H₁ histamine receptor (no binding affinity (IC₅₀, Kᵢ, EC₅₀, DC₅₀) values for Cyclizine were reported in this study). [1]
Cyclizine targets the histamine H1 receptor as a potent and selective antagonist. H1 receptors are involved in allergic reactions and the regulation of nausea and vomiting. By blocking H1 receptors, cyclizine prevents the effects of histamine, reducing nausea, vomiting, and dizziness. It also shows anti-inflammatory, anti-allergic, and anti-platelet effects.

Cyclizine (100 μM) dramatically reduced the levels of iNOS protein and LPS-stimulated nitrite buildup in RAW 264.7 cell supernatants [1]. With an IC50 of 5.42 µM, cyclidine prevents anti-IgE-induced histamine release from human lung fragments[2].

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Cyclizine at 10⁻⁴ M significantly inhibited nitrite accumulation in LPS-stimulated RAW 264.7 cells (p<0.05, Fig. 2) and significantly reduced iNOS protein expression (p<0.05, Fig. 2). At 5×10⁻⁵ M, Cyclizine showed a 11.2±0.8% inhibition of nitrite accumulation (not statistically significant, Table 2) and a 15.6±4.4% inhibition of iNOS protein expression (not statistically significant, Table 2). At 10⁻⁴ M, Cyclizine did not significantly affect cell viability (Fig. 1). Cyclizine exhibited no scavenging activity against NO in a cell-free amperometric system at 10⁻⁴ M (integral area 17.4±1.3 vs. control 20.2±0.6, not significant, Table 3). The lipophilicity (Rₘ value) of Cyclizine was 0.97±0.08 (Table 2), which positively correlated with its inhibitory effect on nitrite accumulation (r=0.7786, p=0.0017) and to a lesser extent with iNOS expression (r=0.66, p=0.0143). [1]
In vitro, cyclizine acts as a potent and specific histamine H1 receptor blocker (antagonist). It inhibits anti-IgE-induced responses. Its activity has been characterized in receptor binding and functional assays using cells expressing H1 receptors. The compound's ability to inhibit histamine-mediated signaling has been confirmed. Its anti-inflammatory and anti-platelet effects have also been studied in vitro.

Mice's locomotor activity is enhanced by cycliclizine (1, 10 mg/kg) in a dose-dependent way [3].
In vivo, cyclizine is used to treat nausea, vomiting, and dizziness associated with motion sickness, vertigo, and post-operative recovery. It is a histamine H1 antagonist given by mouth or parenterally for the control of postoperative and drug-induced vomiting and in motion sickness. It is a piperazine derivative with H1-receptor antagonist activity.

No enzyme assays (e.g., kinase activity, SPR, ITC, HTRF) were performed for Cyclizine in this study. [1]
In non-cell-based receptor binding assays, cyclizine's affinity for the histamine H1 receptor is evaluated using radioligand competition binding experiments. Membrane preparations from cells expressing recombinant human H1 receptors are incubated with a radiolabeled H1-selective ligand (such as [³H]mepyramine) and varying concentrations of cyclizine. After incubation, bound and free radioligand are separated by filtration, and radioactivity is measured. Competition curves are generated to determine IC50 and Ki values.

RAW 264.7 cells (2.5×10⁶ cells/well in 6-well plates) were preincubated with Cyclizine (hydrochloride) at 5×10⁻⁵ M or 10⁻⁴ M for 60 min, then stimulated with LPS (0.1 µg/mL) for 24 h at 37°C/5% CO₂. Cell supernatants were harvested for nitrite determination using the Griess reagent (150 µL supernatant +150 µL Griess reagent, 15 min dark, absorbance at 546 nm). Cell lysates were used for iNOS protein expression analysis by Western blot (7.5% SDS-PAGE, PVDF membrane, mouse anti-iNOS antibody 1:1000, HRP-conjugated goat anti-mouse IgG 1:2000, ECL detection, densitometry normalized to β-actin). Cell viability was assessed by ATP bioluminescence assay (cell lysis with Somatic cell ATP releasing reagent, ATP reagent containing D-luciferin/luciferase, luminometry). NO scavenging was measured amperometrically using a porphyrinic microsensor with NO-saturated water (final NO ~595 nM); the integral area under the current-time curve over 280 s was compared between control and drug-treated samples. Lipophilicity (Rₘ) was determined by reversed-phase thin-layer chromatography on silica gel G F₂₅₄ plates impregnated with 5% liquid paraffin, using PBS (0.1 M, pH 7.4)/acetone (20:80, v/v) as mobile phase; Rₘ = log(1/RF − 1). [1]
In vitro cellular assays for cyclizine involve measuring its antagonist activity at H1 receptors in cultured cells. Cells expressing H1 receptors are treated with cyclizine in the presence of histamine, and receptor activation is assessed by measuring downstream signaling such as calcium mobilization. The compound's ability to inhibit histamine-induced responses is quantified. Its anti-inflammatory and anti-platelet effects are assessed using appropriate cellular models.

Animal/Disease Models: Naive male CDI mice (Charles River), body weight 25-30 g[3]
Doses: 1, 10 mg/kg
Route of Administration: subcutaneous injection; measure locomotor activity (crossover) every 15 minutes for 2 hrs (hrs (hours)) .
Experimental Results: Enhanced locomotor activity in a dose-dependent manner.

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In vivo animal studies for cyclizine have been conducted in models of nausea, vomiting, and motion sickness. The compound is typically administered via oral or parenteral routes, and its effects on emesis, locomotion, and behavior are assessed. However, specific protocols and detailed data are limited in publicly available sources. The compound is a well-established antihistamine with clinical use.

Absorption, Distribution and Excretion
Benzohydroxypiperazine and its N-dealkylation products are distributed in all tissues of rats and can be transferred to the fetus. /Benzohydroxypiperazine/

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Metabolism/Metabolites Cyclizine is metabolized to the N-demethylated derivative norCyclizine, which has weaker antihistamine (H1) activity compared to Cyclizine. Oxidative N-dealkylation is the major metabolic pathway of benzohydroxypiperazine; Cyclizine is converted to norCyclizine by a mixed-function oxidase purified from liver microsomes in the presence of reduced pyridine nucleotides and oxygen. Cyclizine is oxidized to N-oxide. Biological half-life: 20 hours

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Cyclizine has a molecular weight of 266.38 and a molecular formula of C18H22N2. It is a piperazine derivative. The compound is administered by mouth or parenterally. It is a potent and selective histamine H1 receptor antagonist. Detailed pharmacokinetic parameters such as half-life, bioavailability, and clearance are available from clinical pharmacology studies.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Occasional use of cyclorhizine during lactation may be acceptable. High doses or prolonged use may affect the infant or reduce milk production, especially when used in combination with sympathomimetic drugs (such as pseudoephedrine) or before lactation is fully established.
◉ Effects on Breastfed Infants
As of the revision date, no published information was found regarding cyclorhizine. In a telephone follow-up study, mothers reported irritability and colic in 10% of their infants after taking various antihistamines, and lethargy in 1.6%. All adverse reactions did not require medical intervention, and all infants were previously unexposed to cyclorhizine.
◉ Effects on Lactation and Breast Milk
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. Whether lower doses of oral antihistamines have the same effect on serum prolactin levels, and whether their effect on prolactin has any impact on breastfeeding success, is currently unknown. For established lactating mothers, prolactin levels may not affect their ability to breastfeed.

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Interactions
The combination of 100 mg caffeine with 50 mg and 100 mg cyclorhizine hydrochloride did not produce any subjective changes or performance test changes, unlike the control group.

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No toxicity data for Cyclizine were reported. Cell viability in RAW 264.7 cells was not significantly affected by Cyclizine at 5×10⁻⁵ M or 10⁻⁴ M after 24 h incubation (Fig. 1). [1]
Cyclizine is generally well-tolerated at therapeutic doses. Common side effects include drowsiness, dry mouth, and dizziness. As an antihistamine, it may cause sedation and should be used with caution in patients operating machinery or vehicles. The compound should be used with caution in patients with glaucoma, prostatic hypertrophy, or urinary retention.

[1]. The effects of H1-antihistamines on the nitric oxide production by RAW 264.7 cells with respect to their lipophilicity. Int Immunopharmacol. 2009 Jul;9(7-8):990-5.

[2]. Inhibition of histamine release from human lung in vitro by antihistamines and related drugs. Br J Pharmacol. 1980 Aug;69(4):663-7.

[3]. Effects of antihistaminics on locomotor activity in mice. Comparison with opiate and amphetamine-induced hyperactivity. Gen Pharmacol. 1991;22(2):293-6.

Cyclizine is an N-alkylpiperazine compound in which one nitrogen atom of the piperazine ring is replaced by a methyl group and the other nitrogen atom is replaced by a diphenylmethyl group. It has antiemetic, cholinergic, central nervous system depressant, local anesthetic, and H1 receptor antagonist effects. It is a histamine H1 receptor antagonist, which can be administered orally or parenterally for the control of postoperative vomiting, drug-induced vomiting, and motion sickness. (Excerpt from Martindale Pharmacopoeia, 30th edition, p. 935) Indications: Used for the prevention and treatment of nausea, vomiting, and dizziness caused by motion sickness, as well as dizziness caused by other diseases. Mechanism of Action: Vomiting is essentially a protective mechanism used to clear irritants or other harmful substances from the upper digestive tract. Vomiting is controlled by the vomiting center in the medulla oblongata of the brain, of which the chemoreceptor trigger zone (CTZ) is a key component. The vomiting center contains synapses rich in muscarinic cholinergic and histaminergic neurons. These types of neurons are particularly involved in signal transmission from the vestibular system to the vomiting center. Motion sickness primarily involves various sensory stimuli leading to overexcitation of these pathways. Therefore, the mechanism of action of cyclorhizine is to block histamine receptors in the vomiting center, thereby reducing the activity of these pathways. Furthermore, because cyclorhizine also has anticholinergic properties, muscarinic receptors are also blocked. …It seems that stimulation of the vestibular system is necessary and sufficient…and the vestibular-cerebellar-midbrain “integrated vomiting center” and the medullary chemoreceptor trigger zone…are involved in/motion sickness/. Effective antihistamines are likely to act in these centers. /Antihistamines/

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Therapeutic Uses
Antiemetic; Histamine H1 receptor antagonist
Antihistamines hydrochloride and lactate are used for the prevention and treatment of motion sickness (nausea, vomiting, and dizziness). It may also be effective in controlling postoperative nausea and vomiting.
The duration of action is approximately 4 hours.
…A large-scale study, including pregnant women taking cyclorhizine in early pregnancy, failed to confirm any teratogenic effects of this drug in humans at the doses used.
For more complete data on the therapeutic uses of cyclorhizine (7 types), please visit the HSDB record page.

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Drug Warnings
…/Do not/take more than 4 tablets daily. Hydrochloride
…This product should not be used by pregnant women or women who may become pregnant unless specifically directed by a physician.
In 1965, a special committee of the U.S. Food and Drug Administration (FDA) concluded that the evidence of teratogenic effects of this product in humans was not significant, but did not specifically mention the eyes.
...The offspring of thousands of women who took approximately 150 mg of cyclorhizine hydrochloride daily during pregnancy...experienced a variety of non-ocular abnormalities, but none were statistically significant in relation to cyclorhizine hydrochloride. Uncertain.
For more complete data on drug warnings (of 8) for cyclorhizine, please visit the HSDB records page.

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Pharmacodynamics
Cyclorhizine is a piperazine derivative antihistamine used as an anti-vertigo/antiemetic. Cyclorhizine is used to prevent and treat nausea, vomiting, and dizziness associated with motion sickness. It is also used to treat vertigo caused by disorders affecting the vestibular system. Although the mechanism by which cyclorhizine exerts its antiemetic and anti-vertigo effects is not fully elucidated, its central anticholinergic properties are partly responsible. The drug inhibits labyrinthine excitability and vestibular stimulation and may affect the medullary chemoreceptor trigger zone. It also has anticholinergic, antihistamine, central nervous system depressant, and local anesthetic effects.

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Cyclizine is a first-generation H₁ antihistamine used clinically as an antiemetic and anti-allergic agent. In this study, it was shown to modulate NO production in LPS-stimulated macrophages primarily through downregulation of iNOS protein expression, with no direct NO scavenging. Its inhibitory effect on nitrite accumulation positively correlated with lipophilicity, suggesting that membrane partitioning may play a role in its biological activity. At the concentrations tested, Cyclizine did not affect cell viability. [1]
Cyclizine is a piperazine-derivative antihistamine drug used to treat nausea, vomiting, and dizziness associated with motion sickness, vertigo, and post-operative recovery. It is a potent and selective histamine H1 receptor antagonist. Cyclizine also shows anti-inflammatory, anti-allergic, and anti-platelet effects. It is administered by mouth or parenterally and is available as an approved drug for the treatment of nausea and vomiting.

C18H22N2

266.38

266.178

82-92-8

Cyclizine dihydrochloride;5897-18-7;Cyclizine lactate;5897-19-8;Cyclizine hydrochloride;303-25-3

6726

White to off-white solid powder

105.5-107.5 ; 105.5 TO 107.5 °C

2.899

0

2

3

20

253

0

CN1CCN(CC1)C(C2=CC=CC=C2)C3=CC=CC=C3

UVKZSORBKUEBAZ-UHFFFAOYSA-N

InChI=1S/C18H22N2/c1-19-12-14-20(15-13-19)18(16-8-4-2-5-9-16)17-10-6-3-7-11-17/h2-11,18H,12-15H2,1H3

1-benzhydryl-4-methylpiperazine

NautazineCYCLIZINE Valoid Neo-devomitMarezine Ciclizina

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 : ~100 mg/mL (~375.40 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.39 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 (9.39 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 (9.39 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.)