Preclinical Safety Profile of Brimonidine

Angelov, O.; Wiese, A G; Tang-Liu, Diane; Acheampong, Andrew; Ismail, I. M.; Brar, Balbir

doi:10.1177/112067219600600106

Cited by 11 publications

(7 citation statements)

References 8 publications

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“…Aside from exaggerated pharmacology, brimonidine was not associated with toxicity in rabbits or monkeys after chronic ocular administration . Brimonidine was reported not to be carcinogenic after oral administration to mice and rats and induced only hypertrophy of the tunica muscularis and hyperplasia of the intestine in rodents after oral administration . Brimonidine is not genotoxic and not teratogenic or a reproductive toxicant .…”

Section: Introductionmentioning

confidence: 96%

“…Brimonidine is 1000‐fold more selective to α 2A ‐adrenoceptor ( α 2 AR), as compared to the α 1 ‐adrenoceptor ( α 1 AR) and is 7–12‐fold more selective to α 2 AR than the reference compound clonidine . Pharmacological effects of brimonidine include lowering of the intraocular pressure, vasoconstriction and protection of the optic nerve from secondary damage following injuries and the drug can induce sinus bradycardia, sedation, slight hypotension and sinus arrhythmia after oral administration to monkeys . Aside from exaggerated pharmacology, brimonidine was not associated with toxicity in rabbits or monkeys after chronic ocular administration .…”

Section: Introductionmentioning

confidence: 99%

“…Pharmacological effects of brimonidine include lowering of the intraocular pressure, vasoconstriction and protection of the optic nerve from secondary damage following injuries and the drug can induce sinus bradycardia, sedation, slight hypotension and sinus arrhythmia after oral administration to monkeys . Aside from exaggerated pharmacology, brimonidine was not associated with toxicity in rabbits or monkeys after chronic ocular administration . Brimonidine was reported not to be carcinogenic after oral administration to mice and rats and induced only hypertrophy of the tunica muscularis and hyperplasia of the intestine in rodents after oral administration .…”

Section: Introductionmentioning

confidence: 99%

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Protective Effect of Dermal Brimonidine Applications Against UV Radiation‐induced Skin Tumors, Epidermal Hyperplasia and Cell Proliferation in the Skin of Hairless Mice

Bouvier

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Nonne

et al. 2015

Photochem & Photobiology

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Brimonidine at 0.18%, 1% and 2% concentrations applied topically in hairless mice significantly decreased tumor burden and incidences of erythema, flaking, wrinkling and skin thickening induced by UVR. The unbiased median week to tumor ≥1 mm was increased by the 1% and 2% concentrations. The tumor yield was reduced by all concentrations at week 40 for all tumor sizes but the ≥4 mm tumors with the 0.18% concentration. At week 52, the tumor yield was reduced for all tumor sizes and all brimonidine concentrations. The tumor incidence was reduced by all concentrations at week 40 for all tumor sizes, but the ≥4 mm tumor with the 0.18% concentration and at week 52 for all tumor sizes with the 1% and 2% concentrations and with the 0.18% concentration only for the ≥4 mm tumors. Reductions in ≥4 mm tumor incidences compared to the vehicle control group were 54%, 91% and 86% by week 52 for the 0.18%, 1% and 2% concentrations, respectively. Brimonidine at 2% applied 1 h before or just after UVB irradiation on hairless mice decreased epidermal hyperplasia by 23% and 32% and epithelial cell proliferation by 59% and 64%, respectively, similar to an epidermal growth factor receptor (EGFR) inhibitor.

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protective Effect of Dermal Brimonidine Applications Against UV Radiation‐induced Skin Tumors, Epidermal Hyperplasia and Cell Proliferation in the Skin of Hairless Mice

Bouvier

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Nonne

et al. 2015

Photochem & Photobiology

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“…Furthermore, drug binding to melanin has potential implications, such as the generation of a depot or slow-release site, which may explain the higher concentrations of drug in the vitreous humor of rabbits and monkeys following chronic dosing (Table 1). Long-term studies with 0.5 and 0.2% brimonidine have shown that chronic treatment with brimonidine is safe (Angelov et al, 1996), suggesting that there are no detrimental effects of brimonidine binding to melanin. In the ocular samples subjected to HPLC analysis (including the conjunctiva, iris, ciliary body, and aqueous humor from both monkeys and rabbits), 65 to 100% of the radioactivity represented intact brimonidine.…”

Section: Ocular Distribution Of Brimonidinementioning

confidence: 99%

Distribution of Brimonidine into Anterior and Posterior Tissues of Monkey, Rabbit, and Rat Eyes

Acheampong¹,

Shackleton²,

John³

et al. 2002

Drug Metab Dispos

111

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ABSTRACT:The objectives of the study were to evaluate the distribution of brimonidine (␣ 2 -adrenergic agonist) into anterior and posterior ocular tissues. Single or multiple doses of a 0.2 or 0.5% brimonidine tartrate solution were administered to one or both eyes of monkeys or to one eye of rabbits. Brimonidine was administered intraperitoneally to rats. After topical administration, [14 C]brimonidine was rapidly absorbed into the cornea and conjunctiva and distributed throughout the eye. [ 14 C]Radioactivity was higher and cleared more slowly in pigmented tissues (iris/ciliary body, choroid/retina, and optic nerve) than in nonpigmented tissues. Single and multiple dosing led to a similar drug distribution, with higher levels of brimonidine measured in pigmented tissues after multiple dosing. Most of the radioactivity extracted from ocular tissues represented unchanged brimonidine. In the rabbits and the monkey treated in only one eye, levels of radioactivity in the untreated eye were low, consistent with the low systemic levels and rapid drug clearance. Posterior ocular tissue concentrations of radioactivity exceeded systemic blood concentrations. The vitreous humor brimonidine concentrations in monkeys treated topically with 0.2% brimonidine tartrate was 82 ؎ 45 nM. Vitreous levels in rabbits confirmed the penetration of brimonidine to the posterior segment. Similar concentrations of brimonidine (22 to 390 nM) were measured in the vitreous and retina of rats injected intraperitoneally with brimonidine. Both topically applied and systemically administered brimonidine reach the back of the eye at nanomolar concentrations sufficient to activate ␣ 2 -adrenergic receptors. The brimonidine levels achieved at the retina are relevant for neuroprotection models.Brimonidine (AGN 190342 1 ; Fig. 1) is a highly selective ␣ 2 -adrenergic agonist approved for the treatment of open-angle glaucoma. Glaucoma represents a family of ocular diseases characterized by a progressive optic neuropathy and loss of retinal ganglion nerve cells (Adkins and Balfour, 1998). One of the primary risk factors for glaucoma is elevated intraocular pressure. When applied to the eye, brimonidine activates ␣ 2 -adrenergic receptors, resulting in decreased aqueous humor production and increased uveoscleral outflow (Toris et al., 1995). These effects on aqueous humor dynamics lead to a reduction in intraocular pressure.Laboratory studies with brimonidine suggest that activation of ␣ 2 -receptors in the retina and/or optic nerve can promote the survival of retinal ganglion nerve cells (David, 1998). Studies show that intraperitoneal and topical administration of brimonidine promoted retinal ganglion cell survival after calibrated optic nerve compression and ischemia/reperfusion in animal models of neuronal injury Yoles et al., 1999;Donello et al., 2001). Importantly, if the ocular instillation of brimonidine promotes retinal ganglion cell survival in glaucomatous neuropathy, then a new therapeutic approach to glaucoma management may be indicated in ...

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“…Extensive systemic and ocular safety assessment studies in animal models have demonstrated a large safety margin of brimonidine (Angelov et al 1996;Walters 1996).…”

Section: Introductionmentioning

confidence: 99%

Characterization of benzimidazole and other oxidative and conjugative metabolites of brimonidinein vitroand in ratsin vivousing on-line H/D exchange LC-MS/MS and stable-isotope tracer techniques

Rowe

Heidelbaugh

et al. 2007

Xenobiotica

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The characterization of brimonidine metabolites presents some challenges since brimonidine and its metabolites generate few structurally informative fragment ions in the LC-MS/MS spectra. The objective of the current study is to use on-line hydrogen/deuterium (H/D) exchange LC-MS/MS and stable-isotope tracer techniques to further characterize unknown brimonidine metabolites in vitro and in vivo. Brimonidine and D4-brimonidine were co-incubated in rat and human microsomes and rabbit aldehyde oxidase in vitro. In addition, the urine was collected from rats co-administered orally with brimonidine and D4-brimonidine. The hepatic microsomal and urinary metabolites were then characterized by H/D LC-MS/MS system. In addition to previously characterized 2-oxobrimonidine, 3-oxobrimonidine and 2,3-dioxobrimonidine, the results show that oxidation occurs at quinoxaline ring producing oxo-hydroxybrimonidine and hydroxyquinoxaline metabolites. The hydroxyquinoxaline metabolite was only observed in microsomal incubations with hydroxylation at the 7- or 8- position. The dehydro-hydroxybrimonidine metabolites were characterized as 2-oxo or 3-oxo -4', 5'-dehydrobrimonidine. A novel metabolite ((4-bromo-lH-benzoimidazol-5-yl)-imidazolidin-2-ylidene-amine) of benzimidazole derivative of brimonidine in rats in vivo was identified and confirmed with reference standard. In conclusion, on-line H/D exchange LC-MS/MS and stable-isotope tracer techniques are useful for the characterization of brimonidine metabolites.

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Preclinical Safety Profile of Brimonidine

Cited by 11 publications

References 8 publications

Protective Effect of Dermal Brimonidine Applications Against UV Radiation‐induced Skin Tumors, Epidermal Hyperplasia and Cell Proliferation in the Skin of Hairless Mice

Protective Effect of Dermal Brimonidine Applications Against UV Radiation‐induced Skin Tumors, Epidermal Hyperplasia and Cell Proliferation in the Skin of Hairless Mice

Distribution of Brimonidine into Anterior and Posterior Tissues of Monkey, Rabbit, and Rat Eyes

Characterization of benzimidazole and other oxidative and conjugative metabolites of brimonidinein vitroand in ratsin vivousing on-line H/D exchange LC-MS/MS and stable-isotope tracer techniques

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