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
Antihistamines are well absorbed from the gastrointestinal tract after oral administration.
Brompheniramine and dexbrompheniramine maleates appear to be well absorbed from the GI tract.
Distribution of brompheniramine into human body tissues and fluids has not been fully characterized, but the drug appears to be widely distributed. Following oral administration of a single dose of the drug in healthy adults, the apparent volume of distribution reportedly averaged 11.7 L/kg.
Following oral administration of a single 0.13-mg/kg dose of brompheniramine maleate in healthy, fasting adults in one study, peak serum brompheniramine concentrations of 7.7-15.7 ng/mL occurred within 2-5 hours; in most of these individuals, a second lower peak, possibly secondary to enterohepatic circulation, also was observed. The antihistamine effect of brompheniramine, as determined by suppression of the wheal and flare responses induced by intradermal administration of histamine, appears to be maximal within 3-9 hours after a single oral dose of the drug, but suppression of the flare response may persist for up to at least 48 hours; the antipruritic effect appears to be maximal within 9-24 hours.
Brompheniramine and its metabolites are excreted principally in urine. About 40% of an oral dose of brompheniramine is excreted in urine and about 2% in feces within 72 hours in healthy individuals. In healthy individuals, about 5-10% of an oral dose is excreted in urine as unchanged drug ... .
The pharmacokinetics and antihistaminic effect of brompheniramine in seven normal adults /were assessed/. The mean peak serum brompheniramine concentration of 11.6 +/- 3.0 ng/mL occurred at a mean time of 3.1 +/- 1.1 hr. The mean serum half-life value was 24.9 +/- 9.3 hr, the mean clearance rate was 6.0 +/- 2.3 mL/min/kg, and the mean volume of distribution was 11.7 +/- 3.1 L/kg. The mean wheal size was significantly suppressed (P less than or equal to 0.1) at 3, 6, and 9 hr after the brompheniramine dose when mean concentrations ranged from 10.2 +/- 2.9 to 7.0 +/- 2.2 ng/mL. Significant suppression (P less than or equal to 0.05) of mean flare size was found from 3 to 48 hr after the brompheniramine dose, when mean concentrations ranged from 10.2 +/- 2.9 to 2.5 +/- 0.6 nL/mL. The mean pruritus score was significantly suppressed at 9 and 12 hr (P less than or equal to 0.1) and at 24 hr (P less than or equal to 0.05). Brompheniramine had a long half-life and large volume of distribution in normal adults. It also had a prolonged antihistaminic effect in the skin as evidenced by suppression of the wheal and flare response to histamine and by suppression of pruritus.

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Metabolism / Metabolites
Hepatic (cytochrome P-450 system), some renal.
The metabolic and excretory fate of the drug has not been fully characterized. Brompheniramine undergoes N-dealkylation to form monodesmethylbrompheniramine and didesmethylbrompheniramine, and is metabolized to the propionic acid derivative, which is partially conjugated with glycine, and to other unidentified metabolites. Brompheniramine and its metabolites are excreted principally in urine. About 40% of an oral dose of brompheniramine is excreted in urine and about 2% in feces within 72 hours in healthy individuals. In healthy individuals, about 5-10% of an oral dose is excreted in urine as unchanged drug, 6-10% as monodesmethylbrompheniramine, 6-10% as didesmethylbrompheniramine, small amounts as the propionic acid derivative and its glycine conjugate, and the remainder as unidentified metabolites.
Hepatic (cytochrome P-450 system), some renal.

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Biological Half-Life
the pharmacokinetics and antihistaminic effect of brompheniramine in seven normal adults /were assessed/. ... The mean serum half-life value was 24.9 +/- 9.3 hr ...
In healthy adults, the half-life of brompheniramine reportedly ranges from 11.8-34.7 hours.

Toxicity Summary
Brompheniramine works by acting as an antagonist of the H1 histamine receptors. It also functions as a moderately effective anticholingeric agent, likely an antimuscarinic agent 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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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Small, occasional doses of brompheniramine would not be expected to cause any adverse effects in breastfed infants. Larger doses or more prolonged use may cause effects in the infant or decrease the milk supply, particularly in combination with a sympathomimetic such as pseudoephedrine or before lactation is well established. Single bedtime doses after the last feeding of the day may be adequate for many women and will minimize any effects of the drug. The nonsedating antihistamines are preferred alternatives.
◉ Effects in Breastfed Infants
Irritability and disturbed sleep were reported in an 11-week-old breastfed infant whose mother was taking a product containing dexbrompheniramine and etafedrine (d-isoephedrine). These side effects were possibly caused by dexbrompheniramine in breastmilk, but could have been caused by the etafedrine or both drugs.
In one telephone follow-up study, mothers reported irritability and colicky symptoms in 10% of infants exposed to various antihistamines and drowsiness was reported in 1.6% of infants. None of the reactions required medical attention and none of the infants were exposed to brompheniramine or dexbrompheniramine.
◉ Effects on Lactation and Breastmilk
Antihistamines in relatively high doses given by injection can decrease basal serum prolactin in nonlactating women and in early postpartum women. However, suckling-induced prolactin secretion is not affected by antihistamine pretreatment of postpartum mothers. Whether lower oral doses of brompheniramine have the same effect on serum prolactin or whether the effects on prolactin have any consequences on breastfeeding success have not been studied. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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

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Interactions
Concurrent use /of ototoxic medications/ with antihistamines may mask the symptoms of ototoxicity such as tinnitus, dizziness, or vertigo. /Antihistamines/
Concurrent use of monoamine oxidase (MAO) inhibitors with antihistamines may prolong and intensify the anticholinergic and CNS depressant effects of antihistamines; concurrent use is not recommended. /Antihistamines/
Concurrent use /with alcohol or other CNS depression-producing medications/ may potentiate the CNS depressant effects of either these medications or antihistamines; also, concurrent use of maprotiline or tricyclic antidepressants may potentiate the anticholinergic effects of either antihistamines or these medications. /Antihistamines/
Anticholinergic effects may be potentiated when /anticholinergics or other medications with anticholinergic activity/ are used concurrently with antihistamines; patients should be advised to report occurrence of gastrointestinal problems promptly since paralytic ileus may occur with concurrent therapy. /Antihistamines/
For more Interactions (Complete) data for BROMPHENIRAMINE (6 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 pheniramine in which the hydrogen at position 4 of the phenyl substituent is substituted by bromine. A histamine H1 receptor antagonist, brompheniramine is used (commonly as its maleate salt) for the symptomatic relief of allergic conditions, including rhinitis and conjunctivitis. It has a role as a H1-receptor antagonist and an anti-allergic agent. It is a member of pyridines and an organobromine compound.
Histamine H1 antagonist used in treatment of allergies, rhinitis, and urticaria.
Histamine H1 antagonist used in treatment of allergies, rhinitis, and urticaria. [PubChem]
Histamine H1 antagonist used in treatment of allergies, rhinitis, and urticaria.
See also: Brompheniramine Maleate (annotation moved to); Dexbrompheniramine (annotation moved to).

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

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Mechanism of Action
Brompheniramine is an antagonist of the H1 histamine receptors with moderate antimuscarinic actions, as with other common antihistamines such as diphenhydramine. Due to its anticholindergic effects, brompheniramine may cause drowsiness, sedation, dry mouth, dry throat, blurred vision, and increased heart rate.
H1 antagonists inhibit most of the effects of histamine on smooth muscles, especially the constriction of respiratory smooth muscle. /Histamine Antagonists: H1 Antagonists/
H1 antagonists strongly block the increased capillary permeability and formation of edema and wheal brought about by histamine. /Histamine Antagonists: H1 Antagonists/
Antihistamines competitively antagonize most of the smooth muscle stimulating actions of histamine on the H1-receptors of the GI tract, uterus, large blood vessels, and bronchial muscle. Contraction of the sphincter of Oddi and bile duct may be mediated in part by H1-receptors, and opiate-induced contraction of biliary smooth muscle has been antagonized by antihistamines. The drugs only are feebly antagonistic to bronchospasm induced by antigen-antibody reactions. Antihistamines also effectively antagonize the action of histamine that results in increased capillary permeability and the formation of edema. H1-receptor antagonists also suppress flare and pruritus that accompany the endogenous release of histamine. Antihistamines appear to act by blocking H1-receptor sites, thereby preventing the action of histamine on the cell; they do not chemically inactivate or physiologically antagonize histamine nor do they prevent the release of histamine. Antihistamines do not block the stimulating effect of histamine on gastric acid secretion, which is mediated by H2-receptors of the parietal cells. /Antihistamine drugs/
... 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 /were evaluated/. 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. ...

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Therapeutic Uses
Anti-Allergic Agents; Histamine H1 Antagonists
Brompheniramine and dexbrompheniramine share the actions and uses of other antihistamines. Preparations containing brompheniramine maleate or dexbrompheniramine maleate in fixed combination with other agents (e.g., dextromethorphan, guaifenesin, phenylephrine, pseudoephedrine) are used for relief of rhinorrhea, sneezing, lacrimation, itching eyes, oronasopharyngeal itching, and/or other symptoms (e.g., nasal/sinus congestion, cough) associated with seasonal (e.g., hay fever) or perennial (nonseasonal) allergic rhinitis, nonallergic (vasomotor) rhinitis, other upper respiratory allergies, or the common cold. Combination preparations generally should only be used when symptoms amenable to each ingredient are present concurrently.

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Drug Warnings
Like other antihistamines, brompheniramine and dexbrompheniramine should not be used in premature or full-term neonates. Conventional or extended-release preparations of brompheniramine maleate should be used in children younger than 2 or 6 years of age, respectively, only under the direction of a clinician. Brompheniramine maleate should not be used for self-medication in children younger than 6 years of age.
Overdosage and toxicity (including death) have been reported in children younger than 2 years of age receiving nonprescription (over-the-counter, OTC) preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection. There is limited evidence of efficacy for these preparations in this age group, and appropriate dosages (i.e., approved by the US Food and Drug Administration (FDA)) for the symptomatic treatment of cold and cough have not been established. Therefore, FDA stated that nonprescription cough and cold preparations should not be used in children younger than 2 years of age; the agency continues to assess safety and efficacy of these preparations in older children. Meanwhile, because children 2-3 years of age also are at increased risk of overdosage and toxicity, some manufacturers of oral nonprescription cough and cold preparations recently have agreed to voluntarily revise the product labeling to state that such preparations should not be used in children younger than 4 years of age. Because FDA does not typically request removal of products with previous labeling from pharmacy shelves during a voluntary label change, some preparations will have the new recommendation ("do not use in children younger than 4 years of age"), while others will have the previous recommendation ("do not use in children younger than 2 years of age"). FDA recommends that parents and caregivers adhere to the dosage instructions and warnings on the product labeling that accompanies the preparation if administering to children and consult with their clinician about any concerns. Clinicians should ask caregivers about use of nonprescription cough and cold preparations to avoid overdosage.
Some patients, especially children, receiving antihistamines may experience paradoxical excitement characterized by restlessness, insomnia, tremors, euphoria, nervousness, delirium, palpitation, and even seizures. /Antihistamine drugs/
Adverse effects, which vary in incidence and severity with the individual drug, are caused by all antihistamines, although serious toxicity rarely occurs. Individual patients vary in their susceptibility to the adverse effects of these drugs, and such effects may disappear despite continued therapy. Geriatric patients may be particularly susceptible to dizziness, sedation, and hypotension. Most mild reactions may be relieved by a reduction in dosage or changing to another antihistamine. /Antihistamine drugs/
For more Drug Warnings (Complete) data for BROMPHENIRAMINE (17 total), please visit the HSDB record page.

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Pharmacodynamics
Brompheniramine is an antihistaminergic medication of the propylamine class. It is a first-generation antihistamine. In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads 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, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Brompheniramine is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to 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.)