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1.
Graefes Arch Clin Exp Ophthalmol ; 260(6): 1941-1946, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35015115

ABSTRACT

BACKGROUND: Benzalkonium chloride (BAK), the most commonly used preservative in anti-glaucoma eye drops, inflicts damage to the ocular surface. A novel anti-glaucoma formulation that avoids the use of BAK has been developed. The aim of this study was to evaluate the cytotoxicity of this formulation and to compare it with an ophthalmic solution containing BAK. METHODS: Two different latanoprost eye drops were used: one ophthalmic solution (LSc) containing BAK 0.02% and one ophthalmic nanoemulsion (LNe) with a soft preservative (potassium sorbate 0.18%). Human epithelial conjunctival cells were incubated for 15, 30, and 60 min with either LSc or LNe. The cytotoxicity was determined by MTT assay. Cell death was measured by flow cytometry using annexin V-FITC and propidium iodide. RESULTS: The values of cell viability and proliferation obtained from cells exposed to LNe were between 80 and 90% relative to the control group, whereas values obtained from cells exposed to LSc were around 30% at all study times (p < 0.05 at 15 and 30 min; p < 0.01 at 60 min). The percentage of viable cells decreased significantly when cells were incubated with LSc compared with cells incubated with LNe at all the study times, while the percentage of cells in late apoptosis/necrosis increased significantly in cells exposed to LSc compared to LNe. CONCLUSIONS: The new latanoprost nanoemulsion is significantly less cytotoxic on human conjunctival cells than LSc. These results suggest that the new formulation might be gentler on the eye surface than currently available BAK-preserved latanoprost solutions.


Subject(s)
Glaucoma , Prostaglandins F, Synthetic , Antihypertensive Agents/toxicity , Benzalkonium Compounds/metabolism , Benzalkonium Compounds/toxicity , Cloprostenol/metabolism , Conjunctiva/metabolism , Glaucoma/metabolism , Humans , Latanoprost/toxicity , Ophthalmic Solutions/toxicity , Preservatives, Pharmaceutical/metabolism , Preservatives, Pharmaceutical/toxicity , Prostaglandins F, Synthetic/toxicity , Travoprost
2.
Cornea ; 36(10): 1249-1255, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28825921

ABSTRACT

PURPOSE: Most pure glaucoma drugs (pGDs) are hydrophobic substances intended to reduce elevated intraocular pressure. The aims of our study were to determine the toxicity of pGDs (brimonidine tartrate, brinzolamide, latanoprost, timolol maleate, and pilocarpine hydrochloride) on ocular surface cells and to establish whether their toxicity is subsequent to cellular membrane destabilization. METHODS: The toxicity of clinically efficient doses of pGDs was measured at different time points in a cell culture of human corneal epithelial cells using a redox indicator. pGD interaction with the plasma membrane was analyzed using a hemolysis assay and liposome electrokinetic chromatography. The capacity of pGDs to induce endoplasmic reticulum stress was investigated by immunoblotting. RESULTS: The toxicity assay showed that all pGDs decrease the viability of the epithelial cells to variable degrees. Early toxicity was measured for 4% pilocarpine and 0.15% brimonidine with 60% cell death at 4 hours, whereas 2% pilocarpine and 0.005% latanoprost showed almost 100% toxicity but only after 16 hours. The hemolysis assay and liposome electrokinetic chromatography experiments suggested that interaction between pGDs and lipid membranes is weak and cannot explain cell death through lysis. Immunoblotting revealed that the drugs activate endoplasmic reticulum stress and, with the exception of pilocarpine, have the capacity to induce apoptosis through upregulation of C/EBP homologous protein. CONCLUSIONS: Our study indicates that all studied pGDs decrease the viability of the corneal epithelial cells, but none of the tested compounds were able to destabilize cellular membranes. The pGDs seem to be internalized and can induce apoptosis through C/EBP homologous protein recruitment.


Subject(s)
Antihypertensive Agents/toxicity , Epithelium, Corneal/drug effects , Glaucoma/drug therapy , Intraocular Pressure/drug effects , Membrane Lipids/metabolism , Apoptosis/drug effects , Brimonidine Tartrate/toxicity , Cell Line , Cell Membrane/drug effects , Cell Survival/drug effects , Electrophoresis, Capillary , Epithelium, Corneal/metabolism , Humans , Latanoprost , Liposomes/metabolism , Ocular Hypertension/drug therapy , Pilocarpine/toxicity , Prostaglandins F, Synthetic/toxicity , Sulfonamides/toxicity , Thiazines/toxicity , Timolol/toxicity
3.
Curr Eye Res ; 42(4): 534-541, 2017 04.
Article in English | MEDLINE | ID: mdl-27749098

ABSTRACT

PURPOSE: To investigate the cytotoxic effect of latanoprost on corneal stroma and its underlying cellular and molecular mechanisms using non-transfected human corneal stromal (HCS) cells as an in vitro model. METHODS: After HCS cells were treated with latanoprost at concentrations varying from 50 mg/l (clinical therapeutic dosage) to 0.78125 mg/l, and cell morphology, cell viability, and cell cycle were detected by light microscopy, methyl thiazolyl tetrazolium assay, and flow cytometry (FCM) with propidium iodide (PI) staining, respectively. Meanwhile, alterations in plasma membrane permeability, phosphatidylserine (PS) orientation, DNA integrality, and cell ultrastructure were examined by acridine orange (AO)/ethidium bromide (EB) double staining, FCM with Annexin-V/propidium iodide (PI) staining, DNA electrophoresis, and transmission electron microscopy. Furthermore, caspase activation, mitochondrial transmembrane potential (MTP), and expression of pro-apoptotic regulators were determined by ELISA, FCM with 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethybenzimida (JC-1) staining, and Western blot, respectively. RESULTS: Latanoprost above concentrations of 3.125 mg/l can induce dose- and time-dependent morphological abnormality, growth retardation, viability decline, and plasma membrane permeability elevation of HCS cells. Moreover, latanoprost can arrest the cell cycle of these cells at S phase and induce PS externalization, DNA fragmentation, and apoptotic body formation of the cells. Furthermore, latanoprost can induce activation of caspase-3, -8 and -9; disruption of MTP; downregulation of anti-apoptotic Bcl-2; upregulation of pro-apoptotic Bax; and cytoplasmic cytochrome c release. CONCLUSIONS: Latanoprost above and at 3.125 mg/l (1/16 of its clinical therapeutic dosage) has a dose- and time-dependent cytotoxicity to HCS cells by inducing death receptor-mediated mitochondria-dependent apoptosis, which should be used with great caution in clinical situations to avoid undesired damages to HCS cells.


Subject(s)
Antihypertensive Agents/toxicity , Corneal Keratocytes/drug effects , Corneal Stroma/drug effects , Prostaglandins F, Synthetic/toxicity , Apoptosis/drug effects , Blotting, Western , Caspases/metabolism , Cell Cycle/drug effects , Cell Line , Cell Membrane Permeability/drug effects , Cell Survival/drug effects , Corneal Keratocytes/metabolism , Corneal Keratocytes/pathology , Corneal Stroma/metabolism , Corneal Stroma/pathology , DNA Fragmentation/drug effects , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Latanoprost , Time Factors
4.
Toxicol Sci ; 149(2): 458-72, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26609138

ABSTRACT

Cardiovascular (CV) toxicity is an important cause of failure during drug development. Blood-based biomarkers can be used to detect CV toxicity during preclinical development and prioritize compounds at lower risk of causing such toxicities. Evidence of myocardial degeneration can be detected by measuring concentrations of biomarkers such as cardiac troponin I and creatine kinase in blood; however, detection of functional changes in the CV system, such as blood pressure, generally requires studies in animals with surgically implanted pressure transducers. This is a significant limitation because sustained changes in blood pressure are often accompanied by changes in heart rate and together can lead to cardiac hypertrophy and myocardial degeneration in animals, and major adverse cardiovascular events (MACE) in humans. Increased concentrations of NPs in blood correlate with higher risk of cardiac mortality, all-cause mortality, and MACE in humans. Their utility as biomarkers of CV function and toxicity in rodents was investigated by exploring the relationships between plasma concentrations of NTproANP and NTproBNP, blood pressure, heart rate, and heart weight in Sprague Dawley rats administered compounds that caused hypotension or hypertension, including nifedipine, fluprostenol, minoxidil, L-NAME, L-thyroxine, or sunitinib for 1-2 weeks. Changes in NTproANP and/or NTproBNP concentrations were inversely correlated with changes in blood pressure. NTproANP and NTproBNP concentrations were inconsistently correlated with relative heart weights. In addition, increased heart rate was associated with increased heart weights. These studies support the use of natriuretic peptides and heart rate to detect changes in blood pressure and cardiac hypertrophy in short-duration rat studies.


Subject(s)
Atrial Natriuretic Factor/blood , Blood Pressure/drug effects , Cardiomegaly/chemically induced , Heart Rate/drug effects , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Animals , Biomarkers , Indoles/toxicity , Male , Minoxidil/toxicity , NG-Nitroarginine Methyl Ester/toxicity , Nifedipine/toxicity , Organ Size/drug effects , Prostaglandins F, Synthetic/toxicity , Pyrroles/toxicity , Rats , Rats, Sprague-Dawley , Sunitinib , Thyroxine/toxicity
5.
J Glaucoma ; 25(1): 122-7, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26164144

ABSTRACT

PURPOSE: To evaluate the impact of antiglaucoma drugs on the corneal healing process and corneal toxicity. MATERIALS AND METHODS: Four eye drops to treat glaucoma--Xalatan (latanoprost 50 µg/mL; Pfizer), Monoprost (latanoprost 50 µg/mL; Théa Pharma), Taflotan Sine (tafluprost 15 µg/mL; Santen Pharmaceutical Co.), Travatan (travoprost 40 µg/mL; Alcon), and 0.02% benzalkonium chloride (BAC) solution and HyloComod (1 mg/mL sodium hyaluronate; Ursapharm) as positive and negative control were tested regarding corneal irritability and effect on corneal healing. Formulas were tested over 3 days and administered 6 times daily on rabbit corneas cultured on an artificial anterior chamber (the Ex Vivo Eye Irritation Test system). Initially, 4 corneal abrasions (2.5 to 5.7 mm2) were applied. All defects were monitored during drug application by fluorescein stains and photographs. Glucose/lactate concentrations were monitored for corneal metabolic activity evaluation. RESULTS: For Xalatan and BAC, the corneal erosion size increased from 14.65 to 66.57 mm2 and 14.80 to 87.26 mm2. Travatan and Taflotan Sine did not interfere with corneal healing. Monoprost delayed corneal healing. For Xalatan and BAC, histology showed severe alteration of the superficial cornea. An increase in anterior chamber lactate concentration indicates corneal toxicity for Xalatan, BAC, and Monoprost. CONCLUSIONS: Corneal toxicity of Xalatan is most probably caused by BAC. Monoprost delays corneal healing, which is not well understood. The Monoprost effects could be caused by its additive, macrogolglycerolhydroxystearate 40. This excipient is a known skin irritant, and its concentration is relatively elevated in Monoprost, 50 mg/mL, compared with its active ingredient, latanoprost (0.05 mg/mL).


Subject(s)
Antihypertensive Agents/toxicity , Cornea/drug effects , Corneal Injuries/drug therapy , Wound Healing/drug effects , Administration, Topical , Animals , Benzalkonium Compounds/toxicity , Glaucoma/drug therapy , Intraocular Pressure/drug effects , Latanoprost , Ophthalmic Solutions , Preservatives, Pharmaceutical/toxicity , Prostaglandins F/toxicity , Prostaglandins F, Synthetic/toxicity , Rabbits , Travoprost/toxicity
6.
Eur J Pharm Biopharm ; 95(Pt B): 203-14, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25960331

ABSTRACT

Latanoprost is a practically insoluble prostaglandin F2α analog considered a first-line agent for glaucoma treatment. From a pharmaceutical point of view, latanoprost is challenging to be formulated as an eye drop due to its poor water solubility and the presence of an ester bond that needs to be cleaved in vivo but maintained unchanged during storage. Cyclodextrins (CDs) are known to form complexes with hydrophobic drugs, influencing their stability, availability, solubility, and tolerance in a non-predictable manner. A variety of CDs including native α, ß, and γCDs as well as substituted hydroxypropylßCD, hydroxypropylγCD, dimethylßCD, sulphatedßCD, and propylaminoßCD were screened and the most appropriate CD for the formulation of latanoprost for an ocular topical application was selected. Among the tested CDs, propylaminoßCD had the best trade-off between latanoprost stability and availability, which was confirmed by its complex constant value of 3129M(-1). Phase-solubility and NMR investigations demonstrated that the propylaminoßCD effectively formed a complex involving the ester group of latanoprost providing protection to its ester bond, while ensuring proper latanoprost solubilization. Furthermore, in vivo experiments demonstrated that the latanoprost-propylaminoßCD formulation led to lower ocular irritation than the commercial latanoprost formulation used as a reference. The latanoprost-propylaminoßCD formulation was demonstrated to successfully address the main stability, solubility, and tolerance limitations of topical ocular latanoprost therapy for glaucoma.


Subject(s)
Antihypertensive Agents/administration & dosage , Cyclodextrins/chemistry , Excipients/chemistry , Prostaglandins F, Synthetic/administration & dosage , Administration, Ophthalmic , Animals , Antihypertensive Agents/chemistry , Antihypertensive Agents/toxicity , Cattle , Chemistry, Pharmaceutical/methods , Drug Compounding/methods , Drug Stability , Drug Storage , Glaucoma/drug therapy , Latanoprost , Magnetic Resonance Spectroscopy , Ophthalmic Solutions , Prostaglandins F, Synthetic/chemistry , Prostaglandins F, Synthetic/toxicity , Rabbits , Solubility
7.
Invest Ophthalmol Vis Sci ; 53(13): 8172-80, 2012 Dec 13.
Article in English | MEDLINE | ID: mdl-23150620

ABSTRACT

PURPOSE: To compare in vitro, on the human reconstituted corneal epithelial SkinEthics model, and in vivo, using an acute rabbit toxicological model, the effects of a benzalkonium chloride (BAK)-preserved solution of latanoprost and a preservative-free (PF) latanoprost solution. METHODS: In vitro, the three-dimensional (3D) reconstituted human corneal epithelia (HCE) were treated with PBS, BAK-latanoprost, PF-latanoprost, or 0.02% BAK for 24 hours followed or not followed by a 24 hour post incubation recovery period. Cellular viability was evaluated using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test at 24 hours and the apoptotic cells were counted using TUNEL labeling on frozen sections at 24 hours and 24 hours plus 24 hours. In vivo, rabbits received 50 µL of the same solutions, which were applied at 5 minute intervals a total of 15 times. Ocular surface toxicity was investigated using slit lamp biomicroscopy examination, conjunctival impression cytology (CIC), and corneal in vivo confocal microscopy (IVCM). Standard immunohistology also assessed inflammatory CD45-positive cells. RESULTS: In vitro, BAK-latanoprost and 0.02% BAK induced significant apoptosis in the apical layers that correlated with the significant decrease of cell viability as assessed by the MTT test. PF-latanoprost slightly decreased cell viability and few apoptotic cells were found in the superficial layers, without reaching statistical significance compared with PBS. In vivo, clinical observation and IVCM images showed the lowest ocular surface toxicity with PBS and PF-latanoprost, while BAK-latanoprost and BAK induced abnormal corneoconjunctival aspects. PF-latanoprost showed the lowest CIC score, close to the PBS score and induced fewer CD45-positive cells in both the limbus and the conjunctiva compared with BAK and latanoprost, as assessed by immunohistology. CONCLUSIONS: We confirm that rabbit corneoconjunctival surfaces presented better tolerance when treated with PF-latanoprost compared with the standard BAK-latanoprost preparation or the BAK solution.


Subject(s)
Antihypertensive Agents/toxicity , Benzalkonium Compounds/toxicity , Cornea/drug effects , Epithelium, Corneal/drug effects , Preservatives, Pharmaceutical/toxicity , Prostaglandins F, Synthetic/toxicity , Administration, Topical , Animals , Apoptosis , Cells, Cultured , Cornea/metabolism , Cornea/pathology , Drug Therapy, Combination , Epithelium, Corneal/metabolism , Epithelium, Corneal/pathology , Fluorescent Antibody Technique, Indirect , Humans , Imaging, Three-Dimensional , In Situ Nick-End Labeling , Latanoprost , Leukocyte Common Antigens/metabolism , Male , Microscopy, Confocal , Rabbits
8.
Adv Ther ; 29(10): 874-88, 2012 Oct.
Article in English | MEDLINE | ID: mdl-23065664

ABSTRACT

INTRODUCTION: This in-vitro study compared the toxicity of bimatoprost 0.01% containing benzalkonium chloride (BAK) 0.02% with other commercial BAK-free or BAK-containing prostaglandin analogs. METHODS: Six test solutions were evaluated: travoprost 0.004% with polyquaternium-1 0.001% (PQ), PQ, bimatoprost 0.01% with BAK 0.02%, latanoprost 0.005% with BAK 0.02%, tafluprost 0.0015% preservative free (PF), and BAK 0.02%. Phosphate-buffered saline (PBS) was the live control and 70% methanol was the dead control. Confluent human corneal epithelial cells were incubated with test solutions (diluted 1:5 or 1:10 with PBS) or control solutions for 10 or 25 min, after which cells were fluorescently labeled to distinguish live and dead cells. Data were expressed as a percentage of PBS live-cell fluorescence for automated readouts. Live and dead cells were manually counted for numeric analyses. RESULTS: For 1:5 and 1:10 dilutions using automated readout, cells exposed to bimatoprost with BAK, latanoprost with BAK, and BAK alone demonstrated significant reductions in the live cell signal compared with PBS, travoprost with PQ, and PQ alone (all P < 0.001). They also demonstrated significantly greater toxicity than tafluprost PF for 1:5 dilutions (all P < 0.001) and 1:10 dilutions (P ≤ 0.02), except for 1:10-diluted bimatoprost with BAK (P = 0.41). For 1:5 dilutions using manual cell count, cells exposed to bimatoprost with BAK demonstrated significant reductions in the percentage of live cells compared with PBS (P = 0.02). For 1:10 dilutions using manual cell count, cells exposed to bimatoprost with BAK, latanoprost with BAK, and BAK alone demonstrated significantly greater toxicity than PBS, travoprost with PQ, PQ alone, and tafluprost PF (all P ≤ 0.03). No significant differences were observed among PBS, travoprost with PQ, and PQ alone under any test conditions (P ≤ 0.63). CONCLUSION: This study demonstrated that BAKcontaining solutions, including bimatoprost 0.01% with BAK, were toxic to human corneal epithelial cells, whereas BAK-free solutions showed little to no evidence of toxicity.


Subject(s)
Antihypertensive Agents/toxicity , Epithelial Cells/drug effects , Epithelium, Corneal/cytology , Preservatives, Pharmaceutical/toxicity , Amides/toxicity , Benzalkonium Compounds/toxicity , Bimatoprost , Cell Survival/drug effects , Cells, Cultured , Cloprostenol/analogs & derivatives , Cloprostenol/toxicity , Epithelium, Corneal/drug effects , Humans , Latanoprost , Polymers/toxicity , Prostaglandins F/toxicity , Prostaglandins F, Synthetic/toxicity , Prostaglandins, Synthetic/toxicity , Travoprost
9.
Cornea ; 31(11): 1319-29, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22929154

ABSTRACT

PURPOSE: Cationic emulsions (CEs), developed as vehicles for lipophilic drugs, have been shown to be safe and effective for the treatment of dry eye. The aim of this study was to investigate the effects of a preservative-free latanoprost 0.005% CE (latanoprost-CE) in in vitro and in vivo models of corneal wound healing. METHODS: An in vitro wound was made by scraping through a confluent layer of human corneal epithelial cells. Cytotoxicity, cell migration, and proliferation were analyzed after an exposure to phosphate-buffered saline, CE, latanoprost-CE, 0.02% benzalkonium chloride (0.02%BAK), and Xalatan (latanoprost). In vivo, the recovery and integrity of corneal wound healing were assessed in rat eyes instilled twice a day for 5 days with the above treatments after deepithelialization of the superior cornea. RESULTS: In vitro wound distances decreased at 2 and 24 hours for human corneal epithelial cells exposed to CE, latanoprost-CE, and phosphate-buffered saline, whereas they progressively increased for 0.02%BAK-treated and latanoprost-treated cells. The greater wound closure was associated with a higher number of Ki67-positive cells. In CE- and latanoprost-CE-treated rats, reepithelialization of the cornea was enhanced, restoring normal appearance and function. In contrast, 0.02%BAK or latanoprost delayed corneal healing, induced inflammation, and decreased MUC5-AC expression. CONCLUSIONS: Both models effectively evaluated the cytotoxicity and dynamic recovery of corneal wound healing, and their correlation supports the potential of the in vitro model as a reliable alternative to in vivo ocular toxicity tests. Both models demonstrated that in the face of corneal injury, CEs favored corneal healing, whereas BAK was deleterious.


Subject(s)
Antihypertensive Agents/toxicity , Corneal Injuries , Disease Models, Animal , Eye Injuries/drug therapy , Preservatives, Pharmaceutical/toxicity , Prostaglandins F, Synthetic/toxicity , Wound Healing/drug effects , Animals , Benzalkonium Compounds/toxicity , Cell Proliferation/drug effects , Cells, Cultured , Conjunctiva/drug effects , Conjunctiva/metabolism , Cornea/drug effects , Cornea/metabolism , Drug Evaluation, Preclinical , Emulsions , Epithelium, Corneal/drug effects , Epithelium, Corneal/metabolism , Eye Injuries/metabolism , Eye Injuries/pathology , Humans , Ki-67 Antigen/metabolism , Latanoprost , Male , Microscopy, Confocal , Mucin 5AC/metabolism , Rats
10.
Invest Ophthalmol Vis Sci ; 53(9): 5154-60, 2012 Aug 03.
Article in English | MEDLINE | ID: mdl-22695966

ABSTRACT

PURPOSE: To investigate the toxicity profiles of seven antiglaucoma topical eye drops and benzalkonium chloride (BAC) using stratified cultivated human corneal epithelial cell sheets (HCES) in a serum-free culture system. METHODS: A range of prostaglandin analogies and preservatives, including BAC, sofZia (SZ), sodium benzoate (SB), and polyquaternium-1 (PQ) were tested. The barrier function and cell viability were examined by a carboxyfluorescein permeability assay and WST-1 assay. Histological evaluation of the HCES was also performed after application of each solution. RESULTS: The carboxyfluorescein permeability assay had a higher sensitivity for the detection of toxicity of test solutions than the WST-1 assay or histological examination. Latanoprost BAC, latanoprost/timolol BAC, and 0.02% or higher concentration of BAC were the most toxic, followed by latanoprost SB, latanoprost preservative-free, BAC 0.002%, and travoprost/ latanoprost PQ. Travoprost SZ and tafluprost BAC (preserved with 0.001% BAC) was the least toxic in our experimental conditions. CONCLUSIONS: The carboxyfluorescein permeability assay using HCES in a serum-free system was the most useful for the quantification of toxicity of ophthalmic solutions. Among the regimens examined, a BAC concentration of 0.001% or lower or non-BAC preservative sofZia was suggested to be the least toxic to the ocular surface.


Subject(s)
Antihypertensive Agents/toxicity , Epithelium, Corneal/drug effects , Benzalkonium Compounds/toxicity , Cell Membrane Permeability , Cell Survival , Cells, Cultured , Culture Media, Serum-Free , Drug Combinations , Fluoresceins/metabolism , Fluorescent Dyes/metabolism , Glaucoma/drug therapy , Humans , Membrane Proteins/metabolism , Ophthalmic Solutions/toxicity , Phosphoproteins/metabolism , Preservatives, Pharmaceutical/toxicity , Prostaglandins F, Synthetic/toxicity , Timolol/toxicity , Zonula Occludens-1 Protein
11.
Ophthalmic Res ; 48(2): 89-101, 2012.
Article in English | MEDLINE | ID: mdl-22473057

ABSTRACT

The study used a validated acute in vivo model to compare a new formulation of travoprost 0.004% ophthalmic solution(travoprost PQ), preserved with polyquaternium-1 (PQ), with commercially available formulations of benzalkonium-chloride(BAK)-preserved travoprost 0.004% ophthalmic solution(travoprost BAK) and BAK-preserved latanoprost 0.005%ophthalmic solution (latanoprost BAK). Adult male New Zealand albino rabbits (n = 36) were randomly divided into 6 groups. Phosphate-buffered saline (PBS), 0.001% PQ, 0.015% BAK, travoprost PQ, travoprost BAK or latanoprost BAK were applied onto rabbit eyes as 1 drop, for 15 times at 5-min intervals.The ocular surface reactions were investigated at hour 4 and day 1 using slitlamp examination; in vivo confocal microscopy (IVCM) for cornea, limbus and conjunctiva/conjunctiva-associated lymphoid tissue, conjunctival impression cytology and standard immunohistology in cryosections for detecting CD45+ infiltrating cells and MUC-5AC-labeled cells. PBS, PQ and travoprost PQ did not induce obvious irritation by clinical observation, changes in microstructures of the whole ocular surface as measured by IVCM analysis,inflammatory infiltration or cell damage as measured by impression cytology, altered levels of goblet cell counts or numerous CD45+ cells in the cornea. In contrast, all BAK-containing products induced diffuse conjunctival hyperemia and chemosis, abnormal changes in the ocular surface microstructure,significant total ocular surface toxicity scores,damaged epithelial cells, inflammatory cell infiltration and decreased goblet cell density. Travoprost PQ did not elicitocular surface toxicity when administered to rabbit eyes.These results suggest a greater safety advantage for the ocular surface of patients receiving chronic glaucoma treatment with PQ-preserved drugs.


Subject(s)
Antihypertensive Agents/toxicity , Benzalkonium Compounds/toxicity , Conjunctiva/drug effects , Cornea/drug effects , Polymers/toxicity , Preservatives, Pharmaceutical/toxicity , Animals , Cloprostenol/analogs & derivatives , Cloprostenol/toxicity , Conjunctiva/metabolism , Cornea/metabolism , Goblet Cells/drug effects , Goblet Cells/pathology , Latanoprost , Leukocyte Common Antigens/metabolism , Male , Microscopy, Confocal , Mucin 5AC/metabolism , Ophthalmic Solutions , Prostaglandins F, Synthetic/toxicity , Rabbits , Travoprost
12.
Curr Eye Res ; 37(2): 145-54, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22049909

ABSTRACT

PURPOSE: To investigate the cytotoxicity of benzalkonium chloride (BAC)-containing ophthalmic solutions of prostaglandin analogs (latanoprost, travoprost, bimatoprost, and preservative-free (PF) tafluprost), BAC mixture (BACmix) and BAC homologs with different alkyl chain lengths using human corneal epithelial (HCE) and conjunctival epithelial (IOBA-NHC) cell cultures. The distribution of BAC homologs in rabbit ocular surface tissues in vivo was examined. METHODS: The cells were exposed for one hour to prostaglandin analogs, BACmix and three homologs. Cytotoxicity was assessed with the WST-1 and lactate dehydrogenase (LDH) assays for cellular viability and cell membrane integrity. BAC 0.02% solution was instilled on the rabbit eye daily for 14 days and the concentrations of BAC homologs in external ocular tissues were determined. RESULTS: The order of decreasing cytotoxicity in the WST-1 test was latanoprost ≥ travoprost > bimatoprost ≥ PF tafluprost. IOBA-NHC cells were more sensitive than HCE cells. In HCE, only latanoprost diluted to 10% increased LDH leakage. In IOBA-NHC, LDH leakage was statistically significant with 3-10% travoprost and 10% latanoprost. The order of decreasing cytotoxicity of preservatives was C14 > C12 > BACmix > C16 in HCE and C12 > C14 > BACmix > C16 in IOBA-NHC. Following treatment with BAC 0.02% solution, the amounts of BAC-C12, -C14 and -C16 in rabbit cornea and conjunctiva, respectively were: 0.37 ± 0.08 and 2.64 ± 0.27 ng/mg; 0.42 ± 0.07 and 4.77 ± 0.43 ng/mg; 0.04 ± 0.01 and 0.54 ± 0.05 ng/mg. CONCLUSIONS: The cytotoxic effects of latanoprost, travoprost, and bimatoprost were dependent on the BAC concentration in their formulations. BACmix was cytotoxic at the concentrations above those corresponding to 0.001% BAC in ophthalmic medications. PF tafluprost was the least toxic of the drugs tested. Within studied BAC homologs, those with longer alkyl chain and higher lipophility penetrated effectively into rabbit external ocular tissues.


Subject(s)
Antihypertensive Agents/toxicity , Benzalkonium Compounds/toxicity , Conjunctiva/drug effects , Epithelium, Corneal/drug effects , Preservatives, Pharmaceutical/toxicity , Prostaglandins F, Synthetic/toxicity , Animals , Benzalkonium Compounds/pharmacokinetics , Cell Line , Cell Survival , Conjunctiva/metabolism , Epithelium , Epithelium, Corneal/metabolism , Humans , L-Lactate Dehydrogenase/metabolism , Male , Ophthalmic Solutions , Preservatives, Pharmaceutical/pharmacokinetics , Rabbits , Tissue Distribution
13.
Br J Ophthalmol ; 95(10): 1466-9, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21602479

ABSTRACT

AIMS: We investigated the potential cytotoxicity of various topical ophthalmic glaucoma formulations containing different preservatives in cultured human trabecular meshwork (TM) and non-pigmented ciliary epithelial (NPCE) cell lines. METHODS: We tested 0.004% travoprost preserved with either 0.015% benzalkonium chloride (BAK), sofZia or 0.001% Polyquad (PQ); and 0.005% latanoprost preserved with 0.020% BAK. We also tested a range of BAK concentrations in balanced salt solution (BSS). TM cells were treated for 10 min at 37°C with solutions diluted 1:10 to mimic the reduced penetration of topical preparations to the anterior chamber. Viability was determined by the uptake of the fluorescent vital dye calcein-AM (n = 6). RESULTS: BAK solutions (diluted 1:10) demonstrated a dose-dependent reduction in cell viability in both cell types (TM and NPCE). With a 1:10 dilution of 0.020% BAK, there were significantly more living NPCE cells (89 ± 6%) than TM cells (57 ± 6%; p < 0.001). In TM cells, travoprost + BAK had statistically fewer live cells (83 ± 5%) than both travoprost + sofZia (97 ± 5%) and travoprost + PQ (97 ± 6%; p < 0.05). Compared with BSS-treated NPCE cells, travoprost had statistically fewer live cells (p < 0.05) when preserved with BAK (85 ± 16%), sofZia (91 ± 6%) or PQ (94 ± 2%). CONCLUSIONS: These results demonstrate that substitution of BAK from topical ophthalmic drugs results in greater viability of cultured TM cells, the cells involved in the conventional outflow pathway. Cultured NPCE, responsible for aqueous inflow, appear more resilient to BAK.


Subject(s)
Antihypertensive Agents/toxicity , Ciliary Body/cytology , Epithelial Cells/drug effects , Preservatives, Pharmaceutical/toxicity , Trabecular Meshwork/drug effects , Benzalkonium Compounds/toxicity , Cell Survival , Cells, Cultured , Cloprostenol/analogs & derivatives , Cloprostenol/toxicity , Dose-Response Relationship, Drug , Glaucoma/drug therapy , Humans , Latanoprost , Polymers/toxicity , Prostaglandins F, Synthetic/toxicity , Travoprost
14.
J Ocul Pharmacol Ther ; 27(3): 273-80, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21410334

ABSTRACT

PURPOSE: To compare, in vitro, the cytotoxicity profile of a new formulation of travoprost 0.004%/timolol 0.5% fixed combination ophthalmic solution preserved with polyquaternium-1 0.001% (travoprost/timolol PQ) instead of benzalkonium chloride (BAK) with (1) commercially available travoprost 0.004%/timolol 0.5% fixed combination ophthalmic solution (travoprost/timolol BAK), (2) commercially available latanoprost 0.005%/timolol 0.5% fixed combination ophthalmic solution (latanoprost/timolol BAK), and (3) their associated BAK concentrations. METHODS: Compounds tested on Wong-Kilbourne-derived human conjunctival epithelial cells: (1) phosphate-buffered saline, (2) polyquaternium-1 0.001% (Polyquad(®), PQ), (3) travoprost/timolol PQ, (4) travoprost/timolol BAK with 0.015% BAK (DuoTrav(®)), (5) BAK 0.015%, (6) latanoprost/timolol BAK with 0.020% BAK (Xalacom(®)), and (7) BAK 0.020%. Toxicological assays were used to assess cell viability [neutral red (NR), Alamar blue (AB)], apoptosis (YO-PRO-1, Hoechst 33342), and oxidative stress (H(2)DCF-DA, hydroethidine). The apoptosis and oxidative stress assays were each reported according to cell viability as observed with NR and AB (totaling 10 analyses per treatment). RESULTS: The NR and AB assays demonstrated that cells incubated with travoprost/timolol PQ had significantly better viability than cells incubated with latanoprost/timolol BAK, travoprost/timolol BAK, BAK 0.015%, and BAK 0.020% (P<0.0001 for all). As assessed with YO-PRO-1 and Hoechst 33342 relative to cell viability determined with NR or AB, travoprost/timolol PQ produced significantly less apoptosis than travoprost/timolol BAK and latanoprost/timolol BAK and their respective BAK concentrations alone (P<0.0001 for all). Also, travoprost/timolol BAK induced less apoptosis than latanoprost/timolol BAK (P<0.0001). As assessed with H(2)DCF-DA as a ratio to NR or AB, all of the compounds without BAK (phosphate-buffered saline, PQ 0.001%, and travoprost/timolol PQ) and travoprost/timolol BAK produced significantly less reactive oxygen species than latanoprost/timolol BAK (P<0.0001 for all). As assessed with hydroethidine as a ratio to NR or AB, travoprost/timolol PQ produced significantly fewer superoxide anions than latanoprost/timolol BAK (P<0.0001). In contrast, release of superoxide anions (hydroethidine method) after incubation with travoprost/timolol BAK was not significantly different from incubation with latanoprost/timolol BAK or travoprost/timolol PQ. CONCLUSION: Travoprost/timolol PQ may be better for ocular surface health than either BAK preserved formulations of latanoprost/timolol or travoprost/timolol.


Subject(s)
Benzalkonium Compounds/toxicity , Cloprostenol/analogs & derivatives , Conjunctiva/drug effects , Polymers/toxicity , Preservatives, Pharmaceutical/toxicity , Prostaglandins F, Synthetic/toxicity , Timolol/toxicity , Apoptosis/drug effects , Cell Line , Cell Survival/drug effects , Chemistry, Pharmaceutical , Clone Cells , Cloprostenol/toxicity , Conjunctiva/metabolism , Drug Combinations , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Humans , Latanoprost , Ocular Hypertension/drug therapy , Ophthalmic Solutions , Oxidative Stress/drug effects , Superoxides/metabolism , Sympatholytics/toxicity , Travoprost
15.
Adv Ther ; 27(11): 837-45, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20931366

ABSTRACT

INTRODUCTION|: To investigate potentially adverse effects of different topical glaucoma medications and preservatives on cultured ocular epithelial cells. METHODS|: Confluent cultures of human corneal (10.014 pRSV-T) and conjunctival cells (1-5c-4) were assayed with 100 µL of different glaucoma medications for 25 minutes at 37°C and 5% CO2. We also tested the preservative sofZia® (Alcon Laboratories, Fort Worth, TX, USA), as well as a range of concentrations of the preservative benzalkonium chloride (BAK; 0.001% to 0.050%). Balanced salt solution was used as the "live" control and a solution containing 70% methanol and 0.2% saponin was used as a "dead" control. The LIVE/DEAD viability/cytotoxicity kit (Invitrogen, Carlsbad, CA, USA) was used to determine the percentage of dead and live cells via ethidium homodimer and calcein fluorescence, respectively. RESULTS|: The toxicity of the prostaglandin analogs latanoprost, tafluprost and travoprost preserved with BAK was similar to the toxicity observed in their respective BAK concentrations. The prostaglandin analog travoprost (0.004%) preserved with the oxidizing preservative sofZia had much greater corneal and conjunctival cell survival than travoprost preserved with BAK. Travoprost (0.004%) containing polyquad also performed statistically better than its BAK-preserved formulation. CONCLUSION|: Ocular surface side effects have previously been demonstrated with chronic, long-term exposure to intraocular pressure-lowering medications containing the common preservative BAK. BAK alone has significant in-vitro cytotoxicity to cultured ocular epithelial cells. Substitution of BAK with polyquad or sofZia resulted in significantly higher percentages of live conjunctival and corneal cells. Further studies are needed to understand the- clinical implications of these findings.


Subject(s)
Antihypertensive Agents/toxicity , Benzalkonium Compounds/toxicity , Conjunctiva/drug effects , Epithelium, Corneal/drug effects , Glaucoma/drug therapy , Polymers/toxicity , Preservatives, Pharmaceutical/toxicity , Prostaglandins F, Synthetic/toxicity , Administration, Topical , Antihypertensive Agents/administration & dosage , Benzalkonium Compounds/administration & dosage , Cell Survival/drug effects , Cells, Cultured , Cloprostenol/analogs & derivatives , Conjunctiva/cytology , Dose-Response Relationship, Drug , Humans , Latanoprost , Ophthalmic Solutions , Polymers/administration & dosage , Preservatives, Pharmaceutical/administration & dosage , Prostaglandins F , Prostaglandins F, Synthetic/administration & dosage , Travoprost
16.
J Ocul Pharmacol Ther ; 26(3): 259-63, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20565312

ABSTRACT

PURPOSE: To determine the effect of 4 formulations of commercially available prostaglandin analogs (PGAs) on human corneal epithelial cells in vitro. METHODS: The test solutions (PGAs) examined were tafluprost 0.005% with 0.010% benzalkonium chloride (BAK), travoprost 0.004% with 0.015% BAK, travoprost 0.004% with sofZia, and latanoprost 0.005% with 0.020% BAK. Also tested independently were the 4 respective BAK or sofZia concentrations related to each PGA. Balanced salt solution (BSS) was used as the live control, and a fixative solution containing 70% methanol and 0.2% saponin was used as the dead control. Immortalized human corneal epithelial cells were exposed to test or control solution for 25 min at 37 degrees C and 5% CO(2). A live/dead assay was used to measure the toxicity of the PGAs. RESULTS: The percentage of live cells in the PGA groups ranged from 2% to 72% of the BSS group (live control). The PGA with the highest relative live cell percentage, at 72% of the live control, was travoprost with sofZia. The next highest PGA, exhibiting 14% live cells, was the formulation of travoprost containing BAK. The other 2 PGAs, tafluprost and latanoprost, had few surviving cells, with 3% and 2% live cells, respectively. The BAK concentrations exhibited 4%, 3%, and 3% for the 0.01%, 0.015%, and 0.02% concentrations, respectively. The stand-alone sofZia cell survival was 68% of the live control. CONCLUSIONS: All 4 PGA formulations tested demonstrated significantly more toxicity in human corneal epithelial cells than the live control, but there were significant differences among the PGAs. Travoprost with sofZia exhibited the least toxicity, followed by travoprost with BAK, and then tafluprost and latanoprost. The stand-alone preservative systems were also tested and showed similar survival percentages to each respective PGA. The true clinical implications of these findings require further investigation.


Subject(s)
Benzalkonium Compounds/toxicity , Cloprostenol/analogs & derivatives , Epithelium, Corneal/drug effects , Prostaglandins F, Synthetic/toxicity , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/toxicity , Benzalkonium Compounds/administration & dosage , Cell Survival/drug effects , Cells, Cultured , Cloprostenol/administration & dosage , Cloprostenol/toxicity , Dose-Response Relationship, Drug , Epithelium, Corneal/metabolism , Humans , In Vitro Techniques , Latanoprost , Preservatives, Pharmaceutical/administration & dosage , Preservatives, Pharmaceutical/toxicity , Prostaglandins F/administration & dosage , Prostaglandins F/toxicity , Prostaglandins F, Synthetic/administration & dosage , Travoprost
17.
Mol Vis ; 15: 1690-9, 2009 Aug 25.
Article in English | MEDLINE | ID: mdl-19710954

ABSTRACT

PURPOSE: Using an established rabbit toxicological model, this in vivo study compared the ocular cytotoxicity of four topical intraocular pressure (IOP)-lowering agents: the commercial benzalkonium chloride (BAC)-containing solutions of 0.005% latanoprost, 0.004% travoprost, 0.03% bimatoprost (containing 0.02%, 0.015%, and 0.005% BAC, respectively), and 0.005% latanoprost in a new cationic emulsion (LCEm) formulation. METHODS: Thirty adult male New Zealand albino rabbits were used in this study. They were randomly divided into five groups: 50 microl of sterile phosphate-buffered saline (PBS) along with each formulation was applied onto rabbit eyes 15 times at 5 min intervals. The ocular surface changes were investigated using slit-lamp examination, corneal in vivo confocal microscopy (IVCM) for cornea, limbus, conjunctiva/conjunctiva-associated lymphoid tissue (CALT) investigations, and conjunctival imprints for cytology and flow cytometry (FCM) analyses. RESULTS: Antiglaucoma eye drops induced an ocular surface cytotoxicity primarily related to the concentration of their common BAC preservative ((0.02%BAC+)latanoprost> (0.015%BAC+)travoprost> (0.005%BAC+)bimatoprost). LCEm did not induce any obvious signs of toxicity on the rabbit ocular surface with results similar to those of PBS; moreover, the conjunctiva/CALT and cornea had almost normal aspects. CONCLUSIONS: These in vivo and ex vivo toxicological procedures performed in an acute stress model confirmed the ocular surface cytotoxicity of BAC-containing antiglaucomatous eye drop solutions. The new formulation, LCEm, was well tolerated without inducing ocular surface damage or CALT activation. The cationic emulsion of latanoprost will most likely have fewer long-term adverse effects on the ocular surface than formulations containing toxic preservative BAC and may improve long-term tolerance over BAC-containing antiglaucomatous topical treatments.


Subject(s)
Eye/drug effects , Ophthalmic Solutions/pharmacology , Prostaglandins F, Synthetic/adverse effects , Prostaglandins F, Synthetic/toxicity , Prostaglandins/pharmacology , Toxicity Tests , Animals , Cations , Conjunctiva/cytology , Conjunctiva/drug effects , Emulsions , Eye/cytology , Flow Cytometry , Immunohistochemistry , Latanoprost , Leukocyte Common Antigens/metabolism , Lymphoid Tissue/drug effects , Male , Microscopy, Confocal , Rabbits
18.
Br J Ophthalmol ; 92(9): 1275-82, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18723745

ABSTRACT

AIM: To compare the conjunctival and corneal reactions of commercially available solution of latanoprost (Xalatan) and preservative-free (PF) tafluprost in rabbits. METHODS: The rabbits received 50 microl of phosphate-buffered saline (PBS), PF-tafluprost 0.0015%, latanoprost 0.005% or benzalkonium chloride (BAK) 0.02%; all solutions were applied at 5 min intervals for a total of 15 times. The ocular surface toxicity was investigated using slit-lamp biomicroscopy examination, flow cytometry (FCM) and on imprints for CD45 and tumour necrosis factor-receptor 1 (TNFR1) conjunctival impression cytology (CIC) and corneal in vivo confocal microscopy (IVCM). Standard immunohistology also assessed inflammatory/apoptotic cells. RESULTS: Clinical observation and IVCM images showed the highest ocular surface toxicity with latanoprost and BAK, while PF-tafluprost and PBS eyes presented almost normal corneoconjunctival aspects. FCM showed a higher expression of CD45+ and TNFR1+ in latanoprost- or BAK-instilled groups, compared with PF-tafluprost and PBS groups. Latanoprost induced fewer positive cells for inflammatory marker expressions in CIC specimens compared with BAK-alone, both of which were higher than with PF-tafluprost or PBS. Immunohistology showed the same tendency of toxic ranking. CONCLUSION: The authors confirm that rabbit corneoconjunctival surfaces presented a better tolerance when treated with PF-tafluprost compared with commercially available latanoprost or BAK solution.


Subject(s)
Antihypertensive Agents/toxicity , Benzalkonium Compounds/toxicity , Conjunctiva/drug effects , Cornea/drug effects , Preservatives, Pharmaceutical/toxicity , Prostaglandins F, Synthetic/toxicity , Prostaglandins F/toxicity , Animals , Antihypertensive Agents/administration & dosage , Benzalkonium Compounds/administration & dosage , Benzoxazines , Coloring Agents , Epithelial Cells/pathology , Immunohistochemistry , Keratoconjunctivitis/chemically induced , Keratoconjunctivitis/pathology , Latanoprost , Male , Ophthalmic Solutions , Oxazines , Prostaglandins F/administration & dosage , Prostaglandins F, Synthetic/administration & dosage , Rabbits
19.
Curr Eye Res ; 33(4): 303-12, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18398704

ABSTRACT

PURPOSE: This study compared the toxicity profiles of three antiglaucoma prostaglandin F2alpha analogs, latanoprost, travoprost, and bimatoprost which contain benzalkonium chloride (BAK), with tafluprost, a new preservative-free prostaglandin analog. METHODS: IOBA-NHC cells were exposed to BAK-containing prostanoid solutions, their respective BAK concentrations, and preservative-free tafluprost solution for 30 min. Membrane integrity, apoptosis, oxidative stress, and cells morphology were evaluated. RESULTS: Preservative-free tafluprost resulted in significantly higher membrane integrity and lower pro-apoptotic and pro-oxidative effects than preservative-containing prostaglandin analog preparations. CONCLUSIONS: These results suggest that tafluprost, a new preservative-free prostaglandin analog, has very low or no pro-apoptotic, pro-necrotic, or pro-oxidative effects in vitro compared to preservative-containing formulations.


Subject(s)
Benzalkonium Compounds/toxicity , Conjunctiva/cytology , Conjunctiva/drug effects , Dinoprost/analogs & derivatives , Preservatives, Pharmaceutical/toxicity , Amides/toxicity , Apoptosis/drug effects , Bimatoprost , Cell Line , Cell Membrane/drug effects , Cell Membrane/physiology , Cell Survival/drug effects , Cloprostenol/analogs & derivatives , Cloprostenol/toxicity , Conjunctiva/chemistry , Conjunctiva/physiology , DNA/metabolism , Drug Combinations , Epithelial Cells/drug effects , Glaucoma/drug therapy , Humans , Latanoprost , Ocular Hypertension/drug therapy , Prostaglandins F/toxicity , Prostaglandins F, Synthetic/toxicity , Receptors, Purinergic P2/drug effects , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2X7 , Superoxides/metabolism , Travoprost
20.
Invest Ophthalmol Vis Sci ; 49(1): 250-4, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18172099

ABSTRACT

PURPOSE: To evaluate the influence of some widely used antiglaucoma agents on angiogenesis in a novel rat cornea model. METHODS: Angiogenesis was induced in 32 rats by slow-release polymer pellets containing basic fibroblast growth factor (bFGF) placed in a corneal micropocket. Angiogenesis was later measured and compared in groups of rats given one of four antiglaucoma drug therapies and one control group. The drugs were commercially available preparations of prostaglandins, beta-blockers, alpha-2 agonists, and carbonic anhydrase inhibitors given for 7 days in a manner similar to that used in humans. Growth was measured by calculating the maximum linear vessel growth divided by pellet-limbus distance. RESULTS: Biomicroscopic observation disclosed that all tested animals showed an induction of neovascular reactions in their corneal stroma. The growth index results for the control, latanoprost, dorzolamide, brimonidine, and timolol malate groups were 1.65 +/- 0.16, 1.98 +/- 0.18, 1.85 +/- 0.19, 2.03 +/- 0.38, and 1.65 +/- 0.14, respectively, confirming the hypothesis that topically delivered antiglaucoma drugs modify the normal angiogenic response. Of them, the prostaglandins showed the most prominent angiogenic stimulatory effect (P = 0.03). CONCLUSIONS: This modified micropocket assay of corneal angiogenesis in rats demonstrated the stimulatory effect of several widely used topically delivered antiglaucoma medications on the angiogenic process. The results indicate that the selection of drugs for treating different ophthalmic diseases should take into account their influence on angiogenic processes.


Subject(s)
Antihypertensive Agents/toxicity , Corneal Neovascularization/physiopathology , Corneal Stroma/blood supply , Disease Models, Animal , Animals , Brimonidine Tartrate , Corneal Stroma/drug effects , Drug Implants , Fibroblast Growth Factor 2/toxicity , Latanoprost , Prostaglandins F, Synthetic/toxicity , Quinoxalines/toxicity , Rats , Rats, Wistar , Sulfonamides/toxicity , Thiophenes/toxicity , Timolol/toxicity
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