5-HT₂ Receptor
Histamine H1 receptor (H1R) (human H1R, Ki=0.8 nM; rat H1R, Ki=1.2 nM) [2]
Serotonin 2A receptor (5-HT2A) (human 5-HT2A, Ki=3.5 nM) [2]

In vitro activity: Cyproheptadine is an antimuscarinic and an antagonist of histamine and serotonin. Pituitary-dependent Cushings syndrome, anorexia, migraine, pruritic dermatoses, and postgastrectomy-dumping syndrome are among the conditions it is used to treat. The primary quaternary ammonium compound cyproheptadine glucuronide is excreted in the urine. Among the adverse effects of cyproheptadine are tachycardia, hypotension, sedation, and blood dyscrasias.

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Compound 48/80 (1 μg/mL)-activated rat peritoneal mast cells were treated with Cyproheptadine HCl (0.1 μM-10 μM). It dose-dependently inhibited histamine and TNF-α release, with 75% inhibition of histamine at 5 μM and IC50=1.5 μM [2]
- Human 5-HT2A receptor-expressing HEK293 cells were treated with Cyproheptadine HCl (0.01 μM-50 μM). It competitively blocked 5-HT-induced Ca²+ mobilization, EC50=4.2 μM, via antagonizing 5-HT2A receptor [2]

Cyproheptadine, a 5-HT2A receptor antagonist, has been shown to counteract serotonin-induced platelet aggregation caused by ADP both in vitro and in vivo, indicating that it has antiplatelet and thromboprotective properties.

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Mouse appetite regulation model: Male C57BL/6 mice (20-25 g) were orally administered Cyproheptadine HCl (1 mg/kg, 3 mg/kg, 5 mg/kg) once daily for 14 days. The 5 mg/kg dose increased food intake by 45% and body weight by 18% compared to vehicle. Serum leptin level was reduced by 32% (ELISA) [2]
- Rat passive cutaneous anaphylaxis (PCA) model: Intradermal injection of anti-ovalbumin IgE-sensitized rats were given Cyproheptadine HCl (2 mg/kg, 5 mg/kg) via intraperitoneal injection 1 hour before antigen challenge. The 5 mg/kg dose inhibited skin wheal area by 70% and Evans blue extravasation by 65% [2]

H1R binding assay: Prepare membrane fractions from HEK293 cells expressing human/rat H1R or rat brain tissue. Incubate membranes with [3H]-pyrilamine (0.5 nM) and various concentrations of Cyproheptadine HCl (0.001 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]
- 5-HT2A receptor binding assay: Prepare membrane fractions from human 5-HT2A receptor-expressing CHO cells. Incubate membranes with [3H]-ketanserin (0.3 nM) and Cyproheptadine HCl (0.01 nM-100 nM) at 37°C for 90 minutes. Separate bound/free ligand via vacuum filtration, measure radioactivity, and calculate Ki value [2]

Mast cell degranulation assay: Isolate rat peritoneal mast cells via peritoneal lavage. Resuspend cells in buffer and pre-treat with Cyproheptadine HCl (0.1 μM-10 μM) for 30 minutes. Stimulate with compound 48/80 (1 μg/mL) for 60 minutes at 37°C. Centrifuge to collect supernatant, measure histamine via fluorometric assay and TNF-α via ELISA [2]
- 5-HT2A receptor functional assay: Seed HEK293 cells expressing human 5-HT2A receptor in 96-well plates and incubate for 24 hours. Load cells with Ca²+ fluorescent probe, pre-treat with Cyproheptadine HCl (0.01 μM-50 μM) for 30 minutes, then stimulate with 5-HT (10 μM). Monitor fluorescence intensity in real-time to assess Ca²+ mobilization and calculate EC50 [2]

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Mouse appetite regulation experiment: Male C57BL/6 mice (20-25 g) were acclimated to standard diet for 3 days. Cyproheptadine HCl was dissolved in 0.5% carboxymethylcellulose sodium and administered via oral gavage (1 mg/kg, 3 mg/kg, 5 mg/kg) once daily for 14 days. Record daily food intake and weekly body weight; collect serum at the end of the experiment to detect leptin via ELISA [2]
- Rat PCA model: Male Wistar rats (180-220 g) were intradermally injected with anti-ovalbumin IgE (0.1 mL) on the back. After 48 hours, Cyproheptadine HCl was dissolved in physiological saline and administered via intraperitoneal injection (2 mg/kg, 5 mg/kg). One hour later, intravenous injection of ovalbumin (1 mg/kg) + Evans blue (5 mg/kg) was given. Thirty minutes later, rats were euthanized, and skin wheal area and Evans blue extravasation were measured [2]

Absorption, Distribution and Excretion
A study of five healthy male subjects compared the absorption differences of cyproheptadine administered orally and sublingually. Results showed that the mean peak plasma concentration (Cmax) of cyproheptadine administered orally and sublingually was 30.0 mcg/L and 4.0 mcg/L, respectively, with mean areas under the curve (AUC) of 209 mcg·h/L and 25 mcg·h/L, respectively. The time to peak concentration (Tmax) for oral and sublingual administration of cyproheptadine was 4 hours and 9.6 hours, respectively. After oral administration of radiolabeled cyproheptadine, approximately 2%–20% of the radioactive material is excreted in the feces, of which approximately 34% is unmetabolized parent drug (less than 5.7% of the total dose). At least 40% of the radioactive material is recovered in the urine. The clearance rate of H1 receptor antagonists is faster in children than in adults, while the clearance rate is slower in patients with severe liver disease. /H1 Receptor Antagonists/
H1 receptor antagonists are readily absorbed from the gastrointestinal tract. After oral administration, peak plasma concentrations are reached within 2 to 3 hours… /H1 Receptor Antagonists/
To investigate the pharmacokinetics of cyproheptadine (CPH) and its metabolites, we intravenously injected rats with either the parent drug or its anabolic metabolites and determined the plasma concentrations and urinary excretion of CPH and its detectable metabolites. Following intravenous injection of cycloheptane (CPH), the plasma CPH concentration over time followed a biexponential equation, exhibiting a transiently low plasma concentration of desmethylcycloheptane (DMCPH) and a persistently high plasma concentration of desmethylcycloheptane epoxide (DMCPHepo). Following intravenous injection of DMCPH, DMCPH was also eliminated according to a biexponential equation, generating DMCPHepo in plasma. On the other hand, DMCPHepo was not detected in plasma after intravenous injection of cycloheptane epoxide (CPHepo). All administered drugs had large volumes of distribution and were almost entirely excreted in the urine as DMCPHepo, a process that lasted for a considerable period. However, the urinary excretion pattern of DMCPHepo after CPHepo administration differed from that after CPH and MCPH administration. The mean residence time of the epoxidized metabolite, estimated from urinary data, was much longer than that estimated from plasma concentration data. This suggests that when plasma concentrations approach the detection limit, the metabolite may gradually reflux from the tissue bank into the systemic circulation, or some interaction may exist that delays its excretion into the urine. This study indicates that both metabolic pathways of CPH (from DMCPH and CPHepo to DMCPHepo) are possible, but demethylation mainly occurs before epoxidation; furthermore, the widespread and persistent distribution of DMCPHepo in tissues may be related to the reported toxicity of CPH in rats. Twelve diphenhydramine and cyproheptadine derivatives were synthesized, and their H1 receptor antagonistic activity in isolated guinea pig ileum and H2 receptor antagonistic activity in isolated guinea pig right atrium were screened. The compound exhibited high H1 and H2 receptor antagonistic activity. The introduction of diphenhydramine and cyproheptadine components endowed the compounds with high affinity for H1 receptors. All compounds exhibited both competitive and non-competitive antagonistic effects. Nitroethylenediamine compounds with 4-fluoro-4-methyl-substituted diphenhydramine as the H1 receptor antagonist moiety showed the strongest H1 and H2 receptor antagonistic effects. This study investigated the blood-brain barrier transport system of H1 antagonists using primary cultured bovine brain capillary endothelial cells and examined the effects of five H1 antagonists (azelastine, ketotifen, cyproheptadine, emesitine, and cetirizine) on the uptake of radiolabeled pyramine (mepiride). The results showed that multiple H1 antagonists inhibited mepiride uptake. Ketotifen competitively inhibited mepiride uptake, while lipophilic basic drugs significantly inhibited mepiride uptake. These results indicate that H1 receptor antagonists cross the blood-brain barrier via a transport system mediated by the same carrier as lipophilic basic drugs.

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Metabolism/Metabolites
The major metabolite found in human urine has been identified as a quaternary ammonium glucuronide conjugate of cyproheptadine.
In the human body, many pharmacologically active substances containing tertiary amines are metabolized to quaternary ammonium-linked glucuronides via UDP-glucuronyltransferase (UGT), a unique and important metabolic pathway for these compounds. The full-length cDNA encoding human UGT1.4 (the so-called minor human bilirubin UGT) was inserted into the expression vector pREP9 and transfected into human embryonic kidney 293 cells. Stable transfectants were obtained after selection with genimycin. As expected, the expressed protein exhibited low catalytic activity towards bilirubin. However, the expressed human UGT1.4 protein showed glucuronidation activity towards tertiary amine substrates such as imipramine, cyproheptadine, tripachlor, and chlorpromazine, which can form quaternary ammonium-linked glucuronides. Carcinogenic primary amines (β-naphthylamine, benzidine, and 4-aminobiphenyl) can also react with the expressed UGT1.4 protein at a rate approximately 10 times higher than that of quaternary ammonium glucuronide formation. Although many other UGT gene products catalyze the glucuronidation of primary amine substrates, the expressed human UGT1.4 protein is the only UGT isoenzyme confirmed to bind tertiary amine substrates to form quaternary ammonium-linked glucuronides. Cyproheptadine's known metabolites include cyproheptadine N-glucuronide. It is primarily metabolized by the liver (cytochrome P-450 system) and partly by the kidneys. Excretion pathway: In normal subjects, after a single oral administration of 4 mg of 14C-labeled cyproheptadine hydrochloride tablets, 2% to 20% of the radioactive material is excreted in the feces. At least 40% of the radioactive material is excreted in the urine.

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Absorption: Oral bioavailability is 65-70%; peak plasma concentration (Cmax) is reached 1-2 hours after oral administration (4 mg dose: Cmax = 150 ng/mL) [1]
-Distribution: Volume of distribution (Vd) in the human body is 2.5 L/kg; brain/plasma concentration ratio = 0.5, indicating that it has moderate blood-brain barrier penetration [1]
-Metabolism: It is mainly metabolized in the liver by cytochrome P450 (CYP) 3A4 and 2D6 into inactive metabolites [1]
-Excretion: 70% of the dose is excreted in the urine (30% as the original drug and 40% as metabolites), and 25% is excreted in the feces. The elimination half-life (t1/2) in humans is 6-8 hours [1]
- Plasma protein binding rate: Cyproheptadine hydrochloride has a plasma protein binding rate of 85-90% in human plasma [1]

Toxicity Summary
Cyproheptadine competitively binds to HA receptors with free histamine. This antagonizes the effect of histamine on HA receptors, thereby alleviating the adverse symptoms caused by histamine binding to HA receptors. Cyproheptadine also competitively binds to receptors in intestinal smooth muscle and other sites with serotonin. The serotonin antagonism of the hypothalamic appetite center may be the reason why cyproheptadine stimulates appetite. Hepatotoxicity
Unlike most first-generation antihistamines, cyproheptadine has been associated with several clinically significant liver injuries. The few reported cases have an onset time of 1 to 6 weeks, with elevated liver enzymes presenting as cholestatic or mixed types. No immune hypersensitivity or autoimmune features have been observed, and most patients recover rapidly without sequelae. There have been no reports of cyproheptadine causing acute liver failure. Probability Score: C (Possibly a rare cause of clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of medication use during lactation
Cyproheptadine should be avoided during lactation unless intended to lower maternal serum prolactin levels, as it may interfere with lactation, especially when used in combination with sympathomimetic drugs (such as pseudoephedrine) or before lactation is fully established. Non-sedating antihistamines are a better alternative.
◉ Effects on breastfed infants
As of the revision date, no published information on cyproheptadine was found. In a telephone follow-up study, mothers reported that 10% of their infants experienced irritability and colic after taking various antihistamines, and 1.6% experienced lethargy. All adverse reactions did not require medical attention, and all infants were unexposed to cyproheptadine.
◉ Effects on lactation and breast milk
Due to its antiserotonin activity, daily doses of 16 to 24 mg can lower serum prolactin levels in amenorrhea-galactorrhea syndrome. Furthermore, higher doses of injected 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 lactation-induced prolactin secretion. The effects of lower oral doses of cyproheptadine on serum prolactin levels have not been investigated, nor has their effect on prolactin levels been studied to have any impact on breastfeeding success. Prolactin levels in established lactating mothers may not affect their breastfeeding capacity.

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Drug Interactions
Concomitant use may enhance the central nervous system depressant effects of these drugs (alcohol or other central nervous system depressants) or antihistamines; additionally, concomitant use of maprotiline or tricyclic antidepressants may enhance the antihistamine or anticholinergic effects of these drugs. /Antihistamines/
When these drugs (anticholinergics 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 paralytic ileus may occur with concurrent treatment. Antihistamines
Concomitant use of monoamine oxidase (MAO) inhibitors with antihistamines may prolong or enhance the anticholinergic and central nervous system depressant effects of antihistamines; concomitant use is not recommended. Antihistamines
Concomitant use of ototoxic drugs with antihistamines may mask ototoxic symptoms such as tinnitus, dizziness, or vertigo. /Antihistamines/
For more complete data on interactions of cyproheptadine (12 in total), please visit the HSDB record page.

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Acute toxicity: The oral LD50 in rats was 338 mg/kg, and the oral LD50 in mice was 246 mg/kg [2]
-Clinical side effects: Sedation (30-35% of patients), dry mouth (20-25%), dizziness (15-20%), and constipation (10-12%), these side effects are due to H1R antagonism, anticholinergic effects, and drug penetration into the central nervous system [2]
-Drug interactions: Co-administration with CYP3A4 inhibitors (e.g., ketoconazole) can increase plasma concentration by 35%; enhance the sedative effects of alcohol, benzodiazepines, and opioids [1]

[1]. J Anal Toxicol . 1998 Jan-Feb;22(1):72-4.

[2]. PLoS One . 2014 Jan 23;9(1):e87026.

Cyproheptadine is the product of an oxidative coupling reaction between the 5-position of 5H-dibenzo[a,d]cycloheptene and the 4-position of 1-methylpiperidine, forming a double bond between the two segments. It is an antihistamine with sedative effects, as well as antimuscarinic and calcium channel blocking properties. It (especially its hydrochloride sesquihydrate) is used to relieve allergic conditions, including inhaled allergen and food-induced rhinitis, conjunctivitis, urticaria, and angioedema, as well as pruritic skin diseases. Unlike other antihistamines, it is also a serotonin receptor antagonist, and therefore can be used to treat conditions such as vascular headaches and anorexia. It has multiple functions, including H1 receptor antagonism, serotonergic antagonism, antipruritic, antihistamine, and gastrointestinal effects. It belongs to the piperidine class of compounds and is a tertiary amine. Cyproheptadine is a potent competitive antagonist of serotonin and histamine receptors. It is primarily used to treat allergy symptoms, but its use in stimulating appetite and its off-label use in treating serotonin syndrome are more noteworthy. Cyproheptadine is a first-generation antihistamine used to treat allergic rhinitis and urticaria, and can also be used as an appetite stimulant. Cyproheptadine has been associated with rare cases of clinically significant liver injury. Cyproheptadine has only been detected in individuals who have taken the drug. Cyproheptadine is a serotonin antagonist and histamine H1 receptor blocker, used as an antipruritic, appetite stimulant, anti-allergic agent, and for treating post-gastrectomy dumping syndrome. Cyproheptadine competitively binds to H1 receptors with free histamine, thereby antagonizing the effect of histamine on H1 receptors and alleviating the adverse symptoms caused by histamine binding to H1 receptors. Cyproheptadine also competes with serotonin for H1 receptors in intestinal smooth muscle and other sites. Cyproheptadine may have an appetite-stimulating effect by antagonizing serotonin in the hypothalamic appetite center. Cyproheptadine is a serotonin antagonist and histamine H1 receptor blocker, used as an antipruritic, appetite stimulant, antihistamine, and for the treatment of dumping syndrome after gastrectomy. See also: Cyproheptadine hydrochloride (salt form). Drug Indications In the United States, cyproheptadine is a prescription drug indicated for the treatment of various allergic symptoms, including dermatographia, rhinitis, conjunctivitis, and urticaria, and as adjunctive therapy for anaphylactic shock following adrenaline therapy. In Canada, cyproheptadine is an over-the-counter drug indicated for the treatment of itching and appetite stimulation. In Australia, cyproheptadine is also approved for the treatment of vascular headaches. Cyproheptadine is also frequently used to treat serotonin syndrome (off-label use). Mechanism of Action Cyproheptadine appears to exert its antihistamine and antiserotonin effects by competitively binding to their respective receptors with free histamine and serotonin. Its appetite-stimulating effect may be due to its serotonin antagonistic effect on the hypothalamic appetite center. Cyproheptadine…is a serotonin and histamine antagonist… …It is a potent H1 receptor blocker. Due to its binding to 5-HT2A receptors, cyproheptadine also exhibits significant 5-HT receptor blocking activity in smooth muscle. …It has weak anticholinergic activity and mild central nervous system depressant effects.

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Therapeutic Uses
Antiallergic; antipruritic; gastrointestinal; histamine H1 receptor antagonist; serotonin receptor antagonist
It is used for…prevention of such reactions in patients with a known history of blood or plasma reactions, dermatographia, and as adjunctive therapy to adrenaline and other standard treatments after acute symptoms have been controlled, for the treatment of anaphylactic reactions. /HCL/
It may be effective for mild local insect bite reactions, physical allergies, and mild drug and serum reactions characterized by pruritus. It may be effective for pruritus caused by contact dermatitis and varicella. /HCL/
Cyproheptadine has been reported to be effective in preventing migraines in some patients, but controlled studies have shown that its efficacy is only slightly better than placebo.
For more complete data on the therapeutic uses of cyproheptadine (16 in total), please visit the HSDB record page.

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Drug Warnings
Those taking antihistamines should be aware of their sedative effects and should not drive, fly, or operate dangerous machinery while taking such medications. /Anthistamines/
Potential adverse effects on the fetus: No problems were found in animal studies. No human controlled studies have been conducted. Potential side effects in breastfed infants: It is unclear whether excretion occurs. FDA Classification: B (B = Laboratory animal studies have not shown any risk to the fetus, but there are no controlled studies in pregnant women; or animal studies have shown adverse effects (excluding decreased fertility), but controlled studies in pregnant women have not shown any risk to the fetus in early pregnancy and there is no evidence of risk in late pregnancy.)/Excerpt from Table II/
Side effects of cyproheptadine include those common to other H1 receptor antagonists, such as drowsiness. Increased weight and accelerated growth in children have been observed, attributed to interference with the regulation of growth hormone secretion. Small amounts of antihistamines are secreted into breast milk; therefore, their use is not recommended for breastfeeding women due to potential adverse effects on infants, such as abnormal excitement or irritability. /Antihistamines/ For more complete data on drug warnings for cyproheptadine (8 of 8), please visit the HSDB record page.

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Pharmacodynamics
In experimental animals, cyproheptadine has been observed to antagonize a variety of pharmacodynamic effects of serotonin, including bronchoconstriction and vasoconstriction, and has also shown similar efficacy in antagonizing histamine-mediated effects. Its mechanism of action in preventing anaphylactic shock is not fully elucidated, but appears to be related to its antiserotonergic effects.

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Cyproheptadine hydrochloride is a first-generation histamine H1 receptor antagonist with antiserotonin (5-HT2A) and anticholinergic activity [1,2].
Its core mechanisms include competitive antagonism of H1R (blocking allergic reactions) and 5-HT2A receptors (regulating appetite and mood), as well as stabilizing mast cell membranes (inhibiting histamine/TNF-α release)[2].
Indications include allergic rhinitis, chronic urticaria, pruritus, and loss of appetite (e.g., in cancer patients or anorexia), which can relieve allergy symptoms and promote weight gain[2].
Moderate blood-brain barrier penetration gives it a sedative and appetite-stimulating effect, which distinguishes it from non-sedative drugs. Second-generation antihistamines[1,2]
Their long-acting effects (half-life of 6-8 hours) support twice-daily oral administration (4 mg each time) in adults[1].
It has a synergistic effect in treating allergic diseases and appetite disorders, but its sedative side effects limit its use in patients who need to remain alert[2].

C21H22CLN

323.86

323.144

969-33-5

Cyproheptadine hydrochloride sesquihydrate; 41354-29-4; Cyproheptadine; 129-03-3

2913

White to off-white solid powder

440.1ºC at 760mmHg

112.3-113.3
112.3-113.3 °C
215 - 217 °C

194.5ºC

5.437

0

1

0

22

423

0

C1C=CC=C2/C(=C3\CCN(C)CC\3)/C3=CC=CC=C3C=CC=12.Cl

ZPMVNZLARAEGHB-UHFFFAOYSA-N

InChI=1S/C21H21N.ClH/c1-22-14-12-18(13-15-22)21-19-8-4-2-6-16(19)10-11-17-7-3-5-9-20(17)21;/h2-11H,12-15H2,1H3;1H

1-methyl-4-(2-tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,9,11,13-heptaenylidene)piperidine;hydrochloride

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 (7.72 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 (7.72 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 (7.72 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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 (Please use freshly prepared in vivo formulations for optimal results.)