| 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
Systemic bioavailability of the parent drug was only about one third that after an equivalent intramuscular dose (25 mg base) in male volunteers Route of Elimination 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/ View More
Metabolism / Metabolites
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/Toxicokinetics |
Reported Fatal Dose
A 2500 mg ingestion ... proved fatal ... Toxicity Data LD50=65 mg/kg (Orally in mice) Non-Human Toxicity Values 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. Hepatotoxicity Liver test abnormalities have been reported to occur in a small proportion of patients on long term therapy with loxapine, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Instances of clinically apparent acute liver injury have been reported due to loxapine and to the structurally related tricylic amoxapine (not available in the United States), but cases are rare. In reported cases, the onset of jaundice was within 4 to 8 weeks, and the pattern of serum enzyme elevations was typically hepatocellular. Immunoallergic features and autoantibody formation were not prominent. All cases were self-limited without fatalities or residual chronic liver injury. Likelihood score: D (possible rare cause of clinically apparent liver injury). View More
LD50 Rat oral 151 mg/kg Exposure Routes Oral, Intramuscular. Systemic bioavailability of the parent drug was only about one third that after an equivalent intramuscular dose (25 mg base) in male volunteers. Treatment The treatment of overdosage is essentially symptomatic and supportive. Early gastric lavage and extended dialysis might be expected to be beneficial. Centrally-acting emetics may have little effect because of the antiemetic action of loxapine. In addition, emesis should be avoided because of the possibility of aspiration of vomitus. Avoid analeptics, such as pentylenetetrazol, which may cause convulsions. Severe hypotension might be expected to respond to the administration of levarterenol or phenylephrine. Epinephrine should not be used since its use in a patient with partial adrenergic blockade may further lower the blood pressure. Severe extrapyramidal reactions should be treated with anticholinergic antiparkinson agents or diphenhydramine hydrochloride, and anticonvulsant therapy should be initiated as indicated. Additional measures include oxygen and intravenous fluids. (L1712) Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Because no information is available on the use of loxapine during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Loxapine can elevate serum prolactin. The hyperprolactinemia is caused by the drug's dopamine-blocking action in the tuberoinfundibular pathway. The prolactin level in a mother with established lactation may not affect her 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 agent used in schizophrenia.
See also: Loxapine (has active moiety). |
| Molecular Formula |
C18H18N3OCL.HCL
|
|---|---|
| Molecular Weight |
364.26896
|
| Exact Mass |
363.09
|
| 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
|
| 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);
|
| 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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