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1.
Xenobiotica ; 51(1): 5-14, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32662714

RESUMO

MGV354 was being developed as a novel ocular therapy for lowering of intraocular pressure, a key modifiable risk factor for glaucoma. MGV354 is an activator of soluble guanylate cyclase, an enzyme known to be involved in the regulation of IOP. MGV354 has been shown to robustly lower IOP over 24 h after a single topical ocular drop in rabbit and monkey pharmacology models. However, MGV354 failed to produce similar results in patients with ocular hypertension or open-angle glaucoma. With an objective of explaining the lack of efficacy in the clinic, we attempted to study whether human metabolism was significantly different from animal metabolism. The present study documents the investigation of metabolism of MGV354 in an effort to understand potential differences in biotransformation pathways of MGV354 in rabbits, monkeys, and humans. Overall twenty-six metabolites, formed via oxidative and conjugative pathways, were identified in vitro and in vivo. In vitro hepatic metabolism was qualitatively similar across species, with minor but distinct differences. There were no observable interspecies differences in the hepatic and ocular metabolism of MGV354. Although ocular metabolism was not as extensive as hepatic, the results do not explain the lack of efficacy of MGV354 in clinical studies.


Assuntos
Anti-Hipertensivos/metabolismo , Piperidinas/metabolismo , Pirazóis/metabolismo , Piridinas/metabolismo , Animais , Anti-Hipertensivos/uso terapêutico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Humanos , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/tratamento farmacológico , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Coelhos
2.
BMC Ophthalmol ; 20(1): 489, 2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33334316

RESUMO

BACKGROUND: Anterior uveitis secondary to topical brimonidine administration is rare and not well-defined. In glaucoma patients using brimonidine, one must consider this phenomenon to avoid mis-diagnosis and over-treatment with topical steroids which in turn may increase intraocular pressure (IOP). This is the largest case series including the longest patient follow-up in the current literature. METHODS: Sixteen patients (26 eyes) with consultant diagnosed brimonidine-associated anterior uveitis in a tertiary referral glaucoma clinic presenting between 2015 and 2019 were included in this retrospective case series. Clinical records were taken for descriptive analysis. Main outcome measures were the key clinical features, and disease course (therapy, IOP control, patient outcome). RESULTS: Key features were conjunctival ciliary injection and mutton fat keratic precipitation in all eyes. The findings were bilateral in 10 patients. Time between initiation of brimonidine treatment and presentation was 1 week to 49 months. Glaucoma sub-types were mostly pseudo-exfoliative and primary open angle glaucoma. Brimonidine treatment was stopped immediately. Additionally, topical corticosteroids were prescribed in 18 eyes and tapered down during the following 4 weeks. Thirteen eyes did not need surgical or laser treatment (median follow-up time 15 months). No patient showed recurrence of inflammation after cessation of brimonidine. CONCLUSIONS: This type of anterior uveitis is an uncommon but important manifestation which should always be considered in glaucoma patients on brimonidine treatment. Although treatable at its root cause, problems may persist, especially with respect to IOP control. The latter may necessitate glaucoma surgery after the resolved episode of the uveitis.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Tartarato de Brimonidina/efeitos adversos , Uveíte Anterior/induzido quimicamente , Administração Oftálmica , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Glaucoma de Ângulo Aberto/tratamento farmacológico , Humanos , Pressão Intraocular/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/tratamento farmacológico , Soluções Oftálmicas , Estudos Retrospectivos , Uveíte Anterior/diagnóstico
3.
Nat Commun ; 11(1): 5594, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33154371

RESUMO

The underlying pathological mechanisms of glaucomatous trabecular meshwork (TM) damage and elevation of intraocular pressure (IOP) are poorly understood. Here, we report that the chronic endoplasmic reticulum (ER) stress-induced ATF4-CHOP-GADD34 pathway is activated in TM of human and mouse glaucoma. Expression of ATF4 in TM promotes aberrant protein synthesis and ER client protein load, leading to TM dysfunction and cell death. These events lead to IOP elevation and glaucomatous neurodegeneration. ATF4 interacts with CHOP and this interaction is essential for IOP elevation. Notably, genetic depletion or pharmacological inhibition of ATF4-CHOP-GADD34 pathway prevents TM cell death and rescues mouse models of glaucoma by reducing protein synthesis and ER client protein load in TM cells. Importantly, glaucomatous TM cells exhibit significantly increased protein synthesis along with induction of ATF4-CHOP-GADD34 pathway. These studies indicate a pathological role of ATF4-CHOP-GADD34 pathway in glaucoma and provide a possible treatment for glaucoma by targeting this pathway.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Estresse do Retículo Endoplasmático , Glaucoma de Ângulo Aberto/metabolismo , Biossíntese de Proteínas , Fator 4 Ativador da Transcrição/antagonistas & inibidores , Fator 4 Ativador da Transcrição/genética , Animais , Humor Aquoso/metabolismo , Morte Celular , Células Cultivadas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Glaucoma de Ângulo Aberto/tratamento farmacológico , Glaucoma de Ângulo Aberto/patologia , Humanos , Camundongos , Hipertensão Ocular/tratamento farmacológico , Hipertensão Ocular/metabolismo , Hipertensão Ocular/patologia , Nervo Óptico/metabolismo , Nervo Óptico/patologia , Biossíntese de Proteínas/efeitos dos fármacos , Proteína Fosfatase 1/genética , Proteína Fosfatase 1/metabolismo , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Transdução de Sinais , Malha Trabecular/efeitos dos fármacos , Malha Trabecular/metabolismo , Malha Trabecular/patologia , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo
4.
Drugs Today (Barc) ; 56(9): 599-608, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33025953

RESUMO

Ripasudil (K-115) is a novel Rho-associated protein kinase (ROCK) inhibitor. The Rho-ROCK pathway regulates key downstream effectors involved in many cellular functions, in particular in the actin cytoskeleton activity. The clinical effects of ripasudil expected on the eye include an intraocular pressure-lowering effect and a wound-healing activity on corneal endothelial cells, but many other functions are currently under investigation. To date, ripasudil has been approved in Japan (2014) for the treatment of glaucoma and ocular hypertension, and several clinical trials are currently investigating its role in the treatment of Fuchs' corneal dystrophy. In this review, we will discuss its pharmacokinetics, pharmacodynamics and clinical efficacy, focusing also on its safety and tolerability profile.


Assuntos
Glaucoma/tratamento farmacológico , Isoquinolinas/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , Sulfonamidas/uso terapêutico , Ensaios Clínicos como Assunto , Células Endoteliais , Humanos , Japão , Quinases Associadas a rho/antagonistas & inibidores
5.
PLoS One ; 15(8): e0237932, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822410

RESUMO

Increased deposition of fibronectin fibrils containing EDA+fibronectin by TGFß2 is thought to be involved in the reduction of aqueous humor outflow across the trabecular meshwork (TM) of the eye and the elevation in intraocular pressure (IOP) observed in primary open angle glaucoma (POAG). Using a fibronectin-binding peptide called FUD that can disrupt fibronectin fibrillogenesis, we examined if disrupting fibronectin fibrillogenesis would affect IOP in the TGFß2 BALB/cJ mouse model of ocular hypertension. BALB/cJ mice that had been intravitreally injected with an adenovirus (Ad5) expressing a bioactive TGFß2226/228 showed a significant increase in IOP after 2 weeks. When 1µM FUD was injected intracamerally into mice 2 weeks post Ad5-TGFß2 injection, FUD significantly reduced IOP after 2 days. Neither mutated FUD (mFUD) nor PBS had any effect on IOP. Four days after FUD was injected, IOP returned to pre-FUD injection levels. In the absence of TGFß2, intracameral injection of FUD had no effect on IOP. Western blotting of mouse anterior segments expressing TGFß2 showed that FUD decreased fibronectin levels 2 days after intracameral injection (p<0.05) but not 7 days compared to eyes injected with PBS. mFUD injection had no significant effect on fibronectin levels at any time point. Immunofluorescence microscopy studies in human TM (HTM) cells showed that treatment with 2ng/ml TGFß2 increased the amount of EDA+ and EDB+ fibronectin incorporated into fibrils and 2µM FUD decreased both EDA+ and EDB+ fibronectin in fibrils. An on-cell western assay validated this and showed that FUD caused a 67% reduction in deoxycholate insoluble fibronectin fibrils in the presence of TGFß2. FUD also caused a 43% reduction in fibronectin fibrillogenesis in the absence of TGFß2 while mFUD had no effect. These studies suggest that targeting the assembly of fibronectin fibrillogenesis may represent a way to control IOP.


Assuntos
Fibronectinas/metabolismo , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/metabolismo , Peptídeos/uso terapêutico , Malha Trabecular/efeitos dos fármacos , Adolescente , Adulto , Animais , Células Cultivadas , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Feminino , Fibronectinas/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Hipertensão Ocular/induzido quimicamente , Hipertensão Ocular/tratamento farmacológico , Peptídeos/metabolismo , Peptídeos/farmacologia , Malha Trabecular/citologia , Malha Trabecular/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Fator de Crescimento Transformador beta2/toxicidade
6.
Vestn Oftalmol ; 136(4): 76-84, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32779459

RESUMO

Preservative-free fixed combination of 0.0015% Tafluprost and 0.5% Timolol (PF tafluprost/timolol FC) has demonstrated good antihypertensive effect and patient tolerance in randomized controlled clinical trials. PURPOSE: To evaluate efficacy, tolerability, and safety of PF tafluprost/timolol FC in patients with primary open-angle glaucoma (POAG) and ocular hypertension (OH) who couldn't tolerate or gave insufficient response to topical beta-adrenoblockers or prostaglandin analogue monotherapy. MATERIAL AND METHODS: The prospective multicenter European VISIONARY study (EUPAS22204) included 87 patients from 7 ophthalmological centers in Russia with mean age of 63.9±11.8. Primary endpoint was mean IOP change at month 6. The patients were monitored for changes in in the severity of ocular signs and symptoms. RESULTS: Statistically significant (p<0.0001) reduction of mean IOP from baseline was seen at all study visits: 7.3±5.17 mmHg at week 4, 7.4±5.40 mmHg at week 12, and 7.1±5.10 mmHg at month 6. By month 6, IOP has decreased by 20; 25; 30 and 35% from baseline in 77.0%, 58.9%, 43.7%, and 31.0% of study patients, respectively. Conjunctival hyperemia was significantly reduced at all study visits. Significant reductions in dry eye symptoms (p<0.0010), irritation (p=0.0204) and itching (p=0.0010) were also observed. After 6 months on PF tafluprost/timolol FC, 85.7% of patients described it as easy or very easy to tolerate. CONCLUSION: In clinical practice, PF tafluprost/timolol FC provided statistically significant IOP reductions in patients with POAG and OH insufficiently controlled by or intolerant to monotherapy with topical beta-adrenoblockers or a prostaglandin analogue. The highest IOP reduction was seen at week 4 and was maintained over the 6-month study period. There was also a decrease in the severity of symptoms of ocular surface condition.


Assuntos
Glaucoma de Ângulo Aberto/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Combinação de Medicamentos , Humanos , Pressão Intraocular , Estudos Prospectivos , Federação Russa , Timolol , Resultado do Tratamento
7.
Zhonghua Yan Ke Za Zhi ; 56(5): 376-382, 2020 May 11.
Artigo em Chinês | MEDLINE | ID: mdl-32450671

RESUMO

Objective: To explore the potential neuroprotection effects and associated mechanism of baicalin in a rodent acute hypertensive glaucoma model and oxygen-glucose deprivation/reperfusion (OGD/R) induced retinal ganglion cell (RGC) injury. Methods: Experiment research. A rapid and substantial elevation of intraocular pressure was performed to establish an acute hypertensive glaucoma model, and retinal thickness was assessed at 1, 3, 5, and 7 days. The mice were then randomly divided into three groups: normal control group, hypertension group, and baicalin (50 mg/kg) for hypertension group. The effects of baicalin on the RGCs were evaluated by retrograde transporting of Fluoro-Gold. The mRNA levels of tumor necrosis factor-α, interleukine-1ß (IL-1ß), and inducible nitric oxide synthase were detected by real-time PCR, and the protein levels were measured by Western blot in the retina tissue of acute hypertensive glaucoma model. Purified primary RGC survival under OGD/R stress was measured by flow cytometry, which was also performed to measure the survival rate of RGCs pretreated by different doses of baicalin (2.5 µmol/L, 5.0 µmol/L, and 10.0 µmol/L). The effects of baicalin on primary RGCs co-cultured with mouse microglia cell line BV2 were evaluated by flow cytometry. The cytokine IL-1ß in the culture supernatant was measured by immunochemical analyses. Statistical analysis was performed using analysis of variance. Results: Retinal tissue injuries and RGC loss were observed both in vivo and in vitro. Retinal thickness was decreased to 87.32%±0.94% at 3 days (t=6.73, P<0.01), 74.86%±2.43% at 5 days (t=13.40, P<0.01), and 63.53%±2.15% at 7 days (t=19.46, P<0.01). Treatment of 50 mg/kg baicalin significantly promoted the RGC survival from 61.32%±5.94% to 89.93%±10.08% (t=4.84, P<0.01). Baicalin alleviated the retinal damages by suppressing the expression of inflammatory cytokines as revealed by Western blot and real-time PCR. In vitro the RGC survival under OGD/R stress was increased from 51.53%±1.36% to 69.37%±7.09% and 66.23%±4.25% with 5.0, 10.0 µmol/L baicalin administration (t=5.50, 4.53; both P<0.01). BV2 under OGD/R stress did extra damage to RGCs, and baicalin could reverse the damages and increase the survival from 69.37%±7.09% to 73.00%±5.20% (t=2.82, P=0.048) by reducing the release of IL-1ß [(39.97±8.76) pg/ml vs. (61.33±5.78) pg/ml, t=4.19, P=0.010]. Conclusion: Baicalin could alleviate retina tissue injury directly and promote the survival of RGCs by downregulating the expression of inflammatory cytokines and protecting RGCs from ischemia reperfusion injury. (Chin J Ophthalmol, 2020, 56: 376-382).


Assuntos
Anti-Inflamatórios não Esteroides , Flavonoides , Glaucoma , Hipertensão Ocular , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Modelos Animais de Doenças , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Glaucoma/tratamento farmacológico , Camundongos , Hipertensão Ocular/tratamento farmacológico , Células Ganglionares da Retina
8.
Drugs Aging ; 37(6): 457-462, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32447639

RESUMO

Bimatoprost implant (Durysta™), developed by Allergan, is a sustained-release drug delivery system containing bimatoprost, a prostaglandin analogue with ocular hypotensive activity. The implant, administered intracamerally, involves the use of a biodegradable, solid polymer drug delivery system for slow, sustained drug release, designed to lower intraocular pressure (IOP) over a 4- to 6-months period. In March 2020, bimatoprost implant received its first approval, in the USA, for use to reduce IOP in patients with open angle glaucoma (OAG) or ocular hypertension (OHT). Allergan's clinical development programme for bimatoprost implant is ongoing. This article summarizes the milestones in the development of bimatoprost implant leading to this first approval for use in the reduction of IOP in patients with OAG or OHT.


Assuntos
Bimatoprost/farmacologia , Aprovação de Drogas , Próteses e Implantes , Bimatoprost/efeitos adversos , Bimatoprost/uso terapêutico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/tratamento farmacológico , Hipertensão Ocular/fisiopatologia
9.
Am J Ophthalmol ; 217: 10-19, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32335057

RESUMO

PURPOSE: The origin of blood in glaucoma-related disc hemorrhages (DH) remains unknown. A prior clinic-based study of primary open-angle glaucoma (POAG)-related DH showed that they had grayscale pixel intensities more similar to blood from retinal macroaneurysms and adjacent retinal arterioles than to blood from retinal vein occlusions or adjacent retinal venules, suggesting an arterial source. Here we assessed the densitometric profile of DH from fundus photographs in the Ocular Hypertension Treatment Study (OHTS). DESIGN: Retrospective cross-sectional study of prospectively collected images. METHODS: Stereo disc photographs of 161 DH events from 83 OHTS participants (mean age [standard deviation (SD)]: 65.6 [9.2] years; 46.6% female; 13.0% black race) were imported into ImageJ to measure densitometry differences (adjacent arterioles minus DH [ΔA] or venules minus DH [ΔV]). Their size as percentage of disc area, ratio of length to midpoint width, and location relative to the disc margin were also analyzed. We performed t tests to compare ΔA and ΔV, analysis of variance to compare ΔA and ΔV across DH recurrent events, and multivariable linear regression to identify determinants of ΔA and ΔV. RESULTS: Mean (SD) ΔA and ΔV were -2.2 (8.7) and -11.4 (9.7) pixel intensity units, respectively (P < .001). ΔA and ΔV each did not differ significantly across recurrence of DH (P ≥ .92) or between DH events with and without POAG (P ≥ .26). CONCLUSIONS: OHTS DH had densitometric measurements more similar in magnitude to adjacent arterioles than venules, supporting an arterial origin for DH. Vascular dysregulation may contribute to disc hemorrhage formation in ocular hypertension.


Assuntos
Anti-Hipertensivos/uso terapêutico , Densitometria/métodos , Pressão Intraocular/fisiologia , Hipertensão Ocular/complicações , Disco Óptico/irrigação sanguínea , Hemorragia Retiniana/diagnóstico , Vasos Retinianos/diagnóstico por imagem , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/tratamento farmacológico , Hipertensão Ocular/fisiopatologia , Hemorragia Retiniana/etiologia , Hemorragia Retiniana/fisiopatologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Tomografia de Coerência Óptica
10.
Expert Opin Pharmacother ; 21(10): 1269-1282, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32228188

RESUMO

INTRODUCTION: Fixed-combination glaucoma medications have altered the paradigm of ocular hypertension and glaucoma treatment and are in widespread use today. A comprehensive review of fixed-combination medications will help educate and inform providers for optimal patient care. AREAS COVERED: In this review, the authors describe the composition, mechanism of action, efficacy, side effects, and safety profile of fixed-combination agents for the treatment of ocular hypertension and glaucoma as well as comparisons between the most frequently prescribed medications. EXPERT OPINION: Fixed-combination therapeutics provide an effective and efficient means of lowering intraocular pressure with comparable side effects and outcomes to constituent parts with lower patient exposure to preservatives and improvement in compliance.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , Soluções Oftálmicas/uso terapêutico , Anti-Hipertensivos/farmacologia , Humanos , Soluções Oftálmicas/farmacologia
11.
Doc Ophthalmol ; 141(2): 149-156, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32152920

RESUMO

PURPOSE: To investigate long-term structural and functional progression of untreated and treated glaucoma suspects (UGS and TGS). METHODS: Retrospective analysis of serial steady-state pattern electroretinogram (PERG), mean retinal nerve fiber layer thickness (RNFLT), and standard automated perimetry mean deviation (SAP-MD) in UGS (N = 20) and TGS (N = 18). Outcome measures were the rates of change (linear regression slopes) of PERG amplitude, PERG phase, mean RNFLT, and SAP-MD over 9.8 ± 1.3 years (15.6 ± 4.2 visits). RESULTS: The number of patients with significant (P < 0.05) progression slopes for PERG amplitude, PERG phase, RNFLT, and SAP-MD was, respectively, UGS: 5, 0, 4, 2; TGS: 8, 2, 6, 5. In UGS, outcome measures were not correlated with each other. In TGS, both PERG amplitude and RNFLT were significantly (P < 0.05) correlated with SAP-MD (R ≥ 0.58), while PERG amplitude and RNFLT were not correlated with each other (R = 0.43, P = 0.064). The rate of change of SAP-MD was predicted (P < 0.05) by a linear combination of RNFLT slope and PERG amplitude slope. CONCLUSIONS: Results substantiate and extend previous results showing that steady-state PERG amplitude progressively decreased over time in a proportion of glaucoma suspects, with relatively steeper slope in TGS compared to UGS. RNFLT progression also had a steeper slope in TGS compared to UGS; however, progressions of PERG amplitude and RNFLT were not significantly correlated. Both PERG progression and RNFLT progression independently contribute to prediction of visual field progression.


Assuntos
Anti-Hipertensivos/uso terapêutico , Fibras Nervosas/fisiologia , Hipertensão Ocular/tratamento farmacológico , Células Ganglionares da Retina/fisiologia , Adulto , Progressão da Doença , Eletrorretinografia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/diagnóstico , Hipertensão Ocular/fisiopatologia , Reconhecimento Visual de Modelos/fisiologia , Estudos Retrospectivos , Testes de Campo Visual/métodos , Campos Visuais/fisiologia
12.
Invest Ophthalmol Vis Sci ; 61(3): 13, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32176263

RESUMO

Purpose: To investigate the efficacy of intravitreal administration of resveratrol (RSV) in a microbead-induced high intraocular pressure (IOP) murine model for glaucoma. Methods: Experiments were performed using adult C57BL/6JJcl mice. Polystyrene microbeads were injected into the anterior chamber to induce IOP elevation. Retinal flat-mounts and sections were assessed by immunohistochemistry to detect the expression of reactive oxygen species and acetyl-p53 in retinal ganglion cells (RGCs), brain-derived neurotrophic factor (BDNF) in Müller glial cells (MGCs), and the receptor tropomyosin receptor kinase B (TrkB) in RGCs. Light cycler real-time PCR was also used for confirming gene expression of BDNF in primary cultured MGCs exposed to RSV. Results: Microbeads induced high IOP followed by RGC death and axon loss. Administration of RSV rescued RGCs via decreased reactive oxygen species generation and acetyl-p53 expression in RGCs and upregulated BDNF in MGCs and TrkB expression in RGCs, which exhibited a strong cytoprotective action against cell death through multiple pathways under high IOP. Conclusions: Our data suggest that administration of RSV may delay the progress of visual dysfunction during glaucoma and may therefore have therapeutic potential.


Assuntos
Antioxidantes/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , Resveratrol/uso terapêutico , Células Ganglionares da Retina/efeitos dos fármacos , Acetilação , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Citoproteção/fisiologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Pressão Intraocular/efeitos dos fármacos , Injeções Intravítreas , Masculino , Camundongos Endogâmicos C57BL , Microesferas , Hipertensão Ocular/etiologia , Hipertensão Ocular/metabolismo , Hipertensão Ocular/patologia , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/administração & dosagem , Resveratrol/farmacologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo
13.
Clin Ther ; 42(2): 263-275, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32089329

RESUMO

PURPOSE: Many patients with open-angle glaucoma eventually require >2 medications to lower their intraocular pressure (IOP). Fixed-combination ophthalmic solutions can be advantageous in patients who require multiple medications, but the number of fixed combinations combining 3 complementary IOP-lowering agents remains limited. This study assessed the efficacy and safety of a triple fixed combination (TFC) of bimatoprost 0.01%/brimonidine 0.15%/timolol 0.5% ophthalmic solution in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT), compared with a dual fixed combination (DFC) of brimonidine 0.2%/timolol 0.5%. METHODS: Patients with a baseline IOP of 23-34 mm Hg in both eyes and no history of IOP-lowering procedures were eligible for participation in this multicenter, double-masked, randomized, Phase III study. After washout of previous treatment (if applicable), patients were randomized to receive TFC or DFC twice daily in each eye for 3 months. The primary efficacy variable was the change from baseline in mean IOP in the worse eye at week 12 in the modified intent-to-treat (mITT) population. TFC was superior to DFC if the treatment difference (TFC - DFC) favored TFC at week 12 (P ≤ 0.05; 2-sample t test). Secondary and sensitivity analyses were also performed. Safety, including adverse events, was assessed at all visits. FINDINGS: The mITT/safety population included 185 patients (TFC, n = 90; DFC, n = 95). TFC superiority was demonstrated at all postbaseline visits (all, P < 0.001) through week 12 (week 12 treatment difference: ─2.17 mm Hg; 95% CI, ─3.12 to ─1.22). While treatment-related conjunctival hyperemia was more frequent with TFC than with DFC (47.8% vs 23.2%; P < 0.001), consistent with the additional presence of bimatoprost in TFC, most cases were mild and the numbers of patient discontinuations at week 12 were similar between the TFC and DFC groups (11 [12.2%] vs 7 [7.4%] patients; P = 0.266). No unexpected adverse events were reported. IMPLICATIONS: Compared with DFC, TFC provided superior IOP lowering throughout the primary efficacy period. An acceptable tolerability profile was observed through 12 months of use of TFC, offering an effective therapeutic option in patients with POAG or OHT who require multiple medications to control their IOP. Additional studies are required for the assessment of the long-term effects of TFC. ClinicalTrials.gov identifier: NCT01217606.


Assuntos
Anti-Hipertensivos/administração & dosagem , Bimatoprost/administração & dosagem , Tartarato de Brimonidina/administração & dosagem , Hipertensão Ocular/tratamento farmacológico , Soluções Oftálmicas/administração & dosagem , Timolol/administração & dosagem , Idoso , Anti-Hipertensivos/efeitos adversos , Bimatoprost/efeitos adversos , Brasil , Tartarato de Brimonidina/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Pressão Intraocular/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas/efeitos adversos , Timolol/efeitos adversos
14.
Am J Ophthalmol ; 215: 112-117, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32087142

RESUMO

PURPOSE: To test the hypothesis that the correlation between office-hour intraocular pressure (IOP) and peak nocturnal IOP is weakened after using a prostaglandin analog. DESIGN: Before-and-after study. METHODS: Twenty-four-hour IOP data obtained in a sleep laboratory of 51 patients (22 patients with open-angle glaucoma and 29 patients with ocular hypertension) were reviewed. Patients had no IOP-lowering medication upon study entry and were then treated with prostaglandin monotherapy for 4 weeks. Measurements of IOP were taken every 2 hours in the sitting and supine positions during the diurnal/wake period (7:30 AM-9:30 PM) and in the supine position during the nocturnal/sleep period (11:30 PM-5:30 AM). Individual and average IOP readings during office hours (9:30 AM-3:30 PM) and peak IOP during the nocturnal/sleep hours were analyzed using the Pearson correlation coefficient and linear regression. RESULTS: There were statistically significant correlations for all the paired variables for the analyses. Average office-hour IOP had a higher correlation with peak nocturnal IOP than individual office-hour IOP. After the treatment with prostaglandin analog, the correlation between average office-hour IOP and nocturnal peak IOP in the sitting position (r = 0.373) and the supine position (r = 0.386) were reduced from the sitting baseline (r = 0.517) and the supine baseline (r = 0.573) in right eyes. Similar change patterns appeared in left eyes. CONCLUSION: There is a correlation between office-hour IOP reading and peak nocturnal IOP under no IOP-lowering treatment as well as under prostaglandin monotherapy. The strength of correlation was weaker under the treatment compared with baseline.


Assuntos
Anti-Hipertensivos/uso terapêutico , Ritmo Circadiano/fisiologia , Glaucoma de Ângulo Aberto/tratamento farmacológico , Pressão Intraocular/fisiologia , Prostaglandinas Sintéticas/uso terapêutico , Idoso , Feminino , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/tratamento farmacológico , Hipertensão Ocular/fisiopatologia , Postura , Estudos Retrospectivos , Tonometria Ocular
15.
PLoS One ; 15(2): e0229682, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32106236

RESUMO

BACKGROUND: Fixed-combination (FC) therapy is used in primary open-angle glaucoma (POAG) and ocular hypertension (OHT) patients who require more than one medication to reach their target intraocular pressure (IOP). Currently, there are several FC therapies available for the treatment of glaucoma. The FC of latanoprost/timolol (LTFC) is a commonly used FC. Here, we conducted systematic review to compare the IOP-lowering effects of LTFC with other FCs for patients with POAG and OHT. MATERIALS AND METHODS: We searched PubMed, EMBASE, the Cochrane Library, and Web of Science for randomized-controlled clinical trials and cross-over studies. The outcomes were mean IOP and IOP fluctuation after one month of treatment. Meta-analysis was carried out using RevMan (version 5.1) software. After conducting meta-analyses, we rated the quality of each meta-analysis as high, moderate, low, or very low using the "GRADE" system. RESULTS: We included 16 trials in this meta-analysis. Moderate-quality meta-analysis showed that LTFC had a comparable mean IOP to that of a fixed combination of travoprost and timolol (TTFC) [mean difference (MD): 0.07 mmHg] and a fixed combination of dorzolamide and timolol (DTFC) [MD: -0.31 mmHg], and it also had a comparable IOP-fluctuation effect compared to that of TTFC [MD: 0.13 mm Hg] and DTFC [MD: 0.25 mmHg]. Compared to the fixed combination of bimatoprost and timolol (BiTFC), moderate-quality evidence showed a higher mean IOP in the LTFC group [MD 0.76 mmHg], whereas low-quality meta-analysis showed higher IOP fluctuation [MD 1.09 mmHg] in the LTFC group. CONCLUSIONS: LTFC is as effective as TTFC and DTFC, but worse than BiTFC in controlling mean IOP and IOP fluctuation for POAG or OHT patients. The quality of our meta-analyses was assessed as moderate, with the exception of one low-quality analysis that compared the IOP fluctuation of LTFC and BiTFC.


Assuntos
Glaucoma de Ângulo Aberto/tratamento farmacológico , Latanoprosta/administração & dosagem , Hipertensão Ocular/tratamento farmacológico , Timolol/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Bimatoprost/administração & dosagem , Combinação de Medicamentos , Feminino , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Pressão Intraocular/efeitos dos fármacos , Masculino , Hipertensão Ocular/fisiopatologia , Sulfonamidas/administração & dosagem , Tiofenos/administração & dosagem , Travoprost/administração & dosagem , Resultado do Tratamento
16.
Adv Ther ; 37(3): 1114-1123, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31981106

RESUMO

INTRODUCTION: To describe the changes in endothelial cell density (ECD), the coefficient of variation (CV), the percentage of hexagonal cells (%HEX), and central corneal thickness (CCT) following 3 months of therapy with netarsudil 0.02%/latanoprost 0.005% fixed combination, and to compare these changes with those seen with netarsudil 0.02% or latanoprost 0.005% in eyes with ocular hypertension or open-angle glaucoma. METHODS: A subset of subjects enrolled in a Phase 3 evaluation of the intraocular pressure-lowering efficacy and safety of netarsudil 0.02%/latanoprost 0.005% fixed combination once daily (QD) versus each of its individual components underwent corneal endothelial cell imaging by specular microscopy and ultrasound pachymetry at baseline and following 3 months of therapy. Images were evaluated in masked fashion at an independent reading center. Changes from baseline to 3 months in ECD, CV, %HEX, and CCT were compared between treatment groups. RESULTS: Data from 415 subjects obtained at both baseline and Month 3 were included in this post hoc analysis. Changes from baseline to Month 3 in ECD, CV, and %HEX were clinically insignificant in all three groups, and the changes in the netarsudil/latanoprost fixed combination group demonstrated no statistical difference from those seen in the netarsudil and latanoprost groups. Mean CCT decreased more in the fixed combination group (- 6.4 µm) than in either the netarsudil group (- 3.3 µm, p = 0.0248) or the latanoprost group (- 1.2 µm, p < 0.0001). CONCLUSIONS: Netarsudil 0.2%/latanoprost 0.005% fixed combination QD for 3 months in eyes with ocular hypertension or open-angle glaucoma had no clinically significant effects on endothelial cell density or morphology. The significant decrease in CCT in the fixed combination group compared to the two individual component groups may indicate that the potential effects of each drug on CCT are additive, although the magnitude of the observed effects is likely of negligible clinical significance. CLINICALTRIALS. GOV IDENTIFIER: NCT02674854.


Assuntos
Benzoatos/uso terapêutico , Epitélio Posterior/efeitos dos fármacos , Glaucoma de Ângulo Aberto/tratamento farmacológico , Latanoprosta/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , beta-Alanina/análogos & derivados , Idoso , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Pressão Intraocular , Latanoprosta/administração & dosagem , Latanoprosta/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prostaglandinas F Sintéticas/uso terapêutico , Tonometria Ocular , beta-Alanina/administração & dosagem , beta-Alanina/efeitos adversos , beta-Alanina/uso terapêutico
17.
Eur J Ophthalmol ; 30(5): NP32-NP35, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30950286

RESUMO

PURPOSE: To report a case of phacolytic glaucoma with rupture of anterior lens capsule in a case of hypermature cataract. METHODS: Case report and literature review. RESULTS: An 80-year-old woman presented with cloudiness and pain in the left eye for 1 day. The patient had visual acuity limited to perception of light with raised intraocular pressure of 70 mm Hg. Careful slit-lamp evaluation revealed corneal epithelial edema in superior quadrant and a deep and turbid anterior chamber. Ultrasound biomicroscopy confirmed the presence of a deep anterior chamber, a hypermature cataractous nucleus with lax capsular bag, and ruptured anterior lens capsule. The patient underwent extracapsular cataract extraction. Cytological examination of the lenticular fluid revealed the presence of lens protein-laden macrophages. Post-operatively, the patient had best-corrected visual acuity of 6/60 with advanced glaucomatous optic neuropathy. CONCLUSION: Phacolytic glaucoma can present with a cloudy cornea and a turbid anterior chamber mimicking endophthalmitis. Careful examination and ancillary investigations including ultrasound biomicroscopy was helpful in making an accurate diagnosis.


Assuntos
Extração de Catarata , Catarata/complicações , Glaucoma/etiologia , Núcleo do Cristalino/patologia , Idoso de 80 Anos ou mais , Cápsula Anterior do Cristalino/diagnóstico por imagem , Cápsula Anterior do Cristalino/patologia , Câmara Anterior/diagnóstico por imagem , Câmara Anterior/patologia , Anti-Hipertensivos/uso terapêutico , Doenças da Córnea/etiologia , Feminino , Glaucoma/diagnóstico por imagem , Glaucoma/tratamento farmacológico , Humanos , Pressão Intraocular , Núcleo do Cristalino/diagnóstico por imagem , Microscopia Acústica , Hipertensão Ocular/diagnóstico por imagem , Hipertensão Ocular/tratamento farmacológico , Hipertensão Ocular/etiologia , Tonometria Ocular , Acuidade Visual/fisiologia
18.
Expert Opin Pharmacother ; 21(1): 39-45, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31663782

RESUMO

Introduction: Reduction of intraocular pressure (IOP) is the only known modifiable risk factor for prevention and treatment of glaucoma. Rho-kinase (ROCK) inhibitors are a new class of glaucoma medications introduced recently with novel mechanisms of action and favorable safety profiles. Latanoprost, a common first line drug used for treatment of glaucoma, does not adequately control pressures in all cases. Addition of more than one anti-glaucoma medication affects patient compliance and adherence. Fixed-combination eye drops are combinations of two or more active drugs in a single dosage form, thus simplify dosing. New to this group is the fixed combination netarsudil- latanoprost (FCNL).Area covered: This review focuses on FCNL, its pharmacodynamics and pharmacokinetics. It also details the efficacy and safety of individual drugs compared to FCNL.Expert opinion: The combination of latanoprost and netarsudil is a potent medication and modulates all known targets for IOP reduction in a single drop and has been shown to be more effective than either drug alone. FCNL is an alternative for those with inadequately controlled IOP on a prostaglandin analog alone, as well as those for whom a simplified regimen is desirable, or those who are not good candidates for other classes of glaucoma medications.


Assuntos
Benzoatos/administração & dosagem , Glaucoma/tratamento farmacológico , Latanoprosta/administração & dosagem , Hipertensão Ocular/tratamento farmacológico , beta-Alanina/análogos & derivados , Anti-Hipertensivos/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Pressão Intraocular/efeitos dos fármacos , Masculino , Soluções Oftálmicas , beta-Alanina/administração & dosagem
19.
Cutan Ocul Toxicol ; 39(1): 21-24, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31615279

RESUMO

Purpose: To compare the efficacy, safety, and potential advantages of the preservative-free versus preserved brimonidine %0.15 preparations in patients with primer open-angle glaucoma (POAG) or ocular hypertension (OHT).Methods: Forty-two eyes of the 21 treatment-naive patients with POAG or OHT were enrolled in this study. Eyes were randomly assigned to receive brimonidine-purite 0.15% or preservative-free brimonidine 0.15% two times daily. Efficacy of the two eye drops was assessed by measuring the intraocular pressure (IOP) at 9-10 am at baseline and week 4. Safety and potential advantages of the drops were evaluated at weeks 4 in terms of ocular symptoms and tear parameters. Ocular symptom values of the patients were evaluated with a scale of 0-4 (0 = no discomfort and 4 = severe discomfort).Results: Both of the brimonidine tartrate formulations resulted in statistically similar IOP reduction (preserved formulation; -5.2 mmHg [22.9% reduction] preservative-free formulation; -5.7 mmHg [24.1% reduction], p = 0.37). It was found that brimonidine tartrate formulations with and without topical preservatives did not produce a statistically significant difference in pain, stinging, and blurred vision at the upon instillation (p > 0.05). However, the burning sensation was significantly higher in the preservative-free formulation at the first instillation compared to the preserved formulation (p = 0.01). Also, there was no statistically significant difference between the two formulations in terms of symptoms (itching, burning, tearing, stinging, and photophobia) and tear parameters during the day (p > 0.05).Conclusions: Although topical preservative-free brimonidine tartrate treated eyes had a more burning sensation at the first drop, the two formulations were similar in terms of ocular tolerability in the short term period. Also, both formulations were found to reduce IOP at a similar rate.


Assuntos
Tartarato de Brimonidina/uso terapêutico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Conservantes Farmacêuticos/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 2/química , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Adulto , Tartarato de Brimonidina/administração & dosagem , Tartarato de Brimonidina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/química , Soluções Oftálmicas/uso terapêutico , Conservantes Farmacêuticos/química
20.
Br J Ophthalmol ; 104(1): 121-126, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30923134

RESUMO

AIMS: To compare the biomechanically corrected intraocular pressure (IOP) estimate (bIOP) provided by the Corvis-ST with Goldmann applanation tonometry (GAT-IOP) in patients with high-tension and normal-tension primary open-angle glaucoma (POAG; HTG and NTG), ocular hypertension (OHT) and controls. Moreover, we compared dynamic corneal response parameters (DCRs) of the Corvis-ST in POAG, OHT and controls, evaluated the correlation between global visual field parameters mean deviation and pattern SD (MD and PSD) and DCRs in the POAG group. METHODS: 156 eyes of 156 patients were included in this prospective, single-centre, observational study, namely 41 HTG and 33 NTG, 45 OHT cases and 37 controls. Central corneal thickness (CCT), GAT-IOP and bIOP were measured, GAT-IOP was also adjusted for CCT (GATAdj). DCRs provided by Corvis-ST were evaluated, MD and PSD were recorded by 24-2 full-threshold visual field. To evaluate the difference in DCRs between OHT, HTG and NTG, a general linear model was used with sex, medications and group as fixed factors and bIOP and age as covariates. RESULTS: There was a significant difference between GAT-IOP, GATAdj and bIOP in NTG and HTG, OHT and controls. NTG corneas were significantly softer and more deformable compared with controls, OHT and HTG as demonstrated by significantly lower values of stiffness parameters A1 and highest concavity and higher values of inverse concave radius (all p<0.05). There was a significant correlation (p<0.05) between MD, PSD and many DCRs with POAG patients with softer or more compliant corneas more likely to show visual field defects. CONCLUSIONS: Corneal biomechanics might be a significant confounding factor for IOP measurement that should be considered in clinical decision-making. The abnormality of corneal biomechanics in NTG and the significant correlation with visual field parameters might suggest a new risk factor for the development or progression of NTG.


Assuntos
Córnea/fisiopatologia , Pressão Intraocular/fisiologia , Hipertensão Ocular/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Fenômenos Biomecânicos/fisiologia , Estudos de Casos e Controles , Córnea/patologia , Feminino , Glaucoma de Ângulo Aberto/tratamento farmacológico , Glaucoma de Ângulo Aberto/patologia , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/tratamento farmacológico , Hipertensão Ocular/patologia , Estudos Prospectivos , Tonometria Ocular/métodos , Testes de Campo Visual/métodos , Campos Visuais/fisiologia
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