Cyproheptadine (0.01-100 nM; 1 min) suppresses in vitro the serotonin-enhanced ADP-induced platelet aggregation in mice [2]. Cyproheptadine (10 nM) inhibits 15 µM serotonin-enhanced ADP-induced (1 µM) tyrosine phosphorylation in platelets in vitro [2]. P-selectin, GPIIb-IIIa (PAC-1 binding), and human platelet PS exposure (Annexin V) are all inhibited in vitro by cyclopeptadine [2].

Animal/Disease Models: C57BL/6 mice (8-10 weeks old) [2]
Doses: 1 mg/kg
Route of Administration: intraperitoneal (ip) injection; Cyproheptadine can be used for animal modeling and construction of diabetes models. one time/day for 5 days.
Experimental Results: Mice had prolonged occlusion time and tail bleeding time.

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 cyproheptadine hydrochloride labeled with 14C, 2% to 20% of the radioactive material is excreted in the feces. At least 40% of the radioactive material is excreted in the urine.

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 drug interactions of cyproheptadine (12 drugs in total), please visit the HSDB record page.

[1]. Effect of cyproheptadine on serum leptin levels. Adv Ther, 2005. 22(5): p. 424-8.

[2]. The Antidepressant 5-HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin-Enhanced Platelet Function. PLoS One. 2014; 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, use is not recommended for breastfeeding women due to potential adverse effects on infants, such as abnormal excitement or irritability. /Anthistamines/ 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 yet elucidated, but appears to be related to its antiserotonergic effects.

C21H21N

287.39814

323.144

129-03-3

Cyproheptadine hydrochloride;969-33-5;Cyproheptadine-d3;2712455-05-3

2913

White to off-white solid powder

1.115g/cm3

440.1ºC at 760mmHg

298 °C (dec.)(lit.)

194.5ºC

6.03E-08mmHg at 25°C

1.5339 (20ºC)

5.437

0

1

0

22

423

0

JJCFRYNCJDLXIK-UHFFFAOYSA-N

InChI=1S/C21H21N/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

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

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)

DMSO : ~3.17 mg/mL (~11.03 mM)

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.)