Effects of Latanoprost and Bimatoprost on the Expression of Molecules Relevant to Ocular Inflow and Outflow Pathways.
ABSTRACT: BACKGROUND AND PURPOSE:The intraocular pressure (IOP)-lowering and side effects in response to different prostaglandin F2? analogues can be variable, but, the underlying basis for this difference remains unknown. This study investigated the differential changes of cellular proteins relevant to IOP-lowering effects of latanoprost and bimatoprost. METHODS:The human T lymphoblast (MOLT-3) cell line and immortalized human trabecular meshwork (iHTM) cells were studied by quantitative PCR and by immunofluorescence after treatment with either latanoprost or bimatoprost. New Zealand white rabbit eyes were treated topically with each agent and, following euthanasia, anterior segment tissues were studied with immunostaining. RESULTS:In cultured MOLT-3 cells, mRNA expression of both c-fos and matrix metalloproteinase 9 increased significantly in response to each agent. In addition, there was little change in tissue inhibitor of metalloproteinase (TIMP)-3 mRNA, but a significant decrease in TIMP-4. Fibronectin mRNA in MOLT-3 cells was down-regulated with bimatoprost, but was up-regulated with latanoprost. Immunofluorescence analysis of iHTM cells showed that intracellular fibronectin was significantly decreased by bimatoprost, but was increased by latanoprost. Both latanoprost and bimatoprost increased mRNA expression of NF-?B p65 and decreased that of I?B?. Aquaporin-1 mRNA expression was significantly down-regulated by bimatoprost. Immunostaining also revealed a significant decrease of aquaporin-1 in the ciliary epithelium of New Zealand white rabbits after bimatoprost treatment. CONCLUSIONS:Similarities in protein expression produced by latanoprost and bimatoprost in vitro may be relevant to the mechanism for their IOP-lowering effects in vivo. Differences in fibronectin expression and in aquaporin-1 expression in response to each agent may contribute to variability in the IOP-lowering efficacy in some studies.
Project description:BACKGROUND:The purpose of this study was to evaluate the intraocular pressure (IOP)-lowering efficacy and safety of bimatoprost 0.01% or 0.03% as monotherapy in patients treated with latanoprost 0.005% monotherapy who require additional IOP lowering for their ocular hypertension or open-angle glaucoma. METHODS:Two prospective, investigator-masked, randomized, parallel-group, multicenter studies enrolled patients with baseline IOP ?20 mmHg after ?30 days of latanoprost 0.005% monotherapy. Patients were randomized to 12 weeks of study treatment (study 1, bimatoprost 0.01% once daily or bimatoprost 0.01% once daily plus brimonidine 0.1% three times daily; study 2, bimatoprost 0.03% once daily or bimatoprost 0.03% once daily plus fixed-combination brimonidine 0.2%/timolol 0.5% twice daily). Patient evaluations at weeks 4 and 12 included IOP at 8 am, 10 am, and 4 pm and safety assessments. Results in the monotherapy study arms (bimatoprost 0.01% or 0.03%) are presented. RESULTS:Latanoprost-treated baseline mean diurnal IOP (± standard error of the mean) was 22.2±0.3 mmHg and 22.1±0.4 mmHg in the bimatoprost 0.01% and bimatoprost 0.03% treatment arms, respectively (P=0.957). In both treatment arms, mean (± standard error of the mean) reduction in IOP from latanoprost-treated baseline was statistically significant at each time point at both follow-up visits (P<0.001), ranging from 3.7±0.4 (17.0%) mmHg to 4.4±0.4 (19.9%) mmHg with bimatoprost 0.01% and from 2.8±0.5 (12.8%) mmHg to 3.9±0.5 (16.7%) mmHg with bimatoprost 0.03%. Mean percentage IOP reduction from latanoprost-treated baseline was numerically greater with bimatoprost 0.01% than with bimatoprost 0.03% throughout follow-up. The incidence of conjunctival hyperemia of mild or greater severity increased from latanoprost baseline after 12 weeks of treatment only in the bimatoprost 0.03% treatment arm. CONCLUSION:Many patients who do not reach their target IOP on latanoprost can achieve additional IOP lowering and maintain monotherapy by replacing latanoprost with bimatoprost. Reductions in IOP from latanoprost baseline were larger with bimatoprost 0.01% than with bimatoprost 0.03%, and bimatoprost 0.01% had a more favorable tolerability profile.
Project description:To evaluate the efficacy and safety of replacing latanoprost with another prostaglandin analogue (PGA) in patients with glaucoma or ocular hypertension requiring additional intraocular pressure (IOP) lowering while on latanoprost.Prospective, randomised, investigator-masked, multicentre clinical trial. Patients on latanoprost 0.005% monotherapy requiring additional IOP lowering discontinued latanoprost and were randomised to bimatoprost 0.03% (n = 131) or travoprost 0.004% (n = 135). IOP was measured at latanoprost-treated baseline and after 1 month and 3 months of replacement therapy.Baseline mean diurnal IOP on latanoprost was similar between groups. The mean diurnal IOP was significantly lower with bimatoprost than with travoprost at 1 month (p = 0.009) and 3 months (p = 0.024). Overall, 22.0% of bimatoprost patients versus 12.1% of travoprost patients achieved a > or =15% reduction in diurnal IOP from latanoprost-treated baseline at both months 1 and 3 (p = 0.033). At month 3, the additional mean diurnal IOP reduction from latanoprost-treated baseline was 2.1 (95% CI 1.7 to 2.5) mm Hg (11.0%) with bimatoprost and 1.4 (95% CI 0.9 to 1.8) mm Hg (7.4%) with travoprost (p = 0.024). At 3 months, 11.5% of bimatoprost and 16.5% of travoprost patients demonstrated a > or =1-grade increase in physician-graded conjunctival hyperaemia (p = 0.288). Hyperaemia was reported as a treatment-related adverse event in 3.1% of bimatoprost and 1.5% of travoprost patients (p = 0.445).Patients on latanoprost requiring lower IOP achieved a greater additional short-term diurnal IOP reduction when latanoprost was replaced by bimatoprost compared with travoprost. Low rates of hyperaemia were observed in patients treated with bimatoprost or travoprost after switching from latanoprost.
Project description:In patients with ocular hypertension or glaucoma, all treatments aim to lower intraocular pressure (IOP) by modulating aqueous humour (AH) production and/or uveoscleral and trabecular meshwork/Schlemm's canal AH drainage. PG analogues are considered to be the 'gold standard' treatment and are the most frequently used IOP-lowering agents. Recent data support an important role for NO in regulating IOP. Thus, novel PG analogues carrying a NO-donating moiety were recently advanced. Latanoprostene bunod (LBN) and NCX 470, NO-donating derivatives of latanoprost and bimatoprost, respectively, are examples of such compounds. LBN ophthalmic solution, 0.024% (Vyzulta™), showed greater IOP-lowering efficacy compared with that of Xalatan® (latanoprost ophthalmic solution, 0.005%) or 0.5% timolol maleate in clinical settings. NCX 470 was found to be more effective than bimatoprost in animal models of ocular hypertension and glaucoma. Selective EP2 receptor agonists (i.e. taprenepag isopropyl, omidenepag isopropyl and aganepag isopropyl) and non-selective prostanoid receptor agonists (i.e. ONO-9054, sepetaprost isopropyl) that concomitantly stimulate FP and EP3 receptors have also been shown to hold promise as effective IOP-lowering agents. LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.
Project description:For primary open angle glaucoma (POAG), laser treatment or surgery is used when the target intraocular pressure (IOP) cannot be achieved by pharmacological agents, such as prostaglandin (PG) analogs; these drugs also have varied effects. We retrospectively reviewed the medical records of 74 POAG patients (74 eyes) whose IOP was inadequately controlled by PG analogs (bimatoprost [13 eyes], latanoprost [34 eyes], tafluprost [11 eyes], and travoprost [16 eyes]) and underwent primary trabeculectomy. The proportion of patients with no recurrent IOP elevation within 24 months post-trabeculectomy was significantly (P < 0.001) lower in the bimatoprost group (31.3%) than in the latanoprost (83.2%), tafluprost (45.5%), or travoprost groups (65.6%). Deepening of the upper eyelid sulcus (DUES) was observed before trabeculectomy in 18 of 74 eyes (24.3%) treated with bimatoprost (9 eyes; 50.0%), latanoprost (3 eyes; 16.7%), tafluprost (1 eye; 5.5%) and travoprost (5 eyes; 27.8%). The proportion of patients with no recurrent IOP elevation up to 24 months post-trabeculectomy was significantly (P < 0.0001) lower in the DUES(+) group (34.7%) than in the DUES(-) group (74.3%). Multivariate stepwise logistic regression analysis, with no recurrent IOP elevation used as dependent variable, and bimatoprost, latanoprost, travoprost, tafluprost, β-blocker, carbonic anhydrase inhibitor, brimonidine, gender, age, preoperative IOP, mean deviation, duration of PG analog use before surgery, and the number of ophthalmic solutions used as independent variables, identified only bimatoprost as a significant independent factor (P = 0.0368). Thus, the outcome of trabeculectomy varied depending on the PG analog used preoperatively, and bimatoprost use was associated with a high risk of recurrent IOP elevation up to 2 years post-trabeculectomy. This may indicate that the incidence of DUES differed with the PG analog used. Patients with glaucoma who are treated with bimatoprost should be monitored for DUES, and when these patients undergo trabeculectomy, the postoperative course of IOP should be followed carefully.
Project description:INTRODUCTION:The preservative benzalkonium chloride (BAK) is used to preserve several topical, intraocular pressure (IOP)-lowering glaucoma medications but can cause tolerability concerns that may lead to decreased adherence to treatment and ultimately diminish the effectiveness of IOP control. The study aimed to determine the efficacy and tolerability of BAK-free travoprost preserved with polyquaternium-1 in glaucoma patients switched from BAK-preserved latanoprost or bimatoprost. METHODS:This 12-week, open-label study was conducted in Europe between December 2011 and February 2013. We enrolled adult patients with open-angle glaucoma or ocular hypertension who were receiving BAK-preserved latanoprost 0.005% or bimatoprost 0.01% and, in the opinion of the investigator, would benefit from transition to BAK-free travoprost 0.004% preserved with polyquaternium-1 because of tolerability concerns. Assessments included IOP, proportion of patients with IOP ?18 mmHg, ocular surface status, hyperemia, patient treatment preference, and adherence. Adverse events were recorded throughout the study. RESULTS:Of the 202 patients screened, 187 patients were included in the intent-to-treat population (mean age, 66.6 years; range, 19-90 years). The mean IOP significantly reduced from baseline (17.0 mmHg) to week 6 (mean change, -1.17 mmHg; P<0.001) and week 12 (-1.16 mmHg; P<0.001). At week 12, more patients achieved IOP ?18 mmHg (81.2% versus 73.3% at baseline), and ocular surface disease severity improved from baseline to week 12. Most patients preferred BAK-free travoprost (74.9%) versus their previous medication and were very confident in their adherence (84.1%). Reduced visual acuity and eye pruritus were the most common adverse events (2.5% each). CONCLUSION:BAK-free travoprost 0.004% preserved with polyquaternium-1 was efficacious and well tolerated and may be an advantageous prostaglandin analog option for patients with open-angle glaucoma or ocular hypertension who are intolerant to BAK-preserved latanoprost or bimatoprost.
Project description:AIM: To evaluate the existing evidence on relative efficacy and tolerability of topical mono-compound intraocular pressure (IOP)-lowering drugs in treatment of primary open angle glaucoma (POAG) and ocular hypertension (OHT). METHODS: In this systematic review of systematic reviews/meta-analyses of randomized controlled trials a thorough and sensitive search of PubMed, Embase and Cochrane Databases was performed. Individual study methodological quality and quality of evidence were assessed using the AMSTAR checklist and the GRADE system, respectively. The relationships between individual drugs were evaluated based on the best available evidence. RESULTS: Of the 133 initial non-duplicate records, 16 studies met the inclusion criteria. Five achieved an overall "moderate" (none achieved "high") quality of evidence and evaluated prostaglandin analogues (PGAs) - latanoprost, travoprost, and bimatoprost; timolol; "other beta-blockers;" carbonic anhydrase inhibitors (CAI) as a group or dorzolamide separately; and brimonidine. "Moderate quality" refers to efficacy and incidence of conjunctival hyperemia. Quality of evidence regarding other tolerability aspects was low. PGAs should be considered equivalent regarding efficacy, but latanoprost was relevantly better tolerated than the other two. Non-PGA compounds did not relevantly differ between each other in either efficacy or safety. Timolol and brimonidine were relevantly less effective than all PGAs. The same was true for CAI vs bimatoprost. Regarding tolerability, timolol was superior to all PGAs and brimonidine and CAI were superior to bimatoprost. CONCLUSION: No high quality evidence on relative efficacy and tolerability of the most commonly used mono-compound IOP-lowering drugs for POAG/OHT exists. Moderate quality evidence indicates latanoprost as a treatment with the most favorable trade-off between benefits and harms.
Project description:PURPOSE:To evaluate conjunctival hyperemia associated with bimatoprost 0.01% treatment in patients who replace latanoprost 0.005% with bimatoprost 0.01%. METHODS:Randomized, double-masked, vehicle-controlled, multicenter study of patients with ocular hypertension or glaucoma whose intraocular pressure (IOP) was adequately controlled on latanoprost monotherapy. At baseline, patients discontinued latanoprost and were randomized to treatment with once-daily bimatoprost 0.01% (n = 151) or vehicle (n = 71). The primary endpoint was the peak change in macroscopic hyperemia (conjunctival hyperemia evaluated by gross visual inspection) from baseline to month 1. RESULTS:Bimatoprost 0.01% was noninferior to vehicle in the mean [standard deviation] peak change from baseline macroscopic hyperemia at month 1 (0.18 [0.46] in the bimatoprost 0.01% group vs 0.02 [0.32] in the vehicle group, P = 0.009). The between-group difference was 0.15 (95% confidence interval [CI]: 0.04, 0.26), which was within the predefined margin for noninferiority of 0.5 on a hyperemia grading scale of 0 to +3. There were no statistically significant between-group differences in the percentage of patients with a ?1-grade increase in macroscopic hyperemia from baseline. Mean IOP was decreased from baseline (-0.7 to -1.3 mm Hg) in the bimatoprost 0.01% group (P ? 0.002) and was increased from baseline (+3.3 to +3.6 mm Hg) in the vehicle group (P < 0.001) at month 1. There were no statistically significant between-group differences in adverse events. CONCLUSIONS:Bimatoprost 0.01% was noninferior to vehicle with respect to conjunctival hyperemia in this study population. Replacement of latanoprost with bimatoprost 0.01% in patients with ocular hypertension or glaucoma can result in additional IOP reduction without clinically important hyperemia.
Project description:In randomized, controlled trials of open-angle glaucoma (OAG) or ocular hypertension (OHT), bimatoprost 0.01 % improved tolerability while retaining the intraocular pressure (IOP)-lowering efficacy of bimatoprost 0.03 %. Given geographic/racial differences in glaucoma presentation, the APPEAL study assessed the occurrence and severity of hyperemia produced by bimatoprost 0.01 %, and its efficacy, in the Taiwanese clinical setting.In this multicenter, open-label, observational study, treatment-naïve and previously treated patients with OHT or OAG received once-daily bimatoprost 0.01 % for 12 weeks. Hyperemia (primary endpoint) was graded at baseline, week 6, and week 12 using a photonumeric scale (0, +0.5, +1, +2, +3), grouped (??+1, none to mild; ??+2, moderate to severe), and reported as unchanged from baseline, improved, or worsened. IOP assessments followed the same schedule. Supplemental efficacy analyses were conducted based on previous therapies.The intent-to-treat population (N?=?312) included treatment-naïve (13.5 %) and previously treated (86.5 %) patients; mean age was 53.3 years. At baseline, 46.3 % of previously treated patients were receiving prostaglandin analog (PGA) monotherapy. At week 12, 91.2 %, 5.9 %, and 2.9 % of treatment-naïve patients exhibited unchanged, worsened, and improved hyperemia from baseline, respectively; 77.9 %, 12.9 %, and 9.2 % of previously treated patients showed no change, worsening, and improvement, respectively. There were no statistically significant shifts in hyperemia severity in either group, or in subgroups based on previous use of any PGA, any non-PGA, latanoprost, or travoprost monotherapies. In treatment-naïve patients, mean IOP reduction from baseline (18.0?±?3.8 mm Hg) was 3.6 mm Hg at week 12 (P?<?0.0001); 83.3 % had baseline IOP ??21 mm Hg. In previously treated patients, mean additional IOP reduction from baseline (17.8?±?3.9 mm Hg) was 2.6 mm Hg (P?<?0.0001); similar results were observed in patient subgroups based on previous therapies.In the Taiwanese clinical setting, bimatoprost 0.01 % provided significant IOP lowering in treatment-naïve patients (regardless of baseline IOP) and previously treated patients (even those with relatively low IOP on other therapies), while causing no significant changes in hyperemia from baseline.Clinicaltrials.gov NCT01814761 . Registered 18 March 2013.
Project description:<h4>Purpose</h4>Prostaglandin analogues (PGA's) are the mainstay and first line of treatment in current glaucoma practise. Though latanoprost and bimatoprost are the most commonly used PGA's with minimal side effects at lower concentrations like bimaotoprost 0.01%, direct comparison of their cytokine/MMP profile in tears has not been evaluated earlier. The study intends to ascribe PGA to the upregulation of MMPs, Cytokines and Chemokines mediating varied pathways to result in side effects of the drugs.<h4>Methods</h4>Tear sample collection was done from outer canthus of 30 eyes of 30 patients (primary open angle glaucoma (n = 26 and n' = 20), normal tension glaucoma (n = 4 and n' = 10), in latanoprost (n) 0.005% and bimatoprost (n') 0.01% group respectively, with a mean age of 62±10.5 years) on >6 months of PGA use using Tear floTM Schirmer filter strip. Tear samples from 30 eyes of 30 cataract patients without drug treatment were used as the control. Gelatinolytic activity of MMP-9 and MMP-2 were examined by substrate gelatine zymography MMP-1 and TIMP-1 concentrations from tears samples with PGAs were evaluated by ELISA while cytokine concentration in the eluted tears was evaluated using a convenient bioplex kit assay (Milliplex MAP kit, HCYTMAG-60K-PX41, Millipore, Massachusetts, United States). The mean duration of use of PGA in both groups did not differ significantly (median 1.3 years in bimatoprost and 1.1 years in latanoprost eyes, p = 0.6).<h4>Results</h4>The tear MMP-9 expression was higher in eyes receiving latanoprost while the MMP-2 expression was higher in eyes receiving bimatoprost with MMP1 protein levels being higher in the former. Latanoprost treated eyes had marginally elevated tear cytokines involved in tissue remodelling while bimatoprost eyes showed elevated cytokines regulating allergic pathways.<h4>Conclusion</h4>Differential cytokine and MMP expression indicates differential signalling pathways mediating different cellular effects (evident as clinical and side effects) with the two drugs which can be explored further.
Project description:Topical ophthalmic formulations of analogues of the endogenous arachidonic acid cyclooxygenase metabolite, PGF2? , are the standard of care treatment for the blinding disease glaucoma. These are the most potent and efficacious medical therapies for lowering intraocular pressure (IOP), the most important risk factor identified for disease progression. They have few side effects and offer the convenience of once-a-day dosing. It was initially believed that endogenous PGs raised IOP and caused substantial ocular surface adverse effects. However, carefully designed experiments demonstrated that esterification of the carboxylic acid afforded potent and efficacious topical ocular hypotensive activity. The final hurdle to be overcome was improvement of the side effect profile. A hypothesis was advanced that the IOP-lowering effect of PGF2? isopropyl ester was due to activation of its cognate PG-FP receptor, while side effects were largely due to promiscuous interaction with other PG receptors. This hypothesis was validated by modification of the ? chain (carbons 13-20) to a phenyl group. This provided the first marketed FP-class PG agonist analogue (FP-PGA) ocular hypotensive agent, latanoprost. Since the introduction of latanoprost into clinical medicine to lower and control IOP, a number of additional FP-PGAs have been discovered, characterized and marketed, including travoprost, tafluprost, unoprostone isopropyl ester and bimatoprost (an amide). LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.