Histamine H1-receptor antagonist [1]

In guinea-pigs, acrivastine lacks anticholinergic effects [1]
The principal metabolite of acrivastine (a propionic acid analogue) is 2 to 3 times more active than the parent drug in inhibiting histamine-induced bronchospasm in guinea-pigs [1]
In healthy volunteers, acrivastine 2 to 8 mg inhibits the flare and weal response to intradermally injected histamine. A single 8 mg dose produced peak inhibition of flare (80%) and weal (40%) at 90 and 120 minutes, respectively. Approximately 63% of peak flare inhibition and 55% of peak weal inhibition were evident 30 minutes after administration [1]
Acrivastine 4 mg and tripolidine 2.5 mg inhibited the increase in nasal airway resistance induced by intranasal histamine challenge, while acrivastine 2 mg was ineffective [1]
Acrivastine 8 mg administered 30 or 60 minutes prior to challenge significantly reduced the conjunctival inflammatory response to histamine [1]
Acrivastine 8 mg administered 1 or 2 hours before challenge attenuated the bronchial airway response to inhaled histamine, with a faster onset of action than terfenadine 60 mg [1]
Attenuation of histamine-induced bronchoconstriction was evident within 30 minutes of acrivastine ingestion (8 mg) [1]
Acrivastine 4 to 16 mg did not impair psychomotor performance as assessed by adaptive tracking, reaction time, auditory vigilance, tapping tests, or eye movement tests in healthy volunteers, unlike tripolidine 2.5 and 5 mg or diphenhydramine 50 mg [1]
Acrivastine 4 mg did not cause sedation relative to placebo when assessed subjectively or by multiple sleep latency test [1]
Acrivastine combined with alcohol (32 ml) impaired objective tests (adaptive tracking, reaction time, eye movements) but caused less impairment than diphenhydramine 50 mg plus alcohol [1]
Combinations of acrivastine 4 or 8 mg or terfenadine 60 and 120 mg with alcohol caused no greater impairment than alcohol alone, suggesting small enhancement of alcohol effect by acrivastine [1]

For the treatment of allergic rhinitis and chronic urticaria, avastin (usually 8 mg three times daily) is an efficient and well-tolerated antihistamine. Treating seasonal allergic rhinitis with Avastin is more successful than using a placebo and works similarly to clemastine or terfenadine. Akvastine works similarly to commonly used doses of clemastine, hydroxyzine, chlorpheniramine, cyproheptadine, or terfenadine in the treatment of dermatoses in which histamine plays a causative role. It is also more effective than a placebo. Compared to clemastine, avastin is less drowsy, and its side effect profile is similar to that of terfenadine or placebo [1]. Avastin at doses of 4 mg and 8 mg significantly reduced symptoms of seasonal allergic rhinitis, including scores for runny nose, sneezing, and overall scores. Furthermore, the symptom scores for watery eyes and scratchy throat were decreased by 8 mg of acrivastine. When treating seasonal allergic rhinitis, avastin is well tolerated and works well [2].

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In double-blind clinical trials, acrivastine (usually 8 mg three times daily) was more effective than placebo and similar in efficacy to clemastine or terfenadine in seasonal allergic rhinitis [1]
In dermatoses where histamine has a pathogenetic role (chronic urticaria, symptomatic dermographism, cholinergic urticaria, idiopathic acquired cold urticaria), acrivastine 8 mg three times daily was superior to placebo and similar in efficacy to clemastine 1 mg, hydroxyzine 20 mg, chlorpheniramine 4 mg, cyproheptadine 4 mg, or terfenadine 60 mg, also administered three times daily [1]
In patients with atopic eczema, acrivastine 8 mg three times daily or terfenadine 60 mg equally enhanced the benefits of standard treatment (0.05% clobetasone butyrate ointment and aqueous cream) for itching over 10 days [1]
A combination of acrivastine and pseudoephedrine was more effective than either component alone in relieving nasal congestion, sneezing, and rhinorrhoea in seasonal allergic rhinitis. Onset of action of the combination was more rapid than that of terfenadine [1]
In perennial allergic rhinitis, acrivastine 8 mg plus pseudoephedrine 60 mg (conventional formulation) was of similar efficacy to chlorpheniramine 4 mg plus pseudoephedrine 60 mg [1]
Relief of symptoms occurred within 1 or 2 hours after the first dose of acrivastine alone or combined with pseudoephedrine in over 3500 patients [1]

In guinea-pigs, acrivastine was shown to lack anticholinergic effects [1]
In rats and guinea-pigs, brain:plasma concentration ratio of acrivastine after intravenous administration was 0.02 to 0.05, and after oral administration was 0.03 to 0.2, indicating low CNS penetration [1]
The principal metabolite of acrivastine (propionic acid analogue) was tested in guinea-pigs for inhibition of histamine-induced bronchospasm and found to be 2 to 3 times more active than acrivastine [1]

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In guinea-pigs, acrivastine was shown to lack anticholinergic effects [1]
In rats and guinea-pigs, brain:plasma concentration ratio of acrivastine after intravenous administration was 0.02 to 0.05, and after oral administration was 0.03 to 0.2, indicating low CNS penetration [1]
The principal metabolite of acrivastine (propionic acid analogue) was tested in guinea-pigs for inhibition of histamine-induced bronchospasm and found to be 2 to 3 times more active than acrivastine [1]

Absorption, Distribution and Excretion
Following oral administration, acristatin in the compound capsules is rapidly absorbed, with bioavailability comparable to that of acristatin solution. After administration of SEMPREX-D capsules, peak plasma acristatin concentrations were reached at 1.14 ± 0.23 hours. A mass balance study in seven healthy volunteers indicated that acristatin is primarily excreted via the kidneys. During a 72-hour collection period, approximately 84% of the total administered radioactive material was recovered in urine and approximately 13% in feces, for a total recovery rate of approximately 97%. 0.46 ± 0.05 L/kg 2.9 ± 0.7 mL/min/kg Biological Half-Life Following a single oral dose of acristatin, the mean terminal half-life is 1.9 ± 0.3 hours, increasing to 3.5 ± 1.9 hours at steady state. The terminal half-life of propionic acid metabolite is 3.8 ± 1.4 hours.

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Mean peak plasma concentrations (Cmax) of acrivastine (parent drug plus metabolites) of 73 μg/L and 179 μg/L were attained 1.4 and 0.85 hours (tmax) after single doses of 4 mg capsules and 12 mg oral solution, respectively [1]
Repeated administration of acrivastine 2 to 32 mg three times daily for 7 days resulted in dose-related linear increases in Cmax and AUC, with no accumulation. tmax was 1.9 hours [1]
Absorption of acrivastine from the colon is poor, with mean bioavailability 18% of that after oral administration (based on oral vs rectal administration comparison) [1]
Mean apparent volume of distribution (Vd/F) was 0.64 L/kg after single doses and 0.75 L/kg after multiple doses [1]
In rats and guinea-pigs, brain:plasma concentration ratio was 0.02-0.05 (iv) and 0.03-0.2 (oral) [1]
Acrivastine is approximately 50% protein bound, principally to albumin [1]
The principal metabolite is a propionic acid analogue formed by reduction of the acrylic side chain, accounting for about 10% of total plasma drug concentrations and 15-17% of a dose recovered in urine [1]
Unchanged acrivastine comprised 59% of the administered dose recovered in urine. 88% of ingested radioactivity after a single 8 mg dose of [14C] acrivastine was recovered in urine over 48 hours; the remainder was excreted in faeces within 5 days [1]
Apparent total body clearance was 0.26 L/h/kg after a single oral dose and 0.27 L/h/kg after repeated doses [1]
Elimination half-life ranged between 1.4 and 2.1 hours after single or repeated doses in healthy young adults [1]
Mean elimination half-life of the metabolite is 2.3 hours [1]
In elderly volunteers (65-75 years), apparent total body clearance of acrivastine (12.5 L/h/1.73m²) was about 25% lower than in young volunteers, and elimination half-life (2.2 h) was about 35% longer, likely related to decreased creatinine clearance [1]
After 5 days of acrivastine 8 mg three times daily, elimination half-life was 2.17 hours in elderly and 1.71 hours in younger volunteers; AUC was doubled and Cmax increased by about 34% in the elderly [1]

Hepatotoxicity
Acristatin has not been found to be associated with elevated liver enzymes or clinically significant liver injury. Its relative safety is likely related to its rapid metabolism and low-dose use. Likelihood Score: E (Unlikely to cause clinically significant liver injury).
References regarding the safety and potential hepatotoxicity of antihistamines are listed after the "Antihistamines Overview" section.
Drug Category: Antihistamines

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Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation Small, occasional doses of acristatin are not expected to have any adverse effects on breastfed infants. Larger doses or prolonged use may cause infant drowsiness and other adverse reactions, or reduced milk production, especially when used in combination with sympathomimetic drugs (such as pseudoephedrine) or before lactation is fully established. Non-sedating antihistamines are a better option. ◉ Effects on Breastfed Infants As of the revision date, no published information on acristatin has been found. 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. All adverse reactions did not require medical attention.
◉ 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 suckling-induced prolactin secretion. Whether lower doses of oral antihistamines have the same effect on serum prolactin, and whether this effect on prolactin has any impact on breastfeeding success, is currently unstudied. Prolactin levels in lactating mothers may not affect their ability to breastfeed.
Protein Binding
Acrilastine binds to human plasma proteins at a rate of 50 ± 2.0%.

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In clinical trials, acrivastine (4 to 8 mg 2 or 3 times daily) was well tolerated. Most common adverse effects: drowsiness, headache, nervousness, nausea, dry mouth/throat, dizziness [1]
In an analysis of about 2600 patients, incidence of adverse effects with acrivastine was not statistically significantly different from placebo: somnolence (30% vs 32%), headaches (15% vs 18%), dizziness (11% vs 13%), nervousness (8% vs 11%), nausea (6% vs 8%), dry mouth (6% vs 5%) [1]
Withdrawal rate due to adverse effects among 1906 patients with seasonal allergic rhinitis: 2.3% for placebo, 3.5% for acrivastine. In North American patients: <1% for placebo, 1% for acrivastine [1]
Acrivastine caused less drowsiness than clemastine or hydroxyzine; drowsiness was significantly more frequent with cyproheptadine than acrivastine. Acrivastine and terfenadine had similar drowsiness incidence [1]
Combination of acrivastine and pseudoephedrine was associated with dry mouth (8%), insomnia (4%), and CNS stimulation (1%) more frequently than acrivastine alone (6%, <1%, <1%) or placebo (5%, <1%, <1%). Among 1850 patients given the combination, 4% discontinued due to adverse effects vs <1% for placebo [1]
Symptoms of dry mouth/throat occurred in 1-10% of patients receiving acrivastine; headache and dizziness each in 1-7% [1]

[1]. Acrivastine. A review of its pharmacological properties and therapeutic efficacy in allergic rhinitis, urticaria and related disorders. Drugs. 1991 Jun;41(6):927-40.

[2]. Acrivastine in two doses compared with placebo in a multicentre, parallel group study for the treatment of seasonal allergic rhinitis. Br J Clin Pract. 1989 Jan;43(1):11-4.

Acrivastine is a pyridine compound with the structure (pyridin-2-yl)acrylic acid substituted at the 6-position with [(1E)-1-(4-methylphenyl)-3-(pyrrolidine-1-yl)prop-1-en-1-yl]. It is a non-sedating antihistamine used to treat hay fever, urticaria, and rhinitis. It is an H1 receptor antagonist. It is an α,β-unsaturated monocarboxylic acid, belonging to the pyridine class of compounds, and is an N-alkylpyrrolidine, as well as an olefin compound. Acrivastine is a triprolidine analog antihistamine suitable for treating allergies and hay fever. As an H1 receptor antagonist, acrivastine works by blocking the binding of histamine to this receptor, thereby preventing symptoms associated with histamine release, such as itching, vasodilation, hypotension, edema, bronchoconstriction, and tachycardia. Currently, acristatin is used in combination with pseudoephedrine as the FDA-approved combination drug Semprex-D. Acristatin is a histamine-1 receptor antagonist. Its mechanism of action is as a histamine H1 receptor antagonist. Acristatin is a second-generation antihistamine used to treat allergic rhinitis. No clinically significant cases of acute liver injury have been found associated with acristatin. Acristatin is a synthetic alkylamine with non-sedating antihistamine activity. Acristatin limits typical anaphylactic and anaphylactic shock responses, including bronchoconstriction, vasodilation, increased capillary permeability, and gastrointestinal smooth muscle spasms, by competitively blocking histamine H1 receptors. These responses are caused by histamine acting on the bronchi, gastrointestinal smooth muscle, and capillaries. The drug also prevents histamine-induced skin and mucous membrane pain and itching. (NCI05)

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Drug Indications
For the relief of symptoms associated with seasonal allergic rhinitis, such as sneezing, runny nose, itching, tearing, and nasal congestion.
FDA Label

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Acrivastine is a short-acting histamine H1-receptor antagonist with a rapid onset of action (within about 30 minutes) and low sedative potential due to poor CNS penetration [1]
Due to its rapid onset, acrivastine is particularly useful for 'on demand' therapy in patients with intermittent symptoms [1]
Acrivastine relieves nasal congestion less consistently than other symptoms of allergic rhinitis [1]
Recommended adult dosage: 8 mg three times daily in Europe and UK, 4 times daily in the US. No dosage recommendations for children under 12 years or elderly patients [1]
A combination of acrivastine and pseudoephedrine is available as conventional capsules (8/60 mg) three times daily or sustained release (12/90 mg) twice daily. Should not be used with monoamine oxidase inhibitors or adrenergic neuron blocking drugs [1]
Acrivastine requires 3 or 4 times daily administration, which may be a disadvantage compared to once-daily low-sedating antihistamines, but its rapid onset makes it suitable for 'on demand' therapy [1]

C22H24N2O2

348.4382

348.183

87848-99-5

Acrivastine-d7;172165-56-9

5284514

White to off-white solid powder

1.2±0.1 g/cm3

555.1±50.0 °C at 760 mmHg

55.5-59.5 °C(lit.)

289.5±30.1 °C

0.0±1.6 mmHg at 25°C

1.627

4.55

1

4

6

26

514

0

C(/C1C=CC(C)=CC=1)(\C1C=CC=C(/C=C/C(=O)O)N=1)=C/CN1CCCC1

PWACSDKDOHSSQD-IUTFFREVSA-N

InChI=1S/C22H24N2O2/c1-17-7-9-18(10-8-17)20(13-16-24-14-2-3-15-24)21-6-4-5-19(23-21)11-12-22(25)26/h4-13H,2-3,14-16H2,1H3,(H,25,26)/b12-11+,20-13+

(E)-3-[6-[(E)-1-(4-methylphenyl)-3-pyrrolidin-1-ylprop-1-enyl]pyridin-2-yl]prop-2-enoic acid

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 : ~50 mg/mL (~143.50 mM)
H2O : ~1 mg/mL (~2.87 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.17 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 (7.17 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 (7.17 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.)