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
In male volunteers, the systemic bioavailability of the parent drug after intramuscular injection of an equivalent dose (25 mg base) is only about one-third of the intramuscular dose. 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. Following oral administration of 25 mg loxapine, peak serum loxapine concentrations reach 0.006 to 0.013 μg/mL within 2 hours. The major active metabolite in serum is 8-hydroxyloxapine, with maximum concentrations of 0.012–0.038 μg/mL within 2–4 hours after oral administration. Humans /
Loxapine and its metabolites...widely distributed in body tissues...highest concentrations in the brain, lungs, heart, liver, and pancreas...found in cerebrospinal fluid...passes through the placenta...present in the breast milk of lactating mothers /animals, radiopharmaceuticals /
Metabolites /7- and 8-hydroxy-, 7- and 8-hydroxydemethylloxapine; N-oxides of loxapine, 7- and 8-hydroxyloxapine /excreted in urine and feces. Almost no unmetabolized drug is detected...metabolites are present primarily in urine as glucuronide or sulfate conjugates, and primarily in feces as unconjugated forms. Humans Oral /
Metabolism /Metabolites

Hepatic
rapidly and extensively metabolized in the liver via aromatic hydroxylation, N-demethylation, and N-oxidation. Major metabolites: 8-hydroxyloxapine, 7-hydroxyloxapine (active metabolite), 8-hydroxydesmethylloxapine, 7-hydroxydesmethylloxapine, and loxapine-N-oxide (inactive metabolite). (Human, oral)
Contains significant amounts of 7-hydroxyloxapine and 8-hydroxyloxapine N-oxides, which are formed by hydroxylation and N-oxidation. Loxapine metabolites are primarily excreted in the urine as glucuronide or sulfate conjugates. (Human, oral)
Two metabolites: 8-hydroxyloxapine and 8-hydroxyamoxapine. Oral administration.
Loxapine is rapidly and extensively metabolized in the liver via aromatic hydroxylation and N-oxidation. The major metabolites of loxapine are the active 8-hydroxyloxapine and 7-hydroxyloxapine, and the inactive 8-hydroxydesmethylloxapine, 7-hydroxydesmethylloxapine, and loxapine N-oxide. Hydroxyxapine N-oxide is also present in significant quantities.
The known metabolites of loxapine include loxapine N-glucuronide.
Hepatic
Excretion pathway: Metabolites are excreted in urine as conjugates and in feces as unconjugates.
Half-life: Oral administration - 4 hours

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Biological half-life
Oral administration - 4 hours
Serious 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. After a single oral dose of 25 mg, sedation begins within 20-30 minutes; peak effect is reached within 1.5-3 hours; and the duration of effect is approximately 12 hours. Human/

Toxicity Summary
Loxapine is a dopamine antagonist and a serotonin 5-HT2 blocker. The exact mechanism of action of loxapine is not fully understood, but it has been observed in various animals to alter the excitability levels of subcortical inhibitory areas and to have sedative effects, such as calming and inhibition of aggressive behavior. Toxicity Data
LD50 = 65 mg/kg (oral in mice) Interactions Loxapine may have additive or synergistic effects with other central nervous system depressants (including barbiturates and alcohol) or anticholinergic drugs…inhibiting the vasopressive effect of adrenaline. Concomitant use with alcohol or other central nervous system depressants (especially anesthetics, barbiturates, and opioid (narcotic) analgesics) may enhance and prolong…these drugs or loxapine generally have central nervous system depressant effects; dose adjustments to approximately 1/2 to 1/4 of the usual dose may be necessary.
Concomitant use with amphetamines may reduce the efficacy of amphetamines because loxapine produces alpha-adrenergic blocking effects.
Concomitant use with antacids or adsorbent antidiarrheals may inhibit the absorption of oral loxapine.
For more complete data on loxapine interactions (18 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 151 mg/kg
Intraperitoneal LD50 in rats: 35 mg/kg
Subcutaneous LD50 in rats: 350 mg/kg
Intravenous LD50 in rats: 18 mg/kg
For more complete data on loxapine non-human toxicity values (8 in 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 dibenzoxazole drug. It is an antipsychotic and dopaminergic antagonist. Loxapine is a traditional antipsychotic used to treat schizophrenia. Loxapine treatment usually results in a mild elevation of serum transaminases, and in rare cases, is associated with clinically significant acute liver injury. Loxapine has only been observed in individuals who have taken the drug. It is an antipsychotic used to treat schizophrenia. Loxapine is a dopamine antagonist and also a serotonin 2 receptor blocker. The exact mechanism of action of loxapine is not fully understood, but it has been observed in several animals to alter the excitability levels of subcortical inhibitory areas and to have sedative effects, such as calming effects and inhibition of aggressive behavior. An antipsychotic used to treat schizophrenia. See also: Loxapine succinate (salt form); Loxapine hydrochloride (salt form).

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Drug Indications
For the treatment of symptoms 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 standard treatment immediately after acute agitation symptoms are controlled.
Treatment of bipolar disorder, treatment of schizophrenia
Mechanism of Action

Loxapine is a dopamine antagonist and a serotonin 2 receptor blocker. The exact mechanism of action of loxapine is not yet clear, but it has been observed in several animals to alter the excitability levels of subcortical inhibitory areas, accompanied by sedative effects, such as calming effects and inhibition of aggressive behavior.
Studies have shown that loxapine produces sedative effects and significant extrapyramidal responses, lowers the seizure threshold, and has antiadrenergic and anticholinergic effects. /Succinate/
Therapeutic Uses

Antipsychotic drug; dopamine antagonist
This dibenzoxazolidine derivative is effective in treating schizophrenia, but it is unclear whether it has advantages over other antipsychotic drugs. /Succinic acid/
Loxapine is indicated for the treatment of symptoms and characteristics of psychosis. /Included in the US product label/
Loxapine has been used to treat anxiety disorders with depression. /Not included in the US product label/

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Drug Warnings
…Loxapine should only be used in patients who have not responded to established antipsychotic medications. /Succinic acid/
The safety of loxapine use during pregnancy has not been established; therefore, pregnant women or women who may become pregnant should not use this drug unless the potential benefit outweighs the potential risk to the pregnant woman or fetus.
Loxapine is not recommended for use in children under 16 years of age until clinical data on its use in children are accumulated.
Loxapine should be used with caution due to its potential anticholinergic activity, especially when used in combination with anticholinergic anti-Parkinson's drugs, and in patients with glaucoma or a tendency to urinary retention. Because loxapine may have an antiemetic effect, it may mask the symptoms of toxic drug overdose or interfere with the diagnosis of conditions such as intestinal obstruction or brain tumors. Loxapine is contraindicated in patients who are comatose, have severe central nervous system depression of any cause, or are known to be hypersensitive to this drug. For more complete data on drug warnings for loxapine (13 in total), please visit the HSDB record page. Pharmacodynamics: Loxapine is a dibenzoxazine compound, belonging to a subclass of tricyclic antipsychotics. Its chemical structure differs from thioxanthracene, butyrophenone, and phenothiazines. Pharmacologically, loxapine is a sedative. Its exact mechanism of action is not fully understood, but it is generally believed to exert a significant cortical inhibitory effect by antagonizing dopamine and serotonin receptors, thereby exhibiting sedation 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.)