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1.
Expert Rev Clin Pharmacol ; 12(12): 1073-1079, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31842637

RESUMO

Introduction: Netarsudil and latanoprost ophthalmic solution (0.02%/0.005%) is indicated for intraocular pressure (IOP) lowering in open-angle glaucoma (OAG) or ocular hypertension (OHTN). The once-daily agent combines the mechanism of action for each of the individual components and provides a new avenue for long-term intraocular pressure control. This review aims to cover the agent's current efficacy and safety data and opine as to its role in glaucoma management.Areas covered: This article will cover Phase II-III clinical efficacy and safety data as well as basic science literature pertaining to the agent's mechanism of action and pharmacodynamics. In selecting articles for inclusion in this review, a literature search using the PubMed database was carried out. Cross-referencing was carried out where applicable. We did not use any date or language restrictions in electronic searches.Expert opinion: Netarsudil and latanoprost ophthalmic solution plays a pivotal role in management of individuals with OAG and OHTN. The agent may be used as first-line therapy to provide substantial IOP-lowering or when additional lowering is indicated and prostaglandins have provided insufficient IOP lowering. The once-daily dosing regimen decreases the risk of inadequate treatment due to nonadherence.


Assuntos
Benzoatos/administração & dosagem , Glaucoma de Ângulo Aberto/tratamento farmacológico , Latanoprosta/administração & dosagem , Hipertensão Ocular/tratamento farmacológico , beta-Alanina/análogos & derivados , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Benzoatos/efeitos adversos , Combinação de Medicamentos , Humanos , Pressão Intraocular , Latanoprosta/efeitos adversos , Soluções Oftálmicas , beta-Alanina/administração & dosagem , beta-Alanina/efeitos adversos
2.
Invest Ophthalmol Vis Sci ; 60(14): 4606-4618, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31756254

RESUMO

Purpose: To investigate the neuroprotective effects of Lycium barbarum polysaccharides (LBP) against chronic ocular hypertension (OHT) in rats and to consider if effects differed when treatment was applied before (pretreatment) or during (posttreatment) chronic IOP elevation. Methods: Sprague-Dawley rats (10-weeks old) underwent suture implantation around the limbus for 15 weeks (OHT) or 1 day (sham). Four experimental groups were studied, three OHT groups (n = 8 each) treated either with vehicle (PBS), LBP pretreatment or posttreatment, and a sham control (n = 5) received no treatment. LBP (1 mg/kg) pre- and posttreatment were commenced at 1 week before and 4 weeks after OHT induction, respectively. Treatments continued up through week 15. IOP was monitored twice weekly for 15 weeks. Optical coherence tomography and ERG were measured at baseline, week 4, 8, 12, and 15. Eyes were collected for ganglion cell layer (GCL) histologic analysis at week 15. Results: Suture implantation successfully induced approximately 50% IOP elevation and the cumulative IOP was similar between the three OHT groups. When compared with vehicle control (week 4: -23 ± 5%, P = 0.03), LBP pretreatment delayed the onset of retinal nerve fiber layer (RNFL) thinning (week 4, 8: -2 ± 7%, -11 ± 3%, P > 0.05) and arrested further reduction up through week 15 (-10 ± 4%, P > 0.05). LBP posttreatment intervention showed no significant change in rate of loss (week 4, 15: -25 ± 4.1%, -28 ± 3%). However, both LBP treatments preserved the retinal ganglion cells (RGC) and retinal functions up to week 15, which were significantly reduced in vehicle control. Conclusions: LBP posttreatment arrested the subsequent neuronal degeneration after treatment commencement and preserved RGC density and retinal functions in a chronic OHT model, which was comparable with pretreatment outcomes.


Assuntos
Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Degeneração Neural/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , Animais , Doença Crônica , Eletrorretinografia , Feminino , Pressão Intraocular/fisiologia , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Fibras Nervosas/patologia , Hipertensão Ocular/metabolismo , Hipertensão Ocular/fisiopatologia , Ratos , Ratos Sprague-Dawley , Retina/fisiopatologia , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica
3.
Expert Opin Ther Pat ; 29(10): 781-792, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31596641

RESUMO

Introduction: Glaucoma affects more than 70 million people worldwide. One of the major therapeutic options for its management is based on the inhibition of the metalloenzyme carbonic anhydrases (CAs, EC 4.2.1.1). CA inhibitors (CAIs) diminish ocular hypertension in glaucomatous patients by reducing the rate of bicarbonate formation and thus, the secretion of the aqueous humor. Areas covered: This review is intended to cover the major contributions in terms of patent literature reports for the treatment of ophthalmic diseases by means of CAIs in a time frame spanning from 2013 to date. Expert opinion: The patent literature is dominated by innovative pharmaceutical formulations including a CAI alone or in combination with other therapeutic agents. Very few novelties within drug discovery are currently present and they mainly account for new CAI moieties and classical CAIs merged into scaffolds bearing additional chemical functionalities beneficial for the pharmacological treatment of the disease. It is reasonable to expect that in the near future the so-called 'old drugs' will achieve pharmacological performances in the management of ocular hypertension beyond any expectations and thus open a new era of drug repurposing merely based on material science advancements.


Assuntos
Inibidores da Anidrase Carbônica/administração & dosagem , Glaucoma/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Animais , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Anidrases Carbônicas/metabolismo , Desenho de Drogas , Reposicionamento de Medicamentos , Glaucoma/enzimologia , Humanos , Hipertensão Ocular/enzimologia , Patentes como Assunto
4.
Drugs Today (Barc) ; 55(9): 563-574, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31584573

RESUMO

The fixed-dose combination (FDC) of netarsudil 0.02%/ latanoprost 0.005% was approved by the United States Food and Drug Administration (FDA) on March 12, 2019, for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT). Netarsudil is a Rho kinase (ROCK) inhibitor and latanoprost is a prostaglandin analogue (PGA). Once-daily administration of this FDC reduces IOP by enhancing aqueous outflow through both the trabecular pathways (ROCK inhibition) and uveoscleral pathways (PGA). Two phase III clinical trials, MERCURY-1 and MERCURY-2, confirmed significantly greater efficacy of the FDC than the individual components, with IOP reductions of 30% or greater observed in 59-65% of subjects treated with FDC compared with 29-37% of subjects treated with latanoprost alone and 21-29% of subjects treated with netarsudil alone. The FDC was well tolerated with mostly mild ocular side effects and limited systemic side effects. This paper will review the work leading to FDA approval and the clinical indications for the use of this combination.


Assuntos
Benzoatos/uso terapêutico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Latanoprosta/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , beta-Alanina/análogos & derivados , Anti-Hipertensivos/uso terapêutico , Aprovação de Drogas , Quimioterapia Combinada , Humanos , Estados Unidos , United States Food and Drug Administration , beta-Alanina/uso terapêutico
5.
Expert Opin Ther Pat ; 29(10): 805-815, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31486689

RESUMO

Introduction: Glaucoma is a neurodegenerative disease of the eye characterized by selective retinal ganglion cell loss that provokes progressive defects in the visual field. Elevated intraocular pressure (IOP) is an important contributor for the progression of glaucoma. The current therapeutic arsenal for reducing IOP includes prostaglandin analogs, ß-blockers, carbonic anhydrase inhibitors, α-adrenergic agonist, miotics, rho-kinase inhibitors and combinations thereof, generally administered as eye drops. Areas covered: This manuscript reviews the state of art on adrenergic modulators for treating glaucoma. Both monotherapy and fixed-drugs combinations including α2-adrenergic agonists and ß-blockers are discussed as well as drug delivery systems where these classes of drugs are used. The review then covers the patent literature involving adrenoceptors modulators over the period 2013-2019. Expert opinion: While the scientific community is moving forward novel targets and related modulators for treating glaucoma and ocular hypertension, adrenergic modulators held a prominent position in the therapy of glaucoma and related disorders. Indeed, though not embodying anymore the first-choice monotherapy, they are widely marketed worldwide ordinarily in combination with other drugs, are subjects of many studies for identifying new drug compositions and have been assessed as active ingredients in several innovative ocular drug delivery systems.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Antagonistas Adrenérgicos beta/administração & dosagem , Glaucoma/tratamento farmacológico , Antagonistas Adrenérgicos beta/farmacologia , Animais , Combinação de Medicamentos , Sistemas de Liberação de Medicamentos , Desenho de Drogas , Glaucoma/fisiopatologia , Humanos , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/tratamento farmacológico , Patentes como Assunto
6.
J Manag Care Spec Pharm ; 25(9): 1001-1010, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31456491

RESUMO

BACKGROUND: Prostaglandin analogs (PGAs) are considered an initial therapy to manage increased intraocular pressure (IOP) for patients with glaucoma. When the initial PGA treatment fails to lower IOP adequately, the patient may add or change medications or have surgery/laser treatment. OBJECTIVE: To compare medication adherence, duration of therapy, and treatment patterns among 3 PGAs-latanoprost, travoprost, and bimatoprost-as initial therapies for patients with glaucoma or ocular hypertension. METHODS: This was a retrospective cohort study using administrative claims data. The cohort consisted of patients newly diagnosed with glaucoma or ocular hypertension with at least 1 prescription claim for latanoprost, travoprost, or bimatoprost and enrolled in a Medicare Advantage plan between 2007 and 2012. The 24-month medication possession ratio (MPR) was used to measure medication adherence. Discontinuation of first-line PGA therapy was defined as nonpersistence (90-day gap allowance) of the index PGA or a change in therapy during the 24-month follow-up period. Types of second-line therapy (i.e., switch, addition, and surgery) were identified. The 1:1:1 propensity score matching was used. RESULTS: Patients who met the inclusion criteria were propensity score matched, resulting in 1,296 patients per PGA group. Latanoprost users showed higher adherence (50.1%) than travoprost (48.8%) and bimatoprost (43.0%) users. The latanoprost and travoprost groups had significantly higher MPRs than bimatoprost (P < 0.0001). The latanoprost group showed significantly longer duration of first-line therapy (372 days) than the bimatoprost group (343 days; P = 0.003) but not the travoprost group (361 days). After controlling for demographic and clinical characteristics, a Cox proportional hazards model showed that the travoprost and bimatoprost groups had a higher risk of discontinuation of first-line therapy than the latanoprost group (P < 0.0001). The percentage of patients continuing on the index PGA without treatment pattern change (i.e., switches, additions, and surgery) was higher for latanoprost users (52.9%) compared with travoprost (39.0%) or bimatoprost users (42.1%; P < 0.001). CONCLUSIONS: Patients who used latanoprost as their initial therapy were more likely to adhere and persist to the index PGA compared with bimatoprost users. The latanoprost group demonstrated a lower risk of discontinuing first-line therapy than the travoprost and bimatoprost groups. The results may assist ophthalmologists in determining the optimal management of this patient population with respect to treatment patterns. DISCLOSURES: No outside funding supported this study. All authors except Heo and Nair are employed by The University of Texas at Austin College of Pharmacy. Heo was with the Health Outcomes Division, The University of Texas at Austin College of Pharmacy during a portion of this study and is employed by Genesis Research. Nair is employed by Humana. The authors have no financial relationships relevant to this article to disclose. This study was presented as a poster at the 2016 International Society for Pharmacoeconomics and Outcomes Research Annual Meeting, May 2016, Washington, DC.


Assuntos
Anti-Hipertensivos/uso terapêutico , Glaucoma/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Prostaglandinas Sintéticas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pressão Intraocular/efeitos dos fármacos , Masculino , Medicare , Adesão à Medicação , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos
7.
Expert Opin Ther Pat ; 29(10): 753-759, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31438732

RESUMO

Introduction: Glaucoma refers to a heterogeneous group of optic neuropathies characterized by an enhanced intraocular pressure (IOP). To date, there are six available different drug classes for the treatment of glaucoma and ocular hypertension: ß-adrenergic antagonists, prostaglandins, carbonic anhydrase inhibitors, α2-selective adrenergic, muscarinic agonists and rho kinase inhibitors, which act by reducing the production or increasing the drainage of aqueous humor. Areas covered: This manuscript reviews patent US2018244666A1, that describes the synthesis of novel potential rho kinase and monoamine transporters inhibitors with a benzamide or isoquinoline amide scaffolds, and patent US2018256595A1 that investigates the long-term treatment of glaucoma or ocular hypertension with ripasudil, a rho kinase inhibitor. Expert opinion: A variety of netarsudil congeners were synthesized as rho kinases inhibitors in patent US2018244666A1. Results of patent US2018256595A1 showed that ripasudil is among the best candidates for glaucoma long-term treatment, as IOP continuously dropped over the course of the treatment.


Assuntos
Glaucoma/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Quinases Associadas a rho/antagonistas & inibidores , Benzoatos/administração & dosagem , Benzoatos/farmacologia , Glaucoma/patologia , Humanos , Pressão Intraocular/efeitos dos fármacos , Isoquinolinas/administração & dosagem , Isoquinolinas/farmacologia , Hipertensão Ocular/patologia , Patentes como Assunto , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , beta-Alanina/administração & dosagem , beta-Alanina/análogos & derivados , beta-Alanina/farmacologia , Quinases Associadas a rho/metabolismo
8.
BMJ ; 366: l4235, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292128

RESUMO

The studyGazzard G, Konstantakopoulou G, Garway-Heath E, et al. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. Lancet 2019; doi:10.1016/S0140-6736(18)32213-XThis project was funded by the NIHR Health Technology Assessment Programme (project number 09/104/40) and was sponsored by the Moorfields Eye Hospital NHS Foundation Trust.To read the full NIHR Signal, go to https://discover.dc.nihr.ac.uk/content/signal-000774/early-glaucoma-laser-eye-treatment-trabeculoplasty.


Assuntos
Glaucoma de Ângulo Aberto/cirurgia , Terapia a Laser/métodos , Hipertensão Ocular/cirurgia , Glaucoma de Ângulo Aberto/tratamento farmacológico , Humanos , Terapia a Laser/efeitos adversos , Hipertensão Ocular/tratamento farmacológico , Soluções Oftálmicas , Complicações Pós-Operatórias , Prostaglandinas Sintéticas/efeitos adversos , Prostaglandinas Sintéticas/uso terapêutico , Anos de Vida Ajustados por Qualidade de Vida , Resultado do Tratamento
9.
Medicine (Baltimore) ; 98(30): e16597, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348303

RESUMO

BACKGROUND: To evaluated and compared the efficacy and safety of 3 prostaglandin analogues (0.005% latanoprost, 0.004% travoprost, and 0.03% bimatoprost) in treatment of primary open-angle glaucoma (POAG) or ocular hypertension (OHT). METHODS: PubMed, Embase, Cochrane library, Web of science, CNKI, Wanfang, and Vip database, published between January 1, 2000 and June 1, 2018, were systematically examined for randomized controlled trials (RCT) based on prostaglandin analogues for POAG or OHT treatment. Statistical analyses including weighted mean difference (WMD) calculation and odds ratio (OR) were performed using Review Manager Software version 5.3. RESULT: The 17 studies were included in this analysis (N = 2433 participants) with 1∼12 months' follow-ups. The difference of intraocular pressure (IOP) reduction between latanoprost and travoprost group had not significant; there was significant difference of IOP reduction between latanoprost and bimatoprost group in the third month and sixth month; Travoprost was significantly different from bimatoprost in reducing IOP in the third month. Travoprost revealed an elevated risk of conjunctival hyperemia compared with latanoprost. An elevated risk of conjunctival hyperemia and growth of lashes compared with latanoprost. Bimatoprost shows lower ocular tolerability with higher incidence of side effects such as conjunctival hyperemia. CONCLUSIONS: 0.03% bimatoprost appears more effective following long time use (3 and 6 month post-treatment) for IOP control compared to 0.005% latanoprost, and is more effective compared to 0.004% travoprost after being used for a certain period of time (3 months post-treatment); nevertheless, 0.005% latanoprost is better tolerated in patients with POAG or OHT.


Assuntos
Glaucoma de Ângulo Aberto/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Prostaglandinas Sintéticas/uso terapêutico , Bimatoprost/uso terapêutico , Humanos , Pressão Intraocular/efeitos dos fármacos , Latanoprosta/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Travoprost/uso terapêutico
10.
Graefes Arch Clin Exp Ophthalmol ; 257(9): 1931-1939, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31152311

RESUMO

PURPOSE: To determine the risk of initiating ocular hypertension and glaucoma treatment with repeated injections of antivascular endothelial growth factors (anti-VEGF). METHODS: A unique, retrospective cohort study was performed using a large national US medical claim database. The study population included patients who had 1 or more injections of an anti-VEGF agent. Exclusion occurred for any previous glaucoma, glaucoma suspect, glaucoma-related procedure, an ocular steroid injection, or not seeing an eye care provider at least once in each year of follow-up. Cohorts were divided into quartiles based on the number of injections performed over the follow-up period. Patients were observed for 2 and 3 years. The main outcome measure was defined as any new prescription for an ocular antihypertensive medication with a concurrent diagnosis of glaucoma, glaucoma suspect, or ocular hypertension. Multivariate logistic regression determined the odds of initiating glaucoma treatment in each injection quartile while controlling for numerous covariates. Sensitivity analysis assessed outcomes that included new medication only as well as a new medication plus diagnosis of glaucoma. RESULTS: In total, 17,113 and 9992 patients met 2- and 3-year observation end points, respectively. The multivariate odds ratio for initiating glaucoma treatment at 2 years was higher in the highest quartile (OR 1.96, 95% CI 1.39-2.76, p < 0.001) compared with the lowest. The 3-year comparison had similar results with increased odds in the highest quartile (OR 1.51, 95% CI 1.07-2.13, p = 0.006) compared with the lowest. Sensitivity analyses also showed similar results with more injections being associated with initiating treatment (p < 0.053 for all comparisons). CONCLUSIONS: Repeated anti-VEGF injections are associated with an increased odds of initiating treatment for ocular hypertension and glaucoma.


Assuntos
Bevacizumab/administração & dosagem , Glaucoma/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Ranibizumab/administração & dosagem , Idoso , Inibidores da Angiogênese/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Glaucoma/fisiopatologia , Humanos , Masculino , Hipertensão Ocular/tratamento farmacológico , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
11.
Drugs Today (Barc) ; 55(6): 377-384, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31250842

RESUMO

Glaucoma is a main cause of irreversible vision impairment and its prevalence is expected to rise significantly in the near future. Among the current medications, prostaglandin analogues (PGAs) are widely used and considered as a first-line strategy in the management of glaucoma and ocular hypertension (OHT). However, given the non-negligible incidence of adverse ocular effects (conjunctival hyperemia, increase of iris pigmentation and eyelash changes) due to the use of this class of drugs, novel PGAs are being investigated. Omidenepag isopropyl is a selective prostaglandin EP2 receptor agonist which was approved on September 21, 2018, in Japan for the treatment of glaucoma and OHT. In this review, we will discuss its pharmacokinetics, pharmacodynamics and clinical efficacy, focusing also on its safety and tolerability profile.


Assuntos
Anti-Hipertensivos/uso terapêutico , Glaucoma/tratamento farmacológico , Glicina/análogos & derivados , Hipertensão Ocular/tratamento farmacológico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Glicina/uso terapêutico , Humanos , Japão , Resultado do Tratamento
12.
Mar Drugs ; 17(5)2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060323

RESUMO

High intraocular pressure (IOP)-induced retinal ischemia leads to acute glaucoma, which is one of the leading causes of irreversible visual-field loss, characterized by loss of retinal ganglion cells (RGCs) and axonal injury in optic nerves (ONs). Oxidative stress and the inflammatory response play an important role in the ischemic injury of retinal and optic nerves. We focus on 5α-androst-3ß, 5α, 6ß-triol (TRIOL), a synthetic neuroactive derivative of natural marine steroids 24-methylene-cholest-3ß, 5α, 6ß, 19-tetrol and cholestane-3ß, 5α, 6ß-triol, which are two neuroactive polyhydroxysterols isolated from the soft coral Nephthea brassica and the gorgonian Menella kanisa, respectively. We previously demonstrated that TRIOL was a neuroprotective steroid with anti-inflammatory and antioxidative activities. However, the potential role of TRIOL on acute glaucoma and its underlying mechanisms remains unclear. Here, we report TRIOL as a promising neuroprotectant that can protect RGCs and their axons/dendrites from ischemic-reperfusion (I/R) injury in an acute intraocular hypertension (AIH) model. Intravitreal injection of TRIOL significantly alleviated the loss of RGCs and the damage of axons and dendrites in rats and mice with acute glaucoma. As NF-E2-related factor 2 (Nrf2) is one of the most critical regulators in oxidative and inflammatory injury, we further evaluated the effect of TRIOL on Nrf2 knockout mice, and the neuroprotective role of TRIOL on retinal ischemia was not observed in Nrf2 knockout mice, indicating that activation of Nrf2 is responsible for the neuroprotection of TRIOL. Further experiments demonstrated that TRIOL can activate and upregulate Nrf2, along with its downstream hemeoxygenase-1 (HO-1), by negative regulation of Kelch-like ECH (Enoyl-CoA Hydratase) associated Protein-1 (Keap1). In conclusion, our study shed new light on the neuroprotective therapy of retinal ischemia and proposed a promising marine drug candidate, TRIOL, for the therapeutics of acute glaucoma.


Assuntos
Androstanóis/farmacologia , Fator 2 Relacionado a NF-E2/deficiência , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Células Ganglionares da Retina/efeitos dos fármacos , Esteroides/farmacologia , Animais , Técnicas de Cultura de Células , Hipóxia Celular/efeitos dos fármacos , Modelos Animais de Doenças , Glaucoma , Heme Oxigenase-1/metabolismo , Inflamação/tratamento farmacológico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Hipertensão Ocular/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
13.
Invest Ophthalmol Vis Sci ; 60(6): 2023-2033, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31067322

RESUMO

Purpose: To investigate the posttreatment neuronal rescue effects of Lycium barbarum polysaccharides (LBP) in an acute ocular hypertensive (AOH) model. Methods: Intraocular pressure (IOP) was elevated manometrically to 80 mm Hg (AOH) or 15 mm Hg (sham) for 120 minutes in adult Sprague-Dawley rats. Five experimental groups were considered: Three AOH groups were pretreated with PBS (vehicle) (n = 9), LBP 1 mg/kg (n = 8), or 10 mg/kg (n = 13), and one AOH group was posttreated with LBP 10 mg/kg (n = 8), once daily. The sham cannulation group (n = 5) received no treatment. Pretreatments commenced 7 days before and posttreatment 6 hours after AOH, and continued up through postcannulation day 28. All the animals underwent optical coherence tomography and electroretinogram measurements at baseline and postcannulation days 10 and 28. The ganglion cell layer (GCL) densities were quantified at day 28. Results: Both inner retinal layer thickness (IRLT) and positive scotopic threshold response (pSTR) underwent significant reduction (≥50% of thickness and amplitude) in the vehicle group (P < 0.05). Pretreatment with LBP 1 and 10 mg/kg retained 77 ± 11% and 89 ± 8% of baseline IRLT, respectively, and preserved pSTR functions. The posttreatment group showed a significant reduction in IRLT (-35 ± 8%, P < 0.001) and pSTR (∼48% of baseline, P < 0.001) on day 10. By day 28, there was an improvement in functional pSTR (∼72% of baseline, P > 0.05) with no significant further thinning (-40 ± 8%, P = 0.15) relative to day 10. GCL density was reduced in vehicle control (P = 0.0001), but did not differ between sham and pre- and posttreated AOH groups. Conclusions: The rescue effect of LBP posttreatment was observed later, which arrested the secondary degeneration and improved the retinal function.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Pressão Intraocular/fisiologia , Hipertensão Ocular/tratamento farmacológico , Células Ganglionares da Retina/patologia , Campos Visuais/fisiologia , Animais , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Seguimentos , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/diagnóstico , Hipertensão Ocular/fisiopatologia , Ratos , Ratos Sprague-Dawley , Células Ganglionares da Retina/efeitos dos fármacos , Tomografia de Coerência Óptica , Resultado do Tratamento , Campos Visuais/efeitos dos fármacos
14.
Invest Ophthalmol Vis Sci ; 60(6): 2072-2082, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31091314

RESUMO

Purpose: Excessive accumulation of extracellular matrix (ECM) in the trabecular meshwork (TM) reduces aqueous humor outflow, which likely contributes to elevation of IOP in primary open-angle glaucoma (POAG). Salidroside, a phenolic glycoside isolated from Rhodiola rosea is reported to prevent profibrotic responses by inhibiting Smad signaling pathway activated by TGF-ß in liver, lung, and kidney tissues. We tested if salidroside can (1) inhibit TGF-ß2-induced ECM expression in cultured human TM cells, and (2) lower TGF-ß2-induced ocular hypertension in the mouse. Methods: Cultured human TM cells stimulated with 5 ng/mL TGF-ß2 for 48 hours were treated with salidroside for 24 hours. The expressions of fibronectin (FN), collagen type IV (COL-IV), and laminin (LN) were evaluated by quantitative PCR, Western blot, and immunocytochemistry. BALB/cJ mice were injected intravitreally with an adenoviral vector encoding a bioactive mutant of TGF-ß2 (Ad.hTGF-ß2226/228) in one eye to induce ocular hypertension, with the uninjected contralateral or Ad.Empty-injected eyes serving as controls. Mice were treated with a daily intraperitoneal injection of 40 mg/kg salidroside. Conscious mouse IOP values were measured using a TonoLab rebound tonometer. Results: In cultured human TM cells, treatment with TGF-ß2 increased expressions of FN, COL-IV, and LN, as assessed by quantitative PCR, Western blotting, and immunocytochemistry, all of which were significantly and completely ameliorated by 30 µM salidroside. Daily intraperitoneal injections of salidroside (40 mg/kg), starting either at day 0 (same day as Ad.hTGF-ß2226/228 injection) or at day 14, significantly lowered TGF-ß2-induced ocular hypertension in the mouse. In contrast, salidroside did not affect IOP of control eyes. Conclusions: These results demonstrated that salidroside is capable of minimizing TGF-ß2-induced ECM expression in cultured human TM cells. It also reduced TGF-ß2-induced ocular hypertension in the mouse. These findings indicate that this phenolic glycoside may be useful as a novel treatment for POAG.


Assuntos
Matriz Extracelular/metabolismo , Glucosídeos/farmacologia , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/tratamento farmacológico , Fenóis/farmacologia , Malha Trabecular/efeitos dos fármacos , Animais , Células Cultivadas , Colágeno Tipo IV/metabolismo , Fibronectinas/metabolismo , Humanos , Injeções Intraperitoneais , Laminina/metabolismo , Camundongos , Hipertensão Ocular/metabolismo , Malha Trabecular/metabolismo , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Fator de Crescimento Transformador beta2/farmacologia
15.
BMJ Case Rep ; 12(5)2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31129643

RESUMO

We report the case of a 6-year-old girl with juvenile idiopathic arthritis and anterior uveitis who was treated with two doses of intravenous methylprednisolone for acute arthritis. She developed severe ocular hypertension (intraocular pressures (IOPs) of 54 mm Hg in the right eye and 61 mm Hg in the left eye) requiring inpatient therapy with intravenous acetazolamide. The normal range of values for IOP is 12-22 mm Hg. This severe case of acute intraocular hypertension due to systemic steroids highlights the need to consider monitoring of IOPs for children on high-dose topical and systemic steroids with risk factors for raised IOP.


Assuntos
Anti-Inflamatórios/efeitos adversos , Artrite Juvenil/tratamento farmacológico , Metilprednisolona/efeitos adversos , Hipertensão Ocular/etiologia , Uveíte Anterior/tratamento farmacológico , Administração Intravenosa , Anti-Inflamatórios/administração & dosagem , Artrite Juvenil/complicações , Criança , Feminino , Humanos , Metilprednisolona/administração & dosagem , Hipertensão Ocular/tratamento farmacológico , Índice de Gravidade de Doença , Uveíte Anterior/complicações
16.
BMJ Case Rep ; 12(4)2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30948417

RESUMO

Carteolol, a non-selective beta-antagonist with a potential risk of severe bronchial constriction in patients with asthma, is one of the most commonly prescribed medication for managing ocular pressure in glaucoma. We present a case of a 24-year-old woman with a history of atopy but no known asthma who presented an insidious onset of clinical manifestations compatible with drug-induced asthma after the initiation of carteolol for ocular hypertension control. The patient developed progressive chest tightness and dyspnoea for 2 months before the pulmonary function test revealed a positive bronchoprovocation response. She reported significant improvement of respiratory symptoms within 2 weeks after the discontinuation of carteolol, and a negative provocation response was later confirmed by repeat pulmonary function test. In conclusion, eye drops with non-selective beta-antagonising effect can induce asthmatic symptoms in patients without a previous diagnosis of asthma and should be administered with caution in patients with associated risk factors.


Assuntos
Antagonistas Adrenérgicos beta/efeitos adversos , Asma/induzido quimicamente , Carteolol/efeitos adversos , Hipertensão Ocular/tratamento farmacológico , Administração Oftálmica , Antagonistas Adrenérgicos beta/farmacologia , Broncoconstrição/efeitos dos fármacos , Carteolol/farmacologia , Humanos , Hipertensão Ocular/diagnóstico por imagem , Tomografia de Coerência Óptica , Adulto Jovem
17.
Can J Ophthalmol ; 54(2): 223-228, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30975346

RESUMO

OBJECTIVE: The primary goal is to determine if the intraocular pressure reducing effect of generic Sandoz travoprost is equivalent to that of brand-name Travatan Z. The secondary goal is to determine if generic Sandoz travoprost is as well tolerated as Travatan Z. METHODS: This prospective randomized crossover trial allocated 76 patients with primary open-angle glaucoma, normotensive glaucoma, or ocular hypertension in a 1:1 ratio to start with either generic Sandoz travoprost or Travatan Z. Crossover happened after 3 weeks. The primary endpoint, intraocular pressure, was measured in both eyes at baseline, at week 3, and at week 6. The secondary endpoint was tolerability of both drugs as assessed by a questionnaire administered at week 3 and week 6. RESULTS: The intraocular pressure lowering effect of generic Sandoz travoprost was equivalent to that of Travatan Z (18.20 ± 3.41 mmHg and 18.44 ± 3.48 mmHg respectively, p < 0.0001). Tolerability, as measured with a questionnaire, was similar between the two formulations of travoprost. CONCLUSION: This study is the first to compare a brand-name travoprost with one of its generic forms and adds to the body of evidence that generic glaucoma eye drops are as effective and well-tolerated as their brand name counterparts. The intraocular pressure lowering effect of generic Sandoz travoprost is equivalent to that of Travatan Z. Patient tolerance of generic and brand-name travoprost is similar.


Assuntos
Tolerância a Medicamentos , Medicamentos Genéricos/administração & dosagem , Glaucoma de Ângulo Aberto/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/tratamento farmacológico , Travoprost/administração & dosagem , Idoso , Anti-Hipertensivos/administração & dosagem , Estudos Cross-Over , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Masculino , Hipertensão Ocular/fisiopatologia , Soluções Oftálmicas/administração & dosagem , Estudos Prospectivos , Resultado do Tratamento
18.
Int J Mol Sci ; 20(4)2019 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-30813468

RESUMO

Intraocular pressure (IOP) has a tendency to fluctuate throughout the day, reaching its peak in the early morning in healthy subjects or glaucoma patients. Likewise, histamine tone also fluctuates over time, being lower at nighttime. Numerous studies have demonstrated a correlation between short-term IOP fluctuation and glaucoma progression; however, it has not yet been determined whether histamine plays a role in IOP fluctuations. The aim of this research was to establish the distribution of the histamine receptor proteins and respective mRNAs in the eye by western blot, immunohistochemistry and RT-PCR in New Zealand rabbits. Furthermore, we used a transient ocular hypertension (OHT) model induced by injection of 50 µL of 5% hypertonic saline into the vitreous and a stable OHT model (100 µL 0.1% carbomer in the anterior chamber) to address the potential IOP-lowering ability of H3 receptor (H3R) antagonists (ciproxifan, DL76 and GSK189254). IOPs were performed with a Tono-Pen at baseline and 60, 120 and 240 min post treatment after transient OHT induction and, every day for 12 days in the stable OHT model. All histamine receptor subtypes were localized in the rabbit retina and ciliary body/trabecular meshwork. All the treatments lowered IOP in a dose-dependent fashion between 0.3% and 1%. More specifically, the effects were maximal with ciproxifan at 60 min post-dose (IOP60 change = -18.84 ± 4.85 mmHg, at 1%), remained stable until 120 min (IOP120 change = -16.38 ± 3.8 mmHg, at 1%) and decayed thereafter to reach baseline values at 240 min. These effects were highly specific and dependent on histamine release as pre-treatment with imetit (H3R agonist, 1%) or pyrilamine (H1R antagonist, 1%) largely blocked ciproxifan-mediated effects. Color Doppler ultrasound examination was performed to evaluate changes in ophtalmic artery resistivity index (RI) before and after repeated dosing with DL 76, GSK189254, ciproxifan and timolol. Chronic treatments with H3R antagonists and timolol improved the vascular performance of ophthalmic arteries and reduced retinal ganglion cell death. Oxidative stress was also reduced and measured 8-Hydroxy-2'-deoxyguanosine (8OHdG) expression, and by dihidroethydium (DHE) staining. These results demonstrated that the histamine system participates in IOP regulation and that H3R antagonists could represent a future promising therapy for glaucoma. Further studies should be focused on the long-term IOP circadian fluctuations.


Assuntos
Glaucoma/tratamento farmacológico , Glaucoma/fisiopatologia , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Pressão Intraocular , Hipertensão Ocular/tratamento farmacológico , Hipertensão Ocular/fisiopatologia , Animais , Corioide/efeitos dos fármacos , Corioide/metabolismo , Corioide/patologia , Modelos Animais de Doenças , Glaucoma/genética , Antagonistas dos Receptores Histamínicos H3/farmacologia , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Pressão Intraocular/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Modelos Biológicos , Hipertensão Ocular/genética , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Coelhos , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Fatores de Tempo
19.
Acta Diabetol ; 56(6): 675-680, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30799524

RESUMO

AIMS: Intravitreal steroid implants have emerged as an adjunctive therapy in diabetic macular edema (DME) in patients refractory to anti-vascular endothelial growth factor agents. However, the use of these agents in patients with a prior history of steroid-induced ocular hypertension is limited. The present study aimed to analyze long-term intraocular pressure (IOP) response to the dexamethasone implant in patients with DME and a history of steroid-induced increase in IOP. METHODS: In a multicenter retrospective review, 17 eyes with DME and a history of steroid-induced increase in IOP to > 21 mmHg were treated with the dexamethasone implant and followed for 18 months. Patients with a history of vitrectomy of vitreoretinal interface pathology were excluded. The primary outcomes were the change in IOP and use of IOP-lowering agents. RESULTS: Among the study population (17 eyes), there was no significant change in mean IOP from baseline through 18 months (15.9 ± 2.0-14.6 ± 2.8 mmHg; p = 0.18). The number of patients requiring IOP-lowering agents rose from 5 at baseline to 14 at 18 months (p = 0.0049). None of the study eyes required surgical treatment. CONCLUSIONS: Though dexamethasone does predictably lead to an increase in IOP, this adverse effect was effectively managed with topical treatment. The present study suggests that the intravitreal dexamethasone implant may be considered in patients with DME and a history of steroid-induced ocular hypertension who have exhausted first-line treatments.


Assuntos
Dexametasona/administração & dosagem , Retinopatia Diabética/tratamento farmacológico , Implantes de Medicamento/efeitos adversos , Edema Macular/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Adulto , Idoso , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Retinopatia Diabética/complicações , Feminino , Humanos , Pressão Intraocular , Edema Macular/etiologia , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/etiologia , Esteroides/efeitos adversos
20.
Int J Pharm ; 560: 235-245, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30763680

RESUMO

Mucoadhesive olaminosomes are novel nanocarriers designed to control agomelatine release and enhance its bioavailability. Olaminosomes were prepared using oleic acid, oleylamine and sorbitan monooleate adopting thin film hydration technique. Chitosan HCl was added to impart the mucoadhesive properties to the olaminosomes. Mucoadhesive olaminosomes were characterized for their particle size, in-vitro drug release and irritation potentiality in rabbit eyes. The reduction in intraocular pressure (IOP) through 8 h in male New Zealand Albino rabbits was measured after administration of the selected formulations. Histopathological changes in rabbits' eye were also evaluated. Results revealed that increasing the amount of the added oleylamine decreased the particle size of the resulted vesicles and increased the drug release rate. Olaminosomes showed enhanced drug absorption, hence more reduction in IOP was observed. Moreover, using chitosan HCl might increase the residence time of the formulation in the eye and hence improved the absorption of the drug. No histopathological changes in rabbits' eye were detected after the application of mucoadhesive olaminosomes concluding their safety on the ocular tissues. In conclusion, mucoadhesive olaminosomes succeeded in enhancing agomelatine bioavailability in rabbits' eyes confirming the development of a novel ocular nanocarrier for insoluble drugs.


Assuntos
Acetamidas/administração & dosagem , Quitosana/química , Portadores de Fármacos/química , Pressão Intraocular/efeitos dos fármacos , Acetamidas/química , Acetamidas/farmacologia , Adesivos/química , Administração Oftálmica , Aminas/química , Animais , Disponibilidade Biológica , Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Hexoses/química , Masculino , Hipertensão Ocular/tratamento farmacológico , Ácido Oleico/química , Tamanho da Partícula , Coelhos , Solubilidade
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