mTOR; Histamine H1 receptor ( IC50 = 3 nM )

Clemastine Fumarate treatment significantly lowers the innate immune responses of mice to Listeria monocytogenes by interfering with the production of proinflammatory cytokines like TNF-α and IL-6 by extracellular signal-regulated kinase (ERK). This effect is surprising because it is not dependent on blocking the histamine H1 receptor. The result is a significant increase in mortality.[7] Rats that are given Clemastine Fumarate (5–20 mg/kg) show a dose-dependent, significant inhibition of both zymosan paw oedema and croton oil ear oedema simultaneously. At 20 mg/kg, the inhibition is 53.6% and 46.8%, respectively, with ID50 values of 18.0 mg/kg and 20.5 mg/kg, respectively. [6]

In a buffer containing 138 mM NaCl, 6 mM KC1, 1 mM MgSO4, 1 mM Na₂HPO₄, 5 mM NaHCO₃3, 5.5 mM glucose, and 20 mM HEPES-NaOH, pH 7.4, HL-60 cells are suspended at a density of 1×10⁷ cells/mL. The buffer is further enhanced with 0.1% (w/v) bovine serum albumin. Following a 10-minute incubation period at 37 °C, 4 μM of the dye fura-2/AM is added to the cells. After being diluted with the previously mentioned buffer to a concentration of 5×10⁶ cells/mL, the cells are incubated at 37 °C for 45 minutes. Following this, cells are diluted using the previously mentioned buffer until they reach a final concentration of 0.5 × 10⁶ cells/mL, and they are centrifuged at 250 g for 10 minutes at ambient temperature. In the previously mentioned buffer, cells are suspended at 1.0 × 10⁶ cells/mL and stored at 20 °C until measurement. After loading with fura-2/AM, HL-60 cells are suspended in 2 mL of the previously mentioned buffer for a maximum of 4 hours using acryl fluorescence cuvettes. Prior to the addition of histamine (100 μM), HL-60 cells are incubated for 3 minutes at 37 °C with 1 mM Ca2+ and different concentrations of clemastine fumarate. With the cells constantly stirred at 1×103 rpm and at 37 °C, fluorescence is measured with a Ratio II spectrofluorometer. For one minute, the basal fluorescence, or basal [Ca²⁺]_i, is measured. To find the increase in [Ca²⁺]_i, the corresponding peak [Ca²⁺]_i values are subtracted from the basal [Ca²⁺]_i values. The wavelengths of excitation and emission are 500 nm and 340 nm, respectively. The competitive curve is used to calculate the IC50 value.

Male Wistar rats with paw oedema induced by subplantar injection of zymosan and ear oedema induced by croton oil
5-20 mg/kg
Intraperitoneally

Absorption, Distribution and Excretion
Rapidly absorbed from the gastrointestinal tract.
Urinary excretion is the major mode of elimination.

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Metabolism / Metabolites
Antihistamines appear to be metabolized in the liver chiefly via mono- and didemethylation and glucuronide conjugation.

Hepatotoxicity
Despite widespread use, the first generation antihistamines such as clemastine have rarely been linked to liver test abnormalities or to clinically apparent liver injury. The reason for their safety may relate to low daily dose and limited duration of use.
Likelihood score: E (unlikely to be a cause of clinically apparent liver injury).
References on the safety and potential hepatotoxicity of antihistamines are given together after the Overview section on Antihistamines.
Drug Class: Antihistamines

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Small occasional doses of clemastine are acceptable during breastfeeding. Larger doses or more prolonged use may cause drowsiness and other 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
A 10-week-old breastfed infant whose mother was taking clemastine, phenytoin and carbamazepine was drowsy, refused to feed, was irritable, and had high-pitched crying. These side effects were possibly caused by clemastine in breastmilk, but the other drugs could also have contributed.
In one telephone follow-up study, mothers reported irritability and colicky symptoms 10% of infants exposed to various antihistamines and drowsiness was reported in 1.6% of infants. None of the reactions required medical attention.
◉ 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 antihistamines 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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Non-Human Toxicity Values
LD50 Mouse oral 730 mg/kg
LD50 Mouse iv 43 mg/kg
LD50 Rat oral 3550 mg/kg
LD50 Rat iv 82 mg/kg

[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.

Clemastine is 2-[(2R)-1-Methylpyrrolidin-2-yl]ethanol in which the hydrogen of the hydroxy group is substituted by a 1-(4-chlorophenyl)-1-phenylethyl group (R configuration). An antihistamine with antimuscarinic and moderate sedative properties, it is used as its fumarate salt for the symptomatic relief of allergic conditions such as rhinitis, urticaria, conjunctivitis and in pruritic (severe itching) skin conditions. It has a role as a H1-receptor antagonist, an anti-allergic agent, a muscarinic antagonist and an antipruritic drug. It is a N-alkylpyrrolidine and a member of monochlorobenzenes.
An ethanolamine-derivative, first generation histamine H1 antagonist used in hay fever, rhinitis, allergic skin conditions, and pruritus. It causes drowsiness.
Clemastine is a first generation antihistamine that is used for symptoms of allergic rhinitis and the common cold. Clemastine has not been linked to instances of clinically apparent acute liver injury.
Clemastine is a synthetic ethanolamine, with anticholinergic, sedative, and histamine H1 antagonistic activities. Upon administration, clemastine blocks the H1 histamine receptor and prevents the symptoms that are caused by histamine activity on capillaries, bronchial and gastrointestinal smooth muscles, including vasodilation, increased capillary permeability, bronchoconstriction, and spasmodic contraction of gastrointestinal smooth muscles. Clemastine also prevents histamine-induced pain and itching of mucous membranes.
A histamine H1 antagonist used as the hydrogen fumarate in hay fever, rhinitis, allergic skin conditions, and pruritus. It causes drowsiness.
See also: Clemastine Fumarate (has salt form).

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Drug Indication
For the relief of symptoms associated with allergic rhinitis such as sneezing, rhinorrhea, pruritus and acrimation. Also for the management of mild, uncomplicated allergic skin manifestations of urticaria and angioedema. Used as self-medication for temporary relief of symptoms associated with the common cold.

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Mechanism of Action
Clemastine is a selective histamine H1 antagonist and binds to the histamine H1 receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine.

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Therapeutic Uses
For the symptomatic treatment of allergic rhinitis in adults and children 12 years of age and older ...
For the symptomatic treatment of mild allergic urticaria and angioedema in adults and children 12 years of age and older ...
This multicenter, double blind, randomized parallel group study compared 3 wk treatment with either loratadine (Clarityn) 10 mg once daily, or clemastine (Tavegyl) 1 mg twice daily, and placebo in outpatients with active perennial allergic rhinitis. 155 patients were evaluated for efficacy and safety. Grading of four nasal and three non-nasal symptoms, rhinoscopy signs, and therapeutic response was performed on treatment days 6, 13, and 20. Patients recorded daily symptoms and possible adverse experiences in a diary, also indicating when symptoms of active rhinitis were relieved. Loratadine and clemastine were statistically significantly superior to placebo throughout the study (p < 0.05), based on assessment of patients' nasal and eye symptoms, patients' diary scores, rhinoscopy signs of symptoms, and onset of relief. The loratadine group showed a statistically significantly (p < 0.05) faster onset of relief of symptoms compared with the group treated with clemastine. Concerning nasal stuffiness, loratadine was significantly (p < 0.05) superior to clemastine after 1 week's treatment. Reports of adverse reactions showed that significantly (p < 0.05) more patients complained of sedation in the clemastine than in the loratadine group. Regarding other adverse experiences and laboratory tests, the three treatment groups were statistically comparable (p < 0.05). The study showed that compared with placebo both loratadine and clemastine were effective in relieving nasal and eye symptoms in patients with perennial allergic rhinitis. Loratadine was safe and well tolerated and was significantly less sedative than clemastine; loratadine may therefore possess an advantage in clinical use in the treatment of perennial allergic rhinitis.
The effects of cromolyn sodium (sodium cromoglycate), clemastine and ketotifen administered to the nasal mucosa of seasonal and perennial allergic rhinitis patients 30 min before provocation with histamine and allergen were compared in a randomized, double blind, placebo controlled study. Clemastine and cromolyn sodium, but not ketotifen, significantly inhibited the nasal response to increasing concentrations of histamine. None of the drugs administered in the concentrations used significantly inhibited the nasal response to allergen.

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Drug Warnings
Drugs contraindicated during lactation include ... clemastine.
There are no adequate and controlled studies to date using clemastine fumarate alone or in fixed combination with phenylpropanolamine in pregnant women, and the drug should be used during pregnancy only when clearly needed.
Because of the potential for serious adverse reactions to clemastine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
Drugs that have been associated with Significant Effects on some Nursing Infants and should be given to Nursing Mothers with Caution: Clemastine: Drowsiness, irritability, refusal to feed, high-pitched cry, neck stiffness (1 case). /from Table 5/

C25H30CLNO5

459.96

459.181

C, 65.28; H, 6.57; Cl, 7.71; N, 3.05; O, 17.39

14976-57-9

Clemastine; 15686-51-8; Clemastine-d5 fumarate

26987

White to light yellow crystalline powder

1.097 g/cm3

116 °C / 24mmHg

61 °C

211ºC

1.94E-07mmHg at 25°C

1.553

4.754

0

2

6

24

376

2

ClC1C([H])=C([H])C(=C([H])C=1[H])[C@@](C([H])([H])[H])(C1C([H])=C([H])C([H])=C([H])C=1[H])OC([H])([H])C([H])([H])[C@@]1([H])C([H])([H])C([H])([H])C([H])([H])N1C([H])([H])[H].O([H])C(/C(/[H])=C(\[H])/C(=O)O[H])=O

PMGQWSIVQFOFOQ-YKVZVUFRSA-N

InChI=1S/C21H26ClNO.C4H4O4/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;5-3(6)1-2-4(7)8/h3-5,7-8,10-13,20H,6,9,14-16H2,1-2H3;1-2H,(H,5,6)(H,7,8)/b;2-1+/t20-,21-;/m1./s1

(E)-but-2-enedioic acid;(2R)-2-[2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine

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: ≥ 1.43 mg/mL (3.11 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 14.3 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: ≥ 1.43 mg/mL (3.11 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 14.3 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: ≥ 1.43 mg/mL (3.11 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 14.3 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 30% propylene glycol, 5% Tween 80, 65% D5W: 5mg/mL

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Solubility in Formulation 5: 1.43 mg/mL (3.11 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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