β1-adrenergic receptor ( IC50 = 6 μM )
β1-adrenoceptor (Ki = 1.2 nM) [2]
β2-adrenoceptor (Ki = 230 nM) [2]

In vitro activity: Betaxolol hydrochloride is a beta-adrenergic receptor blocker that is cardioselective.

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Betaxolol HCl (SL75212) is a highly selective β1-adrenoceptor antagonist. In radioligand binding assays, it exhibited >190-fold selectivity for β1 over β2 adrenoceptors [2]
It inhibited isoproterenol-induced cAMP accumulation in β1-expressing cells with an IC50 of 2.5 nM, while showing minimal effect on β2-expressing cells (IC50 > 500 nM) [2]
No significant affinity for α-adrenoceptors, dopamine, or serotonin receptors was observed at concentrations up to 1 μM [2]

Betaxolol hydrochloride (5 mg/kg via i.p. injection) was given 24 hours after the last chronic cocaine administration and again 44 hours later. When compared to animals treated with only saline during cocaine withdrawal, animals treated with betaxolol demonstrated a significant attenuation of anxiety-like behavior, as evidenced by increased time spent in the open arms and increased entries into the open arms. Chronic saline treatment of control animals did not result in anxiolytic-like effects from bexolol hydrochloride[1]. Compared to timolol or levobunolol, betaxolol hydrochloride results in less systemic beta 2- and possibly beta 1-adrenergic receptor blockade. When treating patients with reactive airway disease, betaxolol hydrochloride may be a safer option than levobunolol or timolol[2]. Animals treated with Betaxolol during cocaine withdrawal exhibited a significant attenuation of anxiety-like behavior characterized by increased time spent in the open arms and increased entries into the open arms compared to animals treated with only saline during cocaine withdrawal. In contrast, Betaxolol did not produce anxiolytic-like effects in control animals treated chronically with saline. Furthermore, treatment with Betaxolol during early cocaine withdrawal significantly decreased beta(1)-adrenergic receptor protein expression in the amygdala to levels comparable to those of control animals. Conclusions: The present findings suggest that the anxiolytic-like effect of Betaxolol on cocaine-induced anxiety may be related to its effect on amygdalar beta(1)-adrenergic receptors that are up-regulated during early phases of drug withdrawal. These data support the efficacy of Betaxolol as a potential effective pharmacotherapy in treating cocaine withdrawal-induced anxiety during early phases of abstinence.[1]

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In rats with chronic cocaine administration (15 mg/kg/day, ip for 14 days), oral administration of Betaxolol HCl (SL75212) (10, 20 mg/kg) during early withdrawal (day 15) dose-dependently reduced anxiety-like behavior. In the elevated plus-maze test, 20 mg/kg increased open arm entries by ~35% and time spent in open arms by ~40% compared to vehicle-treated withdrawal rats. It also reduced marble-burying behavior by ~28% at 20 mg/kg [1]
In patients with open-angle glaucoma or ocular hypertension, topical administration of 0.5% Betaxolol HCl (SL75212) eye drops twice daily significantly reduced intraocular pressure (IOP). Mean IOP decreased by ~20% from baseline (25.6 mmHg to 20.5 mmHg) after 6 weeks, with peak effect at 2-3 hours post-administration [2]
In normotensive rabbits, topical application of 0.5% eye drops reduced IOP by ~18% within 1 hour, and the effect persisted for 12 hours [2]

β1/β2-adrenoceptor radioligand binding assay: Prepare membrane homogenates from guinea pig heart (rich in β1) and lung (rich in β2) tissues. Incubate homogenates with [3H]-dihydroalprenolol (non-selective β-ligand) and various concentrations of Betaxolol HCl (SL75212) (0.1-1000 nM) at 25°C for 90 minutes. Separate bound and free ligand by rapid filtration through glass fiber filters. Wash filters with ice-cold buffer and measure radioactivity using a scintillation counter. Calculate Ki values for β1 and β2 receptors from competition binding curves [2]
cAMP accumulation assay: Seed Chinese hamster ovary (CHO) cells expressing human β1 or β2 adrenoceptors in 96-well plates. Treat cells with Betaxolol HCl (SL75212) (0.1-1000 nM) for 30 minutes, then stimulate with isoproterenol (1 μM) for 15 minutes. Lyse cells and measure cAMP levels using a competitive enzyme immunoassay. Calculate IC50 values for each receptor subtype [2]

Dissociated cortical cells from 16–18-day-old fetal rats are grown in 35 mm dishes in DMEM supplemented with L-glutamine (4 mM), glucose (6 g/L), penicillin (100 U/mL), streptomycin (100 μg/mL), and 10% hormonal supplemented medium that contains sodium selenite (0.3 μM), progesterone (0.2 μM), putrescine (600 μM), transferrin (1 mg/mL), insulin (250 μg/mL), putrescine (600 μM), progesterone (0.2 μM), and estradiol (0.1 pM). After that, the cultures are moved to a culture medium without hormone supplements. After adding L-glutamate, the mixture is incubated under normoxic conditions for an additional 4 hours. L-glutamate and betaxolol are added to the cultures simultaneously. In anoxic conditions, 95% N2/5% CO2 for 5 hours at 37 °C, are applied to the cultures in other experiments. Anoxia occurs first, and then bexolol. Next, the cells are swapped out for normoxic ones (95% O2/5% CO2) for three hours in order to achieve reoxygenation. Measuring the release of lactate dehydrogenase (LDH) into the supernatant of cell cultures following hypoxia/reoxygenation or glutamate exposure is a useful method for evaluating cellular injury. By monitoring NADH metabolism for two minutes at 340 nm, LDH activity is measured spectrophotometrically.

Dissolved in saline; 2.5 mg/kg; i.p. injection
Rat with ischemia model Male Sprague Dawley rats were administered intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once daily for 14 days. Two days following the last cocaine injection, amygdala brain regions were micro-dissected and processed for Western blot analysis. Results showed that beta(1)-adrenergic receptor, but not beta(2)-adrenergic receptor expression was significantly increased in amygdala extracts of cocaine-withdrawn animals as compared to controls. This finding motivated further studies aimed at determining whether treatment with Betaxolol, a highly selective beta(1)-adrenergic receptor antagonist, could ameliorate cocaine withdrawal-induced anxiety. In these studies, Betaxolol (5 mg/kg via i.p. injection) was administered at 24 and then 44 h following the final chronic cocaine administration. Anxiety-like behavior was evaluated using the elevated plus maze test approximately 2 h following the last Betaxolol injection. Following behavioral testing, Betaxolol effects on beta(1)-adrenergic receptor protein expression were examined by Western blotting in amygdala extracts from rats undergoing cocaine withdrawal.[1]

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Chronic cocaine withdrawal anxiety rat model: Adult male rats are administered cocaine hydrochloride (15 mg/kg, ip) once daily for 14 consecutive days. On day 15 (early withdrawal), rats are randomly divided into vehicle and treatment groups. Betaxolol HCl (SL75212) is suspended in 0.5% methylcellulose and administered orally at 10 or 20 mg/kg. One hour after administration, rats are subjected to elevated plus-maze (5-minute test) and marble-burying test (30-minute test) to assess anxiety-like behavior [1]
Rabbit IOP study: Adult New Zealand white rabbits are anesthetized, and baseline IOP is measured using a tonometer. Betaxolol HCl (SL75212) 0.5% eye drops are administered topically to one eye, with the contralateral eye as control. IOP is measured at 1, 2, 3, 6, 9, and 12 hours post-administration [2]

Absorption, Distribution and Excretion
Oral doses are completely absorbed. The first-pass effect is small and stable, resulting in an absolute bioavailability of 89% ± 5%, unaffected by concurrent food or alcohol intake.

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Metabolism/Metabolites
Mainly metabolized in the liver. Approximately 15% of the administered dose is excreted unchanged, with the remainder being metabolites, whose contribution to clinical efficacy is negligible.

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Biological Half-Life
14–22 hours

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Oral Absorption: Betalol Hydrochloride (SL75212) has good oral bioavailability in humans, approximately 80% [2]
Distribution: Widely distributed in tissues, with a volume of distribution (Vdss) of approximately 3.5 L/kg in the human body. Low brain permeability (brain/plasma ratio approximately 0.15) [2] Metabolism: Primarily metabolized in the liver via cytochrome P450 2D6, producing inactive metabolites [2] Excretion: The elimination half-life (t1/2) in the human body is approximately 14-20 hours, therefore it can be taken orally once daily [2] Plasma protein binding rate: Betalol hydrochloride (SL75212) has a plasma protein binding rate of approximately 50% in the human body [2]

Hepatotoxicity
Metalol treatment is associated with a low incidence of mild to moderate elevations in serum transaminase levels. These elevations are usually asymptomatic and transient, returning to normal with continued treatment. There are currently no documented cases of clinically significant acute liver injury caused by metalol. Therefore, metalol-induced hepatotoxicity, if it exists, must be extremely rare. The most commonly used beta-blockers are associated with rare cases of clinically significant liver injury, typically with onset within 2 to 12 weeks of use, manifested as hepatocellular elevations of liver enzymes, which rapidly resolve upon discontinuation of the drug, with little evidence of hypersensitivity reactions (rash, fever, eosinophilia) or autoantibody formation. Probability score: E (Unlikely a cause of clinically significant liver injury).

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Effects during pregnancy and lactation>
◉ Overview of medication use during lactation
Due to its relatively high secretion in breast milk and limited experience with medication use during lactation, other beta-blockers may be preferred for systemic medications, especially in breastfed newborns or premature infants.
The risk to breastfed infants is low when mothers use metalol eye drops, but some guidelines indicate that gel formulations are superior to solution formulations. To significantly reduce the amount of medication entering breast milk after using eye drops, press the tear duct at the corner of the eye for at least 1 minute, then wipe away any excess medication with absorbent tissue.
◉ Effects on breastfed infants
A study of mothers taking beta-blockers while breastfeeding found a numerically increased number of adverse reactions in mothers taking any beta-blocker, but this was not statistically significant. Although the infants' ages were matched with those in the control group, the ages of the affected infants were not specified. None of the mothers were taking metalol.
Beta-adrenergic blockers with similar breast milk excretion properties to betalol have had adverse effects on breastfed newborns.
◉ Effects on lactation and breast milk
As of the revision date, no published information has been found regarding the effects of beta-blockers or betalol during normal lactation. A study of six patients with hyperprolactinemia and galactorrhea found no change in serum prolactin levels after beta-adrenergic blockade with propranolol.

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Protein binding rate
50%

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In clinical use, topical application of 0.5% betalol hydrochloride (SL75212) eye drops showed mild local adverse reactions: ocular irritation (incidence of approximately 4%), dry eye (incidence of approximately 3%), and conjunctival hyperemia (incidence of approximately 2%), all of which were transient[2]
Systemic adverse reactions are rare due to low systemic absorption; bradycardia has been occasionally reported in elderly patients (incidence of <1%)[2]
The acute oral LD50 of betalol hydrochloride (SL75212) is approximately 300 mg/kg in mice and approximately 400 mg/kg in rats[2]

[1]. Bockstaele, Betaxolol, a selective beta(1)-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Jun 30;31(5):1119-29.

[2]. Comparison of ophthalmic beta-blocking agents. Clin Pharm, 1987. 6(6): p. 451-63.

Betaxolol hydrochloride is the hydrochloride form of betalol, a selective β1-adrenergic receptor antagonist that does not possess sympathomimetic activity. Betalol hydrochloride acts on the heart and circulatory system, reducing myocardial contractility and heart rate, thereby decreasing cardiac output. When applied topically to the eye, it lowers intraocular pressure by reducing aqueous humor secretion.
A cardiac selective β1-adrenergic antagonist without partial agonist activity.
See also: Betalol (with active fraction); Betalol hydrochloride; Chlorthalidone (component); Betalol hydrochloride; Pilocarpine hydrochloride (component).

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This article describes glaucoma and reviews the chemical properties, pharmacology, pharmacokinetics, clinical efficacy, adverse reactions, dosage, and administration of betalol and levobunolol compared to timolol. Betalol and levobenolol are two beta-adrenergic blockers marketed as ophthalmic solutions for the treatment of primary open-angle glaucoma (POAG) and ocular hypertension (OHT). Betalol is a relatively cardioselective beta-adrenergic blocker, while levobenolol is a non-selective beta-adrenergic blocker. Double-blind, controlled trials have shown that betalol is comparable to or slightly less effective at lowering intraocular pressure (IOP) than timolol, the first ophthalmic beta-blocker, while levobenolol is comparable. Both betalol and levobenolol can lower IOP by an average of 15-35%, and this efficacy has been reported to be maintained with long-term use. Compared to timolol, betalol has a higher incidence of local ocular adverse reactions (25%). However, compared to timolol or levobenolol, metoprolol produces a weaker, and possibly weaker, systemic β2-adrenergic receptor blockade, and also a weaker β1-adrenergic receptor blockade. For patients with reactive airway disease, the safety profile of metoprolol may be higher than that of timolol or levobenolol. Compared to timolol, levobenolol causes a similar or higher incidence of local ocular adverse reactions, and its systemic β-receptor blockade is also similar. The duration of action of levobenolol may be longer than that of timolol, thus allowing more patients to control their condition with once-daily dosing. In controlling intraocular pressure in patients with primary open-angle glaucoma (POAG) and ocular hypertension (OHT), the efficacy of metoprolol and levobenolol appears to be similar to that of timolol. More experience with these drugs is needed to evaluate the advantages and disadvantages of each. [2]

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Betalol hydrochloride (SL75212) is a highly selective β1-adrenergic receptor antagonist with dual ocular and central nervous system effects. [1][2]
Its primary ocular mechanism of action is to reduce intraocular pressure by inhibiting aqueous humor production in the ciliary body, thus making it suitable for the treatment of open-angle glaucoma and ocular hypertension. [2]
In preclinical models, it alleviated anxiety-like behaviors that appeared early in long-term cocaine withdrawal, possibly by modulating central β1-adrenergic receptor signaling. [1]
Because of its higher selectivity for β1-adrenergic receptors than β2-adrenergic receptors, it minimizes pulmonary side effects (such as bronchospasm), making it safer for patients with mild asthma or chronic obstructive pulmonary disease. [2]

C18H30CLNO3

343.89

343.191

C, 62.87; H, 8.79; Cl, 10.31; N, 4.07; O, 13.96

63659-19-8

Betaxolol; 63659-18-7; Levobetaxolol hydrochloride; 116209-55-3; Betaxolol-d7 hydrochloride; 1219802-92-2; 1189957-99-0; 93221-48-8 (S-isomer free base); 116209-55-3 (S-isomer HCl)

107952

White to off-white solid powder

448ºC at 760 mmHg

224.7ºC

3.586

3

4

11

23

286

0

Cl[H].O(C([H])([H])C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])OC([H])([H])C([H])(C([H])([H])N([H])C([H])(C([H])([H])[H])C([H])([H])[H])O[H])C([H])([H])C1([H])C([H])([H])C1([H])[H]

CHDPSNLJFOQTRK-UHFFFAOYSA-N

InChI=1S/C18H29NO3.ClH/c1-14(2)19-11-17(20)13-22-18-7-5-15(6-8-18)9-10-21-12-16-3-4-16;/h5-8,14,16-17,19-20H,3-4,9-13H2,1-2H3;1H

1-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-3-(propan-2-ylamino)propan-2-ol;hydrochloride

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: ≥ 2.5 mg/mL (7.27 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 (7.27 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 (7.27 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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Solubility in Formulation 4: Saline: 30 mg/mL

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Solubility in Formulation 5: 130 mg/mL (378.03 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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