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1.
Int J Mol Sci ; 22(8)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33917258

RESUMO

Cataracts are the major cause of blindness worldwide, largely resulting from aging and diabetes mellitus. Advanced glycation end products (AGEs) have been identified as major contributors in cataract formation because they alter lens protein structure and stability and induce covalent cross-linking, aggregation, and insolubilization of lens crystallins. We investigated the potential of the deglycating enzyme fructosamine-3-kinase (FN3K) in the disruption of AGEs in cataractous lenses. Macroscopic changes of equine lenses were evaluated after ex vivo intravitreal FN3K injection. The mechanical properties of an equine lens pair were evaluated after treatment with saline and FN3K. AGE-type autofluorescence (AF) was measured to assess the time-dependent effects of FN3K on glycolaldehyde-induced AGE-modified porcine lens fragments and to evaluate its actions on intact lenses after in vivo intravitreal FN3K injection of murine eyes. A potential immune response after injection was evaluated by analysis of IL-2, TNFα, and IFNγ using an ELISA kit. Dose- and time-dependent AF kinetics were analyzed on pooled human lens fragments. Furthermore, AF measurements and a time-lapse of macroscopic changes were performed on intact cataractous human eye lenses after incubation with an FN3K solution. At last, AF measurements were performed on cataractous human eyes after crossover topical treatment with either saline- or FN3K-containing drops. While the lenses of the equine FN3K-treated eyes appeared to be clear, the saline-treated lenses had a yellowish-brown color. Following FN3K treatment, color restoration could be observed within 30 min. The extension rate of the equine FN3K-treated lens was more than twice the extension rate of the saline-treated lens. FN3K treatment induced significant time-dependent decreases in AGE-related AF values in the AGE-modified porcine lens fragments. Furthermore, in vivo intravitreal FN3K injection of murine eyes significantly reduced AF values of the lenses. Treatment did not provoke a systemic immune response in mice. AF kinetics of FN3K-treated cataractous human lens suspensions revealed dose- and time-dependent decreases. Incubation of cataractous human eye lenses with FN3K resulted in a macroscopic lighter color of the cortex and a decrease in AF values. At last, crossover topical treatment of intact human eyes revealed a decrease in AF values during FN3K treatment, while showing no notable changes with saline. Our study suggests, for the first time, a potential additional role of FN3K as an alternative treatment for AGE-related cataracts.


Assuntos
Catarata/tratamento farmacológico , Catarata/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/farmacologia , Animais , Catarata/diagnóstico , Catarata/etiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ativação Enzimática , Olho/efeitos dos fármacos , Olho/metabolismo , Produtos Finais de Glicação Avançada/administração & dosagem , Cavalos , Humanos , Imuno-Histoquímica , Injeções Intravítreas , Cristalino/efeitos dos fármacos , Cristalino/metabolismo , Camundongos , Fosfotransferases (Aceptor do Grupo Álcool)/administração & dosagem , Fosfotransferases (Aceptor do Grupo Álcool)/uso terapêutico
2.
Ann Agric Environ Med ; 28(1): 122-126, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33775077

RESUMO

INTRODUCTION AND OBJECTIVE: The COVID-19 pandemic causes vital concerns due to the lack of proved, effective, and safe therapy. Chloroquine and hydroxychloroquine seem to be useful, but recently serious concerns regarding their adverse events have risen. The aim of the study was to broaden the general perspective of chloroquine and hydroxychloroquine use in COVID-19 treatment, based on an analysis of their current safety profile among patients with rheumatic diseases. MATERIAL AND METHODS: The study was based on a group of 152 patients with rheumatic diseases, aged 20-78 years, treated either with chloroquine or hydroxychloroquine. Analyzed data included age, gender, comorbidities, type of drug, dosage, treatment duration, and reported adverse events. Cases of drug withdrawal related to adverse events were also recorded. RESULTS: The dosage was consistent in both groups: 250 mg of chloroquine or 200 mg of hydroxychloroquine daily. 77.6% of patients did not experience any adverse reactions to the treatment. Hydroxychloroquine showed better safety profile, with 10.9% of patients reporting side-ffects, compared to 28.9% in patients treated with chloroquine. The overall incidence of ophthalmic complications was 6.6%. For both drugs, no statistically significant correlation between adverse events and age, chronic heart or liver disease, or hypertension was found. CONCLUSIONS: Chloroquine and hydroxychloroquine at lower doses, as used in rheumatic diseases, prove to be relatively safe. Data from the literature show that high dosage as recommended in COVID-19 treatment may pose a risk of toxicity and require precise management, but prophylactic, long-term use of lower, safe doses might be a promising solution.


Assuntos
Antirreumáticos/efeitos adversos , Cloroquina/efeitos adversos , Hidroxicloroquina/efeitos adversos , Doenças Reumáticas/tratamento farmacológico , Adulto , Idoso , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Cloroquina/administração & dosagem , Cloroquina/uso terapêutico , Olho/efeitos dos fármacos , Feminino , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/uso terapêutico , Masculino , Pessoa de Meia-Idade
3.
Int J Nanomedicine ; 16: 609-621, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33531804

RESUMO

Objective: The aim of the current study was to load fenticonazole nitrate, a slightly water-soluble antifungal agent, into terpene-enriched phospholipid vesicles (terpesomes) as a potential delivery system for the management of ocular fungal infection. Methods: Thin film hydration method was used to prepare terpesomes according to a 32 full factorial design to inspect the effect of several variables on vesicles' features. The investigated factors were terpenes type (X1) and terpenes amount (X2) while the dependent responses were encapsulation efficiency percent (Y1), particle size (Y2) and polydispersity index (Y3). Design Expert® program was used to chose the best achieved formula. The selected terpesomes were further optimized via incorporation of a positive charge inducer (stearylamine) to enhance adhesion to the negatively charged mucus covering the eye surface. The in vivo performance of the optimized fenticonazole nitrate-loaded terpesomes relative to drug suspension was evaluated by measuring the antifungal activity (against Candida albicans) retained in the tear's fluid at different time intervals after ocular application in albino rabbits. Results: The optimized terpesomes showed spherical vesicles with entrapment efficiency of 79.02±2.35%, particle size of 287.25±9.55 nm, polydispersity index of 0.46±0.01 and zeta potential of 36.15±1.06 mV. The in vivo study demonstrated significantly higher ocular retention of the optimized fenticonazole nitrate-loaded terpesomes relative to the drug suspension. Moreover, the histopathological studies proved the safety and biocompatibility of the prepared terpesomes. Conclusion: The obtained results verified the potential of the terpesomes for safe and effective ocular delivery of fenticonazole nitrate.


Assuntos
Sistemas de Liberação de Medicamentos , Olho/efeitos dos fármacos , Imidazóis/administração & dosagem , Terpenos/farmacologia , Administração Cutânea , Animais , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Masculino , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Coelhos , Suspensões
4.
Int J Mol Sci ; 22(3)2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499199

RESUMO

Corneal and conjunctival inflammation and dry eye develop in systemic vitamin A deficiency (VAD). The objective of this study was to investigate the lacrimal ocular surface retinoid axis, particularly immunomodulatory effects of retinoic acid (RA) and change in conjunctival myeloid cell number and phenotype in VAD. We discovered that ocular surface epithelial and myeloid cells express retinoid receptors. Both all trans- and 9-cis-RA suppressed production of dry eye relevant inflammatory mediators [interleukin(IL)-1ß, IL-12, regulated upon activation, normal T cell expressed and secreted (RANTES)] by myeloid cells. Systemic VAD was associated with significant goblet cell loss and an increased number of CD45+ immune cells in the conjunctiva. MHCII-CD11b+ classical monocytes were significantly increased in the conjunctiva of VAD C57BL/6 and RXR-α mutated Pinkie strains. RNA seq revealed significantly increased expression of innate immune/inflammatory genes in the Pinkie conjunctiva. These findings indicate that retinoids are essential for maintaining a healthy, well-lubricated ocular surface and have immunomodulatory effects in the conjunctiva that are mediated in part via RXR-α signaling. Perturbation of the homeostatic retinoid axis could potentiate inflammation on the ocular surface.


Assuntos
Olho/efeitos dos fármacos , Inflamação/fisiopatologia , Aparelho Lacrimal/metabolismo , Retinoides/metabolismo , Animais , Quimiocina CCL5/metabolismo , Túnica Conjuntiva/metabolismo , Córnea/metabolismo , Síndromes do Olho Seco/metabolismo , Feminino , Células Caliciformes/metabolismo , Homeostase , Imunidade Inata , Subunidade p35 da Interleucina-12/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/metabolismo , Receptores do Ácido Retinoico/metabolismo , Transdução de Sinais , Tretinoína/química , Vitamina A/metabolismo , Deficiência de Vitamina A/metabolismo
5.
Biomed Pharmacother ; 133: 111092, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378986

RESUMO

This review provides insights into the mechanism underlying the pathogenesis of myopia and potential targets for clinical intervention. Although the etiology of myopia involves both environmental and genetic factors, recent evidence has suggested that the prevalence and severity of myopia appears to be affected more by environmental factors. Current pharmacotherapeutics are aimed at inhibiting environmentally induced changes in visual input and subsequent changes in signaling pathways during myopia pathogenesis and progression. Recent studies on animal models of myopia have revealed specific molecules potentially involved in the regulation of eye development. Among them, the dopamine receptor plays a critical role in controlling myopia. Subsequent studies have reported pharmacotherapeutic treatments to control myopia progression. In particular, atropine treatment yielded favorable outcomes and has been extensively used; however, current studies are aimed at optimizing its efficacy and confirming its safety. Furthermore, future studies are required to assess the efficacy of combinatorial use of low-dose atropine and contact lenses or orthokeratology.


Assuntos
Olho/efeitos dos fármacos , Miopia/tratamento farmacológico , Visão Ocular/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Olho/metabolismo , Olho/fisiopatologia , Humanos , Miopia/metabolismo , Miopia/fisiopatologia , Transdução de Sinais , Resultado do Tratamento
6.
Int J Biol Macromol ; 169: 330-341, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310092

RESUMO

Vancomycin-loaded N,N-dodecyl,methyl-polyethylenimine nanoparticles coated with hyaluronic acid (VCM-DMPEI nanoparticles/HA) were synthesized as an adjuvant for the treatment of bacterial endophthalmitis. The nanoparticles were formulated by experimental statistical design, thoroughly characterized, and evaluated in terms of bactericidal activity and both in vitro and in vivo ocular biocompatibility. The VCM-DMPEI nanoparticles/HA were 154 ± 3 nm in diameter with a 0.197 ± 0.020 polydispersity index; had a + 26.4 ± 3.3 mV zeta potential; exhibited a 93% VCM encapsulation efficiency; and released 58% of the encapsulated VCM over 96 h. VCM and DMPEI exhibited a synergistic bactericidal effect. The VCM-DMPEI nanoparticles/HA were neither toxic to ARPE-19 cells nor irritating to the chorioallantoic membrane. Moreover, the VCM-DMPEI nanoparticles/HA did not induce modifications in retinal functions, as determined by electroretinography, and in the morphology of the ocular tissues. In conclusion, the VCM-DMPEI nanoparticles/HA may be a useful therapeutic adjuvant to treat bacterial endophthalmitis.


Assuntos
Endoftalmite/tratamento farmacológico , Polietilenoimina/análogos & derivados , Vancomicina/farmacologia , Antibacterianos/farmacologia , Linhagem Celular , Portadores de Fármacos , Liberação Controlada de Fármacos , Olho/efeitos dos fármacos , Humanos , Ácido Hialurônico/metabolismo , Ácido Hialurônico/farmacologia , Nanopartículas , Tamanho da Partícula , Polietilenoimina/química , Polietilenoimina/farmacologia , Vancomicina/química
7.
Int J Nanomedicine ; 15: 7825-7840, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116503

RESUMO

Background: Voriconazole (VRC) is a triazole broad spectrum antifungal drug, used in the management of versatile fungal infections, particularly fungal keratitis. The obligatory use of niosomal delivery of VRC may reduce the frequency of dosing intervals resulting from its short biological half time and consequently improve patient compliance. Methods: VRC loaded proniosomes (VRC-PNs) were set by the coacervation technique and completely characterized. The developed formula was comprehensively assessed concerning in- vitro release behavior, kinetic investigation, and its conflict against refrigerated and room temperature conditions. A selected noisomal formula was incorporated into ocusert (VRC-PNs Ocu) formulated by 1% w/w hydroxypropyl methyl cellulose HPMC and 0.1% w/w carbopol 940. Eventually, in vitro antifungal activity against Candida albicans and Aspergillus nidulans was assessed by the cup diffusion method. Results: The optimized VRC-PNs (Pluronic F127: cholesterol weight ratio 1:1 w/w) exhibited the highest entrapment efficiency (87.4±2.55%) with a spherical shape, proper size in nano range and a suitable Zeta potential of 209.7±8.13 nm and -33.5±1.85 mV, respectively. Assurance of drug encapsulation in nanovesicles was accomplished by several means such as attenuated total reflection Fourier-transform infrared spectroscopy, differential scanning calorimetry in addition to powder X-ray diffraction investigations. It displayed a biphasic in vitro release pattern and after 6 months of storage at a refrigerated temperature, the optimized formula preserved its stability. VRC-PNs Ocu proved a very highly significant antifungal activity matched with the free drug or nanosuspension which was extra assured by comparing its mean inhibition zone with that of 5% natamycin market eye drops. Conclusion: In conclusion, VRC-PNs Ocu could be considered as a promising stable sustained release topical ocular nanoparticulate system for the management of fungal infections.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Portadores de Fármacos/química , Composição de Medicamentos , Olho/efeitos dos fármacos , Voriconazol/química , Voriconazol/farmacologia , Animais , Antifúngicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candida albicans/fisiologia , Olho/microbiologia , Infecções Oculares Fúngicas/tratamento farmacológico , Géis , Humanos , Tamanho da Partícula , Tensoativos/química , Voriconazol/uso terapêutico , Água/química
8.
Int J Nanomedicine ; 15: 7861-7875, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116505

RESUMO

Purpose: The topically administered drugs through conventional delivery systems have low bioavailability. Henceforth, the present study was designed to prepare and optimize clarithromycin (CTM)-loaded chitosan nanoparticles (CHNPs) to demonstrate the efficacy against microorganisms. Methods: Clarithromycin-loaded chitosan nanoparticles (CTM-CHNPs) were prepared by ionotropic gelation method. The formulation was optimized by box-Behnken design using the formulation variables like CH (A), STPP concentration (B), and stirring speed (C). Their effects were evaluated on the independent variables like particle size (Y1) and entrapment efficiency (Y2). Further, CTM-CHNPs were evaluated for physicochemical parameters, in-vitro drug release, ex-vivo permeation, bioadhesive study, corneal hydration, histopathology, HET-CAM, and antibacterial study. Results: The optimized formulation (CTM-CHNPopt) showed the low particle size (152±5 nm), which is desirable for ocular delivery. It also showed high encapsulation (70.05%), zeta potential (+35.2 mV), and was found in a spherical shape. The drug release study revealed a sustained drug release profile (82.98±3.5% in 12 hours) with Korsmeyer peppas kinetic (R2=0.996) release model. It showed a 2.7-fold higher corneal permeation than CTM-solution. CHNPs did not exhibit any sign of damage to excised goat cornea, which is confirmed by hydration, histopathology, and HET-CAM test. It exhibited significant (P<0.05) higher antibacterial susceptibility than CTM-solution. Conclusion: The finding of the study concluded that CTM-CHNPs can be used for effective management of bacterial conjunctivitis by increasing the precorneal residence time.


Assuntos
Quitosana/química , Claritromicina/química , Claritromicina/farmacologia , Portadores de Fármacos/química , Olho/efeitos dos fármacos , Nanopartículas/química , Adesividade , Animais , Antibacterianos/efeitos adversos , Antibacterianos/química , Antibacterianos/farmacologia , Claritromicina/efeitos adversos , Preparações de Ação Retardada , Composição de Medicamentos , Tamanho da Partícula
9.
Toxicol Lett ; 334: 1-3, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32916183

RESUMO

The Chemical Countermeasures Research Program (CCRP) was established in 2006 by the National Institute of Allergy and Infectious Diseases (NIAID/NIH) on behalf of the National Institutes of Health Office of the Director (NIH OD). It is a trans-NIH initiative to expedite the discovery and early development of medical countermeasures (MCMs) that can reduce mortality and serious morbidity during and after large consequence public health emergency involving the deliberate or accidental large-scale release of highly toxic chemicals (HTCs).


Assuntos
Planejamento em Desastres/métodos , Olho/efeitos dos fármacos , Substâncias Perigosas/toxicidade , Contramedidas Médicas , Neuropatia Óptica Tóxica/prevenção & controle , Humanos , National Institute of Allergy and Infectious Diseases (U.S.) , Saúde Pública , Estados Unidos
10.
J Med Internet Res ; 22(8): e20007, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32804086

RESUMO

BACKGROUND: Rapid access to evidence is crucial in times of an evolving clinical crisis. To that end, we propose a novel approach to answer clinical queries, termed rapid meta-analysis (RMA). Unlike traditional meta-analysis, RMA balances a quick time to production with reasonable data quality assurances, leveraging artificial intelligence (AI) to strike this balance. OBJECTIVE: We aimed to evaluate whether RMA can generate meaningful clinical insights, but crucially, in a much faster processing time than traditional meta-analysis, using a relevant, real-world example. METHODS: The development of our RMA approach was motivated by a currently relevant clinical question: is ocular toxicity and vision compromise a side effect of hydroxychloroquine therapy? At the time of designing this study, hydroxychloroquine was a leading candidate in the treatment of coronavirus disease (COVID-19). We then leveraged AI to pull and screen articles, automatically extract their results, review the studies, and analyze the data with standard statistical methods. RESULTS: By combining AI with human analysis in our RMA, we generated a meaningful, clinical result in less than 30 minutes. The RMA identified 11 studies considering ocular toxicity as a side effect of hydroxychloroquine and estimated the incidence to be 3.4% (95% CI 1.11%-9.96%). The heterogeneity across individual study findings was high, which should be taken into account in interpretation of the result. CONCLUSIONS: We demonstrate that a novel approach to meta-analysis using AI can generate meaningful clinical insights in a much shorter time period than traditional meta-analysis.


Assuntos
Inteligência Artificial , Infecções por Coronavirus/tratamento farmacológico , Oftalmopatias/etiologia , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/uso terapêutico , Metanálise como Assunto , Pneumonia Viral/tratamento farmacológico , Olho/efeitos dos fármacos , Olho/patologia , Humanos , Pandemias , Fatores de Tempo
12.
PLoS One ; 15(7): e0234818, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32663210

RESUMO

BACKGROUND: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors used to treat EGFR mutation positive non-small-cell lung cancer (NSCLC). Skin rash and diarrhea are well-known and common adverse events in patients receiving erlotinib, whereas other adverse events, including eye, liver, or renal disorders have not been evaluated adequately. This meta-analysis aimed to evaluate the ocular, hepatobiliary, and renal toxicities of erlotinib in patients with NSCLC cancers. METHODS: In total, sixty studies were assessed, and the results of the included studies were quantitatively integrated using meta-analysis. The incidence of ocular, hepatobiliary (alanine aminotransferase [ALT] and bilirubin elevations; other hepatic adverse events), and renal adverse events were estimated. Additionally, the erlotinib-treated groups and the control groups (placebo or other treatment) were compared with respect to ocular disorders and ALT elevation. The study protocol has been registered in the International Prospective Register for Systematic Reviews (PROSPERO) CRD42018093758. RESULTS: The overall incidence of ocular disorders was 3.30% (95% confidence interval [CI] 2.20%-5.00%). The incidence of ALT elevation, bilirubin elevation, and other hepatobiliary disorders was 6.40% (95% CI 3.90%-10.4%), 3.80% (95% CI 2.30%-6.10%), and 1.00% (95% 0.60%-1.80%), respectively. The incidence of renal disorder was 3.10% (95% CI 1.90%-5.00%). The risk of ocular toxicity in the erlotinib treatment group was significantly increased (risk ratio = 2.91; 95% CI 1.70-4.98) compared to that in the control group. ALT elevation was not significantly different between the two groups. CONCLUSION: Based on the results, careful monitoring of ocular toxicity in patients receiving erlotinib should be recommended and closer monitoring of hepatic toxicity should be also recommended in patients with liver-related risk factors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Cloridrato de Erlotinib/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças do Sistema Digestório/etiologia , Intervalo Livre de Doença , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Exantema/etiologia , Olho/efeitos dos fármacos , Oftalmopatias/etiologia , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Nefropatias/etiologia , Neoplasias Pulmonares/genética , Masculino , Mutação , Inibidores de Proteínas Quinases/uso terapêutico
13.
Aquat Toxicol ; 226: 105558, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32673888

RESUMO

The aryl hydrocarbon receptor (Ahr) is a ligand-activated transcription factor that mediates the toxicity of dioxins and dioxin-like compounds (DLCs) in vertebrates. Two clades of the Ahr family exist in teleosts (Ahr1 and Ahr2), and it has been demonstrated that Ahr2 is the main protein involved in mediating the toxicity of dioxins and DLCs in most teleost species. Recently, we characterized the Atlantic cod (Gadus morhua) Ahr1a and Ahr2a receptors. To further explore a possible subfunction partitioning of Ahr1a and Ahr2a in Atlantic cod we have mapped the expression and localization of ahr1a and ahr2a in early developmental stages. Atlantic cod embryos were continuously exposed in a passive-dosing exposure system to the Ahr agonist, benzo[a]pyrene (B[a]P), from five days post fertilization (dpf) until three days post hatching (dph). Expression of ahr1a, ahr2a, and the Ahr-target genes, cyp1a and ahrrb, was assessed in embryos (8 dpf and 10 dpf) and larvae (3 dph) with quantitative real-time PCR analyses (qPCR), while in situ hybridization was used to assess the localization of expression of ahr1a, ahr2a and cyp1a. Quantitative measurements showed an increased cyp1a expression in B[a]P-exposed samples at all sampling points, and for ahr2a at 10 dpf, confirming the activation of the Ahr-signalling pathway. Furthermore, B[a]P strongly induced ahr2a and cyp1a expression in the cardiovascular system and skin, respectively, of embryos and larvae. Induced expression of both ahr2a and cyp1a was also revealed in the liver of B[a]P-exposed larvae. Our results suggest that Ahr2a is the major subtype involved in mediating responses to B[a]P in early developmental stages of Atlantic cod, which involves transcriptional regulation of biotransformation genes, such as cyp1a. The focused expression of ahr1a in the eye of embryos and larvae, and the presence of ahr2a transcripts in the jaws and fin nodes, further indicate evolved specialized roles of the two Ahrs in ontogenesis.


Assuntos
Citocromo P-450 CYP1A1/metabolismo , Gadus morhua/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Benzo(a)pireno/toxicidade , Citocromo P-450 CYP1A1/genética , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Olho/efeitos dos fármacos , Olho/embriologia , Olho/metabolismo , Gadus morhua/genética , Gadus morhua/metabolismo , Larva/efeitos dos fármacos , Larva/genética , Fígado/efeitos dos fármacos , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Poluentes Químicos da Água/toxicidade
14.
Sci Rep ; 10(1): 10202, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576873

RESUMO

The intraocular pressure lowering property of a new rho kinase inhibitor, SB772077B (SB77) has been previously demonstrated in perfused human cadaveric eyes. In this study, the efficacy of SB77 in alleviating the aqueous outflow resistance mediated by cyclic mechanical stress in perfused human cadaveric eyes was investigated. A human anterior segment perfusion culture model was used to investigate the effect of cyclic intraocular pressure (IOP) on aqueous outflow facility in presence or absence of SB77. The status of RhoA activation and the downstream effector molecule myosin-light chain phosphorylation (p-MLC) was investigated by Western blot. Cyclic mechanical stress resulted in decrease in aqueous outflow facility (-19.79 ± 4.93%; p = 0.019) in perfused human eyes and treatment with SB77 (50 µM) significantly enhanced outflow facility by 15% (p = 0.05). The increase in outflow facility by SB77 was confirmed with the inactivation of RhoA/ROCK signaling and decreased expression of extracellular matrix markers. SB77 effectively reduced the outflow resistance mediated by cyclic IOP and thus may be a potential clinical candidate for the management of glaucoma.


Assuntos
Humor Aquoso/efeitos dos fármacos , Olho/efeitos dos fármacos , Pressão Intraocular/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Actinas/metabolismo , Idoso , Animais , Cadáver , Matriz Extracelular/metabolismo , Olho/metabolismo , Humanos , Cadeias Leves de Miosina/metabolismo , Técnicas de Cultura de Órgãos/métodos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Estresse Mecânico , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
15.
Chemosphere ; 258: 127409, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32569959

RESUMO

Perfluorobutanesulfonate (PFBS), an aquatic pollutant of emerging concern, is found to disturb gut microbiota, retinoid metabolism and visual signaling in teleosts, while probiotic supplementation can shape gut microbial community to improve retinoid absorption. However, it remains unknown whether probiotic bacteria can modulate the toxicities of PFBS on retinoid metabolism and visual physiology. In the present study, adult zebrafish were exposed for 28 days to 0, 10 and 100 µg/L PFBS, with or without dietary administration of probiotic Lactobacillus rhamnosus. Interaction between PFBS and probiotic was examined regarding retinoid dynamics (intestine, liver and eye) and visual stimuli transmission. PFBS single exposures remarkably inhibited the absorption of retinyl ester in female intestines, which were, however, restored by probiotic to normal status. Although coexposure scenarios markedly increased the hepatic storage of retinyl ester in females, mobilization of retinol was reduced in livers by single or combined exposures regardless of sex. In the eyes, transport and catalytic conversion of retinol to retinal and retinoic acid were interrupted by PFBS alone, which were efficiently antagonized by probiotic presumably through an indirect action. In response to the availability of retinal chromophore, transcriptions of opsins and arrestin genes were altered adaptively to control visual perception and termination. Neurotransmission across retina circuitry was changed accordingly, centering on epinephrine and norepinephrine. In summary, the present study found the efficient modulation of probiotic on retinoid metabolic disorders of PFBS pollution, which subsequently impacted visual signaling. A future work is warranted to provide mechanistic clues in retinoid interaction.


Assuntos
Fluorcarbonetos/toxicidade , Fenômenos Fisiológicos Oculares/efeitos dos fármacos , Probióticos/farmacologia , Retinoides/metabolismo , Ácidos Sulfônicos/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Animais , Olho/efeitos dos fármacos , Olho/metabolismo , Feminino , Metabolismo dos Lipídeos/efeitos dos fármacos , Opsinas/genética , Transdução de Sinais , Transcrição Genética/efeitos dos fármacos
16.
Metabolism ; 110: 154264, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32445641

RESUMO

BACKGROUND: Bisphosphonates (BPs) are pyrophosphate analogues widely used in diseases related to bone loss and increased bone turnover. Their high affinity for bone hydroxyapatite makes them ideal agents for bone diseases, while preventing them from reaching other cells and tissues. Data of the last decade, however, have demonstrated extra-skeletal tissue deposition and a variety of non-skeletal effects have been recently recognized. As such, BPs have been shown to exert anti-tumor, immunomodulatory, anti-inflammatory and anti-diabetic effects. In addition, new delivery systems (liposomes, nanoparticles, hydrogels) are being developed in an effort to expand BPs clinical application to extra-skeletal tissues and enhance their overall therapeutic spectrum and effectiveness. In the present review, we outline current data on extra-skeletal actions of bisphosphonates and attempt to unravel the underlying pathophysiological mechanisms.


Assuntos
Difosfonatos/farmacologia , Animais , Sistema Cardiovascular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/tratamento farmacológico , Difosfonatos/efeitos adversos , Olho/efeitos dos fármacos , Humanos , Sistema Imunitário/efeitos dos fármacos
17.
PLoS One ; 15(4): e0231841, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298376

RESUMO

Elevated intraocular pressure is the only treatable risk factor for glaucoma, an eye disease that is the leading cause of irreversible blindness worldwide. We have identified cromakalim prodrug 1 (CKLP1), a novel water-soluble ATP-sensitive potassium channel opener, as a new ocular hypotensive agent. To evaluate the pharmacokinetic and safety profile of CKLP1 and its parent compound levcromakalim, Dutch-belted pigmented rabbits were treated intravenously (0.25 mg/kg) or topically (10 mM; 4.1 mg/ml) with CKLP1. Body fluids (blood, aqueous and vitreous humor) were collected at multiple time points and evaluated for the presence of CKLP1 and levcromakalim using a liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) based assay. Histology of tissues isolated from Dutch-belted pigmented rabbits treated once daily for 90 days was evaluated in a masked manner by a certified veterinary pathologist. The estimated plasma parameters following intravenous administration of 0.25 mg/kg of CKLP1 showed CKLP1 had a terminal half-life of 61.8 ± 55.2 min, Tmax of 19.8 ± 23.0 min and Cmax of 1968.5 ± 831.0 ng/ml. Levcromakalim had a plasma terminal half-life of 85.0 ± 37.0 min, Tmax of 61.0 ± 32.0 min and Cmax of 10.6 ± 1.2 ng/ml. Topical CKLP1 treatment in the eye showed low levels (<0.3 ng/mL) of levcromakalim in aqueous and vitreous humor, and trace amounts of CKLP1 and levcromakalim in the plasma. No observable histological changes were noted in selected tissues that were examined following topical application of CKLP1 for 90 consecutive days. These results suggest that CKPL1 is converted to levcromakalim in the eye and likely to some extent in the systemic circulation.


Assuntos
Cromakalim/farmacologia , Cromakalim/farmacocinética , Pró-Fármacos/farmacologia , Pró-Fármacos/farmacocinética , Administração Intravenosa , Administração Tópica , Animais , Humor Aquoso/efeitos dos fármacos , Humor Aquoso/metabolismo , Cromatografia Líquida , Córnea/citologia , Córnea/efeitos dos fármacos , Cromakalim/administração & dosagem , Cromakalim/sangue , Olho/citologia , Olho/efeitos dos fármacos , Olho/metabolismo , Feminino , Espectrometria de Massas , Pró-Fármacos/uso terapêutico , Coelhos , Corpo Vítreo/efeitos dos fármacos , Corpo Vítreo/metabolismo
18.
J Vis Exp ; (157)2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32281978

RESUMO

Many current therapeutics under development for diseases of the posterior pole of the eye are biologics. These drugs need to be administered frequently, typically via intravitreal injections. Encapsulated cells expressing the biologic of choice are becoming a tool for local protein production and release (e.g., via long-term drug delivery). In addition, encapsulation systems utilize permeable materials that allow diffusion of nutrients, waste, and therapeutic factors into and out of cells. This occurs while masking the cells from the host immune response, avoiding the need for suppression of the host immune system. This protocol describes the use of alginate as a polymer in microencapsulation coupled with the electrospray method as a microencapsulation technique. ARPE-19 cells, a spontaneously arising human RPE cell line, has been used in long-term cell therapy experiments due to its lifetime functionality, and it is used here for encapsulation and delivery of the capsules to mouse eyes. The manuscript summarizes the steps for cell microencapsulation, quality control, and ocular delivery.


Assuntos
Produtos Biológicos/química , Terapia Baseada em Transplante de Células e Tecidos/métodos , Sistemas de Liberação de Medicamentos/métodos , Olho/efeitos dos fármacos , Animais , Cápsulas , Modelos Animais de Doenças , Camundongos
19.
Adv Exp Med Biol ; 1244: 295-307, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32301024

RESUMO

Emerging immunotherapy agents, such as immune checkpoint inhibitors, have shown remarkable promise in the treatment of various malignancies. These drugs selectively target different steps in the immune response cascade to upregulate the body's normal response to cancer. Due to the novelty of these therapeutic agents, their toxicity profile is less well understood.Meta-analysis results reveal that the overall prevalence of oral mucositis, stomatitis, and xerostomia is lower with checkpoint inhibitors compared to conventional chemotherapy, and head and neck radiation therapy. However, the widespread use of immunotherapy reveals new oral mucosal barrier adverse events, including bullous pemphigoid, mucous membrane pemphigoid, and lichenoid mucositis. Audiovestibular dysfunction can occur from autoimmune-mediated pathways of immunotherapy (adoptive cell) with limited treatment options. Such auditory complications can lead to speech recognition deficits and sensorineural hearing loss. Ocular toxicities are among the most common adverse events resulting from the use of these agents. The majority of ocular immune-related adverse events (irAEs) are mild, low-grade, non-sight threatening, such as blurred vision, conjunctivitis, and ocular surface disease. Serious and sight-threatening events, including corneal perforation, optic neuropathy, and retinal vascular occlusion, can occur but are infrequent. In this chapter, we review the current evidence on the clinical manifestations of oral, audiovestibular, and ocular immune-related adverse events (i.e., irAEs).


Assuntos
Orelha/patologia , Olho/efeitos dos fármacos , Olho/patologia , Imunoterapia/efeitos adversos , Boca/efeitos dos fármacos , Boca/patologia , Neoplasias/terapia , Humanos
20.
Arq. bras. oftalmol ; 83(2): 109-112, Mar.-Apr. 2020. tab
Artigo em Inglês | LILACS | ID: biblio-1088962

RESUMO

ABSTRACT Purpose: To compare the impact of ocular changes between systemic treatment with doxycycline and low-dose oral isotretinoin in patients with moderate-to-severe papulopustular rosacea. Methods: Patients were randomized to receive either isotretinoin 0.3-0.4 mg/kg (group A) or doxycycline 100 mg/day (group B) for 16 weeks. Ocular symptoms were searched and evaluated, including best-corrected visual acuity (BCVA), Schirmer test, breakup time, rose bengal staining score, and meibomian gland dysfunction grading. The patients were retested at the end of treatment. Results: The present study included 39 patients (30 females and 9 males). Best-corrected visual acuity was > 20/30 in >90% of patients in both groups and did not change after treatment. After treatment, improvement in ocular symptoms and meibomian gland dysfunction was more pronounced in group B (p<0.05); the other parameters did not reach statistical significance. Conclusion: Doxycycline improved meibomian gland dysfunction, ocular symptoms, and ocular surface in patients with rosacea. Even though some patients experienced worsening meibomian gland dysfunction and symptoms, no subject experienced any serious complications after administration of low-dose isotretinoin.


RESUMO Objetivos: Comparar o impacto das alterações oculares entre o tratamento sistêmico de doxiciclina e isotretinoína em baixa dosagem em pacientes com rosácea papulopustulosa moderada a grave. Métodos: Os pacientes form randomizados para receber isotretinoína 0,3 a 0,4 mg/kg (grupo A) ou doxiciclina 100mg/dia (grupo B) por 16 semanas. Os sintomas oculares foram pesquisados e avaliados, incluindo melhor acuidade visual corrigida, teste de Schirmer, tempo de ruptura do filme lacrimal, coloração de rosa bengala e graduação da disfunção de glândula de Meibomius. Os pacientes foram novamente testados no final do tratamento. Resultados: O presente estudo incluiu 39 pacientes (30 mulheres e 9 homens). A melhor acuidade visual corrigida foi >20/30 em >90% dos pacientes em ambos os grupos e não se alterou após o tratamento. A melhora dos sintomas oculares e da disfunção de glândula de Meibomius foi mais pronunciada no grupo B (p<0,05) após o tratamento; as demais variáveis não atingiram significância estatística. Conclusão: A doxiciclina melhorou a disfunção de glândula de Meibomius, os sintomas oculares e a superfície ocular de pa cientes com rosácea. Mesmo que alguns pacientes tenham piorado a disfunção e os sintomas da glândula de Meibomius, nenhum indivíduo apresentou complicações graves após a admi nistração de baixas doses de isotretinoína.


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Isotretinoína/administração & dosagem , Doxiciclina/administração & dosagem , Rosácea/tratamento farmacológico , Fármacos Dermatológicos/administração & dosagem , Disfunção da Glândula Tarsal/tratamento farmacológico , Antibacterianos/administração & dosagem , Índice de Gravidade de Doença , Acuidade Visual , Administração Oral , Resultado do Tratamento , Rosácea/fisiopatologia , Olho/efeitos dos fármacos , Disfunção da Glândula Tarsal/fisiopatologia , Glândulas Tarsais/efeitos dos fármacos
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