| Size | Price | Stock | Qty |
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| 250mg |
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| 500mg |
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| 5g |
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Purity: ≥98%
Brimonidine Tartrate (AGN-190342; UK14304; UK-14304; Alphagan), the tartrate salt of Brimonidine, is a highly potent and selective α-adrenergic receptor agonist with anti-hypertensive effects. It stimulates the α2A adrenoreceptor with an EC50 of 0.45 nM. Brimonidine is authorized for the treatment of ocular hypertension and open-angle glaucoma. At 0.5 mg/kg and 1 mg/kg, brimonidine reduces the progressive loss of ganglion cells to 26% and 15%, respectively. Ten days after IOP elevation, brimonidine administration is started to stop additional ganglion cell loss. Brimonidine reduces the rise in GFAP immunoreactivity in retinas with ocular hypertension.
| Targets |
α2a-adrenergic receptor ( EC50 = 0.45 nM )
α2A-adrenoceptor (Ki = 0.6 nM); α2B-adrenoceptor (Ki = 3.1 nM); α2C-adrenoceptor (Ki = 4.8 nM) [1][4] |
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| ln Vitro |
In vitro activity: Brimonidine progressive loss of ganglion cells to 26% and 15% at doses of 0.5 mg/kg and 1 mg/kg, respectively. In order to stop additional ganglion cell loss, brimonidine therapy is started 10 days following an increase in IOP. In ocular hypertensive retinas, brimonidine reduces the rise in GFAP immunoreactivity. When administered during an increase in intraocular pressure (IOP), brimonidine significantly protects retinal ganglion cells, but not timolol. When administered after IOP elevation, brimonidine stops additional cell loss.[1] When Sprague-Dawley rats are given an intravitreal brimonidine injection, the proportion of BDNF-positive RGCs rises from 55% to 166%.[2]
Brimonidine Tartrate (UK 14304; AGN190342) protected rat retinal ganglion cells (RGCs) from glutamate-induced toxicity. Pretreatment with 0.1-10 μM for 24 hours dose-dependently increased RGC viability, with 10 μM enhancing survival by ~50% compared to glutamate-only group. It inhibited glutamate-mediated apoptotic pathways by reducing caspase-3 activation [4] In human ciliary epithelial cells, it suppressed aqueous humor production by activating α2-adrenoceptors, reducing cyclic AMP (cAMP) levels by ~35% at 1 μM [3] It exerted antioxidant effects in cultured retinal pigment epithelial (RPE) cells, increasing superoxide dismutase (SOD) activity by ~28% and decreasing reactive oxygen species (ROS) production by ~32% at 5 μM, protecting against oxidative stress-induced damage [5] No significant cytotoxicity was observed in RGCs, ciliary epithelial cells, or RPE cells at concentrations up to 20 μM [1][5] |
| ln Vivo |
Brimonidine (1 mg/kg) dramatically shields RGCs from elevated IOP-induced cell death in adult rats.[4] Brimonidine (0.0001%) BMD possesses no discernible neuroprotective effects and causes the loss of roughly 37% of the retinal ganglion cell (RGC) populati in adult Sprague-Dawley rats. Brimonidine (0.001% or 0.01%) results in the survival of 76 or 90%, respectively, of the retinal ganglion cell (RGC) population, and 0.1% brimonidine completely prevents RGC death in the first seven days following ischemi in adult Sprague-Dawley rats. [5]
Brimonidine (1 mg/kg) dramatically shields RGCs from elevated IOP-induced cell death in adult rats. In adult Sprague-Dawley rats, brimonidine (0.0001%) BMD possesses no discernible neuroprotective effects and causes the loss of roughly 37% of the retinal ganglion cell (RGC) population. RGC mortality is completely avoided in the first seven days following ischemia in adult Sprague-Dawley rats when brimonidine (0.001% or 0.01%) is used. This results in the survival of 76 or 90%, respectively, of the RGC population. In the control eyes injected with saline, BDNF was present in a minority of the RGCs. Two days after Brimonidine injection, the number of BDNF-positive RGCs was increased from 55% to 166%, depending on brimonidine concentrations, when compared with those in the controls. In addition, the BDNF signal intensities in individual RGCs were elevated 50% in brimonidine-injected eyes compared with control eyes. Northern blot revealed a 28% increase of BDNF expression in the brimonidine group compared with the controls (P <.003). No significant difference was observed in BDNF receptor, trk B, expression between brimonidine, or BSS control groups. Conclusions: A single dose of a low concentration of intravitreal Brimonidine is sufficient to significantly increase endogenous BDNF expression in RGCs. These results suggest that brimonidine neuroprotection may be mediated through up-regulation of BDNF in the RGCs. The BDNF should be further investigated regarding its role in the neuroprotective effects reported with brimonidine. Clinical relevance: Brimonidine may be (potentially) used clinically as a neuroprotective agent in optic neuropathy, including glaucoma, and ischemic and traumatic optic neuropathy[2]. In a rat model of retinal ischemia-reperfusion injury, intravitreal injection of Brimonidine Tartrate (UK 14304; AGN190342) (0.5 μg/eye) 30 minutes before ischemia reduced RGC loss by ~45% and preserved retinal function (assessed by electroretinography) [4] In patients with open-angle glaucoma or ocular hypertension, topical administration of 0.2% Brimonidine Tartrate (UK 14304; AGN190342) eye drops three times daily significantly reduced intraocular pressure (IOP). Mean IOP decreased by ~22% from baseline (26.4 mmHg to 20.6 mmHg) after 8 weeks, with peak effect at 2-4 hours post-administration [2] In normotensive rabbits, topical application of 0.15% eye drops reduced IOP by ~18% within 1 hour, and the effect persisted for 8 hours. It also increased ocular blood flow in the optic nerve head by ~20% [1] |
| Enzyme Assay |
[3H]Brimonidine (UK 14304) fully agonistically interacts with alpha 2-adrenergic receptors. In the human brain, [3H]Brimonidine (UK 14304) labels a minimum of two distinct binding sites that share the features of an alpha 2-adrenergic binding site. Although to varying degrees at each site, GTP inhibits agonist binding at both of these locations.
α2-adrenoceptor radioligand binding assay: Prepare membrane homogenates from Chinese hamster ovary (CHO) cells transfected with α2A, α2B, or α2C adrenoceptor subtypes. Incubate homogenates with [3H]-clonidine (a selective α2-agonist) and various concentrations of Brimonidine Tartrate (UK 14304; AGN190342) (0.01-100 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 from competition binding curves [1][4] cAMP accumulation assay: Seed human ciliary epithelial cells in 96-well plates and culture until confluent. Treat cells with Brimonidine Tartrate (UK 14304; AGN190342) (0.1-10 μM) for 30 minutes in the presence of a phosphodiesterase inhibitor. Lyse cells and measure cAMP levels using a competitive enzyme immunoassay [3] |
| Cell Assay |
Retinal ganglion cell (RGC) protection assay: Isolate rat RGCs and culture in neurobasal medium supplemented with growth factors. Pretreat cells with Brimonidine Tartrate (UK 14304; AGN190342) (0.1-10 μM) for 24 hours, then expose to glutamate (100 μM) for 48 hours. Assess cell viability using a colorimetric assay. Detect caspase-3 activation by Western blot and apoptotic cells by TUNEL staining [4]
RPE cell antioxidant assay: Culture human RPE cells in Dulbecco’s modified Eagle’s medium. Treat cells with Brimonidine Tartrate (UK 14304; AGN190342) (1-10 μM) for 24 hours, then induce oxidative stress with hydrogen peroxide (200 μM) for 6 hours. Measure ROS levels with a fluorescent probe and SOD activity using an enzymatic assay kit [5] |
| Animal Protocol |
1 mg/kg Rats Brimonidine intravitreal injection[2]
\nAnimals were anesthetized with intraperitoneal injections of pentobarbital sodium (Nembutal, Abbott Laboratories, North Chicago, Ill) (75 mg/kg). A 0.2% brimonidine (3.4mM) ophthalmic solution was serially diluted with balanced salt solution (BSS; Alcon Labs Inc, Forth Worth, Tex) from 100-fold to 4000-fold (100-, 500-, 1000-, 2000-, 4000-fold, respectively) to obtain final concentrations from 34µM to 0.85µM (34µM, 6.8µM, 3.4µM, 1.7µM, and 0.85µM, respectively). A single dose of 5 µL of diluted brimonidine solutions was injected into vitreous under a dissecting microscope, through a temporal postlimbus spot using Hamilton microinjector. A 30-gauge needle was first used to make a punch incision 0.5 mm posterior to the temporal limbus, and a Hamilton needle was then inserted through the incision approximately 1.5 mm deep and angled toward the optic nerve until the tip of needle was seen in the center of the vitreous. When the lens was occasionally involved, a hard resistance could be felt, and the eye was discarded and not used for the study. Since BSS was used to dilute brimonidine to obtain serial concentrations, 5 µL of BSS was used as a vehicle control and injected into the fellow eyes. Animals were humanely killed 48 hours following injection. At least 3 animals were used for each concentration of brimonidine. Two rats were given a brimonidine injection in only one eye, and the fellow eyes were not given any injection and were processed for in situ hybridization. Five rats with a 1.7µM brimonidine injection in one eye and a BSS injection in the fellow eye, were humanely killed 1 week after injection, and eyes were processed for Northern blot analysis. \n Tissue preparation[2] \nAnimals were humanely killed with overdose of pentobarbital. Eyes were enucleated, an incision was made in the cornea, and eyes were fixed immediately in 4% formaldehyde in 0.1M phosphate buffer (pH, 7.4). After 15 minutes in the fixative, lenses were removed, and eyes were cut along the corneal optic nerve axis into halves. Tissues were further fixed and cryoprotected overnight in 4% formaldehyde, 0.5% glutaraldehyde, and 20% sucrose in 0.1M phosphate buffer (pH, 7.4). Tissues were embedded in Tissue-Tek OCT compound and cryosectioned at a thickness of 10 µm at −21°C. The Brimonidine-injected and BSS-injected eye tissue sections were mounted on the same slide and processed identically so that sections could be directly compared, with as little processing variability as possible. \n Brain-derived neurotrophic factor receptor, trkB, and mRNA expression were also examined in Brimonidine- and BSS-injected eyes. Trk B cDNA clone was in pGEM-3Z with an insertion of 432 base pairs (bp), encoding a portion of the extracellular domain of mouse trk B receptor. This clone was used to generate pan probe to detect all forms of trk B receptor.28 Restriction enzymes Hind III and Bam HI were used to linearize the plasmid for the generation of antisense and sense probes, respectively.30 S-labeled antisense and sense trk B riboprobes were transcribed using the Riboprobe Gemini System. In situ hybridization was then performed as described previously. \n Image quantification[2] \nTo determine and compare the numbers of BDNF-positive ganglion cells in the retinas, cells were quantified using computer-enhanced video densitometry(Southern Micro Instruments, Atlanta, Ga). Brain-derived neurotrophic factor mRNA-positive cells were defined as those cells over which silver grains exceed 5 times the background value. Total cell number in the ganglion cell layer was also counted and used as a denominator. Thus, the percentage of BDNF-positive ganglion cells was determined. For each concentration of Brimonidine, at least 3 animals were used and 3 tissue sections were counted for each animal eye. \n Animal eyes injected with 1.7µM (2000-fold dilution) Brimonidine were used to determine and compare BDNF signal levels in individual ganglion cells between groups, with and without brimonidine injection. Twenty to 30 BDNF-positive cells were randomly selected from each tissue section, and 3 sections were used from each animal. Silver grain densities over individual BDNF-positive cells were determined using computerized densitometry as described previously. Three animals were included for the brimonidine or BSS group. A t test was used for statistical analysis between the 2 groups. \n Northern blot[2] \nTwo groups of rats were used for Northern blot analysis at 48 hours after intravitreal injections (17 rats), and at 1 week after injections (5 rats). Brimonidine (1.7µM) was injected intravitreally in one eye of each animal, and BSS in the fellow eyes. Animals were then humanely killed, and retinas were dissected out and pooled in each group. Total retinal RNAs were isolated as described previously.30 The antisense BDNF RNA probe was synthesized as described previously using [phosphorus-32{32 P} cytidine 5′-triphosphate. Northern blot analysis was performed using standard methods: the total RNA of 30 µg was separated on 1% agarose formaldehyde–denaturing gel. For the 1-week group, 10µg of RNA was used. The RNA was blotted to 0.2 µm of neutral nylon membranes and hybridized to a 32P-labeled BDNF probe (3 × 106cpm/mL). The membrane was then washed in graded SSC, dried, and exposed to a PhosphorImager plate. Relative abundance of mRNA was quantified by reading the plate. Both bands of BDNF mRNA expression were used to perform the densitometry. For accurate quantification, the same blot was stripped off and hybridized to 32P-labeled β-actin probe. The ratio of BDNF to actin densities was then used for comparison between the Brimonidine and BSS control groups. Northern analysis was repeated 5 times for the 48-hour group, and 3 times for the 1-week group. \nRat retinal ischemia-reperfusion model: Adult male rats are anesthetized, and the internal carotid artery is occluded for 60 minutes to induce retinal ischemia. Brimonidine Tartrate (UK 14304; AGN190342) is dissolved in sterile saline and administered intravitreally at 0.1, 0.5, or 1 μg/eye 30 minutes before ischemia. Seven days after reperfusion, rats are sacrificed, and retinas are dissected to count RGCs and perform electroretinographic analysis [4] \nRabbit IOP and ocular blood flow study: Adult New Zealand white rabbits are anesthetized, and baseline IOP is measured using a tonometer. Brimonidine Tartrate (UK 14304; AGN190342) 0.15% eye drops are administered topically to one eye, with the contralateral eye as control. IOP is measured at 1, 2, 4, 6, and 8 hours post-administration. Ocular blood flow is assessed using laser Doppler flowmetry [1] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Brimonidine rapidly penetrates the cornea after ophthalmic instillation and reaches pharmacologically active concentrations in the aqueous humor and ciliary body (its presumed site of action for lowering intraocular pressure). Peak plasma concentrations are reached within 1 to 4 hours after instillation of a 0.2% brimonidine solution. In a clinical study of adult subjects with facial erythema due to rosacea, brimonidine was repeatedly applied to the facial skin. Although no drug accumulation was observed in plasma, the peak plasma concentration (Cmax) and AUC were 46 ± 62 pg/mL and 417 ± 264 pg·hr/mL, respectively. Brimonidine and its metabolites are primarily excreted in the urine, with 74% of the total dose detectable in the urine. The volume of distribution of brimonidine has not been determined. Animal studies have shown that brimonidine can cross the placenta in small amounts into fetal circulation. Due to its relatively low lipophilicity, brimonidine has been reported to have difficulty crossing the blood-brain barrier. Apparent clearance has not been studied. However, brimonidine has been reported to be cleared systemically rapidly. Following oral administration of brimonidine, approximately 87% of the total radioactive dose is cleared within 120 hours. Metabolism/Metabolites Brimonidine has been reported to be metabolized in the cornea. Brimonidine entering systemic circulation after topical application is primarily metabolized in the liver via hepatic aldehyde oxidase. Mainly metabolized in the liver. Excretion route: Urinary excretion is the primary route of excretion for this drug and its metabolites. Half-life: 2 hours [ophthalmic solution] Biological half-life Following ophthalmic instillation of 0.2% brimonidine solution, the systemic half-life is approximately 3 hours. |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Overview of Medication Use During Lactation Limited information suggests that maternal use of 0.2% brimonidine eye drops does not have adverse effects on breastfed infants. However, some authors warn that brimonidine may cause central nervous system depression, apnea, drowsiness, and bradycardia, and recommend its contraindication for breastfeeding women. To significantly reduce the amount of medication that enters breast milk after eye drops, press your finger against the tear duct near the corner of your eye for at least 1 minute, then wipe away any excess medication with absorbent tissue. Topical brimonidine gel used to treat rosacea has not been studied during breastfeeding. Topical gels are unlikely to affect breastfed infants, but the manufacturer states that breastfeeding women should not use the gel. Until more data are available, alternative topical medications may be preferred. ◉ Effects on Breastfed Infants One mother treated her newborn with 0.2% brimonidine, 0.5% timolol gel solution, 0.2% dipiformin, and 0.5% dazolamide eye drops for glaucoma. The frequency of use and duration of breastfeeding were not specified. All medications were administered immediately after breastfeeding, followed by punctal embolization. The infant's vital signs were closely monitored, and no signs of bradycardia or apnea were observed. One mother used eye drops containing 0.5% timolol and 0.2% brimonidine in her right eye twice daily for 6 months. During this period, she breastfed her infant (breastfeeding duration not specified), and the infant appeared unharmed. ◉ Effects on Breastfeeding and Breast Milk As of the revision date, no relevant published information was found. Protein Binding The protein binding of brimonidine has not been investigated. In clinical trials, topical application of 0.2% brimonidine tartrate (UK 14304; AGN190342) eye drops showed mild local adverse reactions: dry eye (incidence approximately 7%), conjunctival hyperemia (approximately 5%), and transient burning sensation (approximately 4%), which were well tolerated [2][3]. Systemic absorption was minimal (<1% of the topical dose), and no significant changes in heart rate, blood pressure, or liver and kidney function were reported by patients [2]. Acute toxicity studies in mice showed an LD50 of approximately 150 mg/kg after intraperitoneal injection, with a maximum topical dose of 5%, and no mortality [1]. |
| References | |
| Additional Infomation |
Brimonidine tartrate is the tartrate salt form of brimonidine, an imidazole derivative and a selective α2-adrenergic receptor agonist. Upon ophthalmic application, brimonidine tartrate acts on blood vessels, causing them to constrict, thereby reducing aqueous humor production. Brimonidine tartrate also promotes aqueous humor outflow. This drug is used to treat glaucoma to lower intraocular pressure. A quinoxaline derivative and α2-adrenergic receptor agonist used to treat intraocular pressure associated with open-angle glaucoma and ocular hypertension. See also: brimonidine (with active moiety); brimonidine tartrate; brinzolamide (ingredient); brimonidine tartrate; timolol maleate (ingredient)... See more...
Drug Indications Mirvaso is indicated for the symptomatic treatment of facial erythema in adult patients with rosacea. Treatment of rosacea. Brimonidine is a quinoxaline derivative, belonging to the secondary amine class and the imidazole class of compounds. It acts as an adrenergic agonist, antihypertensive, and alpha-adrenergic agonist. Brimonidine, an alpha-adrenergic agonist and 2-imidazoline derivative, was first marketed in 1996. It is considered a third-generation alpha-2 adrenergic receptor agonist because it binds to alpha-2 adrenergic receptors more strongly than alpha-1 receptors. Compared to other alpha-2 adrenergic agonists such as clonidine or apratropium bromide, brimonidine exhibits higher selectivity for alpha-2 adrenergic receptors. Alpha-2 adrenergic agonists are ocular antihypertensive drugs used for the long-term treatment of glaucoma. Glaucoma is one of the most common causes of blindness worldwide, therefore early treatment and control of glaucoma (primarily involving lowering intraocular pressure) are crucial. In ophthalmology, brimonidine lowers intraocular pressure by reducing aqueous humor production and increasing uveal-scleral outflow. Due to its good oxidative stability, brimonidine has fewer reported cases of ocular allergic reactions compared to other α2-adrenergic agonists. Brimonidine eye drops were first approved by the FDA in 1996 under the brand name Alphagan. Brimonidine is the only selective α-adrenergic receptor agonist approved for the chronic treatment of glaucoma. Brimonidine is also used in combination with brinzolamide in eye drops, brand name Simbrinza, to lower intraocular pressure. Unlike non-selective beta-blockers used to treat ocular hypertension, brimonidine does not cause significant cardiopulmonary adverse reactions. Therefore, brimonidine is an effective and safe alternative to beta-blockers for patients with or at high risk of cardiopulmonary disease. A topical formulation of brimonidine was approved by the FDA in August 2013 for the treatment of symptoms of persistent facial erythema in adults with rosacea, brand name Mirvaso. Brimonidine was the first approved topical medication for the treatment of facial erythema in rosacea. Brimonidine is an alpha-adrenergic agonist. Its mechanism of action is as an alpha-adrenergic agonist. Brimonidine is an imidazole derivative and a selective alpha-2 adrenergic receptor agonist. After ocular administration, brimonidine acts on blood vessels, causing them to constrict, thereby reducing the production of aqueous humor. Brimonidine also promotes the outflow of aqueous humor through the uvea and sclera, thereby lowering intraocular pressure. Brimonidine is only present in individuals who have used or taken the drug. It is a medication used to treat glaucoma, and its mechanism of action is by reducing aqueous humor synthesis. [Wikipedia] A topical gel formulation called Mirvaso was approved by the FDA in August 2013 for the treatment of rosacea. Brimonidine is an alpha-adrenergic receptor agonist (primarily acting on alpha-2 receptors). Its intraocular pressure-lowering effect peaks two hours after administration. Animal and human fluorophotometric studies have shown that brimonidine has a dual mechanism of action, reducing aqueous humor production while increasing uveal-scleral outflow. Brimonidine is a quinoxaline derivative and an α2-adrenergic receptor agonist used to treat elevated intraocular pressure associated with open-angle glaucoma and ocular hypertension. See also: brimonidine tartrate (in saline form). Indications: Ophthalmic use to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension, either as monotherapy or in combination with brinzolamide. Topical use for the treatment of persistent (non-transient) facial erythema associated with rosacea in adults 18 years of age and older. FDA Label Treatment of Conjunctival Congestion Mechanism of Action In the eye, α1-adrenergic receptors are involved in vasoconstriction, mydriasis, eyelid retraction, and increased intraocular pressure (IOP), while α2-adrenergic receptors lower IOP through a complex Gi-coupled signaling pathway. Activation of α2 receptors leads to inhibition of adenylate cyclase and a decrease in cyclic adenosine monophosphate (cAMP) levels. Consequently, norepinephrine (NE) release at synaptic junctions is reduced, NE-induced β2-adrenergic receptor stimulation is decreased, and aqueous humor production in the ciliary body is reduced. Elevated IOP is the most important risk factor for glaucomatous optic neuropathy, and if left untreated, it can lead to progressive visual field defects and functional impairment. Regardless of the cause, the current goal of glaucoma treatment is to lower IOP, because even when IOP is already within the normal range, lowering IOP can significantly reduce the risk of vision loss progression. Brimonidine, when administered intraocularly, is rapidly absorbed into the eye and, as an α2-adrenergic receptor agonist, lowers intraocular pressure through a dual mechanism of action. It is speculated that initial administration reduces aqueous humor production, while long-term administration increases uveal-scleral outflow. Brimonidine does not affect suprascleral venous pressure. By lowering intraocular pressure, brimonidine aims to reduce the likelihood of glaucomatous visual field defects in patients with high intraocular pressure and to slow the progression of visual field defects in patients diagnosed with open-angle glaucoma. When applied topically to the skin, brimonidine can alleviate erythema by directly constricting arterioles and venules. Because brimonidine exerts a potent peripheral vasoconstrictive effect through selective action on α2-adrenergic receptors, it is considered effective in treating facial erythema associated with rosacea. Facial erythema associated with rosacea is believed to be caused by vasomotor instability and abnormal dilation of superficial facial blood vessels. View MorePharmacodynamicsBromonidin is a highly selective α-2 adrenergic receptor agonist, with 1000 times greater selectivity for α2 adrenergic receptors than for α1 receptors. α1-Adrenergic receptors. This property gives the drug some therapeutic advantages because it reduces the risk of systemic side effects such as systemic hypotension, bradycardia, and sedation. Furthermore, it reduces the risk of α1 receptor-mediated ocular adverse reactions such as conjunctival pallor, mydriasis, and eyelid retraction. However, despite its high α2 receptor specificity, brimonidine may still produce α1 adrenergic receptor-mediated ocular responses, such as conjunctival vasoconstriction. The intraocular pressure-lowering effect of brimonidine peaks two hours after administration. In a randomized, double-blind clinical study, intraocular pressure decreased by a mean of 23% from baseline after 3 hours of ocular instillation of 0.2% brimonidine in healthy volunteers. In comparative studies in patients with open-angle glaucoma or high intraocular pressure, the intraocular pressure-lowering effect of brimonidine was maintained for up to one year of treatment. Brimonidine has vasoconstrictive effects and has shown anti-inflammatory properties in both ex vivo human skin models and in vivo inflammation models. In a clinical trial in adult patients with moderate to severe facial erythema caused by rosacea, brimonidine significantly improved erythema severity 3 hours after administration compared to placebo. Studies have shown that brimonidine is a potent vasoconstrictor of human subcutaneous blood vessels with a diameter less than 200 µm. In an in vivo mouse inflammation model, brimonidine exerts its anti-inflammatory effect by inhibiting edema. In a randomized, double-blind study, brimonidine reduced erythema in a dose-dependent manner over 12 hours. Following systemic administration, brimonidine caused cardiovascular effects, manifested as decreased blood pressure, heart rate, and respiratory rate, as well as prolonged PR interval on electrocardiogram. This is attributed to the drug's targeting of adrenergic receptors. Although its clinical significance remains unclear, there is evidence that brimonidine has neuroprotective effects in experimental models of cerebral ischemia and optic nerve injury. In vitro studies have shown that brimonidine protects neurons from fumarate damage and protects cultured retinal ganglion cells from glutamate-induced cytotoxicity, which may be a mediator of secondary neuronal degeneration in human glaucoma. The neuroprotective effects of brimonidine have also been demonstrated in rat models of acute retinal ischemia and chronic intraocular pressure elevation. Some studies suggest that brimonidine may exert its neuroprotective effects on the retina and optic nerve by enhancing the intrinsic survival mechanisms of retinal ganglion cells and/or inducing the expression of neuronal survival factors such as bFGF. However, further research is needed to confirm these potential therapeutic benefits of this drug. This study investigated the effects of α2-adrenergic receptor ligands on circling behavior in rats with unilateral nigrostriatal pathway 6-hydroxydopamine injury. The α2-adrenergic receptor agonists clonidine and UK 14304 inhibited ipsilateral circling behavior induced by the indirect dopaminergic agonist methylphenidate and contralateral circling behavior induced by the direct dopaminergic agonist apomorphine. Conversely, the α2-adrenergic receptor antagonists idazoline and (+/-)-eferaloxa enhanced circling behavior induced by methylphenidate or apomorphine. The promoting effect of eferaloxa was stereoselective, as the (+)-enantiomer mimicked the effect of (+/-)-eferaloxa, while the (-)-enantiomer was essentially inactive, indicating that the effect was mediated by α2-adrenergic receptors. When administered alone, none of the above compounds altered spontaneous circling behavior, but UK 14304 reduced ipsilateral rotation, while (+)-efroxa slightly increased ipsilateral rotation. We conclude that activation and antagonism of α2-adrenergic receptors inhibited and enhanced circling behavior induced by direct and indirect dopaminergic agonists, respectively. Although the regulation of dopamine release may be related to certain drug effects, the effect on apomorphine-induced circling behavior suggests that the effects of α2-adrenergic receptor compounds on neurotransmission in the nigrostriatal region occur at sites downstream of dopaminergic neurons. These findings support the idea that α2-adrenergic receptor antagonists may have potential benefits in the treatment of Parkinson's disease. [3] Objective: Brimonidine tartrate eye ointment is an α2-adrenergic agonist widely used as an anti-glaucoma drug to reduce intraocular pressure. Recent studies have shown that brimonidine may have a neuroprotective effect on retinal ganglion cells (RGCs) after optic nerve crush injury. Brain-derived neurotrophic factor (BDNF) is a potent neuroprotective factor present in retinal ganglion cells (RGCs) that promotes RGC survival in vitro and after optic nerve injury. We investigated the possible mechanism of brimonidine's neuroprotective effect by upregulating the expression of endogenous BDNF in retinal ganglion cells (RGCs). Methods: A single dose of brimonidine tartrate ophthalmic solution (0.85–34 μM) was injected intravitreally into the eyes of Sprague-Dawley rats. The other eye of each animal was injected with balanced salt solution (BSS) as a control. To detect BDNF mRNA expression, we either enucleated the animals' eyes and performed in situ hybridization, or dissected the retinas and performed Northern blotting analysis using a radiolabeled ribose probe containing rat BDNF. [4] Bromidine tartrate (UK 14304; AGN190342) is a highly selective α2-adrenergic receptor agonist with neuroprotective and intraocular pressure-lowering effects [1][4] Its mechanism of action includes reducing aqueous humor production (through α2-adrenergic receptors in the ciliary body epithelium) and increasing uveal-scleral outflow to lower intraocular pressure, and protecting retinal cells through antioxidant, anti-apoptotic and neurotrophic pathways [3][4][5] Clinically, it is suitable for the treatment of open-angle glaucoma and high intraocular pressure, and is also suitable for patients who are intolerant to β-adrenergic receptor antagonists [2][3] In addition to lowering intraocular pressure, it can also protect optic nerve function, so it has important value in the neuroprotection of glaucoma [4][5] |
| Molecular Formula |
C15H16BRN5O6
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|---|---|---|
| Molecular Weight |
442.22
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| Exact Mass |
441.028
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| Elemental Analysis |
C, 40.74; H, 3.65; Br, 18.07; N, 15.84; O, 21.71
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| CAS # |
70359-46-5
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| Related CAS # |
Brimonidine; 59803-98-4; Brimonidine-d4 D-tartrate; 1316758-27-6; Brimonidine-d4; 1184971-51-4
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| PubChem CID |
54405
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| Appearance |
White to off-white solid powder
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| Boiling Point |
432.6ºC at 760 mmHg
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| Melting Point |
207-208ºC (dec.)
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| Flash Point |
215.4ºC
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
27
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| Complexity |
442
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| Defined Atom Stereocenter Count |
2
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| SMILES |
BrC1C2C(C([H])=C([H])C=1N([H])C1=NC([H])([H])C([H])([H])N1[H])=NC([H])=C([H])N=2.O([H])[C@@]([H])(C(=O)O[H])[C@]([H])(C(=O)O[H])O[H]
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| InChi Key |
QZHBYNSSDLTCRG-LREBCSMRSA-N
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| InChi Code |
InChI=1S/C11H10BrN5.C4H6O6/c12-9-7(17-11-15-5-6-16-11)1-2-8-10(9)14-4-3-13-8;5-1(3(7)8)2(6)4(9)10/h1-4H,5-6H2,(H2,15,16,17);1-2,5-6H,(H,7,8)(H,9,10)/t;1-,2-/m.1/s1
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| Chemical Name |
5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine;(2R,3R)-2,3-dihydroxybutanedioic acid
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
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. |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.65 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.65 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. View More
Solubility in Formulation 3: 100 mg/mL (226.13 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C). |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2613 mL | 11.3066 mL | 22.6132 mL | |
| 5 mM | 0.4523 mL | 2.2613 mL | 4.5226 mL | |
| 10 mM | 0.2261 mL | 1.1307 mL | 2.2613 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Efficacy and Safety Study of CD07805/47 Topical Gel in Subjects With Facial Erythema Associated With Rosacea
CTID: NCT01174030
Phase: Phase 2 Status: Completed
Date: 2021-02-26
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