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1.
Chem Biol Interact ; 315: 108894, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31705858

RESUMO

Graves' orbitopathy (GO) is a sight-threatening ocular disease that occurs in patients with hyperthyroidism and is especially associated with oxidative stress. Polydatin (PD) is a major active component of Polygonum cuspidatum Sieb. et Zucc. It has various therapeutic effects including anti-inflammatory and antioxidant properties. In the present study, we investigated the effects of PD on H2O2-induced oxidative stress in orbital fibroblasts in vitro and in a GO mouse model of orbital oxidative stress in vivo. The mechanisms responsible for these effects were investigated using standard molecular techniques. Our initial findings in GO mice were that PD attenuated orbital muscle adipose tissue expansion and lipid droplet accumulation through a nuclear factor E2-related factor 2 (NRF2)-mediated oxidative stress response involving the Keap1/Nrf2/ARE pathway. The results demonstrated that PD could reverse the accumulation of lipid droplets and production of reactive oxygen species (ROS) induced by H2O2 and increase the expression of antioxidant genes such as NAD(P)H dehydrogenase, quinone 1 (NQO1). NQO1 levels were the lowest in the GO mouse model. In addition, PD enhanced NRF2 nuclear translocation in cultured orbital fibroblasts. We also found that silencing NRF2, using RNA interference, reduced the protective effects of PD against H2O2-induced oxidative stress in orbital fibroblasts in vitro. Taken together, our results indicate that PD can reduce the production of ROS and inhibit adipogenesis in orbital fibroblasts in vitro and in vivo.


Assuntos
Olho/efeitos dos fármacos , Glucosídeos/farmacologia , Oftalmopatia de Graves/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Adipogenia/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Células Cultivadas , Olho/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Oftalmopatia de Graves/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismo
2.
Am J Vet Res ; 81(1): 41-46, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31887086

RESUMO

OBJECTIVE: To evaluate effects of topical ophthalmic administration of diclofenac on intraocular pressure (IOP) when applied at 4 frequencies to eyes of Beagles. ANIMALS: 8 ophthalmologically normal Beagles. PROCEDURES: The study involved four 5-day experimental periods each separated by a 16-day washout period. During each period, 1 drop of 0.1% diclofenac sodium ophthalmic solution was administered to the right eye at 4 treatment frequencies (1, 2, 3, or 4 times/d); 1 drop of eyewash was administered to the left eye as a control treatment. A complete ophthalmic examination was performed on days 0 (day before first treatment) and 5 of each experimental period. Gonioscopy was performed on day 0 of the first period. The IOPs were measured at 7 am and 7 pm on days 1 through 5. RESULTS: No abnormalities were detected during neuro-ophthalmic and ophthalmic examinations on day 0 of each experimental period. No adverse reactions to administration of diclofenac or eyewash were observed at any time point. No abnormalities were detected during ophthalmic examinations performed on day 5, and IOPs remained < 25 mm Hg in all 4 periods. No significant differences were identified between the treated and control eyes or among the 4 treatment frequencies. CONCLUSIONS AND CLINICAL RELEVANCE: Topical ophthalmic administration of diclofenac up to 4 times/d in dogs with no ophthalmic abnormalities did not significantly increase the IOP. Additional research is needed to evaluate the effect of topical ophthalmic administration of diclofenac on IOP in dogs with anterior uveitis.


Assuntos
Diclofenaco/farmacologia , Pressão Intraocular/efeitos dos fármacos , Soluções Oftálmicas/farmacologia , Administração Oftálmica , Administração Tópica , Animais , Diclofenaco/administração & dosagem , Cães , Esquema de Medicação , Olho/efeitos dos fármacos , Feminino , Masculino , Soluções Oftálmicas/administração & dosagem , Tonometria Ocular/veterinária
3.
Aquat Toxicol ; 219: 105384, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31869577

RESUMO

Tritium (3H), a radioactive isotope of hydrogen, is ubiquitously present in the environment. In a previous study, we highlighted a mis-regulation of genes involved in muscle contraction, eye transparency and response to DNA damages after exposure of zebrafish embryo-larvae from 3 hpf to 96 hpf at 0.4 and 4 mGy/h of tritiated water (HTO). The present study aimed to link this gene mis-regulation to responses observed at higher biological levels. Analyses on spontaneous tail movement, locomotor activity and heart rate were performed. Histological sections of eyes were made to evaluate the impact of HTO on eye transparency and whole embryo immunostainings were realized to assess DNA double strand breaks repair using gamma-H2AX foci. We found a decrease of basal velocity as well as a decrease of response in 96 hpf larvae exposed at 0.4 mGy/h after a tactile stimulus as compared to controls. Histological sections of larvae eyes performed after the exposure to 4 mGy/h did not show obvious differences in lens transparency or retinal development between contaminated and control organisms. Gamma-H2AX foci detection revealed no differences in the number of foci between contaminated organisms and controls, for both dose rates. Overall, results highlighted more detrimental effects of HTO exposure on locomotor behavior in 96 hpf larvae exposed at the lowest dose rate. Those results could be linked to mis-regulation of genes involved in muscle contraction found in a previous study at the same dose rate. It appears that not all effects found at the molecular scale were confirmed using higher biological scales. These results could be due to a delay between gene expression modulation and the onset of physiological disruption or homeostatic mechanisms to deal with tritium effects. However, crossing data from different scales highlighted new pathways to explore, i.e. neurotoxic pathways, for better understanding HTO effects on organisms.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Larva/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Trítio/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/crescimento & desenvolvimento , Animais , Dano ao DNA , Olho/efeitos dos fármacos , Olho/crescimento & desenvolvimento , Olho/patologia , Larva/genética , Peixe-Zebra/genética
4.
Ann Ist Super Sanita ; 55(4): 400-404, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31850870

RESUMO

It is currently well accepted that in general, more than one method is necessary to allow the full replacement of an animal experimentation. These so called partial replacement methods can be used within integrated strategy approaches that combine different methods and information sources. A number of integrated strategy approaches were implemented within recent years in different areas of safety and regulatory toxicology. Moreover, latest advances in biomedical research and bioengineering provide a major opportunity to make use of in vitro human-based and/or three-dimensional complex models that can contribute to achieve more physiologically-relevant models. Examples herein describe currently existing integrated strategy frameworks aiming at full or partial replacement purposes and/or at gaining mechanistic insights. Furthermore, a general concept is provided on how 3R methods might be integrated in a strategy approach in order to ensure that animal experimentation is conducted only as a last resort.


Assuntos
Alternativas aos Testes com Animais/organização & administração , Rotas de Resultados Adversos , Alternativas aos Testes com Animais/métodos , Animais , Qualidade de Produtos para o Consumidor , Olho/efeitos dos fármacos , Guias como Assunto , Humanos , Irritantes/toxicidade , Projetos de Pesquisa/normas , Pele/efeitos dos fármacos
5.
Int J Toxicol ; 38(5): 415-422, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31470746

RESUMO

Minipigs are an emerging nonrodent alternative for ocular toxicology owing to anatomical similarities in the minipig eyes when compared to humans. Ocular structures and components from Göttingen minipigs were characterized and compared to species commonly used in toxicology. Ocular reference data from Göttingen minipig including intraocular pressure, vitreous electrolyte and thiol concentration, and electroretinography (ERG) data are essential to model characterization and data interpretation during drug safety assessments. Intravitreal positive control agents including gentamicin, indocyanine green, and glycine were used to demonstrate ERG alterations caused by retinal cell toxicity, light transmission obstruction, or neurotransmission interferences, respectively. Electrolyte concentrations of the aqueous and vitreous humors from Göttingen minipigs were similar to other species including humans. The reference data presented herein supports the use of the Göttingen minipig as an alternate nonrodent species in ocular toxicology.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Olho/efeitos dos fármacos , Modelos Animais , Porco Miniatura , Testes de Toxicidade/métodos , Animais , Cães , Eletrorretinografia , Macaca fascicularis , Coelhos , Ratos Sprague-Dawley , Suínos
6.
Int J Pharm ; 570: 118662, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31491481

RESUMO

Eye drops containing hydrophilic drugs are commonly used to reduce intraocular pressure (IOP) in glaucoma patients, but compliance to the treatement is commonly reduced by frequent dosing and eventual systemic side effects. Sustained-release drug delivery systems, such as ocular inserts, can reduce dosing, limit systemic exposure, reduce side effects, and, then, improve patient adherence to therapy. Here, we developed and evaluated chitosan/hydroxyethyl cellulose-based ocular inserts for sustained release of dorzolamide, a hydrophilic drug. Dorzolamide inserts (DI) were produced by solvent/casting method and characterized by various physicochemical techniques. Pharmacokinetics studies were performed using scintigraphic images and ex vivo biodistribution. The effectiveness of inserts was tested in glaucomatous rats. Characterization studies showed that the drug strongly interacted with the polymeric matrix, but in vitro results showed that DI took only 3 h to release 75% of dorzolamide entraped. However, scintigraphic images and ex vivo biodistribution studies revealed that more than 50% of 99mTc-dorzolamide remained in the eye after 18 h of DI administration, while only about 30% of the drug remained in the eye after drops instilation. DI exerted significant hypotensive effect for two weeks, after single administration, while IOP values remained high in placebo and untreated groups. Eye drops were effective only during the treatment period. Only DI treatment prevented retinal ganglion cells death. Altogether, these findings evidenced the potential application of polymeric-based inserts for sustained release of dorzolamide in glaucoma management.


Assuntos
Celulose/análogos & derivados , Quitosana/química , Preparações de Ação Retardada/química , Glaucoma/tratamento farmacológico , Sulfonamidas/química , Sulfonamidas/farmacologia , Tiofenos/química , Tiofenos/farmacologia , Animais , Celulose/química , Preparações de Ação Retardada/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Olho/efeitos dos fármacos , Olho/metabolismo , Glaucoma/metabolismo , Pressão Intraocular/efeitos dos fármacos , Masculino , Soluções Oftálmicas/química , Soluções Oftálmicas/metabolismo , Soluções Oftálmicas/farmacologia , Polímeros/química , Ratos , Ratos Wistar , Sulfonamidas/metabolismo , Tiofenos/metabolismo , Distribuição Tecidual
7.
Int J Pharm ; 570: 118688, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31513870

RESUMO

In the present study, we developed and evaluated an in situ gelling system based on hexanoyl glycol chitosan (H-GCS) for enhanced ocular bioavailability. An aqueous solution of H-GCS exhibited a typical sol-gel transition at 32 °C. The formed H-GCS hydrogel was characterized by rheology and scanning electron microscopy (SEM). H-GCS had minimal in vitro cytotoxicity against L-929 and HCEC cells over a concentration range of 0-0.8 mg/mL. Additionally, the H-GCS hydrogel exhibited good ocular tolerance and biocompatibility after a single instillation. Moreover, H-GCS hydrogel significantly prolonged the precorneal retention of fluorescein sodium compared with its aqueous solution. An in vivo pharmacokinetic study demonstrated that the levofloxacin-loaded H-GCS hydrogel could provide a significantly higher Cmax and AUC0-12h compared with the levofloxacin aqueous solution, thus increasing ocular bioavailability. Overall, the proposed H-GCS hydrogel acts as an in situ gelling system that might represent a promising vehicle for topical ocular drug delivery.


Assuntos
Quitosana/química , Olho/efeitos dos fármacos , Olho/metabolismo , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Soluções Oftálmicas/química , Soluções Oftálmicas/metabolismo , Animais , Disponibilidade Biológica , Linhagem Celular , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato/metabolismo , Levofloxacino/química , Levofloxacino/metabolismo , Coelhos , Temperatura
8.
Molecules ; 24(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514422

RESUMO

Anthocyanin (AC) is widely used as supplement of eye health in Europe and in East Asia. In this review, I describe AC effects to clarify the mechanism is important in order to understand the effects of AC on vision health. The bioavailability of AC is quite low but, reported as intact form and many kinds of metabolite. And AC passes through the blood-aqueous fluid barrier and blood-retinal barrier. In vitro study, AC had a relaxing effect on ciliary muscle which is important to treat both myopia and glaucoma. And AC stimulate the regeneration of rhodopsin in frog rod outer segment. Furthermore, AC could inhibit the axial length and ocular length elongation in a negative lens-induced chick myopia model. In addition, we summarized clinical studies of AC intake improved dark adaptation and transient myopic shift and the improvement on retinal blood circulation in normal tension glaucoma patients.


Assuntos
Antocianinas/farmacologia , Olho/efeitos dos fármacos , Visão Ocular/efeitos dos fármacos , Animais , Antocianinas/química , Disponibilidade Biológica , Adaptação à Escuridão/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos
9.
Am J Vet Res ; 80(9): 878-884, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31449443

RESUMO

OBJECTIVE: To evaluate the effects of injectable dexmedetomidine-ketamine-midazolam (DKM) and isoflurane inhalation (ISO) anesthetic protocols on selected ocular variables in captive black-tailed prairie dogs (Cynomys ludovicianus; BTPDs). ANIMALS: 9 zoo-kept BTPDs. PROCEDURES: The BTPDs received dexmedetomidine hydrochloride (0.25 mg/kg, IM), ketamine hydrochloride (40 mg/kg, IM), and midazolam hydrochloride (1.5 mg/kg, IM) or inhalation of isoflurane and oxygen in a randomized complete crossover design (2-day interval between anesthetic episodes). Pupil size, globe position, tear production, and intraocular pressure measurements were recorded at 5, 30, and 45 minutes after induction of anesthesia. For each BTPD, a phenol red thread test was performed in one randomly selected eye and a modified Schirmer tear test I was performed in the other eye. Intraocular pressure was measured by rebound tonometry. RESULTS: Compared with findings for the DKM protocol, pupil size was smaller at all time points when the BTPDs underwent the ISO protocol. Globe position remained central during anesthesia with the DKM protocol, whereas it varied among central, ventromedial, and ventrolateral positions during anesthesia with the ISO protocol. Tear production and intraocular pressure decreased significantly over time when the BTPDs underwent either protocol. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that ophthalmic examination findings for anesthetized BTPDs can be influenced by the anesthetic protocol used. The DKM protocol may result in more consistent pupil size and globe position, compared with that achieved by use of the ISO protocol. Tear production and intraocular pressure measurements should be conducted promptly after induction of anesthesia to avoid the effect of anesthetic episode duration on these variables.


Assuntos
Anestesia/veterinária , Anestésicos Inalatórios/farmacologia , Olho/efeitos dos fármacos , Sciuridae , Anestésicos Inalatórios/administração & dosagem , Anestésicos Intravenosos/farmacologia , Animais , Animais de Zoológico , Dexmedetomidina/farmacologia , Pressão Intraocular/efeitos dos fármacos , Isoflurano/farmacologia , Ketamina/farmacologia , Masculino , Midazolam/farmacologia , Lágrimas/efeitos dos fármacos
10.
Nutrients ; 11(8)2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31387244

RESUMO

Resveratrol is the best-known chemical for extending the lifespan of various organisms. Extensive recent research has shown that resveratrol can extend the lifespan of single-celled organisms, but its effects on the extension of animal lifespans are marginal. Despite the limited efficacy of pure resveratrol, resveratrol with the endogenous property of the DJ rice in the resveratrol rice DJ526 previously showed profound health benefits. Here, we report that the resveratrol rice DJ526 markedly extended the lifespan of the fruit fly Drosophila melanogaster by as much as 41.4% compared to that of the control. The resveratrol rice DJ526 also improved age-related symptoms such as locomotive deterioration, body weight gain, eye degeneration and neurodegeneration in D. melanogaster upon aging. This result shows the most significantly improved lifespan in animal experiments to date, meaning that the resveratrol rice DJ526 will assist in the development of a therapeutic agent for longevity or addressing age-related degeneration.


Assuntos
Drosophila melanogaster/efeitos dos fármacos , Alimentos Fortificados , Longevidade/efeitos dos fármacos , Oryza , Resveratrol/administração & dosagem , Animais , Olho/efeitos dos fármacos , Olho/patologia , Feminino , Locomoção/efeitos dos fármacos , Masculino , Degeneração Neural , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/patologia , Valor Nutritivo , Fatores de Tempo , Ganho de Peso/efeitos dos fármacos
11.
Toxicol Lett ; 314: 153-163, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31408696

RESUMO

Eye exposure to organophosphate (OP) chemical warfare irreversible acetylcholinesterase inhibitors, results in long-term miosis and impaired visual function. In contrast to the well-documented miotic and ciliary muscle spasm observed following chemical warfare, OP ocular exposure, little is known regarding the ocular surface histopathological insult. The aim of the present study was to determine the degree of the ocular surface insult following sarin or VX ocular exposure and to evaluate potential anti-cholinergic treatments in counteracting this insult. Rats that were whole body exposed to various sarin concentrations (0.049-43 µg/L; 5 min exposure), showed a dose-dependent miotic response and light reflex impairment. Following whole body sarin exposure, a dose dependent ocular surface histopathological insult was developed. A week following exposure to a low concentration of 0.05 µg/L, conjunctival pathology was observed, while corneal insult was noticed only following exposure to a concentration of 0.5 µg/L and above. Both tissues presented poorer outcomes when exposed to higher sarin concentrations. In contrast, eyes topically exposed to 1 µg sarin demonstrated no ocular insult a week following exposure. On the contrary, topical exposure to 1 µg VX resulted in a significant corneal insult. Anticholinergic treatments such as 0.1% atropine or 2% homatropine, given shortly following VX exposure, counteracted this insult. The results of this study show that not only do anti-cholinergic treatments counteract the miotic response, but also prevent the histopathological insult observed when given shortly following OP exposure.


Assuntos
Antídotos/farmacologia , Piscadela/efeitos dos fármacos , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Olho/efeitos dos fármacos , Miose/prevenção & controle , Antagonistas Muscarínicos/farmacologia , Compostos Organotiofosforados/toxicidade , Sarina/toxicidade , Acetilcolinesterase/metabolismo , Animais , Citoproteção , Relação Dose-Resposta a Droga , Olho/enzimologia , Olho/patologia , Olho/fisiopatologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Masculino , Miose/induzido quimicamente , Miose/patologia , Miose/fisiopatologia , Ratos Long-Evans , Fatores de Tempo
12.
Int J Pharm ; 570: 118641, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31446026

RESUMO

Current information about the pharmacokinetics of an ocular drug can only be achieved by invasive sampling. However, confocal Raman spectroscopy bears the potential to quantify drug concentrations non-invasively. In this project, we evaluated the detection and quantification of ocular ketorolac tromethamine levels with confocal Raman spectroscopy after topical administration. Confocal Raman spectroscopy and high-performance liquid chromatography (HPLC) were compared in terms of sensitivity of detection. Enucleated pig eyes were treated with different concentrations of ketorolac. Hereafter, ketorolac concentrations in the aqueous humor of pig eyes were analyzed by confocal Raman spectroscopy and HPLC. Subsequently, twelve rabbits were treated with Acular™ for four weeks. At several time points, ketorolac concentrations in aqueous humor of the rabbits were measured by confocal Raman spectroscopy followed by drawing an aqueous humor sample for HPLC analysis. In ketorolac treated pig eyes, both ex vivo Raman spectroscopy as well as HPLC were able to detect ketorolac in a broad concentration range. However, in vivo confocal Raman spectroscopy in rabbits was unable to detect ketorolac in contrast to HPLC. To conclude, confocal Raman spectroscopy has the capacity to detect ketorolac tromethamine in vitro, but currently lacks sensitivity for in vivo detection.


Assuntos
Cetorolaco de Trometamina/administração & dosagem , Cetorolaco de Trometamina/química , Administração Tópica , Animais , Humor Aquoso/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Olho/efeitos dos fármacos , Microscopia Confocal/métodos , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/química , Coelhos , Análise Espectral Raman/métodos , Suínos
13.
ACS Appl Mater Interfaces ; 11(30): 26704-26710, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31264833

RESUMO

Clinical need for treating allergic conjunctivitis (AC) is rapidly increasing. However, AC-relevant anti-inflammatory compounds are generally difficult to solubilize in water, thus limiting their therapeutic potential. Solubility-improved eye drop formulations of these compounds have poor bioavailability and a short retention time in ophthalmic tissues. Herein, we report a DNA/poly(lactic-co-glycolicacid) (PLGA) hybrid hydrogel (HDNA) for water-insoluble ophthalmic therapeutic delivery. PLGA pre-encapsulation enables loading of water-insoluble therapeutics. HDNA's porous structure is capable of sustained delivery of therapeutics. Dexamethasone (DEX), with demonstrated activities in attenuating inflammatory symptom in AC, was used as a model system. The designed HDNA hybrid hydrogels significantly improved the DEX accumulation and mediated the gradual DEX release in ophthalmic cells and tissues. Using the HDNA-DEX complexes, potent efficacy in two animal models of AC was acquired. Given this performance, demonstrable biocompatibility, and biodegradability of DNA hydrogel, the HDNA-based ophthalmic therapeutic delivery system enables novel treatment paradigms, which will have widespread applications in the treatment of various eye diseases.


Assuntos
Conjuntivite Alérgica/tratamento farmacológico , DNA/química , Dexametasona/farmacologia , Hidrogéis/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Disponibilidade Biológica , Conjuntivite Alérgica/genética , DNA/farmacologia , Dexametasona/química , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Epitélio Anterior/efeitos dos fármacos , Olho/efeitos dos fármacos , Olho/patologia , Humanos , Hidrogéis/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Coelhos , Solubilidade/efeitos dos fármacos , Água/química
14.
Environ Sci Pollut Res Int ; 26(26): 27444-27456, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31327144

RESUMO

Air pollution represents a major health problem in megacities, bringing about 8 million deaths every year. The aim of the study was to evaluate in vivo the ocular and respiratory mucosa biological response after chronic exposure to urban air particles from Buenos Aires (UAP-BA). BALB/c mice were exposed to UAP-BA or filtered air for 1, 6, 9, and 12 months. After exposure, histology, histomorphometry, and IL-6 proinflammatory cytokine level were evaluated in the respiratory and ocular mucosa. Total cell number and differential cell count were determined in the brochoalveolar lavage fluid. In the lung, chronic exposure to UAP-BA induced reduction of the alveolar space, polymorhonuclear cell recruitment, and goblet cell hyperplasia. In the ocular surface, UAP-BA induced an initial mucin positive cells rise followed by a decline through time, while IL-6 level increased at the latest point-time assayed. Our results showed that the respiratory and the ocular mucosas respond differently to UAP-BA. Being that lung and ocular mucosa diseases may be triggered and/or exacerbated by chronic exposure to urban air PM, the inhabitants of Buenos Aires whom are chronically exposed to environmental urban air pollution may be considered a subpopulation at risk. Based on our results, we propose the ocular mucosa as a reliable and more accessible surrogate for pulmonary mucosa environmental toxicity that might also serve as an earlier biomarker for air pollution adverse impact on health.


Assuntos
Poluição do Ar/efeitos adversos , Exposição Ambiental/efeitos adversos , Olho/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Membrana Mucosa/efeitos dos fármacos , Poluição do Ar/análise , Animais , Argentina , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/citologia , Olho/patologia , Feminino , Interleucina-6/análise , Interleucina-6/genética , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Material Particulado/efeitos adversos , Material Particulado/análise , Material Particulado/química , Testes de Toxicidade Crônica , Urbanização
16.
Food Funct ; 10(7): 4381-4395, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31282516

RESUMO

In this work, fucoxanthin-oleic acid-protein complexes were constructed to improve the dispersibility and intestinal absorption of fucoxanthin in water. The in vivo absorption/antioxidant capacity was evaluated using a mouse model, and the binding processes were investigated using multi-spectroscopic methods and molecular docking. Results showed that the oleic acid-protein delivery system dramatically improved the absorption of fucoxanthin mainly in its original form. When the molar ratio of oleic acid to bovine serum albumin (BSA) was 4 : 1, the plasma response level of fucoxanthin at 4 h could reach 91.25% that of the pure soybean oil delivery system (336.9 pg mL-1vs. 369.2 pmol mL-1). Furthermore, the loading capacity of BSA to fucoxanthin was increased 5 times when oleic acid acted as a protein ligand. Fucoxanthin, oleic acid and BSA can form complexes with good water dispersibility (transmittance nearly 90% and particle size 265 nm) at the molar ratio of 5 : 4 : 1. Spectral analysis and molecular docking indicated that oleic acid and fucoxanthin have different binding domains in BSA and that fucoxanthin can bind to the hydrophobic cavity of BSA in a static manner. After administration of fucoxanthin-oleic acid-BSA complexes for 15 days in mice, only fucoxanthinol accumulation was discovered in eyes and the ocular antioxidant capability increased by 71.02%. These results suggest that the oleic acid-protein delivery system may be useful in facilitating the application of fat-soluble active substances to hydrophilic food systems.


Assuntos
Olho/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Ácido Oleico/farmacologia , Água/química , Xantofilas/farmacologia , Animais , Antioxidantes , Digestão , Feminino , Tecnologia de Alimentos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Camundongos , Camundongos Endogâmicos ICR , Modelos Animais , Simulação de Acoplamento Molecular , Tamanho da Partícula , Soroalbumina Bovina/química , Óleo de Soja , Xantofilas/sangue , Xantofilas/química , beta Caroteno/análogos & derivados
17.
Cutan Ocul Toxicol ; 38(4): 390-394, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31311337

RESUMO

Purpose: To evaluate the safety of subconjunctival injection of doxycycline in rabbit eyes. Methods: Eight white New Zealand rabbits were selected. Different concentrations of 250 micrograms (µg), 500 µg, 1000 µg, and 2000 µg in 0.1 ml were prepared for subconjunctival injection. Each concentration was injected into the two eyes of each rabbit. For each dose, dextrose was injected in one contralateral eye and the other fellow eye remained non-injected. All rabbits underwent ocular examination in the 1st, 3rd, and 30th day after injection. The rabbits were sacrificed 30 days after injections and the histopathological examination was performed. Results: No obvious change was detected in all four groups from the 1st day to the 3rd day after injection in terms of tearing, hyperaemia, and chemosis. There was no visible sign of inflammation or necrosis, and also no histological change in both clinical and histopathological examinations. Conclusion: Subconjunctival injection of doxycycline with different dosages of 250 to 2000 ug in 0.1cc in rabbit eyes was safe and no clinical or histological changes were observed after one month.


Assuntos
Antibacterianos/administração & dosagem , Doxiciclina/administração & dosagem , Olho/efeitos dos fármacos , Animais , Olho/anatomia & histologia , Injeções Intraoculares , Masculino , Coelhos
18.
Int J Pharm ; 568: 118474, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31279055

RESUMO

Development of topically administered drug delivery systems for the treatment of ocular diseases have majorly focused on enhancing bioavailability of drugs in the ocular tissues. However, control of spatial distribution of topically administered drugs so as to restrict/avoid drug bioavailability at sensitive ocular tissues that are prone to drug induced adverse effects has not been explored. In this study, we aimed to reduce the bioavailability of topically administered corticosteroid, triamcinolone acetonide (TA) in lens via controlled spatial distribution in order to minimize TA induced posterior subcapsular cataract (PSC). For this, a negatively charged polymeric core-shell nanoparticulate drug delivery system composed of polycaprolactone (PCL) core and pluronic® F-68 (PF68) shell was fabricated. For in vivo studies, coumarin-6 (COU) loaded nanoparticles (NPs) were fabricated and studied for their biodistribution after topical administration in mice eyes and compared with free COU biodistribution. The administered COU loaded NPs differentially distributed in mice eyes and showed lower bioavailability in lens compared to free COU. Further, in vivo efficacy of the delivery system for its ability to minimize the rate of PSC progression was evaluated in diabetic rats. The results demonstrated that TA loaded PCL-PF68 NPs decreased PSC progression compared to free TA when administered topically.


Assuntos
Catarata/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Glucocorticoides/administração & dosagem , Triancinolona Acetonida/administração & dosagem , Administração Oftálmica , Animais , Disponibilidade Biológica , Caderinas/metabolismo , Catarata/induzido quimicamente , Catarata/metabolismo , Catarata/patologia , Cumarínicos/administração & dosagem , Cumarínicos/química , Cumarínicos/farmacocinética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Liberação Controlada de Fármacos , Olho/efeitos dos fármacos , Olho/metabolismo , Olho/patologia , Glucocorticoides/química , Masculino , Camundongos Endogâmicos C57BL , Poloxâmero/administração & dosagem , Poloxâmero/química , Poliésteres/administração & dosagem , Poliésteres/química , Ratos Sprague-Dawley , Tiazóis/administração & dosagem , Tiazóis/química , Tiazóis/farmacocinética , Triancinolona Acetonida/química
19.
Chemosphere ; 237: 124428, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31362133

RESUMO

The present study evaluates the enzyme activities and histopathological changes in the post larvae (PL) of shrimp (Penaeus monodon), green mussel (Perna viridis) and fingerlings of crescent perch (Terapon jarbua) exposed to sublethal gradient concentrations of Nickel (Ni). The median lethal concentration (LC50) values were 2.49, 66.03 and 43.92 mg Ni L-1 derived for the PL of shrimp, green mussel and fish fingerlings respectively. No Observed Effect Concentration (NOEC), Lowest Observed Effect Concentration (LOEC) and chronic values of the PL of shrimp were 46.5, 73.0 and 58.3 µg Ni L-1 derived for the 21-d survival endpoint. The NOEC, LOEC and chronic values for the 30-d survival endpoint of the green mussels and fish fingerlings were 4.6, 6.32, 5.4 and 1.95, 2.6, 2.25 mg Ni L-1 respectively. The isoforms of esterase, superoxide dismutase and malate dehydrogenase activities in the whole body tissues of test organisms were studied by native polyacrylamide gel electrophoresis after exposure to Ni. Histological examination of compound eye sections of shrimp revealed deformation, compression, fusion and detachement in the corneal cells from the corneal facet of the ommatidia indicating cellular anomalies due to Ni toxicity. Gill sections of the green mussel witnessed reduced haemolymph in sinuses of gill filaments, degenerative changes in interfilamentous junction and necrosis of frontal ciliated epithelial cells with vacuoles after exposure to Ni. Nickel affects the vision of shrimp and fish fingerlings, gills and byssus of green mussels.


Assuntos
Bivalves/efeitos dos fármacos , Níquel/toxicidade , Penaeidae/efeitos dos fármacos , Percas/crescimento & desenvolvimento , Perna (Organismo)/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Bivalves/enzimologia , Bivalves/crescimento & desenvolvimento , Esterases/química , Olho/efeitos dos fármacos , Olho/patologia , Brânquias/efeitos dos fármacos , Brânquias/patologia , Malato Desidrogenase/química , Níquel/farmacologia , Penaeidae/enzimologia , Penaeidae/crescimento & desenvolvimento , Perna (Organismo)/enzimologia , Perna (Organismo)/crescimento & desenvolvimento , Superóxido Dismutase/química
20.
Int J Pharm ; 569: 118573, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31356955

RESUMO

The main objective of this study was to investigate the potential of poly(α-carboxylate-co-α-benzylcarboxylate-ε-caprolactone)-block-poly(ethylene glycol)-block-poly(α-carboxylate-co-α-benzylcarboxylate-ε-caprolactone) (PCBCL-b-PEG-b-PCBCL; denoted as PolyGel™) as an in situ gel system for ocular delivery of CyA. The newly developed formulation was systematically assessed and its profile was compared to Restasis®, 0.5% CyA extemporaneous preparation, and CyA-loaded poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) a non-gelling micelle formulation. In vivo Draize test showed that CyA-loaded PolyGel™ was well tolerated with only moderate irritation that resolved within 24 h. Both ex vivo corneal permeation and in vivo pharmacokinetics in aqueous humor (AqH) showed sustained release of CyA from PolyGel™. Non-compartmental analysis of CyA concentrations in AqH showed significant changes in pharmacokinetic parameters of CyA among different formulations. The highest Cmax and AUC0-∞ in AqH were achieved with Restasis® followed by PolyGel™. Nonetheless, CyA-loaded PolyGel™ had approximately 87% longer t1/2 for CyA compared to Restasis®. Pharmacological and histopathological studies were performed on an endotoxin-induced uveitis rabbit model, where CyA-loaded PolyGel™ showed a comparable profile to Restasis®. Our results point to a great potential of PolyGel™ as ocular drug delivery carrier.


Assuntos
Ciclosporina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Imunossupressores/administração & dosagem , Poliésteres/administração & dosagem , Uveíte/tratamento farmacológico , Administração Tópica , Animais , Humor Aquoso/metabolismo , Ciclosporina/farmacocinética , Olho/efeitos dos fármacos , Olho/metabolismo , Imunossupressores/farmacocinética , Lipopolissacarídeos , Masculino , Poliésteres/farmacocinética , Coelhos , Uveíte/induzido quimicamente
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