- Histamine H₁ receptor (antagonist activity, no IC₅₀/Ki provided)[1,3,12]
- Human Ether-à-go-go-Related Gene (hERG) K⁺ channel (IC₅₀ = 12 nM for blocking IHERG current)[7]
- P2X₇ receptor (allosteric sensitizer, enhances ATP-induced cation entry)[8]

- Antihistamine activity: Clemastine competitively blocks H₁ receptors on effector cells (e.g., vascular endothelium, airway smooth muscle), reducing histamine-mediated vasodilation and bronchoconstriction. This effect was confirmed in isolated guinea pig tracheal strips and rat mesenteric artery assays[3,12]
- hERG channel inhibition: In HEK293 cells expressing hERG channels, clemastine (12 nM) significantly reduced peak IHERG current by ~50%, with voltage-dependent binding to the channel pore cavity. Mutations Y652A/F656A in the S6 helix attenuated this effect[7]
- P2X₇ receptor modulation: In HEK293 cells stably expressing P2X₇ receptors, clemastine (1-10 μM) enhanced ATP-induced Ca²⁺ influx, accelerated pore dilation (Yo-Pro-1 uptake), and increased fractional permeability to NMDG⁺. Similar effects were observed in human monocyte-derived macrophages and murine bone marrow-derived macrophages[8]
- Autophagy promotion: In LPS-stimulated H9c2 cardiomyocytes, clemastine (10-50 μM) increased LC3-II/LC3-I ratio, Beclin-1 expression, and autophagosome formation, which was abolished by the autophagy inhibitor 3-methyladenine[11]

- Allergic rhinitis model: Oral clemastine (1 mg) administered 4-6 hours before allergen challenge significantly reduced sneezing frequency (p < 0.01) and rhinorrhea severity in 20 allergic subjects. The effect was dose-dependent and lasted ≥12 hours[6]
- Sepsis-induced myocardial injury: In CLP-induced septic rats, intraperitoneal clemastine (30-50 mg/kg) improved 7-day survival rate (from 30% to 60%), reduced serum cTnI levels, preserved left ventricular ejection fraction, and attenuated mitochondrial fragmentation. Similar protective effects were observed in LPS-stimulated H9c2 cells[11]
- Optic neuritis model: Oral clemastine (1 mg twice daily for 90 days) in 16 patients with acute optic neuritis preserved retinal nerve fiber layer (RNFL) thickness in temporal/superotemporal quadrants and enhanced P100 wave amplitude recovery in visual evoked potentials compared to placebo[10]

- hERG channel electrophysiology: Whole-cell patch-clamp recordings were performed on HEK293 cells expressing hERG channels. Cells were perfused with clemastine (1-100 nM) in Tyrode's solution at 37°C. IHERG tail currents were measured at -40 mV after depolarization to +20 mV. IC₅₀ was calculated using nonlinear regression[7]
- P2X₇ receptor calcium flux assay: HEK293-P2X₇ cells were loaded with Fluo-4 AM and treated with clemastine (1-10 μM) followed by ATP (100 μM). Calcium transients were recorded using fluorescence microscopy. Yo-Pro-1 uptake was quantified by flow cytometry to assess pore formation[8]

H₁ receptor antagonism assay: Guinea pig tracheal ring segments were incubated with clemastine (0.1-10 μM) and challenged with histamine (1 μM). Isometric tension changes were recorded to determine antagonist potency[3,12]
- Autophagy detection: H9c2 cardiomyocytes were treated with clemastine (10-50 μM) and LPS (1 μg/mL). LC3-II/LC3-I ratio and Beclin-1 expression were analyzed by Western blot. Autophagosomes were visualized by transmission electron microscopy[11]

- Sepsis model: Male Sprague-Dawley rats (250-300 g) underwent cecal ligation and puncture (CLP). Clemastine (10-50 mg/kg) was dissolved in 0.9% saline and administered intraperitoneally 30 minutes post-CLP. Survival was monitored for 7 days, and cardiac function was assessed by echocardiography on day 3[11]
- Allergic rhinitis model: Human subjects received oral clemastine (1 mg) or placebo in a double-blind crossover design. Nasal allergen challenges were performed 1, 4, and 6 hours post-dose. Sneeze counts and nasal secretion weights were recorded[6]

Absorption, Distribution and Excretion
Rapidly absorbed via the gastrointestinal tract.
Primarily excreted in the urine.
Metabolism/Metabolites
Anthiamines are primarily metabolized in the liver via monodemethylation, didemethylation and glucuronide conjugation.
- Absorption: Rapidly absorbed orally, with a bioavailability of approximately 40%. Peak plasma concentration (Cmax) is 1–2 ng/mL, reached within 2–4 hours [12].
- Distribution: Widely distributed in tissues (volume of distribution approximately 800 L), and can cross the blood-brain barrier. Plasma protein binding is approximately 95% [12].
- Metabolism: Widely metabolized in the liver via O-dealkylation, oxidation and glucuronide. Major metabolites include demethylcrimetine and its hydroxylated derivatives [12].
- Excretion: Approximately 42% is excreted in the urine (primarily as metabolites), and 27% in the feces. Terminal half-life is approximately 21 hours [12].

Hepatotoxicity
Despite widespread use, first-generation antihistamines (such as chlorpheniramine) are rarely associated with abnormal liver function or clinically significant liver injury. Their safety may be related to their low daily dose and limited duration of use. Likelihood Score: E (Unlikely to cause clinically significant liver injury). References on the safety and potential hepatotoxicity of antihistamines are listed after the "Antihistamines Overview" section. Drug Category: Antihistamines Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Occasional use of low doses of chlorpheniramine during lactation is acceptable. Higher doses or longer use may cause infant drowsiness and other adverse reactions, 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 after the last feeding at bedtime may be sufficient and minimize any adverse effects of the drug. Non-sedating antihistamines are a better alternative.
◉ Effects on Breastfed Infants
A 10-week-old breastfed infant born to a mother taking chlorpheniramine, phenytoin sodium, and carbamazepine experienced lethargy, refusal to feed, irritability, and loud crying. These side effects may be due to chlorpheniramine in breast milk, but other medications may also play a role.
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. None of these reactions required medical attention.
◉ Effects on Lactation and Breast Milk
Injected relatively high 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 antihistamines have the same effect on serum prolactin, and whether the effect on prolactin has any impact on breastfeeding success, has not yet been studied. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.

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- Acute toxicity: LD₅₀ in mice >100 mg/kg (oral). Common adverse reactions include sedation, dry mouth, blurred vision, and urinary retention due to anticholinergic activity [12] - Cardiotoxicity: At supertherapeutic concentrations (≥1 μM), crimetine can prolong the QT interval in isolated cat hearts, but no clinical QT interval prolongation has been reported at therapeutic doses (1–6 mg/day) [7,12] - Drug interactions: Concomitant use with alcohol, opioids, or benzodiazepines may enhance central nervous system depression. Due to the risk of hypertensive crisis, it is contraindicated for use with monoamine oxidase inhibitors [12]

[1]. Mol Pharmacol. 1992 Aug;42(2):227-34.

[2]. Cell Immunol. 1983 Oct 1;81(1):45-60.

[3]. J Pharmacol Exp Ther. 1997 Jan;280(1):114-21.

[4].J Mol Cell Cardiol. 2006 Jan;40(1):107-18.

[5]. J Biol Chem. 2011 Apr 1;286(13):11067-81.

[6]. J Pharmacol Exp Ther. 1997 Jan;280(1):114-21.

[7]. Preprint from Research Square, 29 Jun 2020

[8]. Bioengineered. 2022 Mar;13(3):7134-7146.

[9]. Clemastine. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; January 16, 2017.

Clemastine is 2-[(2R)-1-methylpyrrolidone-2-yl]ethanol, wherein the hydrogen on the hydroxyl group is replaced by 1-(4-chlorophenyl)-1-phenethyl (R configuration). It is a drug with antihistamine, antimuscarinic, and moderate sedative effects; its fumarate is used to relieve symptoms of allergic diseases such as rhinitis, urticaria, conjunctivitis, and pruritic dermatitis. It acts as an H1 receptor antagonist, antihistamine, muscarinic receptor antagonist, and antipruritic. It is an N-alkylpyrrolidine compound belonging to the monochlorobenzene class. It is an ethanolamine derivative and a first-generation histamine H1 receptor antagonist used to treat hay fever, rhinitis, allergic dermatitis, and pruritus. It can cause drowsiness. Clemastine is a first-generation antihistamine used to treat symptoms of allergic rhinitis and the common cold. Clemastine has not been found to be associated with clinically significant cases of acute liver injury.
Cemastine is a synthetic ethanolamine with anticholinergic, sedative, and histamine H1 receptor antagonistic effects. After administration, caemastine blocks H1 histamine receptors, thereby preventing symptoms caused by histamine acting on capillary, bronchial, and gastrointestinal smooth muscle, including vasodilation, increased capillary permeability, bronchoconstriction, and gastrointestinal smooth muscle spasms. Caemastine can also prevent histamine-induced mucosal pain and itching.
A histamine H1 receptor antagonist, in the form of hydrogen fumarate, is used to treat hay fever, rhinitis, allergic dermatitis, and pruritus. It can cause drowsiness.
See also: Caemastine fumarate (in salt form).
Indications
For relief of symptoms associated with allergic rhinitis, such as sneezing, runny nose, itching, and irritation. Also used to treat mild, uncomplicated allergic skin manifestations, such as urticaria and angioedema. Can be used as a self-medication for common cold-related symptoms to provide temporary relief.

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Mechanism of Action
Cermatine is a selective histamine H1 receptor antagonist that binds to histamine H1 receptors. This blocks the action of endogenous histamine, thereby temporarily relieving histamine-induced adverse symptoms.

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- Mechanism of Action: exerts antihistamine effects by blocking H₁ receptors; cardiotoxicity is associated with hERG channel inhibition; neuroprotective effects in optic neuritis may involve autophagy induction and anti-inflammatory pathways [6,7,10,11]
- Therapeutic Use: approved for the treatment of allergic rhinitis, urticaria, and pruritus. Investigated for the treatment of myocardial damage and optic neuritis caused by sepsis [6,10,11]
- FDA Status: available over-the-counter (1 mg tablets) and prescription (2 mg tablets). Pregnancy category B [12]

C21H26CLNO

343.895

343.17

C, 73.35; H, 7.62; Cl, 10.31; N, 4.07; O, 4.65

15686-51-8

Clemastine fumarate;14976-57-9

26987

White to off-white solid powder

1.097 g/cm3

425.2ºC at 760mmHg

211ºC

1.553

5.042

0

2

6

24

376

2

C[C@@](C1=CC=CC=C1)(C2=CC=C(C=C2)Cl)OCC[C@H]3CCCN3C

YNNUSGIPVFPVBX-NHCUHLMSSA-N

InChI=1S/C21H26ClNO/c1-21(17-7-4-3-5-8-17,18-10-12-19(22)13-11-18)24-16-14-20-9-6-15-23(20)2/h3-5,7-8,10-13,20H,6,9,14-16H2,1-2H3/t20-,21-/m1/s1

(2R)-2-[2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine

Clemastine; HS-592; clemastine; 15686-51-8; Meclastin; Mecloprodin; Clemastina; HS592; Clemastinum; HS 592

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.)