Inhibiting HNEpC proliferation greatly with ezelastine can aid in the fight against airway remodeling [5].

In a rat model of diabetic hyperlipidemia Protein B, ezelastine (4 mg/kg; oral; daily; for 8 weeks) dramatically lowers serum alkaline phosphatase (ALP), osteocalcin, blood glucose, and HbA1c and downregulates lipopolysaccharide [2]. In a rat model of diabetic hyperlipidemia, ezelastine (4 mg/kg; oral; daily; for 8 weeks) improves the lipid profile (increasing HDL-c and lowering LDL-c) [2]. In a rat model of diabetic hyperlipidemia, ezelastine (4 mg/kg; oral; daily; for 8 weeks) decreases aortic calcification and calcium deposition [2].

Cell proliferation assay [5]
Cell Types: Human nasal epithelial cells (HNEpC)
Tested Concentrations: 100 μM, 400 μM
Incubation Duration: 21 days
Experimental Results: Inhibition of HNEpC growth.

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Western Blot Analysis[5]
Cell Types: Human nasal epithelial cells (HNEpC)
Tested Concentrations: 100 μM
Incubation Duration: 7 days
Experimental Results: H1R, M1R and M3R levels were Dramatically upregulated.

Animal/Disease Models: Male albino Wistar rat (150-170 g), diabetic hyperlipidemia rat model [2]
Doses: 4 mg/kg
Route of Administration: Orally, one time/day for 8 weeks
Experimental Results: Aortic calcification Improvement, apolipoprotein A expression increased, while apolipoprotein B diminished.

Absorption, Distribution and Excretion
Systemic bioavailability of azelastine hydrochloride following intranasal administration is approximately 40%, reaching Cmax within 2-3 hours. When administered at doses greater than the recommended maximum, greater than proportional increases in both Cmax and AUC were observed.
After an oral dose of radio-labeled azelastine hydrochloride, approximately 75% was excreted in the feces, with less than 10% as unchanged azelastine hydrochloride.
After intravenous and oral administration, the steady-state volume of distribution is 14.5 L/kg.
Based on intravenous and oral administration, azelastine demonstrated a plasma clearance of 0.5 L/h/kg.
After intranasal administration, the systemic bioavailability of azelastine hydrochloride is approximately 40%. Maximum plasma concentrations (Cmax) are achieved in 2-3 hours.
Based on oral, single-dose studies, renal insufficiency (creatinine clearance <50 mL/min) resulted in a 70-75% higher Cmax and AUC compared to normal subjects. Time to maximum concentration was unchanged.
Based on intravenous and oral administration, the steady-state volume of distribution, and plasma clearance are 14.5 L/kg, and 0.5 L/hr/kg, respectively.
In vitro studies with human plasma indicate that the plasma protein binding of azelastine and desmethylazelastine are approximately 88% and 97%, respectively.
For more Absorption, Distribution and Excretion (Complete) data for Azelastine (10 total), please visit the HSDB record page.

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Metabolism / Metabolites
Azelastine hydrochloride is oxidatively metabolized to its main, and biologically active, metabolite desmethylazelastine by the cytochrome P450 enzyme system. Though labels for azelastine state that specific CYP enzyme involvement has not been elucidated, it has been suggested that the N-demethylation of azelastine is primarily catalyzed by CYP3A4, CYP2D6, and CYP1A2.
Azelastine is oxidatively metabolized to the principal active metabolite, desmethylazelastine, by the cytochrome P450 enzyme system. The specific P450 isoforms responsible for the biotransformation of azelastine have not been identified
The major active metabolite, desmethylazelastine, was not measurable (below assay limits) after single-dose intranasal administration of azelastine hydrochloride. After intranasal dosing of azelastine hydrochloride to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations.
The ... pharmacokinetics of azelastine hydrochloride after single and multiple dosing (4.4 mg as tablet, tau = 12 hr) were investigated in 14 volunteers (6 female, 8 male) older than 65 years (70 +/- 5 years, mean +/- SD). ... The RIA co-detects besides azelastine the pharmacodynamically active metabolite N-demethyl-azelastine and thus, the parameters describe the pharmacokinetic behaviour as a resultant from both compounds, i.e. the "active principle". N-Demethylated metabolites are known to have longer half-lives usually than their parent compounds and thus, accumulate in a higher degree during multiple dosing.
Azelastine hydrochloride is oxidatively metabolized to the principal metabolite, N-desmethylazelastine, by the cytochrome P450 enzyme system, however the exact cytochrome P450 isoenzyme involved has not been determined. The major metabolite, desmethylazelastine, also has H1-receptor antagonist activity.
Route of Elimination: Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine. Azelastine hydrochloride is oxidatively metabolized to the principal metabolite, N-desmethylazelastine, by the cytochrome P450 enzyme system.
Half Life: Elimination half-life (based on intravenous and oral administration) is 22 hours. Elimination half-life of the active metabolite, desmethylazelastine, is 54 hours (after oral administration of azelastine).

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Biological Half-Life
Based on intravenous and oral administration, azelastine demonstrated an elimination half-life of 22 hours. Its primary active metabolite, desmethylazelastine, has an elimination half-life of 54 hours.
Based on intravenous and oral administration, the elimination half-life is 22 hours ...
When azelastine hydrochloride is administered orally, desmethylazelastine has an elimination half-life of 54 hours.

Toxicity Summary
Azelastine competes with histamine for the H1-receptor sites on effector cells and acts as an antagonist by inhibiting the release of histamine and other mediators involved in the allergic response.

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Interactions
Concurrent use of Astelin Nasal Spray with alcohol or other CNS depressants should be avoided because additional reductions in alertness and additional impairment of CNS performance may occur.
Cimetidine increased the mean Cmax and AUC of orally administered azelastine hydrochloride by approximately 65%. Ranitidine hydrochloride had no effect on azelastine pharmacokinetics.
Interaction studies investigating the cardiac effects, as measured by the corrected QT interval (QTc), of concomitantly administered oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. Oral erythromycin had no effect on azelastine pharmacokinetics or QTc based on analyses of serial electrocardiograms. Ketoconazole interfered with the measurement of azelastine plasma concentrations; however, no effects on QTc were observed.

[1]. Craig La Force. Review of the pharmacology, clinical efficacy, and safety of azelastine hydrochloridel. Expert Rev Clin Immunol. 2005 Jul;1(2):191-201.
[2]. Mohamed M Elseweidy, et al. Azelastine a potent antihistamine agent, as hypolipidemic and modulator for aortic calcification in diabetic hyperlipidemic rats model. Arch Physiol Biochem. 2020 Jul 2;1-8.
[3]. Carlos D. Zappia, et al. Azelastine potentiates antiasthmatic dexamethasone effect on a murine asthma model. Pharmacol Res Perspect. 2019 Dec; 7(6): e00531.
[4]. Li Yang, et al. Identification of SARS-CoV-2 entry inhibitors among already approved drugs. Acta Pharmacol Sin. 2020 Oct 28 : 1-7.
[5]. Shao-Cheng Liu, et al. Effect of budesonide and azelastine on histamine signaling regulation in human nasal epithelial cells. Eur Arch Otorhinolaryngol. 2017 Feb;274(2):845-853.

Therapeutic Uses
Phthalazines; Anti-Inflammatory Agents, Non-Steroidal; Platelet Aggregation Inhibitors; Bronchodilator Agents; Histamine H1 Antagonists, Non-Sedating; Lipoxygenase Inhibitors
Oral azelastine has been safely administered to over 1400 asthmatic subjects, supporting the safety of administering Astelin Nasal Spray to allergic rhinitis patients with asthma.
Astelin Nasal Spray is indicated for the treatment of the symptoms of seasonal allergic rhinitis such as rhinorrhea, sneezing, and nasal pruritus in adults and children 5 years and older, and for the treatment of the symptoms of vasomotor rhinitis, such as rhinorrhea, nasal congestion and postnasal drip in adults and children 12 years and older. /Include in US product label/
Azelastine is used for the symptomatic treatment of ocular itching associated with allergic conjunctivitis. This indication is based on environmental studies (duration 2-8 weeks) in which therapy with azelastine ophthalmic solution was more effective than vehicle in providing relief of ocular itching in children and adults with allergic conjunctivitis.
THERAPEUTIC CATEGORY: Antihistaminic

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Drug Warnings
Astelin Nasal Spray is contraindicated in patients with a known hypersensitivity to azelastine hydrochloride or any of its components.
... The occurrence of somnolence has been reported in some patients taking Astelin Nasal Spray; due caution should therefore be exercised when driving a car or operating potentially dangerous machinery while using Astelin Nasal Spray. Concurrent use of Astelin Nasal Spray with alcohol or other CNS depressants should be avoided because additional reductions in alertness and additional impairment of CNS performance may occur.
The manufacturer states that there was no evidence of an effect on cardiac repolarization in patients who received azelastine hydrochloride nasal spray (548 mcg twice daily for 56 days) in a placebo-controlled study. Although 3- to 7-millisecond increases in mean QTc intervals were observed with higher oral dosages of the drug, such increases were not considered to be clinically important.
The principal adverse effects of intranasal azelastine are local (e.g., bitter taste, nasal burning, pharyngitis, paroxysmal sneezing), but adverse systemic effects (e.g., somnolence, headache) also can occur. Anaphylactoid reactions, application site reaction, chest pain, aggravated condition, confusion, diarrhea, dyspnea, facial edema, involuntary muscle contractions, paresthesia, parosmia, pruritus, rash, tolerance, urinary retention, vision abnormality, and xerophthalmia have occurred in patients receiving azelastine nasal spray; a causal relationship between these events and the drug have not been established.
For more Drug Warnings (Complete) data for Azelastine (16 total), please visit the HSDB record page.

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Pharmacodynamics
Azelastine antagonizes the actions of histamine, resulting in the relief of histamine-mediated allergy symptoms. Onset of action occurs within 15 minutes with intranasal formulations and as quickly as 3 minutes with ophthalmic solutions. Intranasal formulations have a relatively long-duration of action, with peak effects observed 4-6 hours after the initial dose and efficacy maintained over the entirety of the standard 12 hour dosing interval.

C₂₂H₂₄CLN₃O

381.90

381.16

58581-89-8

Azelastine hydrochloride;79307-93-0;Azelastine-13C,d3

2267

Oil

1.3±0.1 g/cm3

533.9±60.0 °C at 760 mmHg

276.7±32.9 °C

0.0±1.4 mmHg at 25°C

1.642

3.71

0

3

3

27

558

0

O=C1N(C2CCN(C)CCC2)N=C(CC3=CC=C(Cl)C=C3)C4=C1C=CC=C4

MBUVEWMHONZEQD-UHFFFAOYSA-N

InChI=1S/C22H24ClN3O/c1-25-13-4-5-18(12-14-25)26-22(27)20-7-3-2-6-19(20)21(24-26)15-16-8-10-17(23)11-9-16/h2-3,6-11,18H,4-5,12-15H2,1H3

4-[(4-chlorophenyl)methyl]-2-(1-methylazepan-4-yl)phthalazin-1-one

Allergodil Azelastine HCl Astelin Optivar Rhinolast Azeptin

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)

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

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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