H1 Receptor 1.01 mM (IC50)

In order to extend the duration of antihistaminic effects and delay metabolic time, pheniramine inhibits CYP2D6, a particular P450-isozyme[1]. By blocking histamine with an IC50 value of 1.01 mM, pheniramine prevents Ca2+ influx into BC3H-1 cells and controls the activity of the Ca2+ transmembrane in cells[2].In human T-cell acute lymphoblastic leukemia cell lines, pheniramine (0.5, 1.0 mM; 24 h) induces cell apoptosis[3]. The time-dependent inhibition of cell proliferation by pheniramine (1 μM-1 mM; 12-48 h) had inhibitory concentration IC50s of 550 μM for CCRF-CEM cells and 420 μM for Jurkat cells, respectively[3].

In rats, pheniramine (1.75 μM) causes spinal block and a local anesthetic effect[4].

Apoptosis Analysis [3]
Cell Types: Human T-cell acute lymphoblastic leukemia
Cell Types: CCRF-CEM and Jurkat ALL
Tested Concentrations: 0.5, 1.0 mM
Incubation Duration: 24 hrs (hours)
Experimental Results: Induced cells apoptosis with chromatin condenses and marginalizes, and nuclear debris spread into the cytoplasm.

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Cell Viability Assay[3]
Cell Types: Human T-cell acute lymphoblastic leukemia
Cell Types: CCRF-CEM and Jurkat ALL
Tested Concentrations: 1 μM-1 mM
Incubation Duration: 12, 24, 48 hrs (hours)
Experimental Results: Inhibited cell proliferation and survival in a time- and dose-dependent manner.

Animal/Disease Models: Sprague–Dawley rats (300-350 g ; male)[4]
Doses: 0.30, 0.60, 0.90, 1.50, 1.75 μM
Route of Administration: Intrathecal injection; one time
Experimental Results: Resulted the spinal block and displayed dose-dependent effect. demonstrated 100% blockades in motor function, proprioception, and nociception , with full recovery duration of action about 41, 56, and 88 min, respectively, at 1.75 μM.

Absorption, Distribution and Excretion
The administration of 30.5 mg of free base pheniramine resulted in a Cmax of 173-294 ng/L with a Tmax of 1-2.5 h.
Pheniramine is eliminated by metabolism and via renal excretion. 24.3% of pheniramine is present in the urine as the parent drug.

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Metabolism / Metabolites
Pheniramine undergoes N-dealkylation to N-didesmethylpheniramine and N-desmethylpheniramine.

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Biological Half-Life
The terminal half-life of pheniramine administered via IV is 8-17 h.

Effects During Pregnancy and Lactation
◈ What is pheniramine?
Pheniramine is an antihistamine approved to treat allergy symptoms such as stuffy nose and swollen eyes. It has also been used to treat dermatitis (inflammation of the skin) and motion sickness. Pheniramine might be listed as pheniramine maleate on medication labels. Pheniramine can be found in over-the-counter multi-symptom medications.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.
◈ I take pheniramine. Can it make it harder for me to get pregnant?
Studies have not been done to see if pheniramine could make it harder to get pregnant.
◈ Does taking pheniramine increase the chance for miscarriage?
Miscarriage can occur in any pregnancy. Studies have not been done to see if pheniramine increases the chance for a miscarriage.
◈ Does taking pheniramine increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Based on the studies reviewed, it is not known if pheniramine increases the chance for birth defects above the background risk.
◈ Does taking pheniramine in pregnancy increase the chance of other pregnancy related problems?
Based on the studies reviewed, it is not known if pheniramine can cause other pregnancy-related problems, such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth).
◈ Does taking pheniramine in pregnancy affect future behavior or learning for the child?
Studies have not been done to see if pheniramine causes behavior or learning issues for the child.
◈ Breastfeeding while taking pheniramine:
Pheniramine has not been studied for use during breastfeeding. Pheniramine can cause sleepiness in adults, and it is possible that in higher doses, it may do the same for a nursing baby. If you suspect the baby has any symptoms of increased sleepiness (more than usual), trouble feeding, trouble breathing, or limpness, contact the child’s healthcare provider. For this reason, it may not be a preferred antihistamine for long-term use during breastfeeding. If you need to take an antihistamine regularly while breastfeeding, talk with your healthcare provider about which one would be best for you.Infants that are born preterm or are younger than one month of age have a stomach and intestines that are less mature than older babies. This might allow more medication to enter their blood stream. It is possible, but not proven, that antihistamines in general may reduce the amount of breast milk that is made. Be sure to talk to your healthcare provider about all your breastfeeding questions.
◈ If a male takes pheniramine, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
Studies have not been done to see if pheniramine could affect male fertility or increase the chance of birth defects. In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

[1]. Classic histamine H1 receptor antagonists: a critical review of their metabolic and pharmacokinetic fate from a bird's eye view. Curr Drug Metab. 2003 Apr;4(2):105-29.

[2]. Alpha 1-adrenergic and H1-histamine receptor control of intracellular Ca2+ in a muscle cell line: the influence of prior agonist exposure on receptor responsiveness. Mol Pharmacol. 1986 Jun;29(6):531-9.

[3]. Apoptosis of human T-cell acute lymphoblastic leukemia cells by diphenhydramine, an H1 histamine receptor antagonist. Oncol Res. 2004;14(7-8):363-72.

[4]. Spinal anesthesia with diphenhydramine and pheniramine in rats. Eur J Pharmacol. 2011 Dec 30;673(1-3):20-4.

N,N-dimethyl-3-phenyl-3-(2-pyridinyl)-1-propanamine is a tertiary amino compound and a member of pyridines.
Pheniramine is a first-generation antihistamine in the alkylamine class, similar to [brompheniramine] and [chlorpheniramine]. It is used in some over-the-counter allergy as well as cold & flu products in combination with other drugs. Pheniramine's use as an anti-allergy medication has largely been supplanted by second-generation antihistamines such as [cetirizine] and [loratadine].
One of the HISTAMINE H1 ANTAGONISTS with little sedative action. It is used in treatment of hay fever, rhinitis, allergic dermatoses, and pruritus.
See also: Pheniramine Maleate (annotation moved to).

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Drug Indication
Pheniramine is commonly used in over-the-counter products to treat seasonal allergies or cold and flu symptoms.
FDA Label

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Mechanism of Action
Pheniramine competes with histamine for the histamine H1 receptor, acting as an inverse agonist once bound. The reduction in H1 receptor activity is responsible for reduced itching as well as reduced vasodilation and capillary leakage leading to less redness and edema. This can be seen in the suppression of the histamine-induced wheal (swelling) and flare (vasodilation) response. Inverse agonism of the H1 receptor in the CNS is also responsible for the sedation produced by first-generation antihistamines like pheniramine. The binding of pheniramine to H4 receptors, and subsequent inverse agonism, may also contribute to reduced itching by antagonizing inflammation.

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Pharmacodynamics
Pheniramine acts as an antagonist to allergic symptoms stemming from inappropriate histamine release to reduce edema, itching, and redness. The same antihistamine effect also produces sedation by acting in the central nervous system.

C16H20N2

240.34

240.163

86-21-5

Pheniramine maleate;132-20-7

4761

Typically exists as solid at room temperature

1.018 g/cm3

84 °C20 mm Hg(lit.)

30-34 °C(lit.)

179 °F

1.556

3.165

0

2

5

18

221

0

N1C(C(CCN(C)C)C2C=CC=CC=2)=CC=CC=1

IJHNSHDBIRRJRN-UHFFFAOYSA-N

InChI=1S/C16H20N2/c1-18(2)13-11-15(14-8-4-3-5-9-14)16-10-6-7-12-17-16/h3-10,12,15H,11,13H2,1-2H3

N,N-dimethyl-3-phenyl-3-pyridin-2-ylpropan-1-amine

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.)