Morphological changes in the anterior eye segment after long-term treatment with different receptor selective prostaglandin agonists and a prostamide.
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PURPOSE: To investigate long-term changes in the anterior segment of primate eyes treated for one year with different prostaglandin agonists and a prostamide. The results were compared with those obtained after vehicle treatment and in untreated controls. METHODS: Sixteen young cynomolgus monkeys were unilaterally topically treated for 1 year with either bimatoprost 0.03% (prostamide), sulprostone 0.03% (EP(3)/EP(1) agonist), AH13205 0.1% (EP(2) agonist), or latanoprost 0.005% (FP agonist), which all lower IOP in this species at the doses applied. Four animals were treated with the vehicle only. In all cases the left eye was treated, the right eye remained untreated. Six monkeys served as untreated controls. Sections from 4 quadrants each of the circumference of the eyes of 16 drug-treated, 4 vehicle-treated and 6 untreated control animals were investigated qualitatively and quantitatively using light- and electronmicroscopy. The area of widened spaces between ciliary muscle bundles, the number of nerve fiber bundles at the muscle tips, and the width and length of the ciliary muscle were quantitated. RESULTS: The general morphology of the ciliary muscle and trabecular meshwork was normal in appearance and shape in all animals, whereas some localized morphologic changes were observed in the drug-treated animals. The changes were found to be similar in all four treatment groups. In the ciliary muscle, there was a significant increase in optically empty spaces between muscle bundles in the anterior portion of the longitudinal and the reticular ciliary muscle compared with untreated and vehicle-treated control animals. Within these spaces, significantly more myelinated nerve fiber bundles were found in drug-treated compared with normal control animals. Ultrastructurally the spaces were partly covered by endothelial-like cells which, in some areas, were in contact with the basement membrane of the microvasculature. In all treatment groups, there were also changes in the trabecular meshwork region. Significant regional differences among the different quadrants of the eyes and quantitative differences between treatment groups were observed. The ciliary epithelium had a normal appearance in all treatment groups. CONCLUSIONS: After one year of treatment with different prostaglandins and a prostamide, uveoscleral outflow pathways are enlarged and appear organized. Conventional outflow routes were also affected. Long-term treatment with AH13205, latanoprost, sulprostone, or bimatoprost also induces sprouting of nerve fibers. (+info)
Latanoprost stimulates secretion of matrix metalloproteinases in tenon fibroblasts both in vitro and in vivo.
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PURPOSE: To investigate the presence and the possible role of different matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in Tenon capsule fibroblasts. These enzymes are essential for the control of tissue remodeling in the context of wound repair. This aspect is important to further the understanding of and possibly to influence the scarring process of filtering blebs after glaucoma surgery. METHODS: Untreated and latanoprost-treated human Tenon fibroblasts were examined for the presence of MMPs and TIMPs on the mRNA and protein levels. Assays performed included RT-PCR, real-time RT-PCR, immunocytochemistry, Western blot analysis, flow cytometry, and zymography. To investigate the changes in vivo, conjunctival specimens of rabbits treated with latanoprost eye drops were examined by immunohistochemistry. RESULTS: In all assays, both MMP-3 and TIMP-2 were detected. With the real-time RT-PCR technique, MMP-1, -2, -3, -7, -9, and -14 and TIMP-1 and -2 were detected. An upregulation of MMP-3 and TIMP-2 after latanoprost treatment of the fibroblasts was shown and found to occur on the mRNA and the protein levels. The upregulation of MMP-3 and TIMP-2 was confirmed in vivo. CONCLUSIONS: Tenon fibroblasts contain the ability on the mRNA level to synthesize all enzymes of the MMP and TIMP family that are related to remodeling of the extracellular matrix. The levels of MMP-3 and TIMP-2 increase after treatment with latanoprost. Tenon fibroblasts may be the target cells for attempts to influence the tissue levels of MMPs and TIMPs in the context of conjunctival wound healing after glaucoma surgery. (+info)
New fluoroprostaglandin F(2alpha) derivatives with prostanoid FP-receptor agonistic activity as potent ocular-hypotensive agents.
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To find new prostanoid FP-receptor agonists possessing potent ocular-hypotensive effects with minimal side effects, we evaluated the agonistic activities of newly synthesized prostaglandin F(2alpha) derivatives for the prostanoid FP-receptor both in vitro and in vivo. The iris constrictions induced by the derivatives and their effects on melanin content were examined using cat isolated iris sphincters and cultured B16 melanoma cells, respectively. The effects of derivative ester forms on miosis and intraocular pressure (IOP) were evaluated in cats and cynomolgus monkeys, respectively. Of these derivatives, 6 out of 12 compounds were more potent iris constrictors, with EC(50) values of 0.6 to 9.4 nM, than a carboxylic acid of latanoprost (EC(50)=13.6 nM). A carboxylic acid of latanoprost (100 microM) significantly increased the melanin content of cultured B16 melanoma cells, but some 15,15-difluoro derivatives, such as AFP-157 and AFP-172, did not. Topically applied AFP-168, AFP-169 and AFP-175 (isopropyl ester, methyl ester and ethyl ester forms, respectively, of AFP-172) induced miosis in cats more potently than latanoprost. AFP-168 (0.0005%) reduced IOP to the same extent as 0.005% latanoprost (for at least 8 h). These findings indicate that 15,15-difluoroprostaglandin F(2alpha) derivatives, especially AFP-168, have more potent prostanoid FP-receptor agonistic activities than latanoprost. Hence, AFP-168 may be worthy of further evaluation as an ocular-hypotensive agent. (+info)
Intraocular pressure after replacement of current dual therapy with latanoprost monotherapy in patients with open angle glaucoma.
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AIMS: To evaluate the efficacy and safety of replacing current dual ocular hypotensive therapy with latanoprost 0.005% monotherapy in patients with open angle glaucoma. METHODS: This randomised, open label, parallel group, multinational study included 466 patients with open angle glaucoma currently on dual ocular hypotensive therapy, including a beta adrenergic receptor antagonist. Patients were assigned (1:3) to ongoing dual therapy or a switch to monotherapy with latanoprost 0.005% once daily for 6 months. Intraocular pressure (IOP) was measured at 10 am and 5 pm at baseline, month 3, and month 6. Groups were compared for differences in diurnal IOP change, IOP success rates (IOP < or =22 mm Hg with < or =15% increase from baseline), and clinical success rates (not requiring change in therapy). RESULTS: Baseline mean diurnal IOP was 17.8 (SD 2.0) mm Hg in the latanoprost group and 17.6 (2.1) mm Hg in the dual therapy group. After 6 months, mean diurnal IOP was reduced by 0.26 (0.18) (SEM 1.4%) mm Hg (p=0.153) in the group switched to latanoprost and by 0.37 (0.25) (2.1%) mm Hg (p=0.138) in those continuing dual therapy (difference: 0.11 mm Hg; p=0.641). Success rates defined by IOP criteria were 83% for latanoprost and 89% for continued dual therapy (difference: 6%; p=0.122). Clinical success rates were 97% for latanoprost and 99% for dual therapy (difference: 2%; p=0.161). Ocular adverse events were reported by 23% of patients in both treatment groups. CONCLUSION: Latanoprost monotherapy is a safe and effective alternative for many patients with open angle glaucoma requiring dual topical ocular hypotensive therapy for IOP control. (+info)
A 12 week study comparing the fixed combination of latanoprost and timolol with the concomitant use of the individual components in patients with open angle glaucoma and ocular hypertension.
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BACKGROUND: To compare the intraocular pressure (IOP) lowering effect and safety of the fixed combination of latanoprost and timolol with that of the concomitant use of the individual components. METHODS: A 12 week, double masked, randomised, crossover, multicentre study of patients with open angle glaucoma or ocular hypertension and IOP controlled on ocular hypotensive treatment (mean < or =21 mmHg). Patients received either a once daily morning dose of the fixed combination of latanoprost 0.005% and timolol 0.5% or once daily evening latanoprost 0.005% and twice daily timolol 0.5% for six weeks and then switched to the other combination. The primary efficacy endpoint was the within-patient difference in diurnal IOP between fixed and unfixed treatment combinations after six weeks of treatment; a one sided 97.5% confidence interval (CI) for the mean difference in IOP <1.0 mmHg indicated the fixed combination was not inferior to the unfixed combination. Adverse events were recorded at each visit. RESULTS: In all, 190 patients were included in observed cases analyses (93 fixed to unfixed combination; 97 unfixed to fixed combination). Mean IOP at baseline was 16.9 mmHg in both groups. The mean diurnal IOP was 17.0 mmHg after fixed combination treatment and 15.9 mmHg after unfixed combination therapy (p<0.0001). The difference in mean within-patient diurnal IOP was 1.1 mmHg favouring the unfixed combination (95% CI 0.8 to 1.4 mmHg). Both treatments were tolerated well. CONCLUSIONS: Although the primary efficacy endpoint was not met, once daily administration of the fixed combination of latanoprost and timolol was found to be safe and effective. The fixed combination provides a convenient alternative to the three instillations required with the individual components. (+info)
Tonometric changes of latanoprost-induced intraocular pressure reduction after photorefractive keratectomy.
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PURPOSE: To assess whether tonometric measurements of the drop in intraocular pressure (IOP) induced by 0.005% latanoprost are modified after photorefractive keratectomy (PRK). METHODS: Data from 24 randomly selected eyes of 24 patients (12 men and 12 women, mean age +/- SD: 31.7 +/- 6.2 years) who were undergoing bilateral PRK for myopia (-6.38 +/- 2.26 D) were obtained. Objective refraction, central corneal thickness (CCT), anterior radius of corneal curvature (R), and IOP measurements at baseline and 24 hours after 1 drop of 0.005% latanoprost, were performed before and 6 months after PRK. All measured IOPs were recalculated by a correction factor for CCT and R and expressed as true IOP (IOPT) measurements. RESULTS: The mean CCT +/- SD was 544.58 +/- 36.03 and 463.21 +/- 38.59 micro m, and the anterior radius of corneal curvature was 7.73 +/- 0.26 and 8.33 +/- 0.37 mm, before and after PRK, respectively. The mean IOP at baseline was 15.8 +/- 2.92 and 12.23 +/- 2.37 mm Hg, and after latanoprost administration was 12.54 +/- 1.97 and 10.19 +/- 1.47 mm Hg, before and after PRK, respectively. The mean IOPT at baseline was 15.46 +/- 1.08 and 16.18 +/- 2.31 mm Hg, and after latanoprost administration was 11.85 +/- 1.56 and 12.96 +/- 1.71 mm Hg, before and after PRK, respectively. The mean IOP and IOPT reductions after latanoprost administration were, respectively, 3.25 +/- 1.66 and 3.61 +/- 1.7 mm Hg before PRK, and 2.03 +/- 1.42 and 3.22 +/- 1.79 mm Hg after PRK. Pre- and postoperative IOP reduction significantly differed (P < 0.001), but not IOPT. CONCLUSIONS: The effect of hypotensive drugs on IOP readings may be underestimated because of measurement errors due to CCT reduction and R increase after PRK for myopia. Misdiagnosis of reduced pharmacologic efficacy may be avoided if the measured IOP is corrected by a proper nomogram. (+info)
Long term effect of latanoprost on intraocular pressure in normal tension glaucoma.
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AIM: To determine the long term effect of latanoprost on the intraocular pressure (IOP) of patients with normal tension glaucoma (NTG). METHODS: Newly diagnosed patients with NTG were recruited into the study and had their baseline IOPs measured hourly between 8 am and 5 pm using a handheld electronic Tonopen. Patients with fixation threatening field defects were placed immediately into the treatment group while those with non-fixation threatening field defects were randomised into either the treatment group or the control group (no treatment). Treatment consisted of once daily topical latanoprost 0.005%. After a minimum period of 6 months, the patients underwent a second period of IOP phasing. RESULTS: 76 newly diagnosed patients with NTG were recruited-26 had fixation threatening disease, 25 were randomised to treatment, and 25 randomised to the control group. The average duration of treatment was 11 months. The average and maximum diurnal IOP for the patients randomised to treatment were statistically significantly lower than for the control patients at follow up (p<0.05). The treated group as a whole demonstrated a 17% decrease in the average diurnal IOP and a 19% decrease in the maximum diurnal IOP when compared to baseline IOP. 41% of those treated achieved a decrease of at least 20%, but only 10% of patients achieved a decrease of at least 30%. CONCLUSION: Latanoprost had a sustained hypotensive effect in eyes with NTG and 41% of treated patients achieved a reasonable response. However, in the majority of eyes with NTG, latanoprost monotherapy may be insufficient in producing a desirable 30% reduction in IOP. (+info)
Relation between axial length of the eye and hypotensive effect of latanoprost in primary open angle glaucoma.
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AIMS: To study the effect of axial length on the hypotensive effect of latanoprost in primary open angle glaucoma (POAG) in a prospective, observational study. METHODS: The authors measured axial length and baseline intraocular pressure (IOP) of 109 eyes with POAG, and then repeated the IOP measurements at 1, 3, and 6 months after starting treatment with latanoprost. RESULTS: The mean IOP level was significantly lower in eyes with a shorter axial length compared with the eyes with a longer axial length both at 3 and 6 months of treatment (p = 0.03 and p = 0.04, respectively, ANOVA). CONCLUSION: The hypotensive effect resulting from treatment with latanoprost could be related to ocular axial length. (+info)