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Douglas J Rhee - One of the best experts on this subject based on the ideXlab platform.
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Effect of hevin deletion in mice and characterization in trabecular meshwork.
Investigative Opthalmology & Visual Science, 2011Co-Authors: Min Hyung Kang, Douglas J RheeAbstract:Primary open angle glaucoma (POAG) is a major cause of blindness, and elevated intraocular pressure (IOP) is a causative factor for the development and progression of disease.1 In POAG, visual impairment occurs from loss of the visual field through the progressive loss of retinal ganglion cell axons. One of the primary mechanisms of glaucomatous damage is barotrauma at the level of the lamina cribrosa in the optic nerve, causing mechanical compression and decreased ocular perfusion.2 Lowering IOP is the proven treatment for POAG.3 The elevated IOP in POAG is caused by increased resistance to aqueous drainage.4 Aqueous humor drains through both the conventional Pathway, in which the juxtacanalicular portion of the trabecular meshwork (TM) is the anatomic location of the highest resistance to outflow, and the Uveoscleral Pathway.5 In both Pathways, the balance of extracellular matrix (ECM) deposition/turnover has been shown to influence IOP.6 The regulatory mechanisms of ECM turnover remain elusive. Transforming growth factor-beta2 (TGF-β2) is elevated in the aqueous humor of up to 50% of patients with POAG.7,8 TGF-β2 increases IOP and alters ECM in the juxtacanalicular TM.9 Proteins known to modulate ECM in other tissues may play a prominent role in ECM deposition/turnover and IOP regulation in the TM. Matricellular proteins are nonstructural, secreted glycoproteins that regulate ECM turnover in other human tissues.10 The matricellular protein family includes SPARC (secreted protein, acidic and rich in cysteine), thrombospondins 1 and 2, tenascins C and X, hevin, and osteopontin.10 SPARC, the prototypical matricellular protein, is located within the previously described GLC1M locus,11 one of the highest transcribed genes in TM, and is found throughout the TM, especially within the JCT region.10 In response to mechanical stretch, a physiologic stress to TM, SPARC is one of the most highly upregulated genes in TM cell cultures.12 Furthermore, SPARC-null mice have a 15% to 20% lower IOP and enhanced aqueous drainage than their corresponding wild-type mice.13 Hevin is an evolutionary product of a gene duplication of SPARC and shares a high degree, approximately 65%, of structural similarity with SPARC.14 Hevin is known to regulate decorin and collagen fibrillogenesis and to bind to collagen I and myocilin.15–17 Myocilin causes an accumulation of hevin, and mutated myocilin further impairs hevin secretion.16 It is unknown whether hevin is expressed in TM. We sought to investigate the effects of hevin deletion in transgenic mice, characterize the expression of hevin in human and murine TM, and assess the response of SPARC and hevin to TGF-β2. Because of the high degree of similarity to SPARC,14 we hypothesized that hevin will participate in the regulation of IOP, the transgenic deletion of hevin will result in a lower IOP compared with corresponding wild-type mice, and hevin will be expressed throughout the TM.
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Effect of bimatoprost, latanoprost, and unoprostone on matrix metalloproteinases and their inhibitors in human ciliary body smooth muscle cells
Investigative Ophthalmology and Visual Science, 2009Co-Authors: Yen Hoong Ooi, Dong-jin Oh, Douglas J RheeAbstract:PURPOSE: Matrix metalloproteinase (MMP)-mediated turnover of extracellular matrix (ECM) affects outflow resistance in the Uveoscleral Pathway. The balance of MMPs and tissue inhibitors of metalloproteinases (TIMPs) governs the rate of ECM turnover in many tissues. The hypothesis was that a differential effect on MMPs and TIMPs in ciliary body smooth muscle (CBSM) cells would relate to the relative intraocular pressure-lowering effectiveness of the prostaglandin analogues (PGAs) bimatoprost, latanoprost, and unoprostone. METHODS: Human CBSM cells isolated from donor corneoscleral rims were incubated for 24 hours with control (0.015% ethanol in DMEM) or the free acid forms of bimatoprost (0.01 or 0.1 microg/mL), latanoprost (0.03 or 0.3 microg/mL), or unoprostone (0.145 or 1.45 microg/mL). Western blot analysis determined the relative protein concentrations of MMP-1, -2, -3. -9, and -24 as well as TIMP-1 through -4. Zymography measured the relative activity levels of MMP-1, -2, -3, and -9. RESULTS: All PGAs increased MMP-1, -3, and -9. Bimatoprost and latanoprost did not change MMP-2. Unoprostone decreased MMP-2 (21% +/- 3%). On zymography, MMP-1 and -2 did not change. Bimatoprost and latanoprost increased MMP-9 activity by 75% +/- 27% and 75% +/- 24%, respectively. MMP-3 activity was not detected on zymography. All PGAs increased TIMP-3, but only unoprostone increased TIMPs1 and -4 by 100% +/- 20% and 61% +/- 11%, respectively. TIMP-2 was unchanged by bimatoprost and latanoprost, but decreased by unoprostone (35% +/- 8%). CONCLUSIONS: Decreased MMP-2 with concurrent increases of TIMP-1 and -4 by unoprostone may explain the lower clinical efficacy of unoprostone. The MMP/TIMP balance relates to the observed intraocular pressure-lowering effectiveness in clinical studies with PGAs.
Julia A. Balfour - One of the best experts on this subject based on the ideXlab platform.
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Brimonidine
Drugs & Aging, 1998Co-Authors: Julie C. Adkins, Julia A. BalfourAbstract:Synopsis Brimonidine is a highly selective α_2- adrenoceptor agonist which reduces intraocular pressure (IOP) by reducing aqueous humour production and increasing aqueous humour outflow via the Uveoscleral Pathway. Brimonidine is indicated for the topical management of open- angle glaucoma or ocular hypertension. In 3 large comparative studies in patients with open- angle glaucoma or ocular hypertension, the ocular hypotensive efficacy of brimonidine was maintained during treatment periods of up to 1 year. Mean reductions in peak (measured 2 hours after the morning dose) and trough (measured 12 hours after the evening dose) IOP were 5.6 to 5.9 and 3.3 to 3.7mm Hg, respectively, after 3 or 12 months of treatment with brimonidine 0.2% twice daily. The efficacy of brimonidine in this setting was similar to that of timolol 0.5% twice daily at peak only (−6.0mm Hg), and superior to that of betaxolol 0.25% twice daily at both peak (−3.5mm Hg) and trough (−2.7mm Hg). When added to topical β-adrenoceptor antagonist therapy, initial results showed brimonidine 0.2% twice daily to have additive ocular hypotensive efficacy similar to that of pilocarpine 2% 3 times daily. Thus, brimonidine 0.2% may be a useful adjunct in this setting. According to combined data from 2 large comparative studies, the most frequent adverse events associated with brimonidine therapy were oral dryness (30.0% of patients), ocular hyperaemia (26.3%) and ocular burning and/or stinging (24.0%). Ocular allergic reactions including allergic blepharitis, blepharoconjunctivitis and follicular conjunctivitis occurred with an incidence of 9.6% in 1 study. In a third comparative study, the incidence of adverse events associated with brimonidine therapy was lower, with conjunctival hyperaemia (11.4%) the most frequently reported event. Changes in systolic and diastolic blood pressure and, to a lesser extent, heart rate have been reported in patients treated with therapeutic doses of topical brimonidine for up to 12 months, but these changes were not clinically significant. Unlike β-adrenoceptor antagonists, brimonidine is not contraindicated in patients with cardiopulmonary disease, although it should be used with caution in individuals with severe cardiovascular disease. Thus, further studies are warranted to determine the efficacy of brimonidine when used in combination with other glaucoma medications and its efficacy relative to newer drugs such as dorzolamide and latanoprost. However, available data suggest that brimonidine is a promising alternative option for the lowering of IOP in the management of open- angle glaucoma and ocular hypertension, particularly in patients with cardiopulmonary disease in whom topical β -adrenoceptor antagonist therapy is contraindicated. Pharmacodynamic Properties Brimonidine is a highly selective α_2-adrenoceptor agonist which has markedly greater affinity for α_2-adrenoceptors than apraclonidine (23- to 32-fold) and clonidine (6- to 12-fold). Brimonidine lowers intraocular pressure (IOP) by a dual mechanism of action, involving a reduction in aqueous humour production and an increase in aqueous humour outflow via the Uveoscleral Pathway. In patients with ocular hypertension, unilateral treatment with brimonidine 0.2% twice daily for 1 week significantly reduced aqueous humour flow (20%) and increased Uveoscleral outflow (approximately 5-fold) in the treated eye. Aqueous humour flow was also reduced by 12% in the contralateral eye. Brimonidine lowers IOP in animals and humans with normotensive or hypertensive eyes. In humans, single ocular doses of brimonidine 0.08, 0.2 and 0.5% reduced IOP for up to 12 hours, with a peak hypotensive effect occurring at 2 hours. Initial pharmacodynamic studies also suggest that, as with other α_2-adrenoceptor agonists, the drug may have a neuroprotective effect; however, further research is required to confirm this. Although topical brimonidine (50 to 500μg) produced miosis in some animal studies, clinically significant changes in pupil size did not occur in humans. Data from animal and human studies suggest that brimonidine does not significantly alter ocular blood flow. Changes in systolic and diastolic blood pressure and, to a lesser extent, heart rate have been reported in patients and healthy volunteers treated with therapeutic doses of topical brimonidine; however, these changes were not associated with adverse clinical effects. In 3 large comparative studies, brimonidine 0.2% twice daily for up to 12 months had a minimal effect on systolic (mean change −3.52 to +0.64mm Hg) and diastolic blood pressure (−1.7 to +1.04mm Hg) and heart rate (−0.1 to −3.1 beats/min). Pharmacokinetic Properties Studies in rabbits suggest that the intraocular absorption of brimonidine occurs primarily via the cornea and, to a lesser extent, via the conjunctival and scierai Pathways. In this species, the ocular absorption and retention of brimonidine are increased by drug binding to ocular melanin. Peak drug concentration and terminal elimination half-life values in the iris-ciliary body were, respectively, approximately 4- and 580-fold greater in pigmented than albino rabbits’ eyes after a single dose of brimonidine 0.5% (20.1 vs 5.0 mg/L and 580 vs 1 hours). In common with other drugs applied topically to the eye, brimonidine can enter the systemic circulation; peak plasma concentrations were
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Brimonidine. A review of its pharmacological properties and clinical potential in the management of open-angle glaucoma and ocular hypertension.
Drugs & Aging, 1998Co-Authors: Julie C. Adkins, Julia A. BalfourAbstract:Brimonidine is a highly selective alpha 2-adrenoceptor agonist which reduces intraocular pressure (IOP) by reducing aqueous humour production and increasing aqueous humour outflow via the Uveoscleral Pathway. Brimonidine is indicated for the topical management of open-angle glaucoma or ocular hypertension. In 3 large comparative studies in patients with open-angle glaucoma or ocular hypertension, the ocular hypotensive efficacy of brimonidine was maintained during treatment periods of up to 1 year. Mean reductions in peak (measured 2 hours after the morning dose) and trough (measured 12 hours after the evening dose) IOP were 5.6 to 5.9 and 3.3 to 3.7 mm Hg, respectively, after 3 or 12 months of treatment with brimonidine 0.2% twice daily. The efficacy of brimonidine in this setting was similar to that of timolol 0.5% twice daily at peak only (-6.0mm Hg), and superior to that of betaxolol 0.25% twice daily at both peak (-3.5mm Hg) and trough (-2.7mm Hg). When added to topical beta-adrenoceptor antagonist therapy, initial results showed brimonidine 0.2% twice daily to have additive ocular hypotensive efficacy similar to that of pilocarpine 2% 3 times daily. Thus, brimonidine 0.2% may be a useful adjunct in this setting. According to combined data from 2 large comparative studies, the most frequent adverse events associated with brimonidine therapy were oral dryness (30.0% of patients), ocular hyperaemia (26.3%) and ocular burning and/or stinging (24.0%). Ocular allergic reactions including allergic blepharitis, blepharoconjunctivitis and follicular conjunctivitis occurred with an incidence of 9.6% in 1 study. In a third comparative study, the incidence of adverse events associated with brimonidine therapy was lower, with conjunctival hyperaemia (11.4%) the most frequently reported event. Changes in systolic and diastolic blood pressure and, to a lesser extent, heart rate have been reported in patients treated with therapeutic doses of topical brimonidine for up to 12 months, but these changes were not clinically significant. Unlike beta-adrenoceptor antagonists, brimonidine is not contraindicated in patients with cardiopulmonary disease, although it should be used with caution in individuals with severe cardiovascular disease. Thus, further studies are warranted to determine the efficacy of brimonidine when used in combination with other glaucoma medications and its efficacy relative to newer drugs such as dorzolamide and latanoprost. However, available data suggest that brimonidine is a promising alternative option for the lowering of IOP in the management of open-angle glaucoma and ocular hypertension, particularly in patients with cardiopulmonary disease in whom topical beta-adrenoceptor antagonist therapy is contraindicated.
Sheridan M. Hoy - One of the best experts on this subject based on the ideXlab platform.
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Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review in Open-Angle Glaucoma and Ocular Hypertension
Drugs, 2018Co-Authors: Sheridan M. HoyAbstract:Latanoprostene bunod ophthalmic solution 0.024% (hereafter referred to as latanoprostene bunod 0.024%) [Vyzulta™] is a nitric oxide (NO)-donating prostaglandin F_2α analogue approved in the USA for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) or ocular hypertension. It is thought to lower IOP by increasing aqueous humour outflow through the Uveoscleral Pathway (mediated by latanoprost acid) and increasing the facility of aqueous humour outflow through the trabecular meshwork Pathway (mediated by NO). Results from two multinational, phase III studies (APOLLO and LUNAR) and a pooled analysis of these studies demonstrated the noninferiority of latanoprostene bunod 0.024% to timolol ophthalmic solution 0.5% (hereafter referred to as timolol 0.5%) in terms of IOP-lowering efficacy over 3 months in patients with OAG or ocular hypertension, with the superiority of latanoprostene bunod 0.024% over timolol 0.5% subsequently demonstrated in APOLLO and the pooled analysis. Moreover, there was no apparent loss of IOP-lowering effect in subsequent safety extension periods of up to 9 months. The IOP-lowering efficacy seen in APOLLO and LUNAR was confirmed in a phase III study (JUPITER) in Japanese patients, with IOP reductions observed early (week 4) and maintained over the longer-term (12 months). Latanoprostene bunod 0.024% was well tolerated over up to 12 months in these studies, with most ocular treatment-emergent adverse events (TEAEs) being mild to moderate in severity. Thus, current evidence indicates once-daily latanoprostene bunod 0.024% is an effective and well tolerated treatment option for the reduction of IOP in adults with OAG or ocular hypertension.
Naixue Sun - One of the best experts on this subject based on the ideXlab platform.
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Different effects of topical prazosin and pilocarpine on Uveoscleral outflow in rabbit eyes.
Yan ke xue bao = Eye science, 2003Co-Authors: Jianming Wang, Yan-ping Song, Baichao Ren, Naixue SunAbstract:PURPOSE To investigate the effects of topical prazosin and pilocarpine on Uveoscleral outflow (Fu) in rabbits. METHODS Sixteen rabbits were randomly divided into the control group (5 rabbits, only topical application of normal salino in the right eye of each rabbit), Prazosin (PZ) treated group (6 rabbits, only 0.1% Prazosin eyedrop 0.1% in the right eye of each one) and Pilocarpine (PC) treated group (5 rabbits, 1% Pilocarpine eye drop in each right eye). Intraocular pressure (IOP) of bilateral eyes of each rabbit was measured before and 1 h after topical application of the eye drop. And the bilateral eyes were perfused with Fluorescein-isothiocyanate bovine serum albumin (FITC-BSA) as the tracer into the anterior chamber of each rabbit for 30 min at 90 min after topical treatment. Then the rabbits were killed for Fu measurement. RESULTS IOP of PZ-treated eyes decreased [(0.71 +/- 0.07)kPa] in 1 hour after PZ application. IOP of PC-treated eyes decreased [(0.70 +/- 0.08)kPa] in 1 hour after PC application. The average value of Fu was (0.176 +/- 0.048) microliter/min in control eyes. The average value of Fu in PZ-treated eyes was (0.339 +/- 0.018) microliter/min. The average value of Fu in PC-treated eye was (0.123 +/- 0.022) microliter/min. CONCLUSION Both of PZ and PC can decrease IOP in rabbits following topical application. Topical PZ can increase Fu in rabbits and this is one of the mechanisms of PZ-induced IOP decrease. Topical PC can prevent Fu. PC decreases IOP not through Uveoscleral Pathway. This study demonstrates that Uveoscleral Pathway plays an important role in aqueous humor drainage. PZ may be a novel drug for decreasing IOP. FITC-BSA is an effective tracer for studying Uveoscleral Pathway.
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Morphological study of Uveoscleral Pathway following topical Prazosin in free-sympathetic rabbit eyes
2001Co-Authors: Naixue SunAbstract:ObjectiveTo observe the morphology of the Uveoscleral Pathway following topical Prazosin（PZ） in rabbit free-sympathetic eyes．MethodsThe one lateral superior cervical ganglionectomy（SCG） were preformed on each rabbit．PZ drops were installed only on the SCG eyes on 14 days Postoperationly．Microamounts of fluorescein isothiocyanate-bovine serum albumin（FITC-BSA） was infused into anterior chamber of rabbit eyes as the teacer，two rabbits in each group were killed at 2，4，6，8，10，and 12h after PZ instillation．Degress of fluorescent intensity of ciliary body，suprachoroidal space，anterior and posterior sclera，and choroid were observed under fluorescence microscopy．ResultsThe IOP of the SCG eyes was lower after installation of PZ．But the reduced extent is below that of normal rabbit eyes；After installation of PZ，the fluorescent intensity of the ciliary body，suprachoroidal space，anterior and posterior sclera，and choroid was less stronger than the control eyes，but fader than at the same area of the normal eyes obviously．ConclusionThe outflow effects of PZ drops on increasing Uveoscleral Pathway were obviously decreased in the SCG eyes．It depends on the activity of sympathetic nerve system partially．Besides，there are other mechanisms． Key words: Prazosin; Hydrochloride; Uveoscleral; outflow; free-sympathetic; rabbit; eye; intraocular; pressure
Yen Hoong Ooi - One of the best experts on this subject based on the ideXlab platform.
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Effect of bimatoprost, latanoprost, and unoprostone on matrix metalloproteinases and their inhibitors in human ciliary body smooth muscle cells
Investigative Ophthalmology and Visual Science, 2009Co-Authors: Yen Hoong Ooi, Dong-jin Oh, Douglas J RheeAbstract:PURPOSE: Matrix metalloproteinase (MMP)-mediated turnover of extracellular matrix (ECM) affects outflow resistance in the Uveoscleral Pathway. The balance of MMPs and tissue inhibitors of metalloproteinases (TIMPs) governs the rate of ECM turnover in many tissues. The hypothesis was that a differential effect on MMPs and TIMPs in ciliary body smooth muscle (CBSM) cells would relate to the relative intraocular pressure-lowering effectiveness of the prostaglandin analogues (PGAs) bimatoprost, latanoprost, and unoprostone. METHODS: Human CBSM cells isolated from donor corneoscleral rims were incubated for 24 hours with control (0.015% ethanol in DMEM) or the free acid forms of bimatoprost (0.01 or 0.1 microg/mL), latanoprost (0.03 or 0.3 microg/mL), or unoprostone (0.145 or 1.45 microg/mL). Western blot analysis determined the relative protein concentrations of MMP-1, -2, -3. -9, and -24 as well as TIMP-1 through -4. Zymography measured the relative activity levels of MMP-1, -2, -3, and -9. RESULTS: All PGAs increased MMP-1, -3, and -9. Bimatoprost and latanoprost did not change MMP-2. Unoprostone decreased MMP-2 (21% +/- 3%). On zymography, MMP-1 and -2 did not change. Bimatoprost and latanoprost increased MMP-9 activity by 75% +/- 27% and 75% +/- 24%, respectively. MMP-3 activity was not detected on zymography. All PGAs increased TIMP-3, but only unoprostone increased TIMPs1 and -4 by 100% +/- 20% and 61% +/- 11%, respectively. TIMP-2 was unchanged by bimatoprost and latanoprost, but decreased by unoprostone (35% +/- 8%). CONCLUSIONS: Decreased MMP-2 with concurrent increases of TIMP-1 and -4 by unoprostone may explain the lower clinical efficacy of unoprostone. The MMP/TIMP balance relates to the observed intraocular pressure-lowering effectiveness in clinical studies with PGAs.
