4 hours Serum concentrations of loxapine and its metabolites exhibit a biphasic decrease. The first phase half-life is 5 hours, and the second phase half-life is 19 hours. / Following a single oral dose of 25 mg, sedative effects begin within 20-30 minutes; peak effect is reached within 1.5-3 hours; duration of action is approximately 12 hours. Humans/ |
| Toxicity/Toxicokinetics |
Reported Lethal Dose
Ingestion of 2500 mg…confirmed lethal… Toxicity Data LD50=65 mg/kg (oral in mice) Non-human Toxicity Values Toxicity Overview Loxapine is a dopamine antagonist and a serotonin 2 receptor blocker. The exact mechanism of action of loxapine is not yet determined, but changes in the excitability levels of subcortical inhibitory areas have been observed in several animals, accompanied by sedative effects, such as calming and inhibition of aggressive behavior. Hepatotoxicity Liver dysfunction has been reported in a small number of patients taking loxapine long-term, but elevations of liver function indicators exceeding three times the upper limit of normal are uncommon. Aminotransferase abnormalities are usually mild, asymptomatic, and transient, and can be reversed with continued use. There have been reports of loxapine and the structure-related tricyclic amoxapine (not marketed in the US) causing clinically significant acute liver injury, but such cases are rare. In the reported cases, jaundice appeared within 4 to 8 weeks, and the pattern of elevated serum enzymes was typically hepatocellular. Immune hypersensitivity features and autoantibody formation were not prominent. All cases were self-limiting, with no death or sequelae of chronic liver injury. Probability score: D (Possibly a rare cause of clinically significant liver injury). View MoreOral LD50 in rats: 151 mg/kg Route of Exposure Oral, intramuscular injection. The systemic bioavailability of the parent drug was only about one-third of that of the equivalent intramuscular dose (25 mg base) in male volunteers. Treatment: Overdose is primarily treated with symptomatic and supportive care. Early gastric lavage and prolonged dialysis may be effective. Centrally induced emetics may be ineffective due to loxapine's antiemetic effect. Furthermore, emetic induction should be avoided as aspiration of vomit may occur. Stimulants such as pentylenetetrazol should be avoided as they may cause seizures. Severe hypotension may be treated with levofloxacin or phenylephrine. Epinephrine should not be used, as it may further lower blood pressure in patients with partial adrenergic blockade. Severe extrapyramidal reactions should be treated with anticholinergic anti-Parkinson's drugs or diphenhydramine hydrochloride, and anticonvulsant therapy should be initiated as needed. Other measures include oxygen therapy and intravenous fluid administration. (L1712) Effects during pregnancy and lactation ◉ Overview of medication use during lactation As there is no information available on the use of loxapine during lactation, alternative medications may be preferred, especially when breastfeeding newborns or premature infants. ◉ Effects on breastfed infants As of the revision date, no relevant published information was found. ◉ Effects on lactation and breast milk Loxapine can increase serum prolactin levels. Hyperprolactinemia is caused by the drug's dopamine blocking effect on the tuberous infundibulum pathway. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed. |
| References |
[1]. Singh AN, et al. 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]. Labuzek K, et al. 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]. Lee T, et al. 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]. 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. |
| Additional Infomation |
An antipsychotic drug used to treat schizophrenia.
See also: Loxapine (with active ingredient). |
| Molecular Formula |
C18H18N3OCL.HCL
|
|---|---|
| Molecular Weight |
364.26896
|
| Exact Mass |
363.09
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| CAS # |
54810-23-0
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| Related CAS # |
Loxapine;1977-10-2;Loxapine succinate;27833-64-3;Loxapine-d8 hydrochloride;1246820-19-8;Loxapine-d8;1189455-63-7
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| PubChem CID |
71400
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| Appearance |
Typically exists as solid at room temperature
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| Boiling Point |
458.6ºC at 760 mmHg
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| Melting Point |
109-110ºC
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| Flash Point |
231.1ºC
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| LogP |
3.884
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| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
1
|
| Heavy Atom Count |
24
|
| Complexity |
450
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CN1CCN(CC1)C2=NC3=CC=CC=C3OC4=C2C=C(C=C4)Cl.Cl
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| InChi Key |
JSXBVMKACNEMKY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H18ClN3O.ClH/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;1H
|
| Chemical Name |
8-chloro-6-(4-methylpiperazin-1-yl)benzo[b][1,4]benzoxazepine;hydrochloride
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| Synonyms |
Loxapine hydrochloride; Loxapine HCl; LOXITANE C; 54810-23-0; Loxitane IM; UNII-376MYL4MAL; 376MYL4MAL; Loxapine (hydrochloride);
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7452 mL | 13.7261 mL | 27.4522 mL | |
| 5 mM | 0.5490 mL | 2.7452 mL | 5.4904 mL | |
| 10 mM | 0.2745 mL | 1.3726 mL | 2.7452 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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