Aims: To compare the safety and efficacy of unoprostone, brimonidine, and dorzolamide as adjuncti... more Aims: To compare the safety and efficacy of unoprostone, brimonidine, and dorzolamide as adjunctive therapy to timolol in patients with primary open angle glaucoma or ocular hypertension. Methods: This was a randomised, double masked, parallel group, multicentre (14) study. After using timolol maleate 0.5% monotherapy twice a day for 2 weeks, patients (n = 146) with an early morning intraocular pressure (IOP) between 22 and 28 mm Hg, inclusively, received unoprostone isopropyl 0.15% (n = 50), brimonidine tartrate 0.2% (n = 48), or dorzolamide hydrochloride 2.0% (n = 48) twice daily as adjunctive therapy to timolol maleate 0.5% for another 12 weeks. Safety was based on comprehensive ophthalmic examinations, adverse events, and vital signs. Efficacy was based on mean change from baseline in the 8 hour diurnal IOP at week 12. Baseline was defined as values obtained after 2 weeks of timolol monotherapy. Results: Each drug was safe and well tolerated. Burning/stinging was the most common treatment emergent adverse event. No clinically relevant changes from baseline were observed for any ophthalmic examination or vital signs. At week 12, each adjunctive therapy produced statistically significant (p<0.001) reductions from timolol treated baseline in the mean 8 hour diurnal IOP (−2.7 mm Hg, unoprostone; −2.8 mm Hg, brimonidine; −3.1 mm Hg, dorzolamide). The extent of IOP reduction did not differ significantly between unoprostone and either brimonidine (p = 0.154) or dorzolamide (p = 0.101). Conclusion: Unoprostone was safe and well tolerated and provided a clinically and statistically significant additional reduction in IOP when added to stable monotherapy with timolol. Furthermore, unoprostone was not significantly different from brimonidine and dorzolamide as adjunctive therapy to timolol.
Background: Ketotifen fumarate blocks histamine 1 (H 1) receptors, stabilizes mast cells, and act... more Background: Ketotifen fumarate blocks histamine 1 (H 1) receptors, stabilizes mast cells, and acts as an eosinophil inhibitor (decreases chemotaxis and activation of eosinophils). Objective: To assess the efficacy of ketotifen 0.025% ophthalmic solution in the prevention of symptoms of allergic conjunctivitis, using the conjunctival allergen challenge model. Methods: This was a single-center, double-masked, randomized, placebo-controlled, contralateral-eye comparison, allergen challenge trial conducted in the United States. Subjects were randomized to receive ketotifen 0.025% in one eye and placebo in the other. At visits 1 and 2, allergen challenges were performed to determine the allergen concentration eliciting a qualifying reaction for each subject. At the 3 subsequent visits, subjects received 1 drop of ketotifen 0.025% ophthalmic solution in one eye and vehicle solution as placebo in the other eye 15 minutes (visit 3), 6 hours (visit 4), and 8 hours (visit 5) before allergen challenge. The primary efficacy measure was the subject's rating of itching at 3, 7, and 10 minutes after challenge. Results: Of the 89 subjects randomly assigned to masked trial medication at visit 3, 72 completed the study. At visits 3, 4, and 5, mean itching scores were significantly better for ketotifen-treated eyes at all postchallenge time points, compared with placebo (PϽ.001). Also at visits 3, 4, and 5, ketotifen was statistically superior to placebo in reducing ocular hyperemia at all postchallenge time points (PϽ.05). Conclusions: Ketotifen was safe and statistically effective in reducing ocular itching and hyperemia associated with allergic conjunctivitis. Ketotifen's rapid onset of action (within 15 minutes) and extended duration of action (at least 8 hours) make it a valuable treatment for allergic conjunctivitis.
Ketotifen fumarate, formulated for the treatment of allergic conjunctivitis, is a histamine H1-re... more Ketotifen fumarate, formulated for the treatment of allergic conjunctivitis, is a histamine H1-receptor antagonist, mast cell stabilizer, and eosinophil inhibitor (decreases chemotaxis and activation of eosinophils). In this study, healthy volunteers 3 years of age or older received ketotifen fumarate .025% ophthalmic solution (n = 330) or placebo (n = 165) four times daily for 6 weeks. Ketotifen was safe and well tolerated in the adult and pediatric populations, with an incidence of ocular adverse events of 18.2%, compared with 15.2% with placebo. No ocular rebound vasodilation or itching was observed within 48 hours after treatment. Ketotifen has a favorable safety and tolerability profile, which may have a positive impact on compliance, an important aspect of effective symptomatic control of allergic conjunctivitis.
To evaluate the efficacy and safety of intravitreal sirolimus in the treatment of noninfectious u... more To evaluate the efficacy and safety of intravitreal sirolimus in the treatment of noninfectious uveitis (NIU) of the posterior segment (i.e., posterior, intermediate, or panuveitis). Phase III, randomized, double-masked, active-controlled, 6-month study with intravitreal sirolimus. Adults with active NIU of the posterior segment (intermediate, posterior, or panuveitis), defined as a vitreous haze (VH) score >1+. Subjects discontinued NIU medications before baseline, except for systemic corticosteroids, which were allowed only for those already receiving them at baseline and were rapidly tapered after baseline per protocol. Intravitreal sirolimus assigned 1:1:1 at doses of 44 (active control), 440, or 880 μg, administered on Days 1, 60, and 120. The primary efficacy outcome was the percentage of subjects with VH 0 response at Month 5 (study eye) without use of rescue therapy. Secondary outcomes at Month 5 were VH 0 or 0.5+ response rate, corticosteroid tapering success rate (i.e.,...
AND THE UNOPROSTONE MONOTHERAPY STUDY GROUP-EU • PURPOSE: A long-term comparison of the ocular hy... more AND THE UNOPROSTONE MONOTHERAPY STUDY GROUP-EU • PURPOSE: A long-term comparison of the ocular hypotensive efficacy and safety of unoprostone isopropyl 0.15% twice daily with that of timolol maleate 0.5% twice daily and betaxolol HCl 0.5% twice daily. • DESIGN: This was a randomized, multicenter, doublemasked, active-controlled 24-month clinical trial involving 27 centers in Europe and Israel. • METHODS: The study population was composed of patients with primary open-angle glaucoma (including pseudoexfoliation) or ocular hypertension. After washout of antiglaucoma medications, intraocular pressure (IOP) was measured at 0, ؉ 2, ؉ 8, and ؉ 12 hours. Patients were randomized in a 2:1:1 ratio to unoprostone, timolol, or betaxolol. Patients returned for examinations at 2 and 6 weeks and 3 and 6 months. • RESULTS: 556 patients were randomized. Each drug produced a clinically and statistically (P < .001) significant reduction from baseline in 12-hour diurnal IOP at month 6 (؊ 4.3 mm Hg, unoprostone; ؊ 5.8 mm Hg, timolol; ؊ 4.9 mm Hg, betaxolol). Differences in adjusted treatment means between unoprostone and timolol and unoprostone and betaxolol were 1.57 mm Hg (95% CI: 1.00, 2.13) and 0.53 mm Hg (95% CI: ؊ 0.03, 1.09), respectively. Unoprostone was clinically equivalent to betaxolol but did not have as great an IOPlowering effect as timolol. Discontinued for inadequate control of IOP were 7%, 1%, and 4% of the patients for unoprostone, timolol, and betaxolol, respectively. There were no changes of note in visual acuity, pupil size, cup-to-disk ratio, visual fields, or iris color. Changes in heart rate and blood pressure were small, with no clinically significant differences between groups. • CONCLUSIONS: Unoprostone provided a clinically significant IOP-lowering effect equivalent to betaxolol but not to timolol. The side effect profile of unoprostone appears to be comparable to other established IOPlowering agents.
To examine the effect of Pseudomonas aeruginosa on the expression of corneal matrix metalloprotea... more To examine the effect of Pseudomonas aeruginosa on the expression of corneal matrix metalloproteases and the effect of its proteases on activation of corneal matrix metalloproteases in vitro. Rat corneas and human corneal fibroblasts were co-cultivated with two different strains (RPS & 599A) of P. aeruginosa and one strain of Staphylococcus aureus, and the conditioned media were analyzed for proteolytic activity by gelatin and casein zymography. Human corneal fibroblast-conditioned medium was incubated with that from either strain of P. aeruginosa and was analyzed in a similar manner. Normal rat corneas in organ culture produce a 65 kDa gelatinase (inactive matrix metalloprotease-2), whereas thermally injured rat corneas additionally produce gelatinases with molecular masses of 92 kDa (inactive matrix metalloproteases-9) and > 200 kDa. Matrix metalloprotease-2 is also detected in human corneal fibroblast-conditioned medium. Although these matrix metalloproteases are no longer det...
To understand the underlying mechanisms responsible for the easy removal and sloughing of corneal... more To understand the underlying mechanisms responsible for the easy removal and sloughing of corneal epithelium in vitamin A deficiency. An animal model of vitamin A deficiency, the vitamin A-deficient rat (A-rat), transmission electron microscopy, computer-assisted morphometric analysis and indirect immunofluorescence were used to study the adhesion of rat corneal epithelium to its basement membrane with emphasis on structure and molecular composition of the anchoring structures such as the hemidesmosome and bullous pemphigoid antigen. Transmission electron microscopy resolved numerous microseparations of the basal epithelial cell membrane from the basement membrane with intervening segmental basement membrane duplications and electron dense deposits. Morphometric analysis disclosed a statistically significant reduction in the frequency and size of hemidesmosomes. Four weeks after supplementing the diet with retinyl acetate (700 micrograms/week), significant reversal of these same str...
This study assesses the impact of various forms of injury on matrix degrading enzymes in nutritio... more This study assesses the impact of various forms of injury on matrix degrading enzymes in nutritionally compromised rat corneas. In vitamin A-deficient (nutritionally compromised) and normal control corneas, in vivo or ex vivo mild mechanical abrasion did not appreciably alter the activity of either the 65-kDa or the 92-kDa gelatinases. In contrast, after thermal injury, while no appreciable change was detected in activity associated with the 65-kDa gelatinase in either vitamin A-deficient or normal control corneas, 92-kDa gelatinolytic activity was consistently higher in corneas from both groups, although activity associated with nutritionally compromised corneas was much higher. In these corneas, thermal injury also induced the expression of two high molecular weight (approximately 130-kDa and 225-kDa) gelatinases and a 27-kDa caseinase. While gelatinases were totally inactivated by inhibitors of metalloproteinases such as 1,10-phenanthroline and Galardin MPI, the 27-kDa caseinase showed considerable susceptibility to a mixture of serine protease inhibitors (aprotinin, dichloro-isocoumarin and pA-PMSF [(4-amidino-phenyl)-methane-sulphonyl fluoride]. Furthermore, unactivated-lymphoreticular cells from either nutritionally compromised or normal control animals contained a 24- and 27-kDa caseinase, however most of the activity was due to the 24-kDa caseinase. In contrast, glycogen-activated lymphoreticular cells contained a preponderance of the 27-kDa caseinase. Activated-lymphoreticular cells also expressed 92-kDa, 130-kDa and 225-kDa gelatinases. The presence of low molecular weight caseinases in lymphoreticular cells implicates them as the source of these enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)
Purified Pseudomonas aeruginosa elastase cleaved a 65 kDa gelatinase [inactive proenzyme form of ... more Purified Pseudomonas aeruginosa elastase cleaved a 65 kDa gelatinase [inactive proenzyme form of matrix metalloproteinase (MMP-2)] from human corneal fibroblasts into a biologically active fragment with an approximate molecular mass of 58 kDa. However, purified pseudomonal alkaline protease did not cleave MMP-2 appreciably. Since activated MMP-2 is known to degrade native type IV, V and VII collagens, all components of the corneal basement membrane or stroma, our results suggest a new role for pseudomonal elastase in the pathogenesis of corneal infection, inflammation and ulceration.
Injury to a vitamin A-deficient cornea leads to severe acute inflammation often culminating in ul... more Injury to a vitamin A-deficient cornea leads to severe acute inflammation often culminating in ulceration. We report on possible regulatory mechanisms involved in the pathogenesis of corneal inflammation in vitamin A deficiency. Thymocyte comitogenic assay and interleukin (IL)-6 induction in corneal fibroblasts have shown that thermally injured and mechanically abraded vitamin A-deficient rat corneas produce much higher levels of an IL-1-like factor as compared with uninjured or injured, normal control corneas. This was confirmed by antibody capture enzyme immunoassay, which detected high levels of IL-1 alpha and IL-1 beta in injured vitamin A-deficient corneas. To our knowledge this is the first report describing the induction of IL-1 in the vitamin A-deficient cornea by thermal and mechanical injuries. When mechanically injured corneas were screened for chemotactic activity, they were found to contain significantly higher levels of a chemoattractant as compared with similarly injured, normal control corneas. Chemotactic activity [expressed as a percentage of a known chemotactic tripeptide, formyl-methionyl-leucyl-phenylalanine (fMLP), found in medium harvested from vitamin A-deficient corneas] averaged 58.8 +/- 8.9% (SEM) as compared with 12.6 +/- 5.4% in medium conditioned by normal corneas. Checkerboard analysis confirmed that the activity in vitamin A-deficient cornea conditioned medium was chemotactic and not chemokinetic. These results demonstrate a correlation between IL-1 levels and severity of inflammation in the injured vitamin A-deficient rat cornea.
Aims: To compare the safety and efficacy of unoprostone, brimonidine, and dorzolamide as adjuncti... more Aims: To compare the safety and efficacy of unoprostone, brimonidine, and dorzolamide as adjunctive therapy to timolol in patients with primary open angle glaucoma or ocular hypertension. Methods: This was a randomised, double masked, parallel group, multicentre (14) study. After using timolol maleate 0.5% monotherapy twice a day for 2 weeks, patients (n = 146) with an early morning intraocular pressure (IOP) between 22 and 28 mm Hg, inclusively, received unoprostone isopropyl 0.15% (n = 50), brimonidine tartrate 0.2% (n = 48), or dorzolamide hydrochloride 2.0% (n = 48) twice daily as adjunctive therapy to timolol maleate 0.5% for another 12 weeks. Safety was based on comprehensive ophthalmic examinations, adverse events, and vital signs. Efficacy was based on mean change from baseline in the 8 hour diurnal IOP at week 12. Baseline was defined as values obtained after 2 weeks of timolol monotherapy. Results: Each drug was safe and well tolerated. Burning/stinging was the most common treatment emergent adverse event. No clinically relevant changes from baseline were observed for any ophthalmic examination or vital signs. At week 12, each adjunctive therapy produced statistically significant (p<0.001) reductions from timolol treated baseline in the mean 8 hour diurnal IOP (−2.7 mm Hg, unoprostone; −2.8 mm Hg, brimonidine; −3.1 mm Hg, dorzolamide). The extent of IOP reduction did not differ significantly between unoprostone and either brimonidine (p = 0.154) or dorzolamide (p = 0.101). Conclusion: Unoprostone was safe and well tolerated and provided a clinically and statistically significant additional reduction in IOP when added to stable monotherapy with timolol. Furthermore, unoprostone was not significantly different from brimonidine and dorzolamide as adjunctive therapy to timolol.
Background: Ketotifen fumarate blocks histamine 1 (H 1) receptors, stabilizes mast cells, and act... more Background: Ketotifen fumarate blocks histamine 1 (H 1) receptors, stabilizes mast cells, and acts as an eosinophil inhibitor (decreases chemotaxis and activation of eosinophils). Objective: To assess the efficacy of ketotifen 0.025% ophthalmic solution in the prevention of symptoms of allergic conjunctivitis, using the conjunctival allergen challenge model. Methods: This was a single-center, double-masked, randomized, placebo-controlled, contralateral-eye comparison, allergen challenge trial conducted in the United States. Subjects were randomized to receive ketotifen 0.025% in one eye and placebo in the other. At visits 1 and 2, allergen challenges were performed to determine the allergen concentration eliciting a qualifying reaction for each subject. At the 3 subsequent visits, subjects received 1 drop of ketotifen 0.025% ophthalmic solution in one eye and vehicle solution as placebo in the other eye 15 minutes (visit 3), 6 hours (visit 4), and 8 hours (visit 5) before allergen challenge. The primary efficacy measure was the subject's rating of itching at 3, 7, and 10 minutes after challenge. Results: Of the 89 subjects randomly assigned to masked trial medication at visit 3, 72 completed the study. At visits 3, 4, and 5, mean itching scores were significantly better for ketotifen-treated eyes at all postchallenge time points, compared with placebo (PϽ.001). Also at visits 3, 4, and 5, ketotifen was statistically superior to placebo in reducing ocular hyperemia at all postchallenge time points (PϽ.05). Conclusions: Ketotifen was safe and statistically effective in reducing ocular itching and hyperemia associated with allergic conjunctivitis. Ketotifen's rapid onset of action (within 15 minutes) and extended duration of action (at least 8 hours) make it a valuable treatment for allergic conjunctivitis.
Ketotifen fumarate, formulated for the treatment of allergic conjunctivitis, is a histamine H1-re... more Ketotifen fumarate, formulated for the treatment of allergic conjunctivitis, is a histamine H1-receptor antagonist, mast cell stabilizer, and eosinophil inhibitor (decreases chemotaxis and activation of eosinophils). In this study, healthy volunteers 3 years of age or older received ketotifen fumarate .025% ophthalmic solution (n = 330) or placebo (n = 165) four times daily for 6 weeks. Ketotifen was safe and well tolerated in the adult and pediatric populations, with an incidence of ocular adverse events of 18.2%, compared with 15.2% with placebo. No ocular rebound vasodilation or itching was observed within 48 hours after treatment. Ketotifen has a favorable safety and tolerability profile, which may have a positive impact on compliance, an important aspect of effective symptomatic control of allergic conjunctivitis.
To evaluate the efficacy and safety of intravitreal sirolimus in the treatment of noninfectious u... more To evaluate the efficacy and safety of intravitreal sirolimus in the treatment of noninfectious uveitis (NIU) of the posterior segment (i.e., posterior, intermediate, or panuveitis). Phase III, randomized, double-masked, active-controlled, 6-month study with intravitreal sirolimus. Adults with active NIU of the posterior segment (intermediate, posterior, or panuveitis), defined as a vitreous haze (VH) score >1+. Subjects discontinued NIU medications before baseline, except for systemic corticosteroids, which were allowed only for those already receiving them at baseline and were rapidly tapered after baseline per protocol. Intravitreal sirolimus assigned 1:1:1 at doses of 44 (active control), 440, or 880 μg, administered on Days 1, 60, and 120. The primary efficacy outcome was the percentage of subjects with VH 0 response at Month 5 (study eye) without use of rescue therapy. Secondary outcomes at Month 5 were VH 0 or 0.5+ response rate, corticosteroid tapering success rate (i.e.,...
AND THE UNOPROSTONE MONOTHERAPY STUDY GROUP-EU • PURPOSE: A long-term comparison of the ocular hy... more AND THE UNOPROSTONE MONOTHERAPY STUDY GROUP-EU • PURPOSE: A long-term comparison of the ocular hypotensive efficacy and safety of unoprostone isopropyl 0.15% twice daily with that of timolol maleate 0.5% twice daily and betaxolol HCl 0.5% twice daily. • DESIGN: This was a randomized, multicenter, doublemasked, active-controlled 24-month clinical trial involving 27 centers in Europe and Israel. • METHODS: The study population was composed of patients with primary open-angle glaucoma (including pseudoexfoliation) or ocular hypertension. After washout of antiglaucoma medications, intraocular pressure (IOP) was measured at 0, ؉ 2, ؉ 8, and ؉ 12 hours. Patients were randomized in a 2:1:1 ratio to unoprostone, timolol, or betaxolol. Patients returned for examinations at 2 and 6 weeks and 3 and 6 months. • RESULTS: 556 patients were randomized. Each drug produced a clinically and statistically (P < .001) significant reduction from baseline in 12-hour diurnal IOP at month 6 (؊ 4.3 mm Hg, unoprostone; ؊ 5.8 mm Hg, timolol; ؊ 4.9 mm Hg, betaxolol). Differences in adjusted treatment means between unoprostone and timolol and unoprostone and betaxolol were 1.57 mm Hg (95% CI: 1.00, 2.13) and 0.53 mm Hg (95% CI: ؊ 0.03, 1.09), respectively. Unoprostone was clinically equivalent to betaxolol but did not have as great an IOPlowering effect as timolol. Discontinued for inadequate control of IOP were 7%, 1%, and 4% of the patients for unoprostone, timolol, and betaxolol, respectively. There were no changes of note in visual acuity, pupil size, cup-to-disk ratio, visual fields, or iris color. Changes in heart rate and blood pressure were small, with no clinically significant differences between groups. • CONCLUSIONS: Unoprostone provided a clinically significant IOP-lowering effect equivalent to betaxolol but not to timolol. The side effect profile of unoprostone appears to be comparable to other established IOPlowering agents.
To examine the effect of Pseudomonas aeruginosa on the expression of corneal matrix metalloprotea... more To examine the effect of Pseudomonas aeruginosa on the expression of corneal matrix metalloproteases and the effect of its proteases on activation of corneal matrix metalloproteases in vitro. Rat corneas and human corneal fibroblasts were co-cultivated with two different strains (RPS & 599A) of P. aeruginosa and one strain of Staphylococcus aureus, and the conditioned media were analyzed for proteolytic activity by gelatin and casein zymography. Human corneal fibroblast-conditioned medium was incubated with that from either strain of P. aeruginosa and was analyzed in a similar manner. Normal rat corneas in organ culture produce a 65 kDa gelatinase (inactive matrix metalloprotease-2), whereas thermally injured rat corneas additionally produce gelatinases with molecular masses of 92 kDa (inactive matrix metalloproteases-9) and > 200 kDa. Matrix metalloprotease-2 is also detected in human corneal fibroblast-conditioned medium. Although these matrix metalloproteases are no longer det...
To understand the underlying mechanisms responsible for the easy removal and sloughing of corneal... more To understand the underlying mechanisms responsible for the easy removal and sloughing of corneal epithelium in vitamin A deficiency. An animal model of vitamin A deficiency, the vitamin A-deficient rat (A-rat), transmission electron microscopy, computer-assisted morphometric analysis and indirect immunofluorescence were used to study the adhesion of rat corneal epithelium to its basement membrane with emphasis on structure and molecular composition of the anchoring structures such as the hemidesmosome and bullous pemphigoid antigen. Transmission electron microscopy resolved numerous microseparations of the basal epithelial cell membrane from the basement membrane with intervening segmental basement membrane duplications and electron dense deposits. Morphometric analysis disclosed a statistically significant reduction in the frequency and size of hemidesmosomes. Four weeks after supplementing the diet with retinyl acetate (700 micrograms/week), significant reversal of these same str...
This study assesses the impact of various forms of injury on matrix degrading enzymes in nutritio... more This study assesses the impact of various forms of injury on matrix degrading enzymes in nutritionally compromised rat corneas. In vitamin A-deficient (nutritionally compromised) and normal control corneas, in vivo or ex vivo mild mechanical abrasion did not appreciably alter the activity of either the 65-kDa or the 92-kDa gelatinases. In contrast, after thermal injury, while no appreciable change was detected in activity associated with the 65-kDa gelatinase in either vitamin A-deficient or normal control corneas, 92-kDa gelatinolytic activity was consistently higher in corneas from both groups, although activity associated with nutritionally compromised corneas was much higher. In these corneas, thermal injury also induced the expression of two high molecular weight (approximately 130-kDa and 225-kDa) gelatinases and a 27-kDa caseinase. While gelatinases were totally inactivated by inhibitors of metalloproteinases such as 1,10-phenanthroline and Galardin MPI, the 27-kDa caseinase showed considerable susceptibility to a mixture of serine protease inhibitors (aprotinin, dichloro-isocoumarin and pA-PMSF [(4-amidino-phenyl)-methane-sulphonyl fluoride]. Furthermore, unactivated-lymphoreticular cells from either nutritionally compromised or normal control animals contained a 24- and 27-kDa caseinase, however most of the activity was due to the 24-kDa caseinase. In contrast, glycogen-activated lymphoreticular cells contained a preponderance of the 27-kDa caseinase. Activated-lymphoreticular cells also expressed 92-kDa, 130-kDa and 225-kDa gelatinases. The presence of low molecular weight caseinases in lymphoreticular cells implicates them as the source of these enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)
Purified Pseudomonas aeruginosa elastase cleaved a 65 kDa gelatinase [inactive proenzyme form of ... more Purified Pseudomonas aeruginosa elastase cleaved a 65 kDa gelatinase [inactive proenzyme form of matrix metalloproteinase (MMP-2)] from human corneal fibroblasts into a biologically active fragment with an approximate molecular mass of 58 kDa. However, purified pseudomonal alkaline protease did not cleave MMP-2 appreciably. Since activated MMP-2 is known to degrade native type IV, V and VII collagens, all components of the corneal basement membrane or stroma, our results suggest a new role for pseudomonal elastase in the pathogenesis of corneal infection, inflammation and ulceration.
Injury to a vitamin A-deficient cornea leads to severe acute inflammation often culminating in ul... more Injury to a vitamin A-deficient cornea leads to severe acute inflammation often culminating in ulceration. We report on possible regulatory mechanisms involved in the pathogenesis of corneal inflammation in vitamin A deficiency. Thymocyte comitogenic assay and interleukin (IL)-6 induction in corneal fibroblasts have shown that thermally injured and mechanically abraded vitamin A-deficient rat corneas produce much higher levels of an IL-1-like factor as compared with uninjured or injured, normal control corneas. This was confirmed by antibody capture enzyme immunoassay, which detected high levels of IL-1 alpha and IL-1 beta in injured vitamin A-deficient corneas. To our knowledge this is the first report describing the induction of IL-1 in the vitamin A-deficient cornea by thermal and mechanical injuries. When mechanically injured corneas were screened for chemotactic activity, they were found to contain significantly higher levels of a chemoattractant as compared with similarly injured, normal control corneas. Chemotactic activity [expressed as a percentage of a known chemotactic tripeptide, formyl-methionyl-leucyl-phenylalanine (fMLP), found in medium harvested from vitamin A-deficient corneas] averaged 58.8 +/- 8.9% (SEM) as compared with 12.6 +/- 5.4% in medium conditioned by normal corneas. Checkerboard analysis confirmed that the activity in vitamin A-deficient cornea conditioned medium was chemotactic and not chemokinetic. These results demonstrate a correlation between IL-1 levels and severity of inflammation in the injured vitamin A-deficient rat cornea.
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Papers by Naveed Shams