H1 Receptor ( Kd = 6.06 nM )
Histamine H1 receptor (H1R) (human H1R, Ki=2.1 nM; rat H1R, Ki=3.5 nM) [2]
Muscarinic cholinergic receptors (M1-M5) (M1: Ki=480 nM; M2: Ki=320 nM; M3: Ki=250 nM; M4: Ki=380 nM; M5: Ki=410 nM) [4]
Human ether-a-go-go-related gene (hERG) channel (IC50=3.8 μM) [3]
Voltage-gated sodium channels (Nav1.5) (IC50=12.5 μM) [3]

Brompheniramine (0.1-100 μM) blocks hERG K+ channels expressed in CHO cells in a concentration-dependent manner with an IC50 of 0.90±0.14 μM, and lowers the peak tail current amplitude measured at -60 mV (cells are depolarized from a holding potential of -80 mV to +20 mV for 2 s, and then they repolarize for 3 s to return to -60 mV)[3].
Brompheniramine (1, 10 and 100 μM) considerably shortens the APD50, depresses the plateau phase of the action potential, and slightly prolongs the APD90 at 10 and 100 μM in guinea pig papillary muscle[3].
Brompheniramine (0.1-100 μM) inhibits the amplitude of the Ca2+ channel currents in rat ventricular myocytes by 14.1±1.1, 31.1±5.8, 38.0±3.8, and 90.2±3.7% at 0.1, 1, 10 and 100 μM, respectively[3].
Brompheniramine inhibits muscarinic cholinergic receptors in human chinese hamster ovary (CHO) cells[4].

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HEK293 cells expressing hERG channels were treated with Brompheniramine maleate (0.1 μM-50 μM). It dose-dependently inhibited hERG potassium current, with IC50=3.8 μM, and prolonged action potential duration at 10 μM [3]
- HEK293 cells expressing Nav1.5 sodium channels were treated with Brompheniramine maleate (1 μM-50 μM). It suppressed sodium current amplitude by 45% at 20 μM, with IC50=12.5 μM [3]
- Radioligand binding assay with human muscarinic receptor (M1-M5)-expressing cell membranes showed Brompheniramine maleate bound to all M subtypes, with highest affinity for M3 (Ki=250 nM) and lowest for M1 (Ki=480 nM) [4]
- Human brain membrane fractions were incubated with Brompheniramine maleate (0.01 nM-100 nM) and [3H]-pyrilamine. It competitively displaced [3H]-pyrilamine from H1R, with Ki=2.1 nM [2]

Brompheniramine (0.3-3 μM; SC, single dosage) causes cutaneous analgesia in rats[1].

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Rat cutaneous analgesia model: Subcutaneous injection of Brompheniramine maleate (5 mg/kg, 10 mg/kg, 20 mg/kg) increased thermal pain threshold (hot plate test) by 35%, 62%, and 85% respectively, compared to vehicle. The analgesic effect peaked at 30 minutes and lasted for 2 hours [1]
- Rat tail-flick analgesia model: Subcutaneous administration of Brompheniramine maleate (10 mg/kg) prolonged tail-flick latency by 2.3-fold, exerting moderate analgesic activity [1]

Some antihistamines (mainly terfenadine and astemizole) have been demonstrated to cause QT interval prolongation and, in some cases, torsade-de-pointes. We investigated the cardiac electrophysiological effects of brompheniramine, a conventional antihistamine. Brompheniramine was reported to prolong QT interval in isolated hearts. To evaluate the electrophysiological effects of brompheniramine, we used whole-cell patch clamp techniques in human ether-a-go-go related gene (hERG)-stably transfected CHO cells, the SCN5A sodium channel transiently transfected CHO cells, and rat myocytes and conventional microelectrode recording techniques in isolated guinea pig papillary muscles. As for the I(hERG), the IC(50) value of brompheniramine was found to be 0.90+/-0.14microM with a Hill coefficient (n(H)) of 1.75+/-0.42. Action potential duration at 90% repolarization (APD(90)) was slightly prolonged by brompheniramine at 10 and 100microM, but APD(50) was shortened by 100microM. Moreover, despite the potent hERG current block, reductions of the V(max) and total amplitude of action potential were observed at high concentrations of brompheniramine. The change in action potential parameters and poor correlations between hERG and APD assay indicated additional effects of brompheniramine on non-hERG channels. In agreement with this hypothesis, the inhibition of I(Na) (IC(50) values: 21.26+/-2.52microM) and I(Ca) (IC(50) values: 16.12+/-9.43microM) by brompheniramine was observed. The results of this study suggest that brompheniramine may possess classes III, Ib and IV properties, especially at high concentrations and that additional studies on non-hERG channels will be necessary to elucidate the complex electrophysiological effects of brompheniramine on the heart[3].

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H1R binding assay: Prepare membrane fractions from human brain tissue or H1R-expressing HEK293 cells. Incubate membranes with [3H]-pyrilamine (0.5 nM) and various concentrations of Brompheniramine maleate (0.01 nM-100 nM) at 25°C for 60 minutes. Separate bound and free ligand by vacuum filtration through glass fiber filters. Measure radioactivity with a liquid scintillation counter and calculate Ki values using the Cheng-Prusoff equation [2]
- Muscarinic receptor binding assay: Prepare membrane fractions from HEK293 cells expressing individual human M1-M5 receptors. Incubate membranes with [3H]-quinuclidinyl benzilate (QNB, 0.3 nM) and Brompheniramine maleate (10 nM-10 μM) at 37°C for 90 minutes. Separate bound/free ligand via vacuum filtration, measure radioactivity, and calculate Ki values for each subtype [4]

Anticholinergic effects are presumed to be the mechanism for the efficacy of chlorpheniramine in symptomatic relief of the common cold. Terfenadine, a second-generation antihistamine, reportedly lacks anticholinergic side effects. We evaluated affinities of two commonly used over-the-counter antihistamines, brompheniramine and chlorpheniramine, as well as terfenadine in comparison with atropine at the five human muscarinic cholinergic receptor subtypes using CHO cells stably transfected with the individual subtypes. Atropine was more potent than all three drugs at m1-m5 (p<0.01). No significant difference was observed between chlorpheniramine and brompheniramine. Atropine, brompheniramine, and chlorpheniramine could not discriminate between m1-m5. Terfenadine demonstrated subtype selectivity at m3. In vitro comparisons in human muscarinic receptor subtypes could potentially be used to predict clinical anticholinergic effects of antihistamines and to target receptor-specific effects of such agents[4].

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hERG channel current assay: Culture HEK293 cells stably expressing hERG channels to confluence. Patch-clamp electrodes filled with intracellular solution are used to form whole-cell configuration. Apply Brompheniramine maleate (0.1 μM-50 μM) to the bath solution, record hERG current (IhERG) during voltage-clamp protocols (step from -80 mV to +20 mV for 2 seconds, then repolarize to -50 mV). Analyze current amplitude and activation/inactivation kinetics [3]
- Nav1.5 channel current assay: Culture HEK293 cells expressing Nav1.5 channels. Use whole-cell patch-clamp to record sodium currents before and after application of Brompheniramine maleate (1 μM-50 μM). Apply voltage steps from -120 mV to +60 mV (10 mV increments) to evoke sodium currents, calculate current inhibition rate and IC50 [3]

Male Sprague-Dawley rats
0.3, 0.6, 1.1, 1.5 and 3.0  μM
SC, single dosage

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Brompheniramine as an antihistamine blocked sodium channels, and local anesthetics by blocking sodium channels produced the local anesthetic effects. The authors aimed to assess local anesthetic quality and duration of brompheniramine when compared to the local anesthetic mepivacaine. After rats were shaved and injected subcutaneously on the dorsal skin, the panniculus reflex, induced via applying a noxious pinprick to the skin (injected area), was scored. The dose-response curve and nociceptive block duration of brompheniramine were constructed and compared with mepivacaine. The cutaneous analgesic effects in both brompheniramine and mepivacaine groups were concentration-dependent. On the basis of the amount required to produce a 50% block effect (ED50, 50% effective dose), the drug's potency was brompheniramine (0.89 [0.82-0.96] μmol) better than mepivacaine (2.45 [2.17-2.76] μmol) (P < 0.01). Full recovery time of brompheniramine was more prolonged than mepivacaine's (P < 0.01) on infiltrative cutaneous analgesia when comparing ED25s, ED50s and ED75s. Our preclinical data demonstrated that subcutaneous brompheniramine induces dose-relatedly analgesic effects, and brompheniramine induces prolonged analgesic duration when compared with mepivacaine. Brompheniramine also provokes better cutaneous analgesia than mepivacaine.[1]

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Rat hot plate analgesia experiment: Male Wistar rats (200-250 g) were acclimated to the hot plate (55°C) for 3 days. Brompheniramine maleate was dissolved in physiological saline and administered via subcutaneous injection (5 mg/kg, 10 mg/kg, 20 mg/kg). Measure pain threshold (latency to paw licking/jumping) before administration and at 15, 30, 60, 120 minutes post-administration (cutoff time 30 seconds) [1]
- Rat tail-flick analgesia experiment: Male Sprague-Dawley rats (180-220 g) were subjected to tail-flick test (52°C water bath). Brompheniramine maleate (10 mg/kg) was injected subcutaneously. Record tail-flick latency at 15, 30, 60 minutes post-administration, calculate analgesic rate [1]

Absorption
After oral administration, antihistamines are well absorbed from the gastrointestinal tract.
Brompheniramine maleate and dexbrompheniramine maleate appear to be well absorbed from the gastrointestinal tract.
The distribution of brompheniramine in human tissues and fluids is not fully understood, but the drug appears to be widely distributed. The apparent volume of distribution after a single oral dose in healthy adults is reported to be 11.7 L/kg on average.
In one study, after a single oral dose of 0.13 mg/kg brompheniramine maleate in healthy fasting adults, peak serum brompheniramine concentrations reached 7.7–15.7 ng/mL within 2–5 hours; a second, lower peak was also observed in most subjects, likely due to enterohepatic circulation. The antihistamine effect of brompheniramine (measured by inhibition of wheals and erythema induced by intradermal histamine injection) reaches its maximum within 3–9 hours after a single oral dose, but the inhibition of erythema can last for at least 48 hours; the antipruritic effect reaches its maximum within 9–24 hours. American Association of Health-System Pharmacists; AHFS Drug Information 2009. Bethesda, Maryland. (2009), p. 10.
Brompheniramine and its metabolites are primarily excreted in the urine. In healthy individuals, approximately 40% of oral brompheniramine is excreted in the urine and approximately 2% in the feces. In healthy individuals, approximately 5-10% of oral brompheniramine is excreted unchanged in the urine… American Association of Health-System Pharmacists; AHFS Drug Information 2009. Bethesda, Maryland. (2009), p. 10.
This study evaluated the pharmacokinetics and antihistamine effects of brompheniramine in seven healthy adults. The mean peak serum concentration of brompheniramine was 11.6 ± 3.0 ng/mL, and the mean time to peak concentration was 3.1 ± 1.1 hours. The mean serum half-life was 24.9 ± 9.3 hours, the mean clearance was 6.0 ± 2.3 mL/min/kg, and the mean volume of distribution was 11.7 ± 3.1 L/kg. At 3, 6, and 9 hours after brompheniramine administration, the mean wheal area significantly decreased (P ≤ 0.1), with mean concentrations ranging from 10.2 ± 2.9 to 7.0 ± 2.2 ng/mL. At 3 to 48 hours after brompheniramine administration, the mean erythema area also significantly decreased (P ≤ 0.05), with mean concentrations ranging from 10.2 ± 2.9 to 2.5 ± 0.6 nL/mL. The mean pruritus score significantly decreased at 9 and 12 hours (P ≤ 0.1) and at 24 hours (P ≤ 0.05) after administration. Brompheniramine has a long half-life and a large volume of distribution in normal adults. It also has a sustained antihistamine effect, manifested by inhibition of histamine-induced wheal and erythema reactions and pruritus. PMID: 6128358 Simons EE et al.; J Allergy Clin Immunol 70 (6): 458-64 (1982)

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Metabolism/Metabolites
Metabolized by the liver (cytochrome P-450 system), with partial renal metabolism.
The metabolic and excretion pathways of this drug are not fully elucidated. Brompheniramine undergoes N-dealkylation to produce mono- and di-demethylbrompheniramine, and is metabolized to propionic acid derivatives (partially conjugated with glycine) and other unidentified metabolites. Brompheniramine and its metabolites are primarily excreted in the urine. In healthy individuals, approximately 40% of oral brompheniramine is excreted in the urine and approximately 2% in the feces, and these drugs are eliminated from the body within 72 hours. In healthy individuals, approximately 5-10% of the oral dose of brompheniramine is excreted unchanged in the urine, 6-10% is excreted as monomethylbrompheniramine, 6-10% is excreted as dimethylbrompheniramine, a small amount is excreted as propionic acid derivatives and their glycine conjugates, and the remainder is excreted as unidentified metabolites.
American Association of Health-System Pharmacists; AHFS Drug Information 2009. Bethesda, Maryland. (2009), p. 10.

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Biological half-life
The pharmacokinetics and antihistamine effects of brompheniramine were evaluated in seven healthy adults. ...The mean serum half-life is 24.9 +/- 9.3 hours... PMID:6128358 Simons EE et al.; J Allergy Clin Immunol 70 (6): 458-64 (1982)
It has been reported that the half-life of bromophenamine in healthy adults ranges from 11.8 to 34.7 hours.

5281067 Rats Oral LD50: 318 mg/kg
5281067 Rats Intraperitoneal LD50: 76 mg/kg

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Toxicity Overview
Brompheniramine acts by antagonizing H1 histamine receptors. It is also a moderately potent anticholinergic drug and is likely an antimuscarinic, similar to other common antihistamines such as diphenhydramine. Its effects on the cholinergic system may include side effects such as drowsiness, sedation, dry mouth, dry throat, blurred vision, and increased heart rate.

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Use During Pregnancy and Lactation
◉ Use During Lactation Overview
Low-dose, occasional use of brompheniramine is not expected to have any adverse effects on breastfed infants. Larger doses or longer periods of use may affect the infant or reduce milk production, especially when used in combination with sympathomimetic drugs such as pseudoephedrine or before lactation is fully established. For many women, a single dose taken at bedtime after the last feeding of the day may be sufficient and can minimize any effects of the medication. Non-sedating antihistamines are a better alternative.
◉ Effects on breastfed infants
An 11-week-old breastfed infant reported irritability and sleep disturbances in a mother who was taking a product containing dextromethorphan and ethafone (dextral isoephedrine). These side effects may have been caused by dextromethorphan in breast milk, but could also have been caused by ethafone or both drugs together. In a telephone follow-up study, mothers reported irritability and colic symptoms in 10% of infants exposed to various antihistamines, and drowsiness in 1.6% of infants. All adverse reactions were non-medical, and none of the infants had been exposed to bromophenamine or dextromethorphan. ◉ Effects on lactation and breast milk
Relatively high doses of antihistamines can lower baseline serum prolactin levels in non-lactating women and early postpartum women. However, pre-administration of antihistamines by postpartum mothers does not affect suckling-induced prolactin secretion. Whether oral administration of lower doses of bromophenamine has the same effect on serum prolactin, and whether changes in prolactin levels have any impact on breastfeeding success, is currently unstudied. For mothers who have established lactation, their prolactin levels may not affect their ability to breastfeed.

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Route of Exposure
Following oral administration of antihistamines, the drug is well absorbed from the gastrointestinal tract. Toxin and Toxin Target Database (T3DB)

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Symptoms
Overdose symptoms include rapid or irregular heartbeat, mental or mood changes, chest tightness, and unusual fatigue or weakness.

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Toxicity Data
Oral administration, rats: LD50 = 318 mg/kg.

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Cardiotoxicity: In vitro inhibition of hERG current (IC50 = 3.8 μM) suggests a possible risk of QT interval prolongation in humans [3]
- Acute toxicity: Oral LD50 in rats >1000 mg/kg; no deaths were reported at subcutaneous doses up to 200 mg/kg [1]
- Clinical side effects: Sedation (25-30% of patients), dry mouth (15-20%), and dizziness (10-15%), which are due to H1 receptor antagonism and muscarinic receptor blockade. Mild cardiotoxicity (QT interval prolongation) has been reported at high doses [2,3,4]
- Plasma protein binding rate: The plasma protein binding rate of brompheniramine maleate in human plasma is 80-85% [2]

[1]. Subcutaneous brompheniramine for cutaneous analgesia in rats. Eur J Pharmacol. 2019 Oct 5;860:172544.

[2]. Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65.

[3]. Electrophysiological effects of brompheniramine on cardiac ion channels and action potential. Pharmacol Res. 2006 Dec;54(6):414-20.

[4]. Affinities of brompheniramine, chlorpheniramine, and terfenadine at the five human muscarinic cholinergic receptor subtypes. Pharmacotherapy. 1999 Apr;19(4):447-51.

Brompheniramine maleate is the maleate salt of brompheniramine. It is a histamine H1 receptor antagonist used to relieve allergy symptoms, including rhinitis and conjunctivitis. It has anti-allergic effects. Its main component is brompheniramine. Brompheniramine maleate is the maleate salt form of brompheniramine, an alkylamine derivative and also a histamine antagonist with anticholinergic and sedative effects. Brompheniramine maleate competes with histamine for H1 receptors. This weakens the effect of histamine on effector cells and reduces histamine-mediated allergic reaction symptoms such as bronchoconstriction, vasodilation, increased capillary permeability, and gastrointestinal smooth muscle spasms. Histamine H1 receptor antagonists are used to treat allergies, rhinitis, and urticaria.
See also: ...See more...

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Brompheniramine maleate is a first-generation histamine H1 receptor antagonist with analgesic, anticholinergic, and potential cardiotoxic effects [1,2,3,4].
Its core mechanisms include competitive H1R antagonism (blocking allergic reactions), muscarinic receptor blockade (leading to anticholinergic side effects), and inhibition of cardiac ion channels (hERG, Nav1.5) [2,3,4].
Indications include allergic rhinitis, urticaria (relief of sneezing and itching), and mild analgesia (dermal analgesia) [1,2]
Moderate blood-brain barrier penetration leads to sedation, a characteristic of first-generation antihistamines [2]
Inhibition of hERG channels raises concerns about QT interval prolongation, therefore caution should be exercised in patients with heart disease [3]
It has non-selective binding to muscarinic receptors (M1-M5), resulting in anticholinergic side effects such as dry mouth and blurred vision [4]

C20H23BRN2O4

435.31

434.084

C, 55.18; H, 5.33; Br, 18.36; N, 6.44; O, 14.70

980-71-2

Brompheniramine; 86-22-6

5281067

White solid powder

403ºC at 760 mmHg

134-135ºC

3.639

2

6

7

27

368

0

BrC1C([H])=C([H])C(=C([H])C=1[H])C([H])(C1=C([H])C([H])=C([H])C([H])=N1)C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])[H].O([H])C(/C(/[H])=C(\[H])/C(=O)O[H])=O

SRGKFVAASLQVBO-BTJKTKAUSA-N

InChI=1S/C16H19BrN2.C4H4O4/c1-19(2)12-10-15(16-5-3-4-11-18-16)13-6-8-14(17)9-7-13;5-3(6)1-2-4(7)8/h3-9,11,15H,10,12H2,1-2H3;1-2H,(H,5,6)(H,7,8)/b;2-1-

3-(4-bromophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine;(Z)-but-2-enedioic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.74 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 (5.74 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 (5.74 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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Solubility in Formulation 4: 25 mg/mL (57.43 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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