H1 Receptor ( Kd = 6.06 nM )

In CHO cells, hERG K+ channels are expressed and bromfeniramine (0.1-100 μM) blocks them in a concentration-dependent manner with an IC50 of 0.90±0.14 μM and a decrease in peak tail current amplitude measured at -60 mV (cell depolarization for 2 s to +) 20 mV drop from a holding potential of -80 mV, followed by 3 seconds of repolarization back to -60 mV) (3). At 1 μM, brompheniramine sharply reduced the APD50 of guinea pig papillary muscles, blocked the action potential's plateau phase, and marginally extended the APD90 at 10 and 100 μM [3]. Rat ventricular myocytes are exposed to varying concentrations of bromfeniramine (0.1-100 μM), which reduces their Ca2+ channel current amplitude 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]. Chinese hamster ovary (CHO) cells from humans are exposed to bromfeniramine, which inhibits their muscarinic cholinergic receptors [4].

Rats undergo cutaneous analgesia when given a single dose of 0.3–3 μM of bromfeniramine SC [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].

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].

Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat[1] Doses: 0.3, 0.6, 1.1, 1.5 and 3.0 μM
Route of Administration: subcutaneous injection, single dose
Experimental Results: Caused cutaneous analgesia in a dose-dependent manner with an EC50 value of 0.66 μM , and results in prolonged analgesia duration.

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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]

Absorption, Distribution and Excretion
Following oral administration, antihistamines are well absorbed in the gastrointestinal tract. Brompheniramine maleate and dexbrompheniramine maleate appear to be well absorbed in 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 occurred within 2–5 hours, ranging from 7.7–15.7 ng/mL; a second, lower peak was also observed in most subjects, likely due to enterohepatic circulation. The antihistamine effect of bromophenamine can be measured by inhibiting wheals and erythema induced by intradermal histamine injection. It reaches its maximum within 3–9 hours after a single oral administration, but the inhibitory effect on erythema can last for at least 48 hours; the antipruritic effect reaches its maximum within 9–24 hours. Bromophenamine and its metabolites are mainly excreted in the urine. In healthy individuals, approximately 40% of oral bromophenamine is excreted in the urine, and approximately 2% in the feces. Approximately 5–10% of oral bromophenamine in healthy individuals is excreted unchanged in the urine… This study evaluated the pharmacokinetics and antihistamine effects of bromophenamine in 7 healthy adults. The mean peak serum concentration of bromophenamine 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 post-administration, the mean wheal size significantly decreased when the mean concentration decreased from 10.2 ± 2.9 ng/mL to 7.0 ± 2.2 ng/mL (P ≤ 0.1). Within 3 to 48 hours after brompheniramine administration, the mean erythema area significantly decreased (P ≤ 0.05), with the mean concentration ranging from 10.2 ± 2.9 to 2.5 ± 0.6 nL/mL. The mean pruritus score also significantly decreased at 9 and 12 hours (P ≤ 0.1) and at 24 hours (P ≤ 0.05). Brompheniramine has a relatively long half-life and a large volume of distribution in normal adults. It also has a long-lasting antihistamine effect, manifested by inhibiting histamine-induced wheals and erythema, as well as suppressing itching. Metabolism/Metabolites: Primarily metabolized by the liver (cytochrome P-450 system), with partial renal metabolism. The metabolic and excretion pathways of this drug are not fully understood. Brompheniramine undergoes N-dealkylation to produce mono- and di-demethylbrompheniramine, which is then metabolized into 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, with excretion occurring within 72 hours. In healthy individuals, approximately 5-10% of the oral dose is excreted unchanged in the urine, 6-10% as monomethylbrompheniramine, 6-10% as dimethylbrompheniramine, a small amount as propionic acid derivatives and their glycine conjugates, and the remainder as unidentified metabolites. It is primarily metabolized by the liver (cytochrome P-450 system) and partially by the kidneys. The pharmacokinetics and antihistamine effects of brompheniramine were evaluated in seven healthy adults. …The mean serum half-life was 24.9 ± 9.3 hours… The reported half-life of brompheniramine in healthy adults ranges from 11.8 to 34.7 hours.

Toxicity Summary
Brompheniramine works 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. Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Small, occasional doses of brompheniramine are not expected to have any adverse effects on breastfed infants. Larger doses or prolonged 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 minimize any side effects. Non-sedating antihistamines are a better option.
◉ Effects on Breastfed Infants
An 11-week-old breastfed infant experienced irritability and sleep disturbances; the mother 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 that 10% of infants exposed to various antihistamines experienced irritability and colic, and 1.6% experienced lethargy. All adverse reactions required no medical intervention, and none of the infants had been exposed to bromophenamine or dextromethorphan.
◉ Effects on Lactation and Breast Milk
Higher doses of antihistamines can lower basal 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 lower oral doses of brompheniramine have the same effect on serum prolactin, and whether changes in prolactin levels have any impact on breastfeeding success, are currently unknown. For established lactating mothers, prolactin levels may not affect their ability to breastfeed.

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

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Interactions
Concomitant use of ototoxic drugs and antihistamines may mask ototoxic symptoms such as tinnitus, dizziness, or vertigo. Antihistamines
Concomitant use of monoamine oxidase (MAO) inhibitors and antihistamines may prolong and enhance the anticholinergic and central nervous system depressant effects of antihistamines; concomitant use is not recommended.
Antihistamines
Concomitant use of alcohol or other central nervous system depressants may enhance the central nervous system depressant effects of these drugs or antihistamines; in addition, concomitant use of maprotiline or tricyclic antidepressants may enhance the anticholinergic effects of antihistamines or these drugs. /Antihistamines/
When /anticholinergic drugs or other drugs with anticholinergic activity/ are used concomitantly with antihistamines, the anticholinergic effect may be enhanced; patients should be advised to report gastrointestinal problems promptly, as concomitant treatment may lead to paralytic ileus. /Antihistamines/
For more complete data on drug interactions of brompheniramine (6 drugs in total), please visit the HSDB record page.

[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]. Shin WH, Kim KS, Kim EJ. Electrophysiological effects of brompheniramine on cardiac ion channels and action potential. Pharmacol Res. 2006 Dec;54(6):414-20.

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

Brompheniramine is a derivative of phenytoin, in which the hydrogen at the 4-position of the phenyl substituent is replaced by bromine. Brompheniramine is a histamine H1 receptor antagonist, commonly used in the form of maleate to relieve allergy symptoms, including rhinitis and conjunctivitis. It is both an H1 receptor antagonist and an antihistamine. It belongs to the pyridine class of compounds and is also an organobromine compound.
Histamine H1 receptor antagonists are used to treat allergies, rhinitis, and urticaria.
Histamine H1 receptor antagonists are used to treat allergies, rhinitis, and urticaria. [PubChem]
Histamine H1 receptor antagonists are used to treat allergies, rhinitis, and urticaria.
See also: Brompheniramine maleate (note moved to); Dextrobrompheniramine (note moved to).

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Drug Indications
For the treatment of symptoms of the common cold and allergic rhinitis, such as runny nose, itchy eyes, tearing, and sneezing.

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Mechanism of Action
Brompheniramine is an H1 histamine receptor antagonist with moderate anticholinergic activity, similar to other common antihistamines such as diphenhydramine. Due to its anticholinergic effects, brompheniramine may cause drowsiness, sedation, dry mouth, dry throat, blurred vision, and increased heart rate.
H1 receptor antagonists inhibit most of the effects of histamine on smooth muscle, especially the contraction of respiratory smooth muscle. /Histamine Antagonists: H1 Receptor Antagonists/
H1 receptor antagonists strongly block histamine-induced increases in capillary permeability, as well as the formation of edema and wheals. /Histamine Antagonists: H1 Receptor Antagonists/
Antihistamines competitively antagonize most of the smooth muscle stimulatory effects of histamine on H1 receptors in the gastrointestinal tract, uterus, large blood vessels, and bronchi. Contraction of the sphincter of Oddi and bile ducts may be partially mediated by H1 receptors, and antihistamines antagonize opioid-induced contraction of bile duct smooth muscle. These drugs have only a weak antagonistic effect on bronchospasm caused by antigen-antibody reactions. Antihistamines also effectively antagonize the effects of histamine, which can lead to increased capillary permeability and edema. H1 receptor antagonists also inhibit erythema and pruritus associated with the release of endogenous histamine. The mechanism of action of antihistamines appears to be through blocking H1 receptor sites, thereby preventing histamine from acting on cells; they neither chemically inactivate histamine, nor physiologically antagonize it, nor prevent its release. Antihistamines do not block the stimulatory effect of histamine on gastric acid secretion, which is mediated by H2 receptors on parietal cells. /Anthistamines/
... Using stably transfected CHO cells of various subtypes, the affinity of two commonly used over-the-counter antihistamines, brompheniramine and chlorpheniramine, as well as terfenadine and atropine, was evaluated on five human muscarinic cholinergic receptor subtypes. Atropine was more potent on the m1-m5 subtypes than all three drugs (p<0.01). No significant differences were observed between chlorpheniramine and brompheniramine. Atropine, brompheniramine, and chlorpheniramine could not distinguish between M1-M5 subtypes. ...

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Therapeutic Uses
Antihistamine; Histamine H1 receptor antagonist
Brompheniramine and dextrobrompheniramine have similar effects and uses to other antihistamines. Preparations containing brompheniramine maleate or dextrobrompheniramine maleate in a fixed combination with other drugs (e.g., dextromethorphan, guaifenesin, phenylephrine, pseudoephedrine) are used to relieve seasonal (e.g., hay fever) or perennial (non-seasonal) allergic rhinitis, non-allergic (vasomotor) rhinitis, other upper respiratory allergies, or the common cold, including runny nose, sneezing, tearing, itchy eyes, itchy oropharynx, and/or other symptoms (e.g., nasal congestion/sinus congestion, cough). Combination preparations should generally only be used when symptoms that are effectively relieved by each ingredient occur simultaneously.
Drug Warning
As with other antihistamines, brompheniramine and dexbrompheniramine should not be used in premature or full-term newborns. Children under 2 years of age or under 6 years of age should use regular or extended-release formulations of brompheniramine maleate under the guidance of a clinician. Children under 6 years of age should not self-medicate with brompheniramine maleate.
Overdosing and poisoning (including death) have been reported in children under 2 years of age when they took over-the-counter (OTC) medications containing antihistamines, cough suppressants, expectorants, and nasal decongestants (alone or in combination) to relieve symptoms of upper respiratory tract infections. There is currently insufficient evidence to suggest that these medications are effective in children of this age, and the appropriate dose (i.e., the dose approved by the U.S. Food and Drug Administration (FDA)) for treating cold and cough symptoms has not been established. Therefore, the FDA states that over-the-counter cold and cough medications should not be used in children under 2 years of age; the agency will continue to evaluate the safety and efficacy of these medications in older children. Meanwhile, because children aged 2-3 also face the risk of drug overdose and poisoning, some manufacturers of oral over-the-counter cold and cough medicines have recently agreed to voluntarily change their product labels to explicitly state that these medications should not be used in children under 4 years old. Since the FDA typically does not require products with old labels to be removed from pharmacies during voluntary label changes, some medications will adopt the new recommendation ("Not for use in children under 4 years old"), while others will retain the previous recommendation ("Not for use in children under 2 years old"). The U.S. Food and Drug Administration (FDA) recommends that if children are given antihistamines, parents and guardians should strictly adhere to the dosage instructions and warnings on the drug label and consult a doctor about any concerns. Doctors should ask guardians if they have used any over-the-counter cough and cold medicines to avoid overdose. Some patients, especially children, may experience paradoxical excitement after taking antihistamines, characterized by restlessness, insomnia, tremors, euphoria, nervousness, delirium, palpitations, and even seizures. /Antihistamines/
All antihistamines can cause adverse reactions, but serious toxicities are rare. The incidence and severity of adverse reactions vary from drug to drug. Different patients are sensitive to the adverse reactions of these drugs, and these adverse reactions may disappear even with continued treatment. Elderly patients may be particularly prone to dizziness, sedation, and hypotension. Most mild reactions can be relieved by reducing the dose or switching to another antihistamine. /Antihistamines/
For more complete data on drug warnings for bromophenamine (17 in total), please visit the HSDB record page.

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Pharmacodynamics
Bromphenamine is a propylthiophene antihistamine, belonging to the first generation of antihistamines. In an allergic reaction, the allergen interacts with and cross-links with IgE antibodies on the surface of mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a series of complex events occur, ultimately leading to cell degranulation and the release of histamine (and other chemical mediators) from the mast cells or basophils. After histamine is released, it can react with local or systemic tissues through histamine receptors. Histamine acts on H1 receptors, causing itching, vasodilation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine can also increase vascular permeability and intensify pain. Brompheniramine is an alkylamine histamine H1 receptor antagonist (more accurately, a histamine inverse agonist). It can effectively and temporarily relieve symptoms such as sneezing, tearing, itchy eyes, and runny nose caused by hay fever and other upper respiratory allergies.

C16H19BRN2

319.24

318.073

C, 60.20; H, 6.00; Br, 25.03; N, 8.78

86-22-6

Brompheniramine maleate;980-71-2

6834

Oily liquid with slightly yellow color

1.265 g/cm3

403ºC at 760 mmHg

< 25 °C
pH of 2% aq soln about 5; mp: 132-134 °C; crystals /Maleate/
< 25 °C

197.5ºC

1.577

3.927

0

2

5

19

249

0

BrC1C=CC(C(CCN(C)C)C2C=CC=CN=2)=CC=1

ZDIGNSYAACHWNL-UHFFFAOYSA-N

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

3-(4-bromophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine

BROMPHENIRAMINE; 86-22-6; Parabromdylamine; Brompheniraminum; Bromfeniramina; Ilvin; Bromfed; Dimetane;

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.)