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1.
Molecules ; 26(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361825

RESUMO

Lipid-based nanocarriers (LNs) have made it possible to prolong corneal residence time and improve the ocular bioavailability of ophthalmic drugs. In order to investigate how the LNs interact with the ocular mucosa and reach the posterior eye segment, we have formulated lipid nanocarriers that were designed to bear a traceable fluorescent probe in the present work. The chosen fluorescent probe was obtained by a conjugation reaction between fluoresceinamine and the solid lipid excipient stearic acid, forming a chemically synthesized adduct (ODAF, N-(3',6'-dihydroxy-3-oxospiro [isobenzofuran-1(3H),9'-[9H] xanthen]-5-yl)-octadecanamide). The novel formulation (LN-ODAF) has been formulated and characterized in terms of its technological parameters (polydispersity index, mean particle size and zeta potential), while an in vivo study was carried out to assess the ability of LN-ODAF to diffuse through different ocular compartments. LN-ODAF were in nanometric range (112.7 nm ± 0.4), showing a good homogeneity and long-term stability. A TEM (transmission electron microscopy) study corroborated these results of characterization. In vivo results pointed out that after ocular instillation, LN ODAF were concentrated in the cornea (two hours), while at a longer time (from the second hour to the eighth hour), the fluorescent signals extended gradually towards the back of the eye. From the results obtained, LN-ODAF demonstrated a potential use of lipid-based nanoparticles as efficient carriers of an active pharmaceutical ingredient (API) involved in the management of retinal diseases.


Assuntos
Córnea/metabolismo , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Lipídeos/química , Nanopartículas/administração & dosagem , Segmento Posterior do Olho/metabolismo , Compostos de Espiro/administração & dosagem , Animais , Córnea/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Segmento Posterior do Olho/efeitos dos fármacos , Coelhos , Compostos de Espiro/química
2.
Invest Ophthalmol Vis Sci ; 62(9): 21, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34259818

RESUMO

Purpose: The purpose of this study was to evaluate the role of the canonical Wnt signaling in the development of the myopia. Methods: Plasma from adult patients with myopia, myopic animal models including the adenomatous polyposis coli (APC) gene mutation mouse model, and the form deprivation (FD) induced mouse model of myopia were used. Niclosamide, a canonical Wnt pathway inhibitor, was orally administrated in animal models. Plasma levels of DKK-1 were determined by using enzyme-linked immunosorbent assay. Refraction, vitreous chamber depth (VCD), axial length (AL), and other parameters, were measured at the end of the FD treatment. Canonical Wnt signaling changes were evaluated by Western blot analysis and immunostaining analysis. Results: Plasma level of Wnt inhibitor DKK-1 was markedly decreased in patients with myopia. Meanwhile, the canonical Wnt pathway was progressively activated during myopia development in mice. Moreover, inhibition of canonical Wnt signaling by niclosamide in mouse models markedly reduced lens thickness (LT), VCD, and AL elongation, resulting in myopia inhibition. Conclusions: Dysregulation of canonical Wnt signaling is a characteristic of myopia and targeting Wnt signaling pathways has potential as a therapeutic strategy for myopia.


Assuntos
Segmento Anterior do Olho/metabolismo , Miopia/genética , Segmento Posterior do Olho/metabolismo , Refração Ocular/fisiologia , Via de Sinalização Wnt/genética , Adolescente , Adulto , Animais , Segmento Anterior do Olho/diagnóstico por imagem , Segmento Anterior do Olho/efeitos dos fármacos , Biomarcadores/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miopia/metabolismo , Miopia/fisiopatologia , Segmento Posterior do Olho/diagnóstico por imagem , Segmento Posterior do Olho/efeitos dos fármacos , Privação Sensorial , Adulto Jovem
3.
Int J Pharm ; 576: 118987, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-31870961

RESUMO

A novel Liposome Aggregate Platform (LAP) system for prolonged retention of drugs in the posterior eye segment after intravitreal injection (IVT) was developed and evaluated. Calcein, FITC-dextran-4000 (FD4) and Flurbiprofen (FLB), were encapsulated in negatively charged liposomes, and mixed with protamine to produce the LAP. The lipid/protamine ratio was fixed, in order to have a convenient aggregation rate permitting IVT injection and also a sustained release of liposome-entrapped molecules (in vitro) from LAP. In vitro release studies confirmed the potential of LAP system consisted of HPC/DPPG/Chol liposomes and protamine (at 1:1 w/w to lipid), to delay calcein, FD4 and FLB release, compared to free liposomes. In vivo studies demonstrated increased vitreous retention of liposomes and LAP for all molecules, compared to the corresponding solutions; however the retention of FD4 is similar for non-aggregated liposomes and LAP, and calcein retention is only slightly increased by LAP compared to liposomes. The later result may be connected with the visible ocular inflammation caused by both dyes; interestingly inflammation was moderately reduced when dyes were entrapped in liposomes and even more when in LAP. No visible inflammation was demonstrated for FLB, and the LAP system significantly increased the retention of FLB in the ocular tissues (compared to non-aggregated liposomes). Taking into account the capability of the novel LAP system to decrease inflammatory reactions towards calcein and FD4, and prolong the retention of FLB in ocular tissues, it is concluded that such systems, after further optimization, may be considered as promising effective and safe approaches for treatment of posterior segment ocular pathologies.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Flurbiprofeno/administração & dosagem , Lipídeos/química , Lipossomos , Segmento Posterior do Olho/metabolismo , Protaminas/química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Preparações de Ação Retardada , Dextranos/administração & dosagem , Dextranos/química , Dextranos/metabolismo , Composição de Medicamentos , Liberação Controlada de Fármacos , Fluoresceína-5-Isotiocianato/administração & dosagem , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/química , Fluoresceína-5-Isotiocianato/metabolismo , Fluoresceínas/administração & dosagem , Fluoresceínas/química , Fluoresceínas/metabolismo , Flurbiprofeno/química , Flurbiprofeno/farmacocinética , Injeções Intravítreas , Modelos Biológicos , Coelhos , Distribuição Tecidual
4.
J Microencapsul ; 36(7): 603-621, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31500482

RESUMO

Aim: Utility of cow ghee (CG) as permeation enhancer in development of topical ocular microemulsion (ME) for delivery of fluocinolone acetonide (FA) to posterior eye. Methods: For ME preparation, oil, surfactant and cosurfactant were screened based on solubility of FA. Pseudoternary phase diagrams were constructed to determine their ratios. The developed MEs were characterised for their physicochemical properties like size, polydispersity index, zeta potential, and stability etc. They were evaluated for ex vivo permeation and irritation. In vivo pharmacokinetic studies were performed on Sprague dawley rats. Results: Lauroglycol as oil, labrasol as surfactant and Transcutol as cosurfactant were selected. The optimised ratio of oil:surfactant:cosurfactant:water was 4:23:23:50. The developed FA loaded ME fortified with CG was characterised. Ex vivo study revealed higher permeation and non-irritancy. In vivo pharmacokinetic study showed retention of CG fortified ME in posterior rat eye. Conclusion: Present investigation established CG as permeation enhancer for ocular topical formulation.


Assuntos
Anti-Inflamatórios/administração & dosagem , Portadores de Fármacos/química , Emulsões/química , Fluocinolona Acetonida/administração & dosagem , Ghee , Administração Oftálmica , Animais , Anti-Inflamatórios/farmacocinética , Bovinos , Linhagem Celular , Sistemas de Liberação de Medicamentos , Fluocinolona Acetonida/farmacocinética , Ghee/análise , Humanos , Segmento Posterior do Olho/metabolismo , Ratos Sprague-Dawley
5.
Eur J Pharm Biopharm ; 143: 18-23, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31419586

RESUMO

Retinal pigment epithelium (RPE) is a major part of blood-retinal barrier that affects drug elimination from the vitreous to the blood and drug distribution from blood circulation into the eye. Even though drug clearance from the vitreous has been well studied, the role of RPE in the process has not been quantified. The aim of this work was to study the role of RPE clearance (CLRPE) as part of drug elimination from the vitreous and ocular drug distribution from the systemic blood circulation. We determined the bidirectional permeability of eight small molecular weight drugs and bevacizumab antibody across isolated bovine RPE-choroid. Permeability of small molecules was 10-6-10-5 cm/s showing 13-15 fold range of outward and inward permeation, while permeability of bevacizumab was lower by 2-3 orders of magnitude. Most small molecular weight drugs showed comparable outward (vitreous-to-choroid) and inward (choroid-to-vitreous) permeability across the RPE-choroid, except ciprofloxacin and ketorolac that had an over 6 and 14-fold higher outward than inward permeability, respectively, possibly indicating active transport. Six of seven tested small molecular weight drugs had outward CLRPE values that were comparable with their intravitreal clearance (CLIVT) values (0.84-2.6 fold difference). On the contrary, bevacizumab had an outward CLRPE that was only 3.5% of the CLIVT, proving that its main route of elimination (after intravitreal injection) is not RPE permeation. Experimental values were used in pharmacokinetic simulations to assess the role of the RPE in drug transfer from the systemic blood circulation to the vitreous (CLBV). We conclude that for small molecular weight drugs the RPE is an important route in drug transfer between the vitreal cavity and blood, whereas it effectively hinders the movement of bevacizumab from the vitreous to the systemic circulation.


Assuntos
Preparações Farmacêuticas/metabolismo , Segmento Posterior do Olho/metabolismo , Retina/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Animais , Transporte Biológico/fisiologia , Transporte Biológico Ativo/fisiologia , Barreira Hematorretiniana/metabolismo , Bovinos , Corioide/metabolismo , Injeções Intravítreas , Taxa de Depuração Metabólica/fisiologia , Permeabilidade
6.
Artif Cells Nanomed Biotechnol ; 46(sup2): 1074-1081, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29916734

RESUMO

Posterior segment diseases are commonly implicated in the occurrence of curable as well as incurable diseases which could lead to blindness. An example of one such disease is age-related macular degeneration, which would require chronic treatment over an extended period and as such the development of an intravitreal drug delivery system that would optimize patient outcomes is essential. The major contributor of the difficulty in treating diseases in the posterior segment is the structure of the eye, particularly the blood-ocular barriers. This review will focus on the various biodegradable and non-biodegradable injectable intravitreal polymeric hydrogel devices, such as poly(ethylene glycol), poly(lactic-co-glycolic acid), silica, hyaluronic acid/dextran, silk, chitosan/alginate and poly(N-isopropylacrylamide)-based polymers, their compositions as well as the effects and results of these polymeric components on the device as a whole. Furthermore, it will briefly discuss therapeutic agents used in these devices, such as ranibizumab, dexamethasone, Avastin®/bevacizumab and aflibercept, and a potential way forward by employing intelligent polymeric systems.


Assuntos
Hidrogéis/administração & dosagem , Hidrogéis/metabolismo , Segmento Posterior do Olho/metabolismo , Animais , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/metabolismo , Humanos , Injeções Intravítreas
7.
Exp Eye Res ; 164: 95-108, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28822760

RESUMO

Mice are now routinely utilized in studies of aqueous humor outflow dynamics. In particular, conventional aqueous outflow facility (C) is routinely measured via perfusion of the aqueous chamber by a number of laboratories. However, in mouse eyes perfused ex-vivo, values for C are variable depending upon whether the perfusate is introduced into the posterior chamber (PC) versus the anterior chamber (AC). Perfusion via the AC leads to posterior bowing of the iris, and traction on the iris root/scleral spur, which may increase C. Perfusion via the PC does not yield this effect. But the equivalent situation in living mice has not been investigated. We sought to determine whether AC versus PC perfusion of the living mouse eye may lead to different values for C. All experiments were conducted in C57BL/6J mice (all ♀) between the ages of 20 and 30 weeks. Mice were divided into groups of 3-4 animals each. In all groups, both eyes were perfused. C was measured in groups 1 and 2 by constant flow infusion (from a 50 µL microsyringe) via needle placement in the AC, and in the PC, respectively. To investigate the effect of ciliary muscle (CM) tone on C, groups 3 and 4 were perfused live via the AC or PC with tropicamide (muscarinic receptor antagonist) added to the perfusate at a concentration of 100 µM. To investigate immediate effect of euthanasia, groups 5 and 6 were perfused 15-30 min after death via the AC or PC. To investigate the effect of CM tone on C immediately following euthanasia, groups 7 and 8 were perfused 15-30 min after death via the AC or PC with tropicamide added to the perfusate at a concentration of 100 µM. C in Groups 1 (AC perfusion) and 2 (PC perfusion) was computed to be 19.5 ± 0.8 versus 21.0 ± 2.1 nL/min/mmHg, respectively (mean ± SEM, p > 0.4, not significantly different). In live animals in which tropicamide was present in the perfusate, C in Group 3 (AC perfusion) was significantly greater than C in Group 4 (PC perfusion) (22.0 ± 4.0 versus 14.0 ± 2.0 nL/min/mmHg, respectively, p = 0.0021). In animals immediately following death, C in groups 5 (AC perfusion) and 6 (PC perfusion) was computed to be 21.2 ± 2.0 versus 22.8 ± 1.4 nL/min/mmHg, respectively (mean ± SEM, p = 0.1196, not significantly different). In dead animals in which tropicamide was present in the perfusate, C in group 7 (AC perfusion) was greater than C in group 8 (PC perfusion) (20.6 ± 1.4 versus 14.2 ± 2.6 nL/min/mmHg, respectively, p < 0.0001). C in eyes in situ in living mice or euthanized animals within 15-30 min post mortem is not significantly different when measured via AC perfusion or PC perfusion. In eyes of live or freshly euthanized mice, C is greater when measured via AC versus PC perfusion when tropicamide (a mydriatic and cycloplegic agent) is present in the perfusate.


Assuntos
Câmara Anterior/fisiologia , Humor Aquoso/fisiologia , Pressão Intraocular/fisiologia , Segmento Posterior do Olho/fisiologia , Animais , Câmara Anterior/efeitos dos fármacos , Câmara Anterior/metabolismo , Humor Aquoso/metabolismo , Modelos Animais de Doenças , Feminino , Pressão Intraocular/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas Muscarínicos/farmacologia , Segmento Posterior do Olho/efeitos dos fármacos , Segmento Posterior do Olho/metabolismo , Malha Trabecular/metabolismo , Tropicamida/farmacologia
8.
Invest Ophthalmol Vis Sci ; 58(10): 4003-4014, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28800647

RESUMO

Purpose: The purpose of this study is to evaluate effects of vitrectomy (PPV) and lens extraction with intraocular lens implantation (PE/IOL) on molecular oxygen (pO2) distribution, aqueous humor antioxidant-oxidant balance, aqueous humor dynamics, and histopathologic changes in the trabecular meshwork (TM) in the older macaque monkey. Methods: Six rhesus monkeys underwent PPV followed by PE/IOL. pO2, outflow facility, and intraocular pressure (IOP) were measured. Aqueous and vitreous humor specimens were analyzed for antioxidant status and 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative damage. TM specimens were obtained for immunohistochemical and quantitative PCR analysis. Results: pO2 at baseline revealed steep gradients in the anterior chamber and low levels in the posterior chamber (PC) and around the lens. Following PPV and PE/IOL, pO2 significantly increased in the PC, around the IOL, and angle. IOP increased following both surgical interventions, with no change in outflow facility. Histopathologic analysis did not show changes in TM cell quantification, but there was an increase in 8-OHdG. Quantitative PCR did not reveal significant differences in glaucoma-related gene expression. Aqueous and vitreous humor analysis revealed decreased ascorbate and total reactive antioxidant potential and increased 8-OHdG in the aqueous humor only in the surgical eyes. Conclusions: Oxygen distribution in the older rhesus monkey is similar to humans at baseline and following surgical interventions. Our findings of histopathologic changes of TM oxidative damage and alterations in the oxidant-antioxidant balance suggest a potential correlation of increased oxygen exposure with oxidative stress/damage and the development of open angle glaucoma.


Assuntos
Antioxidantes/metabolismo , Humor Aquoso/metabolismo , Implante de Lente Intraocular , Cristalino/cirurgia , Oxigênio/metabolismo , Vitrectomia , 8-Hidroxi-2'-Desoxiguanosina , Envelhecimento/fisiologia , Animais , Segmento Anterior do Olho/metabolismo , Ácido Ascórbico/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Pressão Intraocular/fisiologia , Macaca mulatta , Reação em Cadeia da Polimerase , Segmento Posterior do Olho/metabolismo , Pseudofacia/metabolismo , Malha Trabecular/metabolismo
9.
Expert Opin Drug Deliv ; 14(4): 525-537, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27485251

RESUMO

INTRODUCTION: Anterior and posterior segment eye diseases are highly challenging to treat, due to the barrier properties and relative inaccessibility of the ocular tissues. Topical eye drops and systemically delivered treatments result in low bioavailability. Alternatively, direct injection of medication into the ocular tissues is clinically employed to overcome the barrier properties, but injections cause significant tissue damage and are associated with a number of untoward side effects and poor patient compliance. Microneedles (MNs) has been recently introduced as a minimally invasive means for localizing drug formulation within the target ocular tissues with greater precision and accuracy than the hypodermic needles. Areas covered: This review article seeks to provide an overview of a range of challenges that are often faced to achieve efficient ocular drug levels within targeted tissue(s) of the eye. It also describes the problems encountered using conventional hypodermic needle-based ocular injections for anterior and posterior segment drug delivery. It discusses research carried out in the field of MNs, to date. Expert opinion: MNs can aid in localization of drug delivery systems within the selected ocular tissue. And, hold the potential to revolutionize the way drug formulations are administered to the eye. However, the current limitations and challenges of MNs application warrant further research in this field to enable its widespread clinical application.


Assuntos
Sistemas de Liberação de Medicamentos , Oftalmopatias/tratamento farmacológico , Animais , Humanos , Agulhas , Soluções Oftálmicas/administração & dosagem , Segmento Posterior do Olho/metabolismo
10.
Exp Eye Res ; 153: 101-109, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27742547

RESUMO

The purpose of this work was to determine the effect of injection volume, formulation composition, and time on circumferential spread of particles, small molecules, and polymeric formulation excipients in the suprachoroidal space (SCS) after microneedle injection into New Zealand White rabbit eyes ex vivo and in vivo. Microneedle injections of 25-150 µL Hank's Balanced Salt Solution (HBSS) containing 0.2 µm red-fluorescent particles and a model small molecule (fluorescein) were performed in rabbit eyes ex vivo, and visualized via flat mount. Particles with diameters of 0.02-2 µm were co-injected into SCS in vivo with fluorescein or a polymeric formulation excipient: fluorescein isothiocyanate (FITC)-labeled Discovisc or FITC-labeled carboxymethyl cellulose (CMC). Fluorescent fundus images were acquired over time to determine area of particle, fluorescein, and polymeric formulation excipient spread, as well as their co-localization. We found that fluorescein covered a significantly larger area than co-injected particles when suspended in HBSS, and that this difference was present from 3 min post-injection onwards. We further showed that there was no difference in initial area covered by FITC-Discovisc and particles; the transport time (i.e., the time until the FITC-Discovisc and particle area began dissociating) was 2 d. There was also no difference in initial area covered by FITC-CMC and particles; the transport time in FITC-CMC was 4 d. We also found that particle size (20 nm-2 µm) had no effect on spreading area when delivered in HBSS or Discovisc. We conclude that (i) the area of particle spread in SCS during injection generally increased with increasing injection volume, was unaffected by particle size, and was significantly less than the area of fluorescein spread, (ii) particles suspended in low-viscosity HBSS formulation were entrapped in the SCS after injection, whereas fluorescein was not and (iii) particles co-injected with viscous polymeric formulation excipients co-localized near the site of injection in the SCS, continued to co-localize while spreading over larger areas for 2-4 days, and then no longer co-localized as the polymeric formulation excipients were cleared within 1-3 weeks and the particles remained largely in place. These data suggest that particles encounter greater barriers to flow in SCS compared to molecules and that co-localization of particles and polymeric formulation excipients allows spreading over larger areas of the SCS until the particles and excipients dissociate.


Assuntos
Excipientes/administração & dosagem , Fluoresceína/administração & dosagem , Polímeros/administração & dosagem , Segmento Posterior do Olho/metabolismo , Animais , Corioide/metabolismo , Sistemas de Liberação de Medicamentos , Excipientes/farmacologia , Fluoresceína/farmacocinética , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/farmacocinética , Injeções Intraoculares , Modelos Animais , Agulhas , Tamanho da Partícula , Polímeros/farmacocinética , Coelhos , Esclera/metabolismo , Distribuição Tecidual/efeitos dos fármacos
11.
Curr Eye Res ; 41(12): 1571-1579, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27337054

RESUMO

Purpose/Aim of the study: Connective tissue growth factor (CTGF) is a key player in the control of extracellular matrix remodeling, fibrosis, and angiogenesis. It is also involved in the modification of the trabecular meshwork, thus potentially modulating outflow facility and intraocular pressure (IOP). As a consequence, CTGF might be relevant for the development of elevated IOP, a major risk factor in glaucoma-pathogenesis. While comprehensive information on the origins of CTGF in the human eye is not available, the goal of this study is to identify ocular sources of CTGF using morphological methods. MATERIALS AND METHODS: Human donor eyes were prepared for immunohistochemical analysis of CTGF, α-smooth muscle-actin (ASMA), and CD31. Confocal laser scanning microscopy was used for documentation. RESULTS: In the cornea, CTGF-immunoreactivity (CTGF-IR) was detected in the epithelium, mainly in basal layers, stromal keratinocytes, and endothelial cells. Adjacent conjunctiva showed also CTGF-IR in epithelial cells. In the iris, both, the sphincter and dilator muscles displayed CGTF-IR, as did iris and ciliary body vessels, deriving at this location from the vascular endothelium, as detected with CD31, but not from vascular smooth muscle cells, as detected with ASMA. In the ciliary body, CTGF-IR was detected in smooth-muscle cells of the ciliary muscle and further in the non-pigmented epithelium. In the retina, CTGF-IR was detected in the NFL and weakly in the IPL/OPL. In the choroid, the choriocapillaris and blood vessels displayed CTGF-IR. Further, few cells in the optic nerve head and the lamina cribrosa were CTGF-positive. CONCLUSION: CTGF was detected in various structures of the human eye. Since CTGF has been also described in aqueous humor, the identified structures might be the sources of CTGF in the aqueous humor. By means of aqueous flow, CTGF is transported into the trabecular meshwork, where it could change outflow facility and therefore affecting IOP homeostasis.


Assuntos
Segmento Anterior do Olho/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Matriz Extracelular/metabolismo , Glaucoma/metabolismo , Segmento Posterior do Olho/metabolismo , Idoso , Idoso de 80 Anos ou mais , Segmento Anterior do Olho/patologia , Feminino , Glaucoma/diagnóstico , Humanos , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Segmento Posterior do Olho/patologia
12.
Invest Ophthalmol Vis Sci ; 57(4): 1643-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27054516

RESUMO

PURPOSE: To compare the effects of post-penetrating keratoplasty (PK) and post-keratoprosthesis (KPro) surgery-related inflammation on the posterior segment of the eye and to assess inhibition of tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1ß) on these effects. METHODS: BALB/C (syngeneic) or C57BL/6 (allogeneic) corneas were transplanted onto BALB/C host beds as part of PK or miniature KPro (m-KPro) implantation. Intraocular pressure (IOP) was measured via an intracameral pressure sensor; tissues were harvested and analyzed 8 weeks after surgery. Expression of TNFα and IL-1ß in the retina was analyzed using real-time quantitative (q)PCR. Optic nerve degeneration (axon count, circularity, and area) was assessed quantitatively using ImageJ software. After m-KPro implantation, mice were treated with saline, anti-TNFα, or anti-IL-1ß antibody, and axonal loss was assessed after 10 weeks. RESULTS: Mean IOP was within normal limits in the operated and fellow eyes in all groups. The mRNA expression of TNFα and IL-1ß was highest in m-KPro groups with either syngeneic or an allogeneic carrier. We observed optic nerve degeneration in both allogeneic PK and m-KPro implanted eyes with an allogeneic carrier. However, TNFα blockade significantly reduced axonal loss by 35%. CONCLUSIONS: Allogeneic PK and m-KPro implants with an allogeneic carrier lead to chronic inflammation in the posterior segment of the eye, resulting in optic nerve degeneration. In addition, blockade of TNFα prevents axonal degeneration in this preclinical model of allogeneic m-KPro (alloKPro) implantation.


Assuntos
Órgãos Artificiais , Bioprótese/efeitos adversos , Córnea , Ceratoplastia Penetrante/efeitos adversos , Degeneração Neural/etiologia , Doenças do Nervo Óptico/etiologia , Segmento Posterior do Olho/patologia , Animais , Axônios/patologia , Expressão Gênica/fisiologia , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Pressão Intraocular , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Doenças do Nervo Óptico/metabolismo , Doenças do Nervo Óptico/patologia , Segmento Posterior do Olho/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Retina/metabolismo , Transplante Homólogo , Transplante Isogênico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética
13.
Exp Eye Res ; 145: 58-67, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26474497

RESUMO

Nepafenac ophthalmic suspensions, 0.1% (NEVANAC(®)) and 0.3% (ILEVRO™), are topical nonsteroidal anti-inflammatory drug (NSAID) products approved in the United States, Europe and various other countries to treat pain and inflammation associated with cataract surgery. NEVANAC is also approved in Europe for the reduction in the risk of postoperative macular edema (ME) associated with cataract surgery in diabetic patients. The efficacy against ME suggests that topical administration leads to distribution of nepafenac or its active metabolite amfenac to the posterior segment of the eye. This article evaluates the ocular distribution of nepafenac and amfenac and the extent of local delivery to the posterior segment of the eye, following topical ocular instillation in animal models. Nepafenac ophthalmic suspension was instilled unilaterally in New Zealand White rabbits as either a single dose (0.1%; one drop) or as multiple doses (0.3%, one drop, once-daily for 4 days, or 0.1% one drop, three-times daily for 3 days and one morning dose on day 4). Nepafenac (0.3%) was also instilled unilaterally in cynomolgus monkeys as multiple doses (one drop, three-times daily for 7 days). Nepafenac and amfenac concentrations in harvested ocular tissues were measured using high-performance liquid chromatography/mass spectrometry. Locally-distributed compound concentrations were determined as the difference in levels between dosed and undosed eyes. In single-dosed rabbit eyes, peak concentrations of locally-distributed nepafenac and amfenac showed a trend of sclera > choroid > retina. Nepafenac peak levels in sub-samples posterior to the eye equator and inclusive of the posterior pole (E-PP) were 55.1, 4.03 and 2.72 nM, respectively, at 0.25 or 0.50 h, with corresponding amfenac peak levels of 41.9, 3.10 and 0.705 nM at 1 or 4 h. By comparison, peak levels in sclera, choroid and retina sub-samples in a band between the ora serrata and the equator (OS-E) were 13- to 40-fold (nepafenac) or 11- to 23-fold (amfenac) higher, indicating an anterior-to-posterior directional concentration gradient. In multiple-dosed rabbit eyes, with 0.3% nepafenac instilled once-daily or 0.1% nepafenac instilled three-times daily, cumulative 24-h locally-distributed levels of nepafenac in E-PP retina were similar between these groups, whereas exposure to amfenac once-daily dosing nepafenac 0.3% was 51% of that achieved with three-times daily dosing of 0.1%. In single-dosed monkey eyes, concentration gradients showed similar directionality as observed in rabbit eyes. Peak concentrations of locally-distributed nepafenac were 1580, 386, 292 and 13.8 nM in E-PP sclera, choroid and retina, vitreous humor, respectively, at 1 or 2 h after drug instillation. Corresponding amfenac concentrations were 21.3, 11.8, 2.58 and 2.82 nM, observed 1 or 2 h post-instillation. The data indicate that topically administered nepafenac and its metabolite amfenac reach pharmacologically relevant concentrations in the posterior eye segment (choroid and retina) via local distribution, following an anterior-to-posterior concentration gradient. The proposed pathway involves a choroidal/suprachoroidal or periocular route, along with an inward movement of drug through the sclera, choroid and retina, with negligible vitreal compartment involvement. Sustained high nepafenac concentrations in posterior segment tissues may be a reservoir for hydrolysis to amfenac.


Assuntos
Benzenoacetamidas/farmacocinética , Fenilacetatos/farmacocinética , Segmento Posterior do Olho/metabolismo , Uveíte Posterior/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Benzenoacetamidas/administração & dosagem , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Instilação de Medicamentos , Macaca fascicularis , Masculino , Soluções Oftálmicas , Fenilacetatos/administração & dosagem , Segmento Posterior do Olho/efeitos dos fármacos , Coelhos , Distribuição Tecidual , Uveíte Posterior/metabolismo
14.
Curr Eye Res ; 41(5): 653-61, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26237665

RESUMO

PURPOSE: To investigate the efficacy of a topical hydrogel ring for drug delivery to the posterior segment of the rabbit eye. MATERIALS AND METHODS: Novel hydrogel corneal lenses (CL), scleral/corneal lenses (S/CL), and rings were prepared using poly(hydroxyethyl methacrylate). The devices were immersed in 0.3% ofloxacin ophthalmic solution (OOS) to homogeneously distribute the drug throughout the hydrogel. The medicated CL, S/CL, Ring 1 (standard ring), or Ring 2 (shape-optimized ring) was applied to the surface of the cornea, cornea/bulbar conjunctiva, or bulbar conjunctiva of albino rabbits, respectively. Medicated rings did not touch the corneal surface. In another group, one OOS drop was administered to the eye. After 0.25-8 hours, the hydrogel devices were removed and ocular tissues were harvested. High-performance liquid chromatography (HPLC) was used to measure the ofloxacin concentration in the devices and tissues. The drug concentrations in the posterior segment tissues were compared among ofloxacin delivery methods. RESULTS: One hour after placement, eyes treated with Ring 1 or S/CL had markedly higher ofloxacin levels in the posterior segment tissues (conjunctiva, sclera, and retina/choroid) than eyes treated with topical OOS or a CL. Lower levels of ofloxacin were found in anterior segment tissues (cornea and aqueous humor) in eyes treated with Ring 1 compared to those treated with S/CL. Ring 2 most effectively delivered ofloxacin to the retina/choroid. The tissue ofloxacin concentration in the fellow eye was markedly lower than the eye treated with Ring 2. CONCLUSIONS: Our results suggest that hydrogel rings are effective in delivering topical ophthalmic drugs to the posterior segment. The drugs are most likely delivered via the transconjunctival/scleral route by lateral diffusion across the bulbar conjunctiva and through the sclera. Systemic drug delivery to the posterior segment is minimal.


Assuntos
Sistemas de Liberação de Medicamentos/instrumentação , Hidrogel de Polietilenoglicol-Dimetacrilato , Ofloxacino/administração & dosagem , Segmento Posterior do Olho/metabolismo , Administração Tópica , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Cromatografia Líquida de Alta Pressão , Modelos Animais , Ofloxacino/farmacocinética , Soluções Oftálmicas/administração & dosagem , Coelhos
15.
PLoS One ; 10(6): e0130986, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26107400

RESUMO

We developed an inhibitory peptide that specifically acts against mitochondrial µ-calpain (Tat-µCL, 23 amino acid, 2857.37 Da) and protects photoreceptors in retinal dystrophic rats. In the present study, we topically administered Tat-µCL to the eyes of Sprague-Dawley rats for 7 days to determine both the delivery route of the peptide to the posterior segment of the eye and the kinetics after topical application in adult rats. Distribution of the peptide was determined by immunohistochemical analysis, and enzyme-linked immune-absorbent assay was used to quantify the accumulation in the retina. Peptides were prominently detected in both the anterior and posterior segments of the eye at 1 h after the final eye drop application. Immunohistochemically positive reactions were observed in the retina, optic nerve, choroid, sclera and the retrobulbar tissues, even in the posterior portion of the eye. Immunoactivities gradually diminished at 3 and 6 h after the final eye drop. Quantitative estimations of the amount of peptide in the retina were 15.3, 5.8 and 1.0 pg/µg protein at 1, 3 and 6 h after the final instillation, respectively. Current results suggest that while the topically applied Tat-µCL peptide reaches the posterior segment of the retina and the optic nerve, the sufficient concentration (> IC50) is maintained for at least 6 h in the rat retina. Our findings suggest that delivery of topically applied peptide to the posterior segment and optic nerve occurs through the conjunctiva, periocular connective tissue, sclera and optic nerve sheath.


Assuntos
Calpaína/antagonistas & inibidores , Soluções Oftálmicas/farmacocinética , Peptídeos/farmacocinética , Segmento Posterior do Olho/efeitos dos fármacos , Retina/efeitos dos fármacos , Administração Tópica , Sequência de Aminoácidos , Animais , Transporte Biológico , Calpaína/genética , Calpaína/metabolismo , Corioide/efeitos dos fármacos , Corioide/metabolismo , Túnica Conjuntiva/efeitos dos fármacos , Túnica Conjuntiva/metabolismo , Feminino , Expressão Gênica , Dados de Sequência Molecular , Soluções Oftálmicas/síntese química , Soluções Oftálmicas/farmacologia , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/metabolismo , Peptídeos/síntese química , Peptídeos/farmacologia , Segmento Posterior do Olho/metabolismo , Ratos , Ratos Sprague-Dawley , Retina/metabolismo , Esclera/efeitos dos fármacos , Esclera/metabolismo , Distribuição Tecidual
17.
Invest Ophthalmol Vis Sci ; 56(5): 3075-83, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26024091

RESUMO

PURPOSE: The cellular mechanisms linking elevated IOP with glaucomatous damage remain unresolved. Mechanical strains and short-term increases in IOP can trigger ATP release from retinal neurons and astrocytes, but the response to chronic IOP elevation is unknown. As excess extracellular ATP can increase inflammation and damage neurons, we asked if sustained IOP elevation was associated with a sustained increase in extracellular ATP in the posterior eye. METHODS: No ideal animal model of chronic glaucoma exists, so three different models were used. Tg-Myoc(Y437H) mice were examined at 40 weeks, while IOP was elevated in rats following injection of hypertonic saline into episcleral veins and in cynomolgus monkeys by laser photocoagulation of the trabecular meshwork. The ATP levels were measured using the luciferin-luciferase assay while levels of NTPDase1 were assessed using qPCR, immunoblots, and immunohistochemistry. RESULTS: The ATP levels were elevated in the vitreal humor of rats, mice, and primates after a sustained period of IOP elevation. The ecto-ATPase NTPDase1 was elevated in optic nerve head astrocytes exposed to extracellular ATP for an extended period. NTPDase1 was also elevated in the retinal tissue of rats, mice, and primates, and in the optic nerve of rats, with chronic elevation in IOP. CONCLUSIONS: A sustained elevation in extracellular ATP, and upregulation of NTPDase1, occurs in the posterior eye of rat, mouse, and primate models of chronic glaucoma. This suggests the elevation in extracellular ATP may be sustained in chronic glaucoma, and implies a role for altered purinergic signaling in the disease.


Assuntos
Trifosfato de Adenosina/metabolismo , Antígenos CD/genética , Apirase/genética , Modelos Animais de Doenças , Glaucoma/metabolismo , Pressão Intraocular/fisiologia , Segmento Posterior do Olho/metabolismo , Animais , Antígenos CD/metabolismo , Apirase/metabolismo , Contagem de Células , Doença Crônica , Feminino , Immunoblotting , Imuno-Histoquímica , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ratos , Ratos Endogâmicos BN , Reação em Cadeia da Polimerase em Tempo Real , Células Ganglionares da Retina/patologia , Transdução de Sinais
18.
Expert Opin Drug Deliv ; 12(9): 1513-26, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25745885

RESUMO

INTRODUCTION: Many macromolecular therapeutics designed to treat posterior segment eye diseases (PSEDs) are administered through frequent ocular injection, which can further deteriorate eye health. Due to the high frequency of injection and the high cost of the therapeutics, there is a need to develop new ways in which to deliver these therapeutics: ways which are both safer and more cost effective. AREAS COVERED: Using the most common PSED, age-related macular degeneration, as an example of a debilitating ocular disease, this review examines the key barriers limiting the delivery of macromolecular therapeutics to the posterior segment of the eye and defines the key requirements placed on particulate drug delivery vehicles (DDVs) to be suitable for this application. Recent developments in macromolecular drug delivery to treat this disease as well as the remaining shortcomings in its treatment are surveyed. Lastly, an emerging class of DDVs potentially suited to this application, called cubosomes, is introduced. EXPERT OPINION: Based on their excellent colloidal stability and high internal surface area, cubosomes hold great potential for the sustained release of therapeutics. Novel production methods and a better understanding of the mechanisms through which drug release from these particles can be controlled are two major recent developments toward successful application.


Assuntos
Sistemas de Liberação de Medicamentos , Degeneração Macular/tratamento farmacológico , Preparações Farmacêuticas/administração & dosagem , Animais , Liberação Controlada de Fármacos , Excipientes/química , Olho/metabolismo , Olho/fisiopatologia , Humanos , Substâncias Macromoleculares/administração & dosagem , Segmento Posterior do Olho/metabolismo
19.
Drug Discov Today ; 20(4): 491-5, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25448755

RESUMO

The development of safe and convenient drug delivery strategies for treatment of posterior segment eye diseases is challenging. Although intravitreal injection has wide acceptance amongst clinicians, its use is associated with serious side-effects. Recently, the suprachoroidal space (SCS) has attracted the attention of ophthalmologists and pharmaceutical formulators as a potential site for drug administration and delivery to the posterior segment of the eye. This review highlights the major constraints of drug delivery to the posterior eye segment, key anatomical and physiological features of the SCS and drug delivery applications of this route with emphasis on microneedles along with future perspectives.


Assuntos
Corioide/efeitos dos fármacos , Preparações Farmacêuticas/administração & dosagem , Segmento Posterior do Olho/efeitos dos fármacos , Administração Oftálmica , Animais , Química Farmacêutica , Corioide/anatomia & histologia , Corioide/metabolismo , Portadores de Fármacos , Desenho de Equipamento , Humanos , Injeções Intraoculares , Miniaturização , Agulhas , Absorção Ocular , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Segmento Posterior do Olho/anatomia & histologia , Segmento Posterior do Olho/metabolismo
20.
Math Biosci ; 255: 11-20, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24946303

RESUMO

A computational model was developed to simulate drug distribution in the posterior segment of the eye after intravitreal injection and ocular implantation. The effects of important factors in intravitreal injection such as injection time, needle gauge and needle angle on the ocular drug distribution were studied. Also, the influences of the position and the type of implant on the concentration profile in the posterior segment were investigated. Computational Fluid Dynamics (CFD) calculations were conducted to describe the 3D convective-diffusive transport. The geometrical model was constructed based on the human eye dimensions. To simulate intravitreal injection, unlike previous studies which considered the initial shape of the injected drug solution as a sphere or cylinder, the more accurate shape was obtained by level-set method in COMSOL. The results showed that in intravitreal injection the drug concentration profile and its maximum value depended on the injection time, needle gauge and penetration angle of the needle. Considering the actual shape of the injected solution was found necessary to obtain the real concentration profile. In implant insertion, the vitreous cavity received more drugs after intraocular implantation, but this method was more invasive compared to the periocular delivery. Locating the implant in posterior or anterior regions had a significant effect on local drug concentrations. Also, the shape of implant influenced on concentration profile inside the eye. The presented model is useful for optimizing the administration variables to ensure optimum therapeutic benefits. Predicting and quantifying different factors help to reduce the possibility of tissue toxicity and to improve the treatment efficiency.


Assuntos
Sistemas de Liberação de Medicamentos , Modelos Biológicos , Segmento Posterior do Olho/metabolismo , Simulação por Computador , Implantes de Medicamento , Análise de Elementos Finitos , Fluoresceína/administração & dosagem , Fluoresceína/farmacocinética , Humanos , Hidrodinâmica , Injeções Intravítreas , Conceitos Matemáticos , Absorção Ocular , Segmento Posterior do Olho/anatomia & histologia , Segmento Posterior do Olho/efeitos dos fármacos
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