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

[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].

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].

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]

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]

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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.63 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.63 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.63 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)