A23187-induced LTC4 and ECP release from eosinophils is dose-dependently inhibited by pemirolast (1 μM-1 mM) [1]. Pemirolast (0.1 mM and 1 mM) also prevents eosinophil ECP release that is triggered by FMLP and PAF [1]. By limiting human eosinophil activation, pirazolast reduces the production of granular proteins LTQ and ECP, which helps to alleviate and regulate allergic disorders [1]. Human conjunctival mast cells' histamine production is not substantially inhibited by pemirolast (100 nM-1 mM; 1–15 minutes) [2]. Pemirolast (0.1 μg/mL-0.01 mg/mL) suppresses the production of 1,2-diacylglycerol and the degranulation reaction of antigen and compound 48/80 in rat peritoneal mast cells, thereby inhibiting the signal transmission phospholipase C. and phosphatidyl acid and AZ activation [3].

Pemirolast blocks rats' release of sensory neuropeptides, which effectively reduces paclitaxel allergic reactions [4]. Half an hour after starting paclitaxel (15 mg/kg; i.v.) at a dose of 1 mg/kg, pemirolast (0.1-1 mg/kg; i.v.) inhibits and reverses the decrease in arterial PaO2 caused by paclitaxel-induced pulmonary vascular hyperpermeability. 4]. Thirty minutes after paclitaxel injection (15 mg/kg; iv), pemirolast (1 mg/kg; iv) reverses the increases in sensory neuropeptide (CGRP, substance P, and neurokinin A) concentrations caused by paclitaxel [4]. Pemirolast (10 mg/kg/d; oral; days 4-5) inhibits the release of substance P in rat cerebrospinal fluid (CSF) induced by cisplatin and significantly reduces kaolin intake on days 3 and 4[5].

Animal/Disease Models: Male Wistar rats (6 weeks old, 160-250 g) [5]
Doses: 10 mg/kg
Route of Administration: po (oral gavage); 5 days: 1 hour or 30 minutes before and after cisplatin administration
Experimental Results: Inhibition of cisplatin-induced increase in kaolin intake at 24, 48, 72 and 96 hrs (hrs (hours)) (5 times in total) (2-10 mg/kg; iv) on days 3 and 4 without reduction in normal feed intake .

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Animal/Disease Models: Male Wistar rats (6 weeks old, 160-250 g) [5]
Doses: 10 mg/kg
Route of Administration: po (oral gavage); 4 days: 30 days before cisplatin (5 mg/kg; iv) administration minutes and 24, 48, 72 and 96 hrs (hrs (hours)) after dosing (four times in total).
Experimental Results: Significant reversal of cisplatin-induced elevation of substance P levels in cerebrospinal fluid to vehicle levels.

Absorption, Distribution and Excretion
Following topical administration, about 10-15% of the dose was excreted unchanged in the urine.
A mean peak plasma level of 4.7 ng/mL occurred after 2 weeks of administration. /Pemirolast potassium/
Elimination: Renal, 84 to 90% of dose eliminated within 24 hours, about 10 to 15% of the dose was excreted unchanged. /Pemirolast potassium/
Pemirolast potassium is excreted in the milk of lactating rats at concentrations higher than those in plasma. It is not known whether pemirolast potassium is excreted in human milk.
Topical ocular administration of one to two drops of Alamast ophthalmic solution in each eye four times daily in 16 healthy volunteers for two weeks resulted in detectable concentrations in the plasma. The mean (+/- SE) peak plasma level of 4.7 +/- 0.8 ng/mL occurred at 0.42 +/- 0.05 hours and the mean half-life was 4.5 +/- 0.2 hours. /Pemirolast potassium/

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Metabolism / Metabolites
Hepatic (Ophthalmic)

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Biological Half-Life
4.5 hours (Ophthalmic)
...Mean half-life was 4.5 +/- 0.2 hours. /Pemirolast potassium/

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Although no published data exist on the use of pemirolast during lactation, maternal milk levels are likely to be very low after the use eye drops.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Interactions
The effect of a newly developed anti-allergic drug, pemirolast potassium (TBX), on the pharmacokinetics and metabolism of theophylline was investigated under steady-state conditions in seven healthy male volunteers. A sustained-release theophylline formulation (100 mg twice daily at 12 h intervals) was given as monotherapy and coadministered with TBX (10 mg twice daily at 12 h). Plasma concentration-time curves and the urinary excretion of theophylline and its major metabolites after administration of theophylline alone and after coadministration with TBX were compared. No significant adverse effects from this study were observed. There were no significant differences in the total body clearance, renal clearance and maximum concentration of theophylline between the two treatments, although coadministration of TBX significantly delayed the time to reach maximum concentration of theophylline. In the case of urinary excretion, no significant changes in the fraction of urinary excretion of theophylline and its metabolites were observed. These results indicate that TBX has little or no effect on the pharmacokinetics and metabolism of theophylline and suggest that TBX is safe for asthma patients receiving theophylline therapy for treatment of chronic obstructive airway diseases.

[1]. Kawashima T, et al. Inhibitory effect of pemirolast, a novel antiallergic drug, on leukotriene C4 and granule protein release from human eosinophils. Int Arch Allergy Immunol. 1994;103(4):405-9.
[2]. Yanni JM, et al. Comparative effects of topical ocular anti-allergy drugs on human conjunctival mast cells. Ann Allergy Asthma Immunol. 1997 Dec;79(6):541-5.
[3]. Fujimiya H, et al. Effect of a novel antiallergic drug, pemirolast, on activation of rat peritoneal mast cells: inhibition of exocytotic response and membrane phospholipid turnover. Int Arch Allergy Appl Immunol. 1991;96(1):62-7.
[4]. Itoh Y, et al. Pemirolast potently attenuates paclitaxel hypersensitivity reactions through inhibition of the release of sensory neuropeptides in rats. Neuropharmacology. 2004 May;46(6):888-94.
[5]. Tatsushima Y, et al. Pemirolast reduces cisplatin-induced kaolin intake in rats. Eur J Pharmacol. 2011 Jul 1;661(1-3):57-62.

Pemirolast is a pyridopyrimidine.
Pemirolast potassium is a slightly yellow powder that is soluble in water. It is a mast cell stabilizer that acts as an antiallergic agent. As an ophthalmic aqueous sterile solution, pemirolast is used for the prevention of itching of the eyes caused by allergies such as hay fever, and allergic conjunctivitis. Pemirolast is potentially useful for prophylaxis of pulmonary hypersensitivity reactions to drugs such as paclitaxel.
Pemirolast is a Mast Cell Stabilizer. The physiologic effect of pemirolast is by means of Decreased Histamine Release.
Pemirolast is a pyrimidinone derivative with anti-allergic activity. Pemirolast blocks the antigen-mediated calcium ion influx into mast cells. This prevents mast cell degranulation, resulting in mast cell stabilization and inhibition of the release of inflammatory mediators, such as histamine and leukotrienes, which are involved in the allergic process. Pemirolast also prevents inflammatory mediator release from eosinophils.

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Drug Indication
For the prevention of itching of the eyes caused by allergies such as hay fever, and allergic conjunctivitis
FDA Label

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Mechanism of Action
Pemirolast binds to the histamine H₁ receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine. Pemirolast has also been observed to inhibit antigen-stimulated calcium ion influx into mast cells through the blockage of calcium channels. Pemirolast inhibits the chemotaxis of eosinophils into ocular tissue, and prevents inflammatory mediator release from human eosinophils.
To determine whether pemirolast, a new antiallergic drug, inhibits the activation of eosinophils, we investigated the effect of pemirolast on the release of leukotriene C4 (LTC4) and eosinophil cationic protein (ECP) from human eosinophils. Calcium ionophore A23187 caused both LTC4 and ECP release from human eosinophils, whereas PAF and FMLP induced only ECP release from the eosinophils. Pemirolast (10(-6) to 10(-3) M) inhibited A23187-induced LTC4 release from the eosinophils in a dose-dependent fashion with 77% inhibition at 10(-3) M. Pemirolast (10(-5) to 10(-3) M) inhibited A23187-induced ECP release from the eosinophils in a dose-dependent fashion with 42% inhibition at 10(-3) M. Pemirolast (10(-4) and 10(-3) M) also inhibited PAF-induced and FMLP-induced ECP release from the eosinophils. We conclude that pemirolast prevents the activation of human eosinophils to inhibit LTC4 and ECP release. These results suggest that pemirolast might be useful in controlling allergic diseases by inhibiting eosinophil activation. /Pemirolast potassium/
Pemirolast is a mast cell stabilizer and inhibits the release of inflammatory mediators from cells associated with Type I immediate hypersensitivity reactions. The drug has been observed to block antigen-stimulated calcium ion influx into mast cells. Pemirolast also inhibits the chemotaxis of eosinophils into ocular tissue, and prevents inflammatory mediator release from human eosinophils. /Pemirolast potassium/

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Therapeutic Uses
Antiallergic
Pemirolast ophthalmic solution is indicated for the prophylaxis of itching of the eye associated with allergic conjunctivitis. /Included in US product labeling/ /Pemirolast potassium/
The preventive effect of pemirolast against restenosis after coronary stent placement was evaluated. Eighty-four patients with 89 de novo lesions who underwent successful coronary stenting were assigned to the pemirolast group (40 patients, 45 lesions) and the control group (44 patients, 44 lesions). Administration of pemirolast (20 mg/day) was initiated from the next morning after stenting and continued for 6 months of follow-up. Quantitative coronary angiography was performed immediately after stenting and at follow-up. Angiographic restenosis was defined as diameter stenosis > or = 50% at follow-up. Intravascular ultrasound study conducted at follow-up angiography was used to measure vessel cross-sectional area (CSA), stent CSA, lumen CSA, neointima CSA (stent CSA--lumen CSA), and percentage neointima CSA (neointima CSA/stent CSA x 100%) at the minimal lumen site. There were no significant differences in baseline characteristics between the two groups. Restenosis rate was significantly lower in the pemirolast group than in the control group (15.0% vs 34.1% of patients, 13.3% vs 34.1% of lesions, p < 0.05, respectively). The intravascular ultrasound study at follow-up (36 lesions in the pemirolast group, 33 in the control group) found no significant differences in vessel CSA and stent CSA between the two groups(17.3 +/- 2.2 vs 16.8 +/- 2.4 mm2, 8.6 +/- 1.9 vs 8.4 +/- 1.7 sq mm, respectively). However, lumen CSA was significantly larger in the pemirolast group than in the control group (5.5 +/- 1.3 vs 4.4 +/- 1.1 sq mm, p < 0.05). Moreover, neointima CSA and percentage neointima CSA were significantly smaller in the pemirolast group (3.1 +/- 1.1 vs 4.0 +/- 1.2 sq mm, p < 0.05 and 36.2 +/- 15.9% vs 47.4 +/- 15.6%, p < 0.01). /Pemirolast potassium/

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Drug Warnings
Headaches, rhinitis, and cold/flu symptoms occurred in 10-25% of patients in clinical trials. ... Ocular burning/stinging, dry eye, foreign body sensation, and ocular discomfort, which occurre in 1-2% of patients, were the most common adverse ocular effects reported in clinical studies. /Pemirolast potassium/
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./ /Pemirolast potassium/
Pemirolast potassium is excreted in the milk of lactating rats at concentrations higher than those in plasma. It is not known whether pemirolast potassium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Alamast ophthalmic solution is administered to a nursing woman. /Pemirolast potassium/
The following ocular and non-ocular adverse reactions were reported at an incidence of less than 5%: Ocular: burning, dry eye, foreign body sensation, and ocular discomfort. Non-Ocular: allergy, back pain, bronchitis, cough, dysmenorrhea, fever, sinusitis, and sneezing/nasal congestion. /Pemirolast potassium/
The preservative in ALAMAST, lauralkonium chloride, may be absorbed by soft contact lenses. Patients who wear soft contact lenses and whose eyes are not red should be instructed to wait at least ten minutes after instilling ALAMAST before they insert their contact lenses. /Pemirolast potassium/

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Pharmacodynamics
Pemirolast is used for the prophylactic treatment of itching of the eye associated with allergic conjunctivitis. Pemirolast potassium is a mast cell stabilizer that inhibits the in vivo Type I immediate hypersensitivity reaction. Pemirolast inhibits the antigen-induced release of inflammatory mediators (e.g., histamine, leukotriene C4, D4, E4) from human mast cells. Allergic reactions lead to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H₁-receptors, produces pruritis and vasodilatation (allowing blood fluids to enter the area to cause swelling). Pemirolast is a histamine H1 antagonist. It competes with histamine for the normal H₁-receptor sites on effector cells of blood vessels to provide effective, temporary relief of watery and itchy eyes.

C10H8N6O

228.21012

228.076

69372-19-6

Pemirolast potassium;100299-08-9

57697

Crystals from dimethylformamide

1.64 g/cm3

454.8ºC at 760 mmHg

310-311ºC (decomposes)

228.9ºC

0.183

1

5

1

17

489

0

CC1=CC=CN2C1=NC=C(C2=O)C3=NNN=N3

HIANJWSAHKJQTH-UHFFFAOYSA-N

InChI=1S/C10H8N6O/c1-6-3-2-4-16-9(6)11-5-7(10(16)17)8-12-14-15-13-8/h2-5H,1H3,(H,12,13,14,15)

9-methyl-3-(2H-tetrazol-5-yl)pyrido[1,2-a]pyrimidin-4-one

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 : ~100 mg/mL (~438.19 mM)
DMF :< 1 mg/mL

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.)