latanoprost and Disease-Models--Animal

The A3 adenosine receptor (A3AR) is a known therapeutic target for glaucoma treatment. In this study, we developed HL3501 and examined its selectivity profile and in vitro and in vivo effects.. For the rabbit model, intraocular pressure (IOP) was increased by laser photocoagulation of the trabecular meshwork (TM). The rabbits were then topically treated with HL3501, latanoprost, timolol, or vehicle for 3 weeks. For the mouse model, HL3501, latanoprost, or vehicle was administered following induced IOP elevation by dexamethasone (Dex). The IOP of all rabbits and mice was measured. Electroretinography was performed on both eyes of dark-adapted anesthetized mice on days 0 and 21. The mice's eyes were enucleated at the end of the treatment for immunofluorescence staining.. HL3501 was highly specific to the A3AR and inhibitory of A3AR function. In the rabbit glaucoma model, HL3501 and latanoprost significantly decreased the IOP. In the Dex-treated mouse model, HL3501 and latanoprost significantly decreased the IOP and increased the b-wave amplitude as compared with the vehicle treatment. HL3501 and latanoprost also inhibited fibronectin and α-smooth muscle actin expression induced by Dex treatment.. HL3501 had effects similar to those of latanoprost in reducing ocular hypertension in animal models. HL3501 could be used as a novel approach to treat glaucoma.. HL3501 is a novel preclinical compound targeting the A3 adenosine receptor, which may also be a new treatment option to fill the unmet needs of many glaucoma patients.

Topics: Animals; Disease Models, Animal; Glaucoma; Humans; Intraocular Pressure; Latanoprost; Mice; Purinergic P1 Receptor Antagonists; Rabbits; Receptors, Purinergic P1

Retinal arachidonic acid (ARA) levels in form-deprived eyes decline in guinea pigs. As prostaglandin F2α (PGF2α) is an ARA metabolite and endogenous agonist of prostaglandin F receptor (FP), we have been suggested that down-regulation of PGF2α-FP receptor signalling pathway contributes to myopia onset. To test this hypothesis, this study determines whether: (i) retinal PGF2α levels decline during the development of form deprivation myopia (FDM) in guinea pigs; (ii) FP receptor agonism and antagonism alter emmetropization and myopia development. Pigmented guinea pigs were randomly assigned to normal vision and form-deprived groups. Ultraperformance liquid chromatography coupled with a mass spectrometer (UPLC-MS) measured retinal PGF2α levels 2 weeks after form deprivation (FD). The selective FP agonist, latanoprost acid (LAT) and its corresponding antagonist, AL8810, were peribulbarly injected into each group. An eccentric infrared photorefractor (EIR) monitored refraction. A-scan ultrasonography measured axial elongation (AL) and vitreous chamber depth (VCD). Tonometry measured the intraocular pressure (IOP). Retinal PGF2α levels declined in form-deprived eyes compared to those in normal eyes. Neither LAT nor AL8810 affected IOP with or without FD. On the other hand, after 4 weeks of daily 0.5 μg AL8810 treatment, a myopia of -1.99 ± 0.34 dioptre (D) developed, but LAT had no effect on emmetropization in a normal visual environment. Nevertheless, daily 30 μg LAT treatment for 4 weeks inhibited FDM development by 41% (vehicle control: -8.39 ± 0.45 D; LAT: -4.95 ± 0.39 D; two-way anova with repeated measures, p < 0.05). Down-regulation of PGF2α-FP receptor signalling pathway may contribute to myopia onset as retinal PGF2α declined in myopic eyes and antagonism of FP receptor by AL8810 induced a myopic shift in normal vision environment. Meanwhile, up-regulation of this pathway by LAT inhibited FDM development. However, the mechanism underlying LAT-induced FDM inhibition needs further clarification. This uncertainty exists because its inhibition of FDM suggests that LAT strengthens the scleral framework which reduces axial elongation. On the other hand, its IOP-lowering effect is attributed to thinning and weakening the scleral framework in glaucoma treatment.

Topics: Animals; Arachidonic Acid; Chromatography, High Pressure Liquid; Dinoprost; Disease Models, Animal; Down-Regulation; Guinea Pigs; Intraocular Pressure; Latanoprost; Mass Spectrometry; Myopia; Prostaglandins F, Synthetic; Receptors, Prostaglandin; Retina; Signal Transduction; Tonometry, Ocular; Up-Regulation

To determine whether latanoprost, a prostaglandin analog proven to be very effective in reducing intraocular pressure (IOP) in humans, can also slow myopia progression in the guinea pig form deprivation (FD) model.. Two-week-old pigmented guinea pigs underwent monocular FD and daily topical latanoprost (0.005%, n = 10) or artificial tears (control, n = 10) starting 1 week after the initiation of FD, with all treatments continuing for a further 9 weeks. Tonometry, retinoscopy, and high-frequency A-scan ultrasonography were used to monitor IOP, refractive error, and ocular axial dimensions, respectively.. Latanoprost significantly reduced IOP and slowed myopia progression. Mean interocular IOP differences (±SEM) recorded at baseline and week 10 were -0.30 ± 0.51 and 1.80 ± 1.16 mm Hg (P = 0.525) for the control group and 0.07 ± 0.35 and -5.17 ± 0.96 mm Hg (P < 0.001) for the latanoprost group. Equivalent interocular differences for optical axial length at baseline and week 10 were 0.00 ± 0.015 and 0.29 ± 0.04 mm (P < 0.001; control) and 0.02 ± 0.02 and 0.06 ± 0.02 mm (P = 0.202; latanoprost), and for refractive error were +0.025 ± 0.36 and -8.2 ± 0.71 diopter (D) (P < 0.001; control), and -0.15 ± 0.35 and -2.25 ± 0.54 D (P = 0.03; latanoprost).. In the FD guinea pig model, latanoprost significantly reduces the development of myopia. Although further investigations into underlying mechanisms are needed, the results open the exciting possibility of a new line of myopia control therapy.

Topics: Administration, Ophthalmic; Animals; Antihypertensive Agents; Axial Length, Eye; Disease Models, Animal; Disease Progression; Guinea Pigs; Intraocular Pressure; Latanoprost; Myopia; Ophthalmic Solutions; Retinoscopy; Sensory Deprivation; Tonometry, Ocular

To evaluate the influence of prostaglandin (PG) analogues on the ciliary zonular fibers of the crystalline lens using scanning electron microscopy (SEM) of rabbit eyes, and to measure the matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) levels of the aqueous humor and crystalline lens treated with topical PG analogues Methods: Fifty eyes from 25 New Zealand white rabbits were divided into five groups of five rabbits each. In the control group, balanced salt solution was administered via the topical route once a day to the eyes. The benzalkonium chloride (BAC) group was treated with 0.02% BAC, the Latanoprost group with 0.005% latanoprost, the Travoprost group with 0.004% Travoprost, and the Bimatoprost group with 0.03% Bimatoprost for 10 months. We examined the ciliary zonular fibers using SEM. We also measured the MMP and TIMP levels of the aqueous humor and crystalline lens.. SEM revealed some splitting of zonular fibers in eyes treated with topical PG analogues when compared with the control and BAC groups. The MMP-1 and TIMP-1 levels after treatment with the PG analogues did not differ significantly from the control and BAC groups (P > 0.05). There was no significant difference in MMP-1, MMP-3, TIMP-1, and MMP-1/TIMP-1 levels in the lens among all five groups.. PG analogues may induce zonular change in rabbits microscopically. There was no association between zonular changes and the levels of certain types of MMP or TIMP in the aqueous humor or crystalline lens after topical treatment with PG analogues.

Topics: Animals; Antihypertensive Agents; Aqueous Humor; Bimatoprost; Ciliary Body; Disease Models, Animal; Glaucoma; Intraocular Pressure; Latanoprost; Lens, Crystalline; Matrix Metalloproteinase 1; Matrix Metalloproteinase 3; Microscopy, Electron, Scanning; Ophthalmic Solutions; Prostaglandins, Synthetic; Rabbits; Tissue Inhibitor of Metalloproteinase-1

To compare the safety and efficacy of fixed-dose tafluprost/timolol combination (Taf/T-FDC) with those of fixed-dose latanoprost/timolol combination (Lat/T-FDC) by measuring the intraocular pressure (IOP)-lowering effect, ocular pharmacokinetics, and ocular surface toxicity.. The IOP-lowering effect of Taf/T-FDC and Lat/T-FDC in ocular normotensive monkeys was evaluated at 4 and 8 h after instillation in study A, at 12, 14, 16, and 18 h after instillation in study B, and at 24, 26, 28, and 30 h after instillation in study C. Drug penetration into the eye was evaluated by measuring the concentrations of timolol, tafluprost acid (active metabolic form of tafluprost), and latanoprost acid (active metabolic form of latanoprost) using liquid chromatography coupled with tandem mass spectrometry after single instillation of Taf/T-FDC or Lat/T-FDC to Sprague Dawley rats. Cytotoxicity following 1-30 min exposure of SV40-transformed human corneal epithelial cells to Taf/T-FDC or Lat/T-FDC was analyzed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assays. Undiluted and 10-fold diluted solutions of each FDC were evaluated.. The IOP-lowering effect of Taf/T-FDC was almost equivalent to that of Lat/T-FDC at 4-8 h after instillation. The peak IOP reduction of Taf/T-FDC and Lat/T-FDC was observed at 8 h after instillation, and there is no difference between the two. The difference between them was observed at 24-30 h after instillation, and Taf/T-FDC demonstrated a significantly greater IOP-lowering effect than Lat/T-FDC at 24-30 h after instillation. The IOP-lowering effect of Taf/T-FDC was sustained up to 30 h after instillation, while that of Lat/T-FDC had almost disappeared at 28 h after instillation. Timolol concentrations in aqueous humor after Taf/T-FDC instillation were higher than those after Lat/T-FDC instillation (Cmax, 3870 ng/mL vs 1330 ng/mL; AUCinf, 3970 ng·h/mL vs 1250 ng·h/mL). The concentrations of tafluprost acid and latanoprost acid in aqueous humor after instillation of Taf/T-FDC and Lat/T-FDC, respectively, were similar to those after instillation of mono-preparations of tafluprost and latanoprost, respectively. The cytotoxic effect of Taf/T-FDC to the human corneal epithelial cells was significantly lower than that of Lat/T-FDC at all evaluated time points in both undiluted and 10-fold diluted FDCs.. Taf/T-FDC provides increased IOP-lowering effect duration and lower potential ocular surface toxicity than Lat/T-FDC.

Topics: Animals; Antihypertensive Agents; Area Under Curve; Cell Line; Chromatography, Liquid; Disease Models, Animal; Drug Combinations; Female; Glaucoma; Humans; Intraocular Pressure; Latanoprost; Macaca fascicularis; Male; Metabolic Clearance Rate; Ocular Hypertension; Prostaglandins F; Prostaglandins F, Synthetic; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Time Factors; Timolol; Treatment Outcome

To assess the ability of latanoprost-eluting contact lenses to lower the intraocular pressure (IOP) of glaucomatous eyes of cynomolgus monkeys.. Preclinical efficacy study of 3 treatment arms in a crossover design.. Female cynomolgus monkeys with glaucoma induced in 1 eye by repeated argon laser trabeculoplasty.. Latanoprost-eluting low-dose contact lenses (CLLO) and high-dose contact lenses (CLHI) were produced by encapsulating a thin latanoprost-polymer film within the periphery of a methafilcon hydrogel, which was lathed into a contact lens. We assessed the IOP-lowering effect of CLLO, CLHI, or daily latanoprost ophthalmic solution in the same monkeys. Each monkey consecutively received 1 week of continuous-wear CLLO, 3 weeks without treatment, 5 days of latanoprost drops, 3 weeks without treatment, and 1 week of continuous-wear CLHI. On 2 consecutive days before initiation of each study arm, the IOP was measured hourly over 7 consecutive hours to establish the baseline IOP. Two-tailed Student t tests and repeated-measures analysis of variance were used for statistical analysis.. Intraocular pressure.. Latanoprost ophthalmic solution resulted in IOP reduction of 5.4±1.0 mmHg on day 3 and peak IOP reduction of 6.6±1.3 mmHg on day 5. The CLLO reduced IOP by 6.3±1.0, 6.7±0.3, and 6.7±0.3 mmHg on days 3, 5, and 8, respectively. The CLHI lowered IOP by 10.5±1.4, 11.1±4.0, and 10.0±2.5 mmHg on days 3, 5, and 8, respectively. For the CLLO and CLHI, the IOP was statistically significantly reduced compared with the untreated baseline at most time points measured. The CLHI demonstrated greater IOP reduction than latanoprost ophthalmic solution on day 3 (P = 0.001) and day 5 (P = 0.015), and at several time points on day 8 (P < 0.05).. Sustained delivery of latanoprost by contact lenses is at least as effective as delivery with daily latanoprost ophthalmic solution. More research is needed to determine the optimal continuous-release dose that would be well tolerated and maximally effective. Contact lens drug delivery may become an option for the treatment of glaucoma and a platform for ocular drug delivery.

Topics: Animals; Anterior Eye Segment; Antihypertensive Agents; Coated Materials, Biocompatible; Contact Lenses; Delayed-Action Preparations; Disease Models, Animal; Dose-Response Relationship, Drug; Equipment Design; Female; Follow-Up Studies; Glaucoma; Intraocular Pressure; Latanoprost; Macaca fascicularis; Prostaglandins F, Synthetic; Tomography, Optical Coherence; Tonometry, Ocular

Steroid-induced ocular hypertension (SIOH) is associated with topical and systemic use of steroids. However, SIOH-associated anterior and posterior segment morphological changes in rats have not been described widely. Here we describe the pattern of intraocular pressure (IOP) changes, quantitative assessment of trabecular meshwork (TM) and retinal morphological changes and changes in retinal redox status in response to chronic dexamethasone treatment in rats. We also evaluated the responsiveness of steroid-pretreated rat eyes to 5 different classes of antiglaucoma drugs that act by different mechanisms. Up to 80% of dexamethasone treated animals achieved significant and sustained IOP elevation. TM thickness was significantly increased and number of TM cells was significantly reduced in SIOH rats compared to the vehicle-treated rats. Quantitative assessment of retinal morphology showed significantly reduced thickness of ganglion cell layer (GCL) and inner retina (IR) in SIOH rats compared to vehicle-treated rats. Estimation of retinal antioxidants including catalase, superoxide dismutase and glutathione showed significantly increased retinal oxidative stress in SIOH animals. Furthermore, steroid-treated eyes showed significant IOP lowering in response to treatment with 5 different drug classes. This indicated the ability of SIOH eyes to respond to drugs acting by different mechanisms. In conclusion, SIOH was associated with significant morphological changes in TM and retina and retinal redox status. Additionally, SIOH eyes also showed IOP lowering in response to drugs that act by different mechanisms of action. Hence, SIOH rats appear to be an inexpensive and noninvasive model for studying the experimental antiglaucoma drugs for IOP lowering and neuroprotective effects.

Topics: Animals; Antihypertensive Agents; Brimonidine Tartrate; Catalase; Dexamethasone; Disease Models, Animal; Female; Glutathione; Intraocular Pressure; Latanoprost; Male; Ocular Hypertension; Oxidative Stress; Pilocarpine; Prostaglandins F, Synthetic; Quinoxalines; Rats, Sprague-Dawley; Retina; Sulfonamides; Superoxide Dismutase; Thiophenes; Timolol

The purpose of this study was to determine whether a better IOP reduction can be observed in conscious, normotensive monkeys treated with ONO-9054, a novel dual EP3 and FP receptor agonist, compared with prostaglandin F2α analogs.. The binding affinities and agonistic activities of ONO-AG-367, a carboxylic acid of ONO-9054, to prostanoid receptors were assessed. The IOP-lowering effect of ONO-9054 in monkeys was analyzed after a single (0.3, 3, or 30 μg/mL) or 7-day repeated (30 μg/mL, every day) topical ocular administration. Ophthalmologic and histopathologic evaluations of the eye were performed after 4-week ocular administration of ONO-9054 (30 μg/mL, twice a day) in monkeys.. The ONO-AG-367 exhibited high affinity for both EP3 and FP receptors and potent agonist activity, with EC50 values of 28.6 nM for the EP3 receptor and 22.3 nM for the FP receptor. Single and repeated topical ocular administration of ONO-9054 caused IOP reductions in normotensive monkeys. The maximum IOP reductions on day 7 observed with ONO-9054 (7.3 ± 0.8 mm Hg) were significantly greater than those observed with latanoprost (50 μg/mL, 4.9 ± 0.4 mm Hg) or travoprost (40 μg/mL, 5.1 ± 0.6 mm Hg). In ophthalmologic and histopathologic evaluations, slight and transient mydriasis was occasionally observed and no histopathologic lesions attributable to ONO-9054 were noted.. A more profound and longer-lasting reduction in IOP in normotensive monkeys can be observed with ONO-9054, which simultaneously stimulates both EP3 and FP receptors, compared with prostaglandin analogs.

Topics: Animals; Antihypertensive Agents; Dinoprost; Disease Models, Animal; Follow-Up Studies; Intraocular Pressure; Latanoprost; Macaca fascicularis; Ocular Hypotension; Ophthalmic Solutions; Prostaglandins F, Synthetic; Receptors, Prostaglandin; Receptors, Prostaglandin E, EP3 Subtype

To investigate the effects of topical prostaglandin analogue drugs on the differentiation of adipocytes.. Differentiation of 3T3-L1 preadipocytes was induced with isobutylmethylxanthine, dexamethasone, and insulin. 3T3-L1 cells were exposed to 0.008, 0.08, 0.2 µM of latanoprost and travoprost. Reverse transcription polymerase chain reaction for mRNA expression of lipoprotein lipase and peroxisome proliferator-activated receptor γ 2 (PPARγ2), and glycerol-3-phosphate dehydrogenase (G3PDH) assays were performed to examine the effects on early and late differentiation, respectively. Also, glycerol assays were done to evaluate the effect of prostaglandin analogues on lipolysis after differentiation.. Both prostaglandin analogues inhibited differentiation of preadipocytes. Topical prostaglandin analogues significantly decreased G3PDH activity, a marker of late differentiation. However, topical prostaglandin analogues did not change mRNA expressions of lipoprotein lipase and PPARγ2, markers of early differentiation. The activities of the early markers of differentiation were not changed significantly before and after growth arrest. Compared to latanoprost, travoprost decreased G3PDH activity more significantly (p < 0.05). Both prostaglandin analogues did not affect the lipolysis of differentiated adipocytes (p > 0.05).. Prostaglandin analogues display an inhibitory effect on the differentiation of adipocytes when the cells start to differentiate especially in the late stage of differentiation. Thus, commercial topical prostaglandin analogues may decrease the fat contents of eyelids.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Antihypertensive Agents; Cell Differentiation; Disease Models, Animal; Glaucoma; Latanoprost; Lipolysis; Mice; Neuroprotective Agents; Ophthalmic Solutions; Prostaglandins F, Synthetic; Prostaglandins, Synthetic

A new murine model of Ménière's disease has been developed, based on long-term administration of vasopressin. Induction of vestibular dysfunction in the present animal model can cause additional stress, by reducing inner ear blood flow. Latanoprost, a selective agonist for the FP prostanoid receptor, may become a new remedy for Ménière's disease.. The purpose of this study was to develop a more suitable animal model, with a closer resemblance to the pathophysiological process in Ménière's disease.. Adult CBA/J or ICR mice were treated by subcutaneous injection of vasopressin for 5 days up to 8 weeks. Morphological analyses were performed of the cochlea, vestibular end organs and endolymphatic sac. The effect of latanoprost on the development of endolymphatic hydrops was also examined.. All experimental animals showed mild to moderate endolymphatic hydrops, increasing in severity as the vasopressin treatment was prolonged. Animals treated with vasopressin for 8 weeks showed severe endolymphatic hydrops with partial loss of outer hair cells and spiral ganglion cells. These animals also had a reversible vestibular dysfunction following intratympanic injection of epinephrine. Latanoprost inhibited the development of endolymphatic hydrops caused by vasopressin.

Topics: Animals; Biopsy, Needle; Cochlea; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Endolymphatic Sac; Immunohistochemistry; Injections, Subcutaneous; Latanoprost; Meniere Disease; Mice; Mice, Inbred CBA; Mice, Inbred ICR; Prostaglandins F, Synthetic; Random Allocation; Reference Values; Risk Assessment; Time Factors; Vasopressins

The application of intratympanic latanoprost (PGF2α analog) has been recently used to alleviate vertigo, disequilibrium and to improve hearing in Meniere's disease patients. However, there is no known report on the effect of topically applied latanoprost on hearing and cochlear hemodynamic parameters including cochlear blood flow (CBF) and vascular conductance. Our goal was to assess the influence of topically applied latanoprost on cochlear blood flow (CBF) and hearing.. Twenty male Sprague-Dawley rats were randomly divided into the group A, 50 μl of latanoprost (1 ml containing 50 μg, n=10) and group B, 100 μl (1 ml containing 50 μg, n=10). Topical application of latanoprost was performed at the right side, and the left side was applied with phosphate buffered saline (PBS) as a negative control. Five rats at each group were used to measure cochlear blood flow (CBF). And the others at each group were used for hearing test by auditory brainstem response (ABR). After physiological examination, bullas were extracted. The changes of cochlear hair cells were observed by performing the field emission-scanning electron microscopy (FE-SEM).. The CBF of both groups was found to be decreased compared to the PBS applied left side. Significant decrement of CBF was observed in group B compared to the group A. Significant elevation of hearing threshold at high frequencies was observed in both groups compared to the PBS applied group. However, inner and outer hair cells were intact.. Topically administered latanoprost decreased the CBF and impaired hearing. Based on our findings, additional studies are required to evaluate the side effects of intratympanic latanoprost before its use in clinical practice.

Topics: Administration, Topical; Animals; Blood Flow Velocity; Cochlea; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Evoked Potentials, Auditory, Brain Stem; Hearing; Latanoprost; Male; Prostaglandins F, Synthetic; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values

To investigate the toxic-inflammatory effects of prostaglandin analogs on the ocular surface.. Twenty-three rats were divided into four groups. Bimatoprost 0.03% (I), latanoprost 0.005% (II), and travoprost 0.004% (III) were applied during 6 months; a control group (IV) received no treatment. Dysplasia and keratinization were evaluated on the ocular surface. In the subepithelial area, the number of lymphocytes and mast cells were counted morphologically, and collagen staining densities were compared subjectively in groups.. The ratio of keratinization was 3/12 and 1/10, in groups I and II. The lymphocyte cell counts were 1.4 ± 0.19, 2.2 ± 0.39, 2.27 ± 0.33, and 1.87 ± 0.35 (p > .05). The mast cell counts were 2.58 ± 0.5, 5.4 ± 1.1, 5.7 ± 0.58, and 3.0 ± 0.59. They were significantly higher in groups II and III than in group I (p < .05). Mean collagen density scores were 1.00 ± 0.85, 2.00 ± 0.00, and 1,73 ± 0.70. Group II and III scores were higher than group I scores (p < .05).. Latanoprost and travoprost seem to have more toxic-inflammatory effects on the ocular surface than bimatoprost.

Topics: Amides; Animals; Antihypertensive Agents; Bimatoprost; Cloprostenol; Conjunctiva; Conjunctival Diseases; Cornea; Corneal Diseases; Disease Models, Animal; Follow-Up Studies; Glaucoma; Intraocular Pressure; Latanoprost; Male; Ophthalmic Solutions; Prostaglandins F, Synthetic; Prostaglandins, Synthetic; Rats; Rats, Wistar; Travoprost

To characterize the microbead-induced ocular hypertension (OHT) mouse model and investigate its potential use for preclinical screening and evaluation of ocular hypotensive agents, we tested the model's responses to major antiglaucoma drugs.. Adult C57BL/6J mice were induced to develop OHT unilaterally by intracameral injection of microbeads. The effects of the most commonly used ocular hypotensive drugs, including timolol, brimonidine, brinzolamide, pilocarpine, and latanoprost, on IOP and glaucomatous neural damage were evaluated. Degeneration of retinal ganglion cells (RGCs) and optic nerve axons were quantitatively assessed using immunofluorescence labeling and histochemistry. Thickness of the ganglion cell complex (GCC) was also assessed with spectral-domain optical coherence tomography (SD-OCT).. A microbead-induced OHT model promptly responded to drugs, such as timolol, brimonidine, and brinzolamide, that lower IOP through suppressing aqueous humor production and showed improved RGC and axon survival as compared to vehicle controls. Accordingly, SD-OCT detected significantly less reduction of GCC thickness in mice treated with all three aqueous production suppressants as compared to the vehicle contol-treated group. In contrast, drugs that increase aqueous outflow, such as pilocarpine and latanoprost, failed to decrease IOP in the microbead-induced OHT mice.. Microbead-induced OHT mice carry dysfunctional aqueous outflow facility and therefore offer a unique model that allows selective screening of aqueous production suppressant antiglaucoma drugs or for studying the mechanisms regulating aqueous humor production. Our data set the stage for using GCC thickness assessed by SD-OCT as an imaging biomarker for noninvasive tracking of neuronal benefits of glaucoma therapy in this model.

Topics: Animals; Antihypertensive Agents; Aqueous Humor; Brimonidine Tartrate; Carbonic Anhydrase Inhibitors; Disease Models, Animal; Drug Evaluation, Preclinical; Feasibility Studies; Intraocular Pressure; Latanoprost; Mice; Mice, Inbred C57BL; Microspheres; Muscarinic Agonists; Ocular Hypertension; Optic Nerve; Pilocarpine; Prostaglandins F, Synthetic; Quinoxalines; Retinal Ganglion Cells; Sulfonamides; Thiazines; Timolol; Tomography, Optical Coherence

Benzalkonium chloride (BAK), a common preservative in eye drops, can induce ocular surface toxicity that may decrease glaucoma therapy compliance. The ocular hypotensive effect, pharmacokinetic (PK) profiles, and local tolerance of a preservative-free latanoprost 0.005% cationic emulsion (Catioprost(®)), and a BAK-preserved latanoprost 0.005% solution (Xalatan(®)), were compared.. The ocular hypotensive effect was evaluated in monkeys with elevated intraocular pressure (IOP) induced by laser photocoagulation of the trabecular meshwork. Each monkey (n=8) received both latanoprost formulations once daily for 5 consecutive treatment days in a crossover design with at least a 2-week washout period between treatments. IOP was measured at baseline (on day 1, no instillation), on vehicle treatment day (day 0), and on treatment days 1, 3, and 5 before drug instillation and then hourly for 6 h. In rabbits, the ocular and systemic concentrations of latanoprost free acid were determined following a single instillation and the local tolerance of twice daily instillations over 28 days was assessed.. Both the preservative-free and BAK-preserved latanoprost formulations shared the same efficacy profile with the maximum IOP reduction occurring 2 h after each morning dose (-15%, -20%, and -26%; -15%, -23%, and -23% on days 1, 3, and 5, respectively) and lasting through 24 h. The equivalence in efficacy was confirmed by the PK data demonstrating similar area under the curves (AUCs). While both formulations were well tolerated, the incidence of conjunctival hyperemia was reduced by 42% with the BAK-free latanoprost cationic emulsion.. In animal models, a preservative-free latanoprost cationic emulsion was as effective as Xalatan(®) for lowering IOP with an improved ocular tolerance profile.

Topics: Animals; Antihypertensive Agents; Benzalkonium Compounds; Cations; Chemistry, Pharmaceutical; Disease Models, Animal; Dose-Response Relationship, Drug; Emulsions; Eye; Female; Intraocular Pressure; Latanoprost; Macaca fascicularis; Male; Ocular Hypertension; Ophthalmic Solutions; Preservatives, Pharmaceutical; Prostaglandins F, Synthetic; Rabbits; Tissue Distribution; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Animals; Antihypertensive Agents; Benzalkonium Compounds; Cell Proliferation; Cells, Cultured; Conjunctiva; Cornea; Corneal Injuries; Disease Models, Animal; Drug Evaluation, Preclinical; Emulsions; Epithelium, Corneal; Eye Injuries; Humans; Ki-67 Antigen; Latanoprost; Male; Microscopy, Confocal; Mucin 5AC; Preservatives, Pharmaceutical; Prostaglandins F, Synthetic; Rats; Wound Healing

The IOP lowering effects of NCX 139, a new chemical entity comprising latanoprost amide and a NO-donating moiety, were compared to those of the respective des-nitro analog in in vitro assays and in rabbit and dog models of ocular hypertension. The NO donor, molsidomine as well as the prostamide bimatoprost (Lumigan(®)) and the prostaglandin agonist, latanoprost (Xalatan(®)) were also investigated for comparison. NCX 139 but not its des-nitro analog resulted in NO-mediated vascular relaxant effect in pre-contracted rabbit aortic rings (EC(50)=0.70±0.06 μM; E(max)=80.6±2.9%). Like bimatoprost (IC(50)=3.07±1.3 μM) or latanoprost (IC(50)=0.48±0.15 μM), NCX 139 displaced (3)H-PGF2α binding on recombinant human prostaglandin-F (FP) receptors with an estimated potency of 0.77±0.13 μM. In transient ocular hypertensive rabbits, bimatoprost and latanoprost were not effective while molsidomine elicited a dose-dependent reduction of IOP confirming the responsiveness of rabbits to NO but not to FP receptor agonists. NCX 139 tested at a therapeutically relevant dose, significantly lowered IOP while the des-nitro analog was not effective (0.03% NCX 139, Δ(max)=-12.8±2.0 mmHg). In glaucomatous dogs, 0.03% NCX 139 decreased IOP to a greater extent compared to an equimolar dose of the respective des-nitro derivative (Δ(max)=-4.6±1.0 and -2.7±1.3 mmHg, respectively for NCX 139 and its des-nitro analog). Albeit with low potency, NCX 139 also resulted effective in normotensive dogs while it did not reduce IOP in normotensive rabbits. NCX 139, a compound targeting two different and important mechanisms, is endowed with ocular hypotensive effects more evident in hypertensive conditions which may be of interest in the search of more effective treatments for hypertensive glaucoma.

Topics: Amides; Animals; Antihypertensive Agents; Aorta; Bimatoprost; Chromatography, High Pressure Liquid; Cloprostenol; Dinoprost; Disease Models, Animal; Dogs; Glaucoma; Intraocular Pressure; Latanoprost; Male; Molsidomine; Nitrates; Nitric Oxide; Nitric Oxide Donors; Ocular Hypertension; Prostaglandins F, Synthetic; Rabbits; Tandem Mass Spectrometry; Tonometry, Ocular; Vasodilation; Vasodilator Agents

The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as reference drug. NO, downstream effector cGMP, and latanoprost acid were determined in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 μg) and 0.12% (36 μg), respectively. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 μg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, respectively. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aqueous humor as was cGMP in aqueous humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension.

Topics: Administration, Topical; Animals; Antihypertensive Agents; Aqueous Humor; Cell Line; Ciliary Body; Cyclic GMP; Dinoprost; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Female; Glaucoma; Guanylate Cyclase; Intraocular Pressure; Iris; Latanoprost; Macaca fascicularis; Male; Nitric Oxide; Nitric Oxide Donors; Ocular Hypertension; Prostaglandins F, Synthetic; Rabbits; Rats; Tonometry, Ocular

The aim of this study was to use a validated acute rabbit model to test the toxicity of a novel formulation of fixed-combination travoprost 0.004%/timolol 0.5% ophthalmic solution, which contains the antimicrobial preservative polyquaternium-1 (PQ), compared with the commercial formulation of fixed combinations travoprost 0.004%/timolol 0.5% ophthalmic solution and latanoprost 0.005%/timolol 0.5% ophthalmic solution, which both contain the preservative benzalkonium chloride (BAK).. Adult male New Zealand albino rabbits (n=24) were randomly divided into four groups. Phosphate-buffered saline (PBS), travoprost/timolol PQ, travoprost/timolol BAK, or latanoprost/timolol BAK were instilled onto rabbit eyes one drop, 15 times at 5 minute intervals. The ocular surface reactions were investigated at hour 4 and day 1 using slit lamp examination; in-vivo confocal microscopy (IVCM) for cornea, limbus, and conjunctiva-associated lymphoid tissue (CALT); conjunctival impression cytology; and standard immunohistology in cryosections for detecting CD45+ infiltrating cells and MUC-5AC-labeled cells.. Travoprost/timolol PQ was better tolerated than travoprost/timolol BAK or latanoprost/timolol BAK. This improved tolerance was evident via clinical observation under slit lamp, IVCM in different layers of the cornea and conjunctiva, conjunctival impression cytology of superficial epithelium aspects, and immunohistochemistry for inflammatory infiltration of CD45+ cells in the cornea and goblet cell distribution. Travoprost/timolol PQ was similar to PBS in regards to in-vivo findings, the Draize test for ocular irritation, and epithelial and limbal aspects as evaluated with IVCM. Treatment with either travoprost/timolol PQ or PBS produced no obvious inflammatory infiltration inside and outside the CALT follicles, yielded similar IVCM toxicity scores and CD45+ cell counts, and eyes treated with either solution had normal goblet cells.. The fixed combination of travoprost/timolol with 0.001% PQ had decreased ocular surface toxicity relative to the BAK-containing solutions. The potential benefit to the human ocular surface with oncedaily dosing needs to be evaluated clinically.

Topics: Animals; Anti-Bacterial Agents; Antihypertensive Agents; Benzalkonium Compounds; Cell Survival; Cloprostenol; Conjunctiva; Disease Models, Animal; Drug Combinations; Epithelium, Corneal; Latanoprost; Male; Ocular Hypertension; Ophthalmic Solutions; Polymers; Preservatives, Pharmaceutical; Prostaglandins F, Synthetic; Rabbits; Timolol; Travoprost; Treatment Outcome

Purpose. To determine the neuroprotective properties of a latanoprost acid derivative (ACS67) that donates the gas hydrogen sulfide (H(2)S). Methods. Ischemia to the rat retina was induced by elevation of intraocular pressure. Electroretinograms (ERGs) were recorded and the retinas analyzed 2 days later by immunohistochemistry, Western blot analysis, and RT-PCR. Hydrogen peroxide (H(2)O(2)) was used to impose an insult on RGC-5 cells in culture. The nature of the insult to cultures was quantified by the resazurin-reduction assay procedure, staining for reactive oxygen species (ROS) and for apoptosis. ACS67, its sulfurated moiety (ACS1), and latanoprost were tested for both their toxicity and ability to blunt the negative effect of H(2)O(2) on RGC-5 cells. In addition, an assay was used to see whether any of the substances influenced glutathione (GSH) levels in RGC-5 cells. Results. Partial damage to the retina in situ after ischemia was characterized by an alteration of the ERG, a reduction in the retinal localization of specific antigens and a reduction and elevation of defined retinal proteins and mRNAs. Optic nerve axonal proteins were also drastically reduced by ischemia. Most of these changes were significantly blunted by an intravitreal injection of ACS67 directly after ischemia. ACS67, ACS1, and the antioxidant epigallocatechin gallate (EGCG) all stimulated GSH levels and significantly attenuated H(2)O(2)-induced toxicity to RGC-5 cells, whereas latanoprost did not. Conclusions. ACS67 acts as an H(2)S donor through its donating moiety ACS1 and as a consequence is able to act as a neuroprotectant.

Topics: Animals; Blotting, Western; Caspases; Cells, Cultured; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Electroretinography; Fluorescent Antibody Technique, Indirect; Glial Fibrillary Acidic Protein; Glutathione; Hydrogen Peroxide; Hydrogen Sulfide; Latanoprost; Nitric Oxide Synthase Type I; Oxidative Stress; Prostaglandins F, Synthetic; Rats; Reperfusion Injury; Retinal Diseases; Retinal Ganglion Cells; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thioctic Acid; Thy-1 Antigens

To investigate quantitatively the effect of elevated intraocular pressure (IOP) on the microvasculature of the optic nerve with and without topical treatment with two hypotensive drugs, timolol and latanoprost.. Three groups of rats underwent cauterization of three episcleral veins to produce elevated IOP in the right eye. Two of these groups were treated with timolol or latanoprost for 3 months. Eyeballs were incubated with anti-GLUT-1 polyclonal antibody. GLUT-1-positive capillaries of the optic nerve head (ONH) and optic nerve exit (ON) were examined and analyzed for their number per square millimeter, volume fraction, length per unit volume, surface area per unit volume, and mean diameter.. An increase in IOP resulted in a significant decrease in microvessel density in the laminar region (LR) and postlaminar region (PR) and ON compared with the control group. The other parameters fell significantly in all regions of the optic nerve. Topical treatment with timolol or latanoprost did not modify the density of the capillaries, although the other parameters increased significantly compared with the untreated experimental group. Additionally, the mean diameter of the capillaries in the LR and the PR recovered after treatment.. The results indicate that the capillaries of the LR and the PR of the ONH are the most susceptible to IOP elevation. The authors suggest that timolol and latanoprost have a certain vascular action by increasing the available blood volume, surface area per unit volume, length per unit volume, and diameter of the capillaries of the ONH in these two regions.

Topics: Administration, Topical; Animals; Antihypertensive Agents; Capillaries; Disease Models, Animal; Glucose Transporter Type 1; Immunoenzyme Techniques; Intraocular Pressure; Latanoprost; Male; Ocular Hypertension; Optic Disk; Optic Nerve; Prostaglandins F, Synthetic; Rats; Rats, Wistar; Timolol

The aim of this study was to evaluate the reaction of Müller cells in an experimental rat model of intraocular pressure (IOP) and their response to treatment with ocular hypotensive drugs. Episcleral vein cauterization in unilateral eyes of Wistar rats was performed to produce elevated IOP. The animals were divided into five groups: control, experimental, and experimental treated with timolol, latanoprost or brimonidine. Histological sections of retina were studied by immunochemistry with antibodies to glial fibrillary acidic protein (GFAP), and the percentage of labeled area was measured to evaluate the degree of reactive gliosis. In the experimental group, the Müller cells showed hypertrophy and a significant increase in GFAP (4.39+/-0.32%) in relation to retinas of the control group (2.05+/-0.14%). Gliosis was detected in all three treated groups, with a varying increase in GFAP intensity. The timolol-treated group showed the most intense and persistent glial reactivity after 3 months of treatment (13.89+/-0.63%). Treatment with brimonidine, however, resulted in a decrease in the level of GFAP immunoreactivity (8.37+/-0.4%). The group treated with latanoprost showed the lowest glial reactivity (4.8+/-0.36%). Given that all three drugs are effective hypotensive agents, their neuroprotective effect could be related with other factors, such as gliosis, which, over long periods may have noxious effects on the neurons. Thus, hypotensives like brimonidine, and specially latanoprost, may afford greater neuroprotection to the ganglion cells by attenuating the retinal glial reaction.

Topics: Animals; Antihypertensive Agents; Brimonidine Tartrate; Disease Models, Animal; Glaucoma; Glial Fibrillary Acidic Protein; Gliosis; Intraocular Pressure; Latanoprost; Male; Neuroglia; Prostaglandins F, Synthetic; Quinoxalines; Rats; Rats, Wistar; Retina; Timolol; Tonometry, Ocular

Although some of the COX-2 metabolites and prostaglandins have been implicated in stroke and excitotoxicity, the role of prostaglandin F(2alpha) (PGF(2alpha)) and its FP receptor have not been elucidated in the pathogenesis of ischemic-reperfusion (I/R) brain injury. Here we investigated the FP receptor's contribution in a unilateral middle cerebral artery (MCA) occlusion model of focal cerebral ischemia in mice. The MCA in wild type (WT) and FP knockout (FP(-/-)) C57BL/6 male mice was transiently occluded with a monofilament for 90 min. After 96 h of reperfusion, the FP(-/-) mice had 25.3% less neurological deficit (P < 0.05) and 34.4% smaller infarct volumes (P < 0.05) than those of the WT mice. In a separate cohort, physiological parameters were monitored before, during, and after ischemia, and the results revealed no differences between the groups. Because excitotoxicity is an acute mediator of stroke outcome, the effect of acute NMDA-induced neurotoxicity was also tested. Forty-eight hours after unilateral intrastriatal NMDA injection, excitotoxic brain damage was 20.8% less extensive in the FP(-/-) mice (P < 0.05) than in the WT counterparts, further supporting the toxic contribution of the FP receptor in I/R injury. Additionally, we investigated the effect of post-treatment with the FP agonist latanoprost in mice subjected to MCA occlusion; such treatment resulted in an increase in neurological deficit and infarct size in WT mice (P < 0.05), though no effects were observed in the latanoprost-treated FP(-/-) mice. Together, the results suggest that the PGF(2alpha) FP receptor significantly enhances cerebral ischemic and excitotoxic brain injury and that these results are of importance when planning for potential development of therapeutic drugs to treat stroke and its acute and/or long term consequences.

Topics: Analysis of Variance; Animals; Antihypertensive Agents; Brain Infarction; Brain Injuries; Brain Ischemia; Disease Models, Animal; Excitatory Amino Acid Agonists; Latanoprost; Mice; Mice, Inbred C57BL; Mice, Knockout; N-Methylaspartate; Nervous System Diseases; Prostaglandins F, Synthetic; Receptors, Prostaglandin; Receptors, Prostaglandin E

This study was planned to investigate the neuroprotective potentials of three commercially available prostaglandin analogues (PGA), in the ischemia and reperfusion model (I/R). Thirty New Zealand rabbits were divided into 5 groups and except for the control group (non-ischemic, non-treated), 0.9% NaCl, bimatoprost, latanoprost, or travoprost were applied to both eyes of animals of the respective groups for 1 week. At the end of treatment, ischemia was induced in both eyes of the 4 treatment groups by anterior chamber irrigation of the animals for 60 min. Following 24 h reperfusion, the animals were sacrificed. Enucleated eyes and retinal tissues were investigated by light microscopy, electron microscopy, immunohistochemicstry for retinal histopathology, intracellular and apoptotic cells and by retinal morphometry. Vitreous samples were biochemically investigated for probable role of reactive oxygen species, by measuring xanthine oxidase (XO) activity. Analysis of morphometric measurements and vitreous XO activity revealed significant differences between the PGA-treated groups and the NaCl-treated group (P<0.05). Similarly, apoptotic cell counts in different retinal layers showed that PGA-treated groups had fewer apoptotic cells in all retinal layers than the NaCl-treated ischemic group (P<0.05). PGA may have high protective potential for different retinal layers and cells. Biochemical analysis of vitreous showed that all PGAs decreased vitreous XO activity significantly compared to the NaCl-treated group (P<0.05). However we could not find any statistically significant differences among the analogues. PGAs may reduce the injury induced by I/R, through the inhibition of XO activity, and it seems that their effects are elicited through numerous pathways.

Topics: Amides; Animals; Antihypertensive Agents; Apoptosis; Bimatoprost; Cloprostenol; Disease Models, Animal; Latanoprost; Male; Neuroprotective Agents; Prostaglandins F, Synthetic; Prostaglandins, Synthetic; Rabbits; Reactive Oxygen Species; Reperfusion Injury; Retina; Retinal Diseases; Travoprost; Vitreous Body; Xanthine Oxidase

To evaluate the influence of some widely used antiglaucoma agents on angiogenesis in a novel rat cornea model.. 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.. 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).. 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.

Topics: Animals; Antihypertensive Agents; Brimonidine Tartrate; Corneal Neovascularization; Corneal Stroma; Disease Models, Animal; Drug Implants; Fibroblast Growth Factor 2; Latanoprost; Prostaglandins F, Synthetic; Quinoxalines; Rats; Rats, Wistar; Sulfonamides; Thiophenes; Timolol

The aim of the present study is to evaluate the neuroprotective effect of two antiglaucomatous substances, regardless of their hypotensive effect in the eye. Brimonidine, which does not reduce IOP when administered intraperitoneally, and latanoprost, which has a renowned hypotensive effect topically. We examined rat retinal ganglion cell (RGC) survival and size distribution in experimental glaucoma in response to different glaucomatous agents. IOP was elevated by episcleral vein cauterization (EVC) prior to the application of different treatments: (I) PBS application (control group), (II) intraperitoneal administration of brimonidine (a general hypotensive agent), (III) topical application of latanoprost (an ocular hypotensive agent), and (IV) latanoprost combined with brimonidine. After 12 weeks, RGCs were retrogradely labeled with fluorogold and RGC density was analyzed. EVC caused a significant increase (42%) in IOP in each group before drug treatment. After 12weeks of EVC, RGC survival in control vs. EVC rats was 78.9+/-3.2%. No IOP reduction was observed in brimonidine injected rats, but RGC survival at 12 weeks was total (103.7+/-2.7%). In latanoprost treated rats, IOP dropped by around 22% and 94.7+/-3.7% of the RGC population survived. Finally in the latanoprost+brimonidine combined group, IOP was significantly reduced by 25% and 94.4+/-2.2% of RGCs survived. Surprisingly, whereas EVC led to a 6% increase in RGC soma size, brimonidine treatment was associated with a 9% reduction in the soma size of RGCs at 12 weeks. We conclude that brimonidine exerts a neuroprotective effect via a mechanism which is independent of IOP reduction. These findings indicate that cell survival in glaucoma may be enhanced by neuroprotective strategies which are independent of IOP reduction. No synergistic neuroprotective effect was observed when both treatments were applied simultaneously.

Topics: Animals; Antihypertensive Agents; Brimonidine Tartrate; Cell Survival; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; Glaucoma, Open-Angle; Intraocular Pressure; Latanoprost; Neuroprotective Agents; Prostaglandins F, Synthetic; Quinoxalines; Rats; Rats, Sprague-Dawley; Retinal Ganglion Cells

To compare the ocular hypotensive effects of 15-keto latanoprost (KL) with the commercial preparation of latanoprost (Xalatan; Pfizer, New York, NY) in monkey eyes with laser-induced unilateral glaucoma and to evaluate the effects of topical 0.005% KL on aqueous humor dynamics in normal monkey eyes.. Intraocular pressure (IOP) was measured hourly for 6 hours beginning at 9:30 AM on day 1 (untreated baseline); day 2 (vehicle only); and treatment days 1, 3, and 5 (topical, 30 microL of study drug) in the glaucomatous eyes of four to eight monkeys with unilateral laser-induced glaucoma. KL concentrations of 0.0001%, 0.001%, and 0.01% and latanoprost at 0.005% were studied separately, with a minimum washout period of 2 weeks between studies. Tonographic outflow facility (C) and fluorophotometric aqueous humor flow rates (F) were measured in nine normal monkeys before and after a single topical dose of 0.005% KL in one eye, with a vehicle-only control in the fellow eye.. When applied once daily to glaucomatous monkey eyes, all three concentrations of KL and a 0.005% concentration of latanoprost produced significant (P < 0.05) reductions in IOP, with the maximum reduction on treatment day 5, regardless of the drug or concentration studied. The maximum reduction (P < 0.001) from vehicle-only baseline IOP was (mean +/- SEM) 3.0 +/- 0.3 mm Hg (9%) for 0.0001% KL, 7.6 +/- 0.6 mm Hg (23%) for 0.001% KL, 6.3 +/- 0.4 mm Hg (18%) for 0.01% KL, and 6.6 +/- 0.6 mm Hg (20%) for 0.005% latanoprost. After application of a single dose of 0.005% KL in nine normal monkey eyes, neither C nor F was altered (P > 0.80) when compared with untreated baseline values or vehicle-treated control eyes.. The reduction in IOP produced by 0.001% KL was equivalent to, and at some measured time points, greater than the effect produced by 0.005% latanoprost. The IOP reduction by KL in normal monkeys appeared to have no effect on aqueous humor production or tonographic outflow facility and may thus indicate a drug-induced increase in uveoscleral outflow.

Topics: Animals; Antihypertensive Agents; Aqueous Humor; Dinoprost; Disease Models, Animal; Female; Fluorophotometry; Glaucoma; Intraocular Pressure; Latanoprost; Macaca fascicularis; Prostaglandins F, Synthetic; Tonometry, Ocular

Intraocular pressure (IOP)-lowering effects of investigational antiglaucoma drugs often need comparison with existing drugs, but detailed data showing comparative efficacy of antiglaucoma drugs with different mechanism of action has not been reported so far. This study was designed to establish baseline information of the IOP-lowering effect of three currently used antiglaucoma drugs in three experimental models in rabbits, so that they act as a benchmark for the efficacy evaluation of the future experimental antiglaucoma drugs. The IOP-lowering effect of single-drop application of pilocarpine, timolol and latanoprost was studied in normotensive, water loading and steroid-induced models of glaucoma in rabbits. The noncontact tonometer was used for the first time to estimate IOP in rabbits. The peak IOP-lowering effect of pilocarpine, timolol and latanoprost in normotensive rabbit eye was 18.23%, 20% and 22.56%, respectively. In water-loading model, the maximum protection against the rise in IOP was shown by latanoprost (40.27%), followed by timolol (31.39%) and pilocarpine (28.91%). In steroid-pretreated rabbit eyes, peak IOP-lowering effects of pilocarpine, timolol and latanoprost were 25.65%, 34.21% and 35.06%, respectively. Therefore, the latanoprost was found to be most effective in all three models followed by timolol and pilocarpine. The results of this study can be used for future preclinical investigations for the assessment of IOP-lowering activity of potential antiglaucoma drugs.

Topics: Adrenal Cortex Hormones; Animals; Anterior Chamber; Cholinergic Agonists; Conjunctival Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Glaucoma; Instillation, Drug; Intraocular Pressure; Latanoprost; Male; Ophthalmic Solutions; Pilocarpine; Prednisolone; Prostaglandins F, Synthetic; Rabbits; Timolol; Tonometry, Ocular; Treatment Outcome

The aim of the present study was to evaluate the effects of the prostaglandin F2 alpha analog, latanoprost, on the intraocular pressure (IOP) in rodent eyes. Rodents have been increasingly used in glaucoma research; however, conflicting results regarding the actions of prostaglandins on rodent IOP have been published. In Wistar rats, a single dose of latanoprost (60 ng) produced a biphasic change in IOP: an initial rise in pressure (2.1+/-0.7 mmHg) peaking at 2 h, followed by a prolonged hypotension with a peak reduction in IOP (5.2+/-0.7 mmHg) at 5 h. Both the hyper and hypotensive actions of latanoprost were dose-related with ED50 values of 108 and 5.2 ng, respectively. These responses were antagonized by pretreatment with 4% pilocarpine. In Brown Norway rats and C57BL/6 mice, a single dose of latanoprost also produced a biphasic response in IOP with an initial rise in pressure peaking between 1 and 2 h, followed by prolonged hypotension from 4 to 8 h. These results demonstrate that in rodents the IOP response to topical latanoprost is characterized by an initial hypertension followed by a prolonged hypotension. This prolonged hypotension is similar to that measured in monkeys and humans. Taken together, these results support the idea that rodents can serve as in vivo models to study the actions of ocular hypotensive agents, such as prostaglandins.

Topics: Animals; Antihypertensive Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Intraocular Pressure; Latanoprost; Male; Mice; Mice, Inbred C57BL; Prostaglandins F, Synthetic; Rats; Rats, Inbred BN; Rats, Wistar; Species Specificity

The rat has been used increasingly in glaucoma research, but many aspects regarding the regulation of its intraocular pressure (IOP) are still unknown. For example, it is not clear whether glaucoma medications can lower IOP in the rat similarly to human. This information will be valuable in evaluating this animal model for its usefulness in predicting drug effects in patients. Hence, we tested the acute IOP effects of selected glaucoma drugs topical administered onto the rat eye. In these studies, IOP was measured using the Tono-Pen XL tonometer. After a correlation between the IOP reported by the Tono-Pen and actual IOP was established, IOP measurements were obtained in slightly sedated adult rats. Effects of glaucoma medications were tested in two groups of animals. One group (12 h/L) was housed in a 12-h/12-h light/dark cycle. The other (24 h/L) was housed under constant light. Exposure of the animals to constant light increased their basal IOP from 20.5+/-0.6 mmHg (mean+/-S.E.M., n=12) to 32.0+/-0.5 mmHg. At 3 h after topical administration, Betoptic S lowered IOP by 4.3+/-1.7 mmHg (n=6) and 3.7+/-0.3 mmHg (n=6) in the 12 and 24h/L rats, respectively. Pilocarpine did not affect rat IOP. Xalatan produced a biphasic response in the rat. At 3h after topical administration, it increased IOP by 7.9+/-1.4 and 7.0+/-1.0 mmHg in the 12 and 24 h/L rats, respectively. By the next day, it decreased IOP by 3.0+/-1.0 and 6.0+/-0.8 mmHg in the 12 and 24 h/L rats, respectively. The IOP-enhancing effect of Xalatan was dose-dependent. The present study indicates that IOP responses of the rat to different pharmacological agents are not identical to those of the human. In the rat, Betoptic S, but not pilocarpine, lowered IOP. Xalatan initially increased then decreased IOP.

Topics: Animals; Antihypertensive Agents; Betaxolol; Disease Models, Animal; Dose-Response Relationship, Drug; Intraocular Pressure; Latanoprost; Male; Pilocarpine; Prostaglandins F, Synthetic; Rats; Rats, Inbred BN; Rats, Wistar; Species Specificity; Tonometry, Ocular

To establish a mouse model for the pharmacological analysis of antiglaucoma drugs, considering the effect of variations in IOP during 24 hours on the drugs' effects, and to evaluate the effect of a newly developed FP agonist, tafluprost, on mouse IOP, in comparison with three clinically available prostaglandin (PG) analogues.. Inbred adult ddY mice were bred and acclimatized under a 12-hour light-dark cycle. With mice under general anesthesia, a microneedle method was used to measure IOP. A single drop of 3 muL of either drug or vehicle solution was topically applied once into one eye in each mouse, in a blinded manner, with the contralateral, untreated eye serving as the control. IOP reduction was evaluated by the difference in IOP between the treated and untreated eyes in the same mouse. First, to determine the period feasible for demonstrating a larger magnitude of ocular hypotensive effect, the 24-hour diurnal variation in mouse IOP was measured, and 0.005% latanoprost was applied at the peak or trough time of variation in 24-hour IOP. The time point of the most hypotensive effect was selected for further studies, to evaluate the effects of PG analogues. Second, mice received tafluprost (0.0003%, 0.0015%, 0.005%, or 0.015%), latanoprost (0.001%, 0.0025%, or 0.005%), travoprost (0.001%, 0.002%, or 0.004%), or isopropyl unoprostone (0.03%, 0.06%, or 0.12%), and each corresponding vehicle solution. IOP was then measured at 1, 2, 3, 6, 9, and 12 hours after drug administration. The ocular hypotensive effects of the other three PG analogues were compared with that of tafluprost. All experiments were conducted in a masked study design.. The IOP in the untreated mouse eye was higher at night than during the day. Latanoprost significantly lowered IOP at night (21.4%), compared with the IOP in the untreated contralateral eye 2 hours after administration. The maximum IOP reduction was 20.2% +/- 2.0%, 18.7% +/- 2.5%, and 11.2% +/- 1.8% of that in the untreated eye 2 hours after administration of 0.005% tafluprost, 0.005% latanoprost, and 0.12% isopropyl unoprostone, respectively, whereas it was 20.8% +/- 4.6% at 6 hours with 0.004% travoprost (n = 7 approximately 17). The order of ocular hypotensive effects of three clinically used PG analogues in mice was comparable to that in humans. Area under the curve (AUC) analysis revealed dose-dependent IOP reductions for each PG analogue. Tafluprost 0.005% decreased IOP more than 0.005% latanoprost at 3, 6, and 9 hours (P = 0.001-0.027) or 0.12% unoprostone at 2, 3, and 6 hours (P = 0.0004-0.01).. The 24-hour variation in mouse eyes should be taken into consideration when evaluating the reduction of IOP. The mouse model was found to be useful in evaluating the pharmacological response to PG analogues. A newly developed FP agonist, 0.005% tafluprost, lowered normal mouse IOP more effectively than did 0.005% latanoprost.

Topics: Animals; Antihypertensive Agents; Circadian Rhythm; Cloprostenol; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Intraocular Pressure; Latanoprost; Male; Mice; Mice, Inbred Strains; Ophthalmic Solutions; Prostaglandins F; Prostaglandins F, Synthetic; Time Factors; Travoprost

To compare the ocular hypotensive effect of the commercially available preparations of bimatoprost or travoprost added to latanoprost in monkey eyes with laser-induced unilateral glaucoma.. Four monkeys with unilateral laser-induced glaucoma were used in each treatment group and received drops in the glaucomatous eye only. Intraocular pressure (IOP) was measured hourly for 6 hours, beginning at 9:30 am on day 1 (untreated baseline), days 6 and 7 (single-agent therapy), and days 13 and 14 (2-drug combination therapy). On days 2 through 7, 1 drop of the scheduled single agent was given immediately after the 9:30 am IOP measurement, and on days 8 through 14, the second scheduled drug was given 5 minutes after the first. The following 5 different dosing protocols were studied: latanoprost with bimatoprost added, bimatoprost with latanoprost added, latanoprost with travoprost added, travoprost with latanoprost added, and latanoprost with a second dose of latanoprost added.. There were no statistically significant (P =.95) differences among the mean baseline IOPs in any of the 5 treatment groups. When applied as single agents, latanoprost, bimatoprost, and travoprost all produced significant (P<.05) and equivalent (P =.98) reductions in IOP. The mean +/-SEM maximum reduction (P<.05) from baseline IOP was 7.0 +/- 0.4 mm Hg (20% reduction) with travoprost alone, 6.5 +/- 1.6 mm Hg (18%) with bimatoprost alone, and 7.5 +/- 1.0 mm Hg (22%) with latanoprost alone. The mean +/-SEM maximum additive reductions in IOP were 3.0 +/- 0.6 mm Hg (P<.05) for travoprost added to latanoprost; 2.0 +/- 0.4 mm Hg (P<.05) for latanoprost added to travoprost; 4.8 +/- 1.3 mm Hg (P<.05) for bimatoprost added to latanoprost; 4.3 +/- 0.6 mm Hg (P<.05) for latanoprost added to bimatoprost; and 0.3 +/- 0.5 mm Hg (P>.60) for latanoprost added to itself. The combination of bimatoprost and latanoprost produced a greater (P<.05) lowering of IOP at trough and peak than the combination of travoprost and latanoprost.. Latanoprost, bimatoprost, and travoprost used as monotherapy produced significant and equivalent reductions in IOP in glaucomatous monkey eyes. The IOP effects of the commercial concentrations of bimatoprost or travoprost were additive to that of latanoprost, with bimatoprost showing a greater additive response than travoprost. Clinical Relevance Because treatment with multiple medications is common among patients with glaucoma, determining which glaucoma medications produce an additive ocular hypotensive response when used in combination has practical implications for clinicians.

Topics: Amides; Animals; Antihypertensive Agents; Bimatoprost; Cloprostenol; Disease Models, Animal; Drug Therapy, Combination; Female; Glaucoma; Intraocular Pressure; Latanoprost; Lipids; Macaca fascicularis; Prostaglandins F, Synthetic; Travoprost

Xalatan treatment has been reported both clinically and experimentally to promote recurrences of herpetic keratitis. Our goal was to determine the effects of topical Xalatan and its components on the recovery of ocular herpes simplex virus type 1 (HSV-1) in the Induced Reactivation (IR) and Spontaneous Shedding (SS) HSV-1/NZW rabbit latency models using virological outcome measures.. HSV-1 latently-infected rabbits in both the IR and SS studies were divided into different topical treatment groups to evaluate commercial Xalatan, its preservatives, and vehicle against appropriate negative and positive controls. In the IR Studies, 91 rabbits received intra-stromal injections of water in both eyes to promote ocular shedding of latent HSV-1. All eyes were then treated and cultured for 10 days. In the SS Studies, 65 rabbits were treated and cultured in both eyes for 30 days.. Dexamethasone, a positive control, promoted extensive ocular shedding of HSV-1 in both the IR and SS Models. In general, neither Xalatan nor its components demonstrated any adverse effects, but some experimental variation was noted. All groups demonstrated comparable recovery of latent HSV-1 from respective trigeminal ganglia.. Our experimental studies support the world wide clinical epidemiological experience that commercial Xalatan does not appear to promote HSV-1 ocular shedding.

Topics: Administration, Topical; Animals; Antihypertensive Agents; Cornea; Disease Models, Animal; Female; Herpesvirus 1, Human; History, 20th Century; Keratitis, Herpetic; Latanoprost; Prostaglandins F, Synthetic; Rabbits; Recurrence; Trigeminal Ganglion; Virus Activation

Latanoprost, a selective FP prostanoid receptor agonist used in the treatment of glaucoma, has a hypertrichotic side effect. Using the macaque model of androgenetic alopecia, we examined the effect of latanoprost on hair growth. Eight monkeys were divided into 2 groups; one group received a daily topical application of 50 microg/ml of latanoprost for 5 months; a control group had a daily application of vehicle. For an additional 3 months, 2 monkeys from each group were given 500 microg/ml latanoprost, while the remaining monkeys continued with the previous treatment. Hair growth was evaluated by monthly photographs and phototricho-graphic analysis. Fifty microg/ml of latanoprost caused minimal hair growth. Latanoprost at 500 microg/ml induced moderate to marked hair regrowth with 5-10% conversion of vellus hairs to intermediary or terminal hairs. The vehicle group showed no effect. Further evaluation of latanoprost as an agent for treatment of human androgenetic alopecia is indicated.

Topics: Administration, Topical; Alopecia; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hair; Latanoprost; Macaca; Male; Pilot Projects; Prostaglandins F, Synthetic; Random Allocation; Reference Values; Treatment Outcome

To study the effect of acute or chronic intracameral injection of hyaluronic acid on intraocular pressure (IOP) in rats.. Acute or chronic injections of hyaluronic acid were performed unilaterally in the rat eye's anterior chamber, whereas the contralateral eye was injected with saline solution. IOP was assessed daily or weekly by a tonometer in conscious rats. IOP was also assessed in both experimental groups at several intervals during the light-dark cycle.. A single injection of hyaluronic acid induced an increase of IOP that lasted for 8 days (P < 0.01), whereas its chronic administration during 9 weeks induced a significant and sustained increase in IOP, compared with the eye injected with vehicle (P < 0.01). This hyaluronic acid-induced hypertension was significantly decreased by the application of 1 drop of brimonidine (0.2%), latanoprost (0.005%), or timolol (0.5%). Significant daily variations of IOP were observed in both control and hyaluronic acid-injected eyes, peaking during the dark phase (P < 0.001, ANOVA).. These results suggest that the intracameral administration of hyaluronic acid could be a model of ocular hypertension in rats.

Topics: Animals; Anterior Chamber; Antihypertensive Agents; Brimonidine Tartrate; Disease Models, Animal; Hyaluronic Acid; Injections; Intraocular Pressure; Latanoprost; Male; Ocular Hypertension; Prostaglandins F, Synthetic; Quinoxalines; Rats; Rats, Wistar; Timolol; Tonometry, Ocular

Subconjunctival fibroblasts play a critical role in scarring and treatment failure in fistulizing surgery for glaucoma. The proliferation of subconjunctival fibroblasts appears to be modulated by topical glaucoma medications. This study was conducted to evaluate the effects of latanoprost and brimonidine on subconjunctival fibroblast proliferation in rabbit eyes.. Twelve pigmented Dutch-belted rabbits were divided into treatment groups of four: latanoprost 0.005%, brimonidine 0.2%, or balanced saline solution (BSS) each were administered to one treatment group, both eyes of each rabbit, twice a day, 6 days a week for 10 weeks. The eyes were then enucleated along with the conjunctiva, fixed, processed, and evaluated by light microscopy and immunohistochemistry using anti-proliferating cell nuclear antigen (PCNA) and anti-muscle-specific actin antibody (HHF-35). Fibroblast cell counts were performed at magnification x40.. In all groups, few inflammatory cells were seen in the subconjunctival space under light microscopy. PCNA staining revealed a statistically significant increase in the mean number of labeled fibroblasts in the group receiving brimonidine compared with the control (BSS) group. The group receiving latanoprost also had a significantly higher mean number of labeled fibroblasts than the groups receiving brimonidine or BSS. Only a few fibroblasts stained positively with the anti HHF antibody. Eyes treated with latanoprost, however, had significantly higher numbers of positively labeled cells than eyes treated with brimonidine or BSS.. When applied to rabbit eyes, latanoprost and brimonidine appear to increase the number of positively labeled proliferating subconjunctival fibroblasts.

Topics: Adrenergic alpha-Agonists; Animals; Brimonidine Tartrate; Cell Count; Cell Division; Conjunctiva; Disease Models, Animal; Fibroblasts; Glaucoma; Intraocular Pressure; Latanoprost; Microfilament Proteins; Ophthalmic Solutions; Proliferating Cell Nuclear Antigen; Prostaglandins F, Synthetic; Quinoxalines; Rabbits