Potent reduction of intraocular pressure by nipradilol plus latanoprost in ocular hypertensive rabbits.
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The present study was performed to evaluate the intraocular pressure (IOP)-lowering effect of nipradilol in combination with latanoprost on ocular normotensive and hypertensive rabbits. IOP was measured using an applanation pneumatonograph under topical application of 0.4% oxybuprocaine hydrochloride for corneal anesthesia. Ocular hypertension was induced by injection of 0.1 ml hypertonic saline (5% NaCl) into the vitreous body. Saline, nipradilol, latanoprost, sodium nitroprusside (SNP) or indomethacin was then instilled just after 5% NaCl injection. All drugs were instilled in the inferior conjunctival sac, using 50 microl drops. If more than two drugs were used, they were applied 5 min apart. Nipradilol lowered IOP in both ocular normotensive rabbits and ocular hypertensive rabbits, whereas latanoprost did not lower IOP in either. When nipradilol was applied in combination with latanoprost, the reduction in ocular hypertension was significantly enhanced, compared to the effect of nipradilol alone. A significantly potent reduction in ocular hypertension was also observed by the SNP-latanoprost combination. The IOP-lowering effects of SNP in combination with latanoprost were abolished by treatment with indomethacin. These results indicate that the IOP-lowering effect of latanoprost was enhanced when applied in combination with nipradilol or SNP, both of which have nitric oxide (NO)-donating actions. Since both combined effects were abolished by treatment with indomethacin, the mechanisms by which nipradilol combined with latanoprost lowered ocular hypertension may be related, at least in part, to the production of prostaglandins via the NO-donating action of nipradilol. (+info)
Effects of glaucoma drugs on ocular hemodynamics in normal tension glaucoma: a randomized trial comparing bimatoprost and latanoprost with dorzolamide [ISRCTN18873428].
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BACKGROUND: Reduced choroidal perfusion is hypothesized to play a role in the pathogenesis of normal tension glaucoma. Thus the impact of antiglaucomatous eye drops on ocular perfusion has been the focus of recent research and the subject of intensive investigations. The present study investigates whether topically applied latanoprost or bimatoprost influence ocular perfusion in patients with normal tension glaucoma and compares these effects with that changes detected after the treatment with dorzolamide. METHODS: Ocular hemodynamics were assessed by color Doppler imaging (CDI) shortly before and after a one-month treatment with either latanoprost, bimatoprost or dorzolamide. Primary end-points of the study were peak systolic and end-diastolic blood flow velocities in the short posterior ciliary artery (SPCA) under the new therapy. Intraocular pressure (IOP) and additional perfusion parameters in the SPCA and other retrobulbar vessels were tracked as observational parameters. n = 42 patients with normal tension glaucoma were enrolled in the study. RESULTS: Systolic and diastolic blood flow velocities in the SPCA showed no significant alteration after the treatment with latanoprost or bimatoprost. Dorzolamide lead to increase of peak systolic velocity. IOP was reduced by all three agents in a range reported in the literature. CONCLUSION: Topically applied latanoprost and bimatoprost act in a hemodynamically neutral manner and have the capability to lower IOP even in patients with normal tension glaucoma and low initial IOP level. Dorzolamide accelerates blood flow in systole. None of the tested compounds has a negative impact on hemodynamics in the short posterior ciliary arteries. (+info)
Efficacy and safety of latanoprost for glaucoma treatment: a three-month multicentric study in India.
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PURPOSE: To evaluate the short-term efficacy and safety of 0.005% topical latanoprost in Indian eyes. DESIGN: Prospective non-randomised open-label multicentric trial. METHODS: One hundred and fifty patients with ocular hypertension (OHT), primary open-angle, pseudoexfoliation or pigmentary glaucoma were enrolled at four centers. Each center contributed at least 20 patients. Following baseline measurements, 0.005% latanoprost was applied topically once daily in the evening for three months. Patients were examined at 2, 6 and 12 weeks. The primary outcome measure was mean intraocular pressure (IOP) reduction. The mean diurnal variation of IOP (difference between highest and lowest IOP) at baseline and at 12-weeks was compared. RESULTS: One hundred and thirty of 150 enrolled patients completed the study. One randomly selected eye of each patient was included for analysis. At three months, latanoprost reduced the mean IOP from 24.9 (+/- 3.16) mmHg at baseline to 16.10 (+/- 2.7) mmHg, a reduction of 35.25%. 83% had a reduction in IOP of > 25%. The IOP reduction was maintained throughout the study period, and was not affected by gender or age of the patient. One eye did not show any response to the drug. Daytime diurnal variation of IOP was reduced from 4.5 to 2.9 mmHg. 20 patients had conjunctival hyperemia. Six patients had side effects requiring withdrawal from the study. CONCLUSIONS: In this short-term multicentric study, latanoprost effectively reduced IOP and stabilised the diurnal curve in Indian eyes. There were no clinically significant ocular or systemic adverse effects. (+info)
Effects of the combination of bimatoprost and latanoprost on intraocular pressure in primary open angle glaucoma: a randomised clinical trial.
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AIMS: To evaluate the effect of the combination of bimatoprost and latanoprost on intraocular pressure (IOP) in primary open angle glaucoma (POAG). METHODS: An open label randomised clinical trial was conducted, which included 18 glaucomatous patients (36 eyes). In the first 4 weeks, latanoprost 0.005% was prescribed for both eyes of the patients and any other antiglaucoma medication was discontinued. In the next 4 weeks (phase 1), bimatoprost 0.03% was combined with latanoprost in one randomly assigned eye (case eye) of each patient. In the next 4 weeks (phase 2), bimatoprost was discontinued in the case eyes, while bimatoprost was substituted for latanoprost in the fellow eye (control eye). The IOP was measured at the end of the first 4 weeks (baseline measurement) and weekly during phases 1 and 2. RESULTS: In the case eyes, the mean IOP increased along the first phase (1.8 mm Hg; p = 0.006) when compared to baseline measurements. The IOP returned to previous values after discontinuation of bimatoprost in phase 2. In the control eyes, the mean IOP did not change throughout the study. CONCLUSION: The combination of bimatoprost and latanoprost in POAG increases the IOP and should not be considered as a therapeutic option. (+info)
Acute effects of PGF2alpha on MMP-2 secretion from human ciliary muscle cells: a PKC- and ERK-dependent process.
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PURPOSE: Studies were designed to evaluate the cellular mechanisms associated with prostaglandin (PG)F(2alpha)-induced matrix metalloproteinase (MMP)-2 secretion from human ciliary muscle (HCM) cells. METHODS: The secretion and activity of MMP-2 was determined by Western blot analysis and zymography, using conditioned medium and HCM cells. ERK1/2 activity was measured by in-gel kinase assay and Western blot analysis with anti-phospho-ERK1/2 antibodies. RESULTS: PGF(2alpha) increased the secretion of MMP-2 in a dose-dependent manner with an EC(50) of 2.7 x 10(-8) M. The addition of 1 muM PGF(2alpha) also increased MMP-2 secretion in a time-dependent manner with maximum secretion occurring at 4 hours after administration. At 4 hours, the maximum increase in MMP-2 secretion and activity were 112% +/- 32% and 88% +/- 18%, respectively. The secretory action of PGF(2alpha) was inhibited by pretreatment with a protein kinase C (PKC) inhibitor, chelerythrine chloride; the FP receptor antagonist, AL-8810; and the MEK inhibitor, PD-98059. The addition of PGF(2alpha) and latanoprost acid increased ERK1/2 activity by 117% +/- 12% and 75% +/- 9%, respectively. The PGF(2alpha)- and latanoprost-acid-induced ERK1/2 activation was blocked by the presence of PKC inhibitors and downregulation of PKC by prolonged incubation with a phorbol ester. CONCLUSIONS: These data provide evidence that FP receptor activation leads to an increase in the secretion and activation of MMP-2 through PKC- and ERK1/2-dependent pathways. FP-agonist-induced activation of ERK1/2 was blocked by PKC inhibitors, indicating that PKC activation is required for ERK1/2 activation and MMP-2 secretion from HCM cells. In the ciliary muscle, the functional responses to ERK1/2 activation include secretion of MMP-2, supporting the hypothesis that increases in uveoscleral outflow facility induced by PG administration involves the secretion and activation of MMP-2. (+info)
Prostaglandin analogues and mouse intraocular pressure: effects of tafluprost, latanoprost, travoprost, and unoprostone, considering 24-hour variation.
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PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. (+info)
In vitro study of inflammatory potential and toxicity profile of latanoprost, travoprost, and bimatoprost in conjunctiva-derived epithelial cells.
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PURPOSE: Conjunctiva-derived epithelial cells were used to investigate, in vitro, the expression of various inflammation-associated markers known to be overexpressed in patients with glaucoma after contact with the three major commercially available eye drops containing prostaglandin analogues. The impact on cellular viability and apoptosis in the same cell line was evaluated, to address the possible proinflammatory and/or toxic origin of the most frequent clinical impairments induced by prostanoids (i.e., conjunctival hyperemia). METHODS: Conjunctiva-derived cells were treated in vitro with the commercial solutions of latanoprost, travoprost, bimatoprost, prostaglandin (PG)F2alpha, tumor necrosis factor (TNF)-alpha, and different concentrations of benzalkonium chloride (BAC). Expressions of three inflammation- and immune-related markers, intercellular adhesion molecule (ICAM)-1, platelet-endothelial cell adhesion molecule (PECAM)-1 and HLA DR, were evaluated with flow cytometry after 24 to 72 hours of contact at low, subtoxic concentrations. Toxicological tests were also performed with cold-light cytofluorometry, in which cellular viability and apoptosis were evaluated with the neutral red and Hoechst/propidium iodide tests, respectively. RESULTS: TNFalpha induced or stimulated expression of the three inflammatory markers, whereas the PGF2alpha, latanoprost, travoprost, and bimatoprost solutions did not induce an increase in these markers and even produced a marked reduction of ICAM-1 and PECAM-1 expression in those solutions most concentrated in BAC, thus suggesting a toxic phenomenon in cellular membranes induced by the preservative rather than the medication itself. Cytotoxic assays confirmed this hypothesis and showed significant toxicity with prostaglandin analogues after prolonged contact, proportional to the concentration of BAC in the solution and similar to that of the corresponding concentration of BAC alone, bimatoprost having both the least concentration of BAC and the least cytotoxic in these experimental conditions. CONCLUSIONS: The comparison of latanoprost, travoprost, and bimatoprost, in their commercial formulations, showed that none of them appeared to induce direct stimulation of the inflammatory pathways involving adhesion molecules or class II antigens, although these markers have been found ex vivo in conjunctival specimens from patients treated with prostaglandins. In fact, their toxicity was mild and seemed to be primarily related to the concentration of BAC, their common preservative, which may be the major factor responsible for long-term ocular surface reactions in patients receiving topical prostaglandins, but most likely is not a factor in early and transient conjunctival hyperemia. (+info)
Latanoprost induces matrix metalloproteinase-1 expression in human nonpigmented ciliary epithelial cells through a cyclooxygenase-2-dependent mechanism.
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Prostaglandins (PGs) have been implicated in the regulation of intraocular pressure (IOP) by facilitating the remodeling of tissues involved in aqueous humor outflow. A contribution of cyclooxygenase-2 (COX-2)-dependent PGs to this process was emphasized by a recent study showing an impaired COX-2 expression in the nonpigmented ciliary epithelium (NPE) of patients with primary open-angle glaucoma. With the use of human NPE cells (ODM-2), the present study therefore investigated the effect of the antiglaucomatous drug latanoprost (PGF2alpha analog) on the expression of COX-2 and its association with the induction of matrix metalloproteinases (MMPs). In NPE cells, latanoprost led to a concentration- and time-dependent increase of COX-2 mRNA levels. Up-regulation of COX-2 expression was accompanied by phosphorylations of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK and was abrogated by specific inhibitors of both pathways. PGE2 formation by latanoprost was abolished by the selective COX-2 inhibitor NS-398 and by the F-prostaglandin receptor antagonist AL-8810. Moreover, latanoprost led to a delayed up-regulation of MMP-1 mRNA, whereas the expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 remained unchanged. Latanoprost-induced MMP-1 mRNA and protein expression was abolished by NS-398 and by COX-2-silencing small-interfering RNA. In line with this finding, MMP-1 expression was also induced by PGE2, a major COX-2 product. As a whole, our results show that MMP-1 expression by latanoprost requires prior up-regulation of COX-2. Induction of COX-2- and subsequent MMP-1 expression in the NPE may represent a potential mechanism underlying the IOP-lowering and antiglaucomatous action of latanoprost. (+info)