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ABSTRACT: A previously healthy 2-year-old boy presented with a left sixth cranial nerve palsy. There was a family history of multiple sclerosis and optic neuritis. Neuroimaging showed multiple foci of T2/FLAIR hyperintense signal abnormality in both cerebral hemispheres and in the brainstem. The initial diagnosis was suspicious for demyelinating disease. However, there was no clinical improvement after a course of corticosteroids, and there was no change in his follow-up MRI. He later developed bilateral sixth nerve palsies, with esotropia addressed with bilateral medial rectus botulinum toxin injections. A brain biopsy was planned. However, his 3-month-old sister was separately admitted for fever and pancytopenia. She had markedly elevated ferritin, D-dimer, triglycerides, sIL-2R, CXCL9, and IL-18 and low fibrinogen. Her bone marrow biopsy showed hemophagocytosis. Genetic testing of both siblings revealed biallelic mutations in the PRF1 locus. The final diagnosis of familial hemophagocytic lymphohistiocytosis Type 2 was made. Both siblings underwent chemotherapy. The boy's sixth nerve palsies and MRI abnormalities resolved. Both siblings then went on to undergo bone marrow transplant.
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Doenças do Nervo Abducente , Esotropia , Linfo-Histiocitose Hemofagocítica , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Nervo Abducente , Doenças do Nervo Abducente/diagnóstico , Doenças do Nervo Abducente/etiologia , Doenças do Nervo Abducente/tratamento farmacológico , Medula Óssea , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológicoRESUMO
There are many obstacles to effective cancer chemotherapy, including drug penetration and accumulation in tumors and drug systemic toxicity. The penetration of therapies into tumors is limited by the dense tumor matrix and by compression of the tumor vasculature. We have developed spiropyran-based nanoparticles that shrink from 103 to 49 nm upon irradiation at 365 nm. That shrinkage enhanced tissue penetration and drug release. Irradiation of s.c. HT-1080 tumors in nude mice administered i.v. docetaxel-containing nanoparticles was more effective treatment than free docetaxel or encapsulated docetaxel without irradiation. Irradiation at the tumor site also resulted in less systemic toxicity than if the nanoparticles were irradiated before injection, presumably because of less systemically distributed free drug. The enhanced efficacy of nanoparticles in irradiated tumors may have been related to the observed enhanced tumor penetration by nanoparticles and decompression of tumor blood vessels, which may also increase nanoparticle delivery into tumors.
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Antineoplásicos/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/efeitos da radiação , Neoplasias/tratamento farmacológico , Raios Ultravioleta , Benzopiranos , Células HeLa , Humanos , Indóis , Nanopartículas/química , Nitrocompostos , Sais de Tetrazólio , Tiazóis , Fatores de TempoRESUMO
The acute respiratory distress syndrome (ARDS), a devastating lung disease that has no cure, is exacerbated by life-supportive mechanical ventilation that worsens lung edema and inflammation through the syndrome of ventilator-induced lung injury. Recently, the membrane ion channel transient receptor potential vanilloid 4 (TRPV4) on alveolar macrophages was shown to mediate murine lung vascular permeability induced by high-pressure mechanical ventilation. The objective of this study was to determine whether inhalation of nanoparticles (NPs) containing the TRPV4 inhibitor ruthenium red (RR) prevents ventilator-induced lung edema in mice. Poly-lactic-co-glycolic acid NPs containing RR were evaluated in vitro for their ability to block TRPV4-mediated calcium signaling in alveolar macrophages and capillary endothelial cells. Lungs from adult C57BL6 mice treated with nebulized NPs were then used in ex vivo ventilation perfusion experiments to assess the ability of the NPs to prevent high-pressure mechanical ventilation-induced lung edema. Poly-lactic-co-glycolic acid NPs (300 nm) released RR for 150 hours in vitro, and blocked TRPV4-mediated calcium signaling in cells up to 7 days after phagocytosis. Inhaled NPs deposited in alveoli of spontaneously breathing mice were rapidly phagocytosed by alveolar macrophages, and blocked increased vascular permeability from high-pressure mechanical ventilation for 72 hours in ex vivo ventilation perfusion experiments. These data offer proof of principle that inhalation of NPs containing a TRPV4 inhibitor prevents ventilator damage for several days, and imply that this novel drug delivery strategy could be used to target alveolar macrophages in patients at risk of ventilator-induced lung injury before initiating mechanical ventilation.
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Nanopartículas/administração & dosagem , Edema Pulmonar/prevenção & controle , Rutênio Vermelho/administração & dosagem , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controle , Administração por Inalação , Animais , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade/efeitos dos fármacos , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/metabolismo , Edema Pulmonar/metabolismo , Respiração/efeitos dos fármacos , Respiração Artificial/métodos , Canais de Cátion TRPV/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Ventiladores MecânicosRESUMO
We describe a new antifouling surface coating, based on aggregation of a short amphiphilic four-armed PEG-dopamine polymer into particles and on surface binding by catechol chemistry. An unbroken and smooth polymeric coating layer with an average thickness of approximately 4 µm was formed on top of titanium oxide surfaces by a single step reaction. Coatings conferred excellent resistance to protein adhesion. Cell attachment was completely prevented for at least eight weeks, although the membranes themselves did not appear to be intrinsically cytotoxic. When linear PEG or four-armed PEG of higher molecular weight were used, the resulting coatings were inferior in thickness and in preventing protein adhesion. This coating method has potential applicability for biomedical devices susceptible to fouling after implantation.
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Incrustação Biológica/prevenção & controle , Dopamina/química , Polietilenoglicóis/química , Animais , Catecóis/química , Bovinos , Sobrevivência Celular , Dopamina/síntese química , Fibroblastos/citologia , Camundongos , Estrutura Molecular , Peso Molecular , Células NIH 3T3 , Polietilenoglicóis/síntese química , Soroalbumina Bovina/química , Propriedades de Superfície , Titânio/químicaRESUMO
Lipid phase separation may be a mechanism by which lipids participate in sorting membrane proteins and facilitate membrane-mediated biochemical signaling in cells. To provide new tools for membrane lipid phase manipulation that avoid direct effects on protein activity and lipid composition, we studied phase separation in binary and ternary lipid mixtures under the influence of three nonlipid amphiphiles, vitamin E (VE), Triton-X (TX)-100, and benzyl alcohol (BA). Mechanisms of additive-induced phase separation were elucidated using coarse-grained molecular dynamics simulations of these additives in a liquid bilayer made from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dilinoleoyl-sn-glycero-3-phosphocholine [corrected]. From simulations, the additive's partitioning preference, changes in membrane thickness, and alterations in lipid order were quantified. Simulations showed that VE favored the DPPC phase but partitioned predominantly to the domain boundaries and lowered the tendency for domain formation, and therefore acted as a linactant. This simulated behavior was consistent with experimental observations in which VE promoted lipid mixing and dispersed domains in both gel/liquid and liquid-ordered/liquid-disordered systems. From simulation, BA partitioned predominantly to the DUPC phase, decreased lipid order there, and thinned the membrane. These actions explain why, experimentally, BA promoted phase separation in both binary and ternary lipid mixtures. In contrast, TX, a popular detergent used to isolate raft membranes in cells, exhibited equal preference for both phases, as demonstrated by simulations, but nonetheless, was a strong domain promoter in all lipid mixtures. Further analysis showed that TX increased membrane thickness of the DPPC phase to a greater extent than the DUPC phase and thus increased hydrophobic mismatch, which may explain experimental observation of phase separation in the presence of TX. In summary, these nonlipid amphiphiles provide new tools to tune domain formation in model vesicle systems and could provide the means to form or disperse membrane lipid domains in cells, in addition to the well-known methods involving cholesterol enrichment and sequestration.
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Membrana Celular/química , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , 1,2-Dipalmitoilfosfatidilcolina/química , Álcool Benzílico/química , Colesterol/química , Géis , Bicamadas Lipídicas/química , Conformação Molecular , Octoxinol/química , Fosfatidilcolinas/química , Lipossomas Unilamelares/química , alfa-Tocoferol/químicaRESUMO
PURPOSE: We present a case of successful surgical management of an infant with X-linked retinoschisis with a giant retinal tear and retinal detachment of the right eye. OBSERVATIONS: A 10-month-old male presented with retinoschisis of both eyes and a retinal detachment of the right eye. The patient underwent two-stage pars plana vitrectomy utilizing perfluoro-N-octane to stabilize the detached retina and facilitate posterior hyaloid separation. Retained perfluoro-N-octane tamponade was later exchanged with silicone oil. The retina remained attached at last follow up. CONCLUSIONS AND IMPORTANCE: Retinal detachment repair in infants presents unique challenges. This is a safe and effective strategy for complex retinal detachment repair in the infant population.
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PURPOSE: To assess the effect of dry eye disease (DED) in graft donors on dendritic cell (DC) maturation, host T-cell sensitization, and corneal allograft rejection. METHODS: Corneas of control (healthy donor) and DED mice (C57BL/6) were transplanted onto fully allogeneic naive BALB/c recipients (n = 10 mice/group). Long-term allograft survival was evaluated for 8 weeks. Corneas and draining lymph nodes (dLNs) were harvested at posttransplantation day 14 (n = 5 mice/group). The frequencies of MHCII CD11c DCs in the donor corneas and host dLNs and the frequencies of interferon (IFN)-γ and IL-17 CD4 T cells and Foxp3 expression by Tregs in host dLNs were investigated using flow cytometry. The enzyme-linked immunospot assay was used to assess host T-cell allosensitization through direct and indirect pathways (n = 3/group). RESULTS: Recipients of DED donor corneas showed significantly reduced graft survival (10%) compared with control mice (50% survival, P = 0.022), and had significantly increased frequencies of mature DCs in the grafted cornea (DED donor 44.0% ± 0.36% vs. healthy donor 35.4 ± 0.5%; P < 0.0001) and host dLNs (DED donor 25.1% ± 0.66% vs. healthy donor 13.7% ± 1.6%; P = 0.005). Frequencies of IFN-γ and IL-17 T cells were increased in the dLNs of recipients of DED corneas, whereas the expression (mean fluorescence intensity) of Foxp3 in Tregs was decreased significantly in these mice (DED donor 6004 ± 193 vs. healthy donor 6806 ± 81; P = 0.0002). Enzyme-linked immunospot analysis showed that the direct pathway of allosensitization was significantly amplified in recipients of grafts with DED (P = 0.0146). CONCLUSIONS: Our results indicate that DED in the donor is a significant risk factor for subsequent corneal allograft rejection.
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Córnea , Transplante de Córnea , Síndromes do Olho Seco/complicações , Rejeição de Enxerto/etiologia , Doadores de Tecidos , Animais , Células Dendríticas/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Sobrevivência de Enxerto/fisiologia , Interferon gama/metabolismo , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microscopia Confocal , Linfócitos T/imunologia , Transplantados , Transplante Heterotópico , Transplante HomólogoRESUMO
PURPOSE: We report a case of ophthalmomyiasis interna successfully removed in toto with pars plana vitrectomy. OBSERVATIONS: An 84-year-old woman with recent close contact with lambs presented with a new floater. Examination revealed subretinal tracks pathognomonic for ophthalmomyiasis and a larva suspended in the vitreous. The larva was successfully removed in toto with pars plana vitrectomy by aspiration through the vitreous cutter. CONCLUSIONS AND IMPORTANCE: Aspiration with pars plana vitrectomy can be considered a primary therapeutic modality for botfly larvae suspended in the vitreous. In our case, in toto removal of the larvae reduced the risk of inflammatory reaction.
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PURPOSE: To delineate and compare the kinetics of corneal angiogenesis after high-risk (HR) versus low-risk (LR) corneal transplantation. METHODS: In mice, intrastromal sutures were placed in the recipient graft bed 2 weeks before allogeneic transplantation to induce angiogenesis and amplify the risk of graft rejection. Control (LR) graft recipients did not undergo suture placement, and thus the host bed remained avascular at the time of transplantation. Graft hemangiogenesis and opacity scores were evaluated for 8 weeks by slit-lamp biomicroscopy. Immunohistochemistry was used to measure CD31 (blood vessels) and LYVE-1 (lymphatic vessels) cells. RESULTS: Biphasic kinetics were observed for hemangiogenesis in both HR and LR transplant recipients using clinical and immunohistochemical assessments. The biphasic kinetics were composed of a rise-fall (phase 1) followed by a second rise (phase 2) in the degree of vessels. Compared with LR recipients, HR recipients showed higher hemangiogenesis (whole cornea and graft) throughout 8 weeks. Analyzing grafts revealed sustained presence of lymphatic vessels in HR recipients; however, lymphatic neovessels regressed in LR recipients 2 weeks posttransplantation. In contrast to HR host beds, the LR host bed microenvironment cannot sustain the growth of lymphatic neovessels in allografts, whereas it can sustain continued hemangiogenesis. CONCLUSIONS: The sustained presence of lymphatic vessels in HR host beds can facilitate host immunity against allografts and is likely associated with ongoing higher risk of rejection of these grafts in the long term, suggesting that therapeutic interventions targeting inflammation and lymphatic vessels need to be sustained long term in the HR corneal transplant setting.
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Córnea/irrigação sanguínea , Neovascularização da Córnea/metabolismo , Transplante de Córnea , Rejeição de Enxerto/metabolismo , Linfangiogênese , Vasos Linfáticos/metabolismo , Animais , Biomarcadores/metabolismo , Vasos Sanguíneos/metabolismo , Neovascularização da Córnea/patologia , Modelos Animais de Doenças , Técnica Indireta de Fluorescência para Anticorpo , Glicoproteínas/metabolismo , Rejeição de Enxerto/patologia , Vasos Linfáticos/patologia , Masculino , Proteínas de Membrana Transportadoras , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Transplante HomólogoRESUMO
RATIONALE: We report a case of paraproteinemic keratopathy associated with monoclonal gammopathy of undetermined significance, treated with keratoprosthesis as a primary penetrating procedure. Histopathological findings and a world literature review are presented. PATIENT CONCERNS: A 74 year old female recently diagnosed with monoclonal gammopathy undetermined significance presented with progressive blurry vision bilaterally. DIAGNOSES: Examination revealed corneal opacities consistent with paraproteinemic keratopathy. INTERVENTIONS: Corneal transplantation with the Boston Type I keratoprosthesis was performed on the right and, a year later, on the left. OUTCOMES: Visual outcomes were good. Histopathological staining of host corneal buttons were consistent with monoclonality, and electron microscopy revealed fibrillar extracellular aggregates within intervening normal stroma. LESSONS: Corneal deposits may be the only manifestation of monoclonal gammopathy of undetermined significance in patients who are otherwise systemically asymptomatic. Ophthalmologists who encounter corneal opacities may order the appropriate diagnostic studies to determine the presence of occult systemic disease. Risk of graft failure after penetrating keratoplasty from recurring opacities is high, so keratoprosthesis as a primary penetrating procedure may afford superior long-term outcomes. Host corneal buttons retrieved from penetrating keratoplasty or corneal biopsy may be sent for histopathological examination to confirm the diagnosis.
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Doenças da Córnea/etiologia , Opacidade da Córnea/etiologia , Gamopatia Monoclonal de Significância Indeterminada/complicações , Paraproteinemias/complicações , Idoso , Doenças da Córnea/cirurgia , Opacidade da Córnea/cirurgia , Transplante de Córnea , Feminino , Humanos , Transtornos da Visão/etiologiaRESUMO
Many bio-adhesive materials adhere weakly to tissue due to their high water content and weak structural integrity. Others provide desirable adhesive strength but suffer from rigid structure and lack of elasticity after administration. We have developed two water-free, liquid four-armed PEG pre-polymers modified with NHS or with NH2 end groups which upon mixing changed from liquids to an elastic solid. The sealant and adhesive properties increased with the amount of the %v/v PEG4-NHS pre-polymer, and achieved adhesive properties comparable to those of cyanoacrylate glues. All mixtures showed minimal cytotoxicity in vitro. Mixtures of 90%v/v PEG4-NHS were retained in the subcutaneous space in vivo for up to 14days with minimal inflammation. This material's combination of desirable mechanical properties and biocompatibility has potential in numerous biomedical applications. STATEMENT OF SIGNIFICANCE: Many bio-adhesive materials adhere weakly to tissue (e.g. hydrogels) due to their high water content and weak structural integrity. Others provide desirable mechanical properties but suffer from poor biocompatibility (e.g. cyanoacrylates). This study proposes a new concept for the formation of super strong and tunable tissue glues. Our bio-materials' enhanced performance is the product of new neat (without water or other solvents) liquid polymers that solidify after administration while allowing interactions with the tissue. Moreover, the elastic modulus of these materials could easily be tuned without compromising biocompatibility. This system could be an attractive alternative to sutures and staples since it can be applied more quickly, causes less pain and may require less equipment while maintaining the desired adhesion strength.
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Adesivos/química , Adesivos Teciduais/química , Adesivos/toxicidade , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Fenômenos Biomecânicos , Elasticidade , Técnicas In Vitro , Masculino , Teste de Materiais , Camundongos , Células NIH 3T3 , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Reologia , Suínos , Resistência à Tração , Adesivos Teciduais/toxicidadeAssuntos
Tronco Encefálico/diagnóstico por imagem , Seio Cavernoso/anormalidades , Movimentos Oculares/fisiologia , Transtornos da Motilidade Ocular/etiologia , Seio Cavernoso/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/fisiopatologia , Adulto JovemRESUMO
PURPOSE: We tested the feasibility of using titanium to enhance adhesion of the Boston Keratoprosthesis (B-KPro), ultimately to decrease the risk of implant-associated complications. METHODS: Cylindrical rods were made of poly(methyl methacrylate) (PMMA), PMMA coated with titanium dioxide (TiO2) over a layer of polydopamine (PMMATiO2), smooth (Ti) and sandblasted (TiSB) titanium, and titanium treated with oxygen plasma (Tiox and TiSBox). Topography and surface chemistry were analyzed by scanning electron microscopy (SEM), atomic force microscopy (AFM), and X-ray photoelectron spectroscopy (XPS). Adhesion force between rods and porcine corneas was measured ex vivo. Titanium sleeves, smooth and sandblasted, were inserted around the stem of the B-KPro and implanted in rabbits. Tissue adhesion to the stem was assessed and compared to an unmodified B-Kpro after 1 month. RESULTS: X-ray photoelectron spectroscopy demonstrated successful deposition of TiO2 on polydopamine-coated PMMA. Oxygen plasma treatment did not change the XPS spectra of titanium rods (Ti and TiSB), although it increased their hydrophilicity. The materials did not show cell toxicity. After 14 days of incubation, PMMATiO2, smooth titanium treated with oxygen plasma (Tiox), and sandblasted titanium rods (TiSB, TiSBox) showed significantly higher adhesion forces than PMMA ex vivo. In vivo, the use of a TiSB sleeve around the stem of the B-KPro induced a significant increase in tissue adhesion compared to a Ti sleeve or bare PMMA. CONCLUSIONS: Sandblasted titanium sleeves greatly enhanced adherence of the B-KPro to the rabbit cornea. This approach may improve adhesion with the donor cornea in humans as well. TRANSLATIONAL RELEVANCE: This approach may improve adhesion with donor corneas in humans.
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A photoactive electrospun material producing reactive oxygen species (ROS) upon light irradiation is reported. The phototoxicity of the generated ROS is spatially restricted to the fiber-tissue interface by conjugation of the photosensitizer to a macromolecule. Photo-triggered ROS is produced on demand and repeatedly. It induces death of mammalian cells growing on the material surface with high spatial resolution.
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Morte Celular/efeitos dos fármacos , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodos , Animais , Linhagem Celular , Camundongos , Células NIH 3T3 , Processos Fotoquímicos , Poliésteres/farmacologia , Polilisina/farmacologia , Espectrometria de FluorescênciaRESUMO
Clinical translation of sustained release formulations for local anesthetics has been limited by adverse tissue reaction. Exparel™ (DepoFoam bupivacaine) is a new liposomal local anesthetic formulation whose biocompatibility near nerve tissue is not well characterized. Exparel™ injection caused sciatic nerve blockade in rats lasting 240 min compared to 120 min for 0.5% (w/v) bupivacaine HCl and 210 min for 1.31% (w/v) bupivacaine HCl (same bupivacaine content as Exparel™). On histologic sections four days after injection, median inflammation scores in the Exparel™ group (2.5 of 4) were slightly higher than in groups treated with bupivacaine solutions (score 2). Myotoxicity scores in the Exparel™ group (2.5 of 6) were similar to in the 0.5% (w/v) bupivacaine HCl group (3), but significantly less than in the 1.31% (w/v) bupivacaine HCl group (5). After two weeks, inflammation from Exparel™ (score 2 of 6) was greater than from 0.5% (w/v) bupivacaine HCl (1) and similar to that from 1.31% (w/v) bupivacaine HCl (1). Myotoxicity in all three groups was not statistically significantly different. No neurotoxicity was detected in any group. Tissue reaction to Exparel™ was similar to that of 0.5% (w/v) bupivacaine HCl. Surveillance for local tissue injury will be important during future clinical evaluation.
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Anestésicos Locais/administração & dosagem , Bupivacaína/administração & dosagem , Lipossomos/química , Nervo Isquiático/efeitos dos fármacos , Animais , Injeções , Masculino , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/ultraestruturaRESUMO
PURPOSE: Ocular local anesthetics currently used in routine clinical practice for corneal anesthesia are short acting and their ability to delay corneal healing makes them unsuitable for long-term use. In this study, we examined the effect of the site 1 sodium channel blocker tetrodotoxin (TTX) on the duration of corneal anesthesia, applied with either proparacaine (PPC) or the chemical permeation enhancer octyl-trimethyl ammonium bromide (OTAB). The effect of test solutions on corneal healing was also studied. METHODS: Solutions of TTX, PPC, and OTAB, singly or in combination, were applied topically to the rat cornea. The blink response, an indirect measure of corneal sensitivity, was recorded using a Cochet-Bonnet esthesiometer, and the duration of corneal anesthesia was calculated. The effect of test compounds on the rate of corneal epithelialization was studied in vivo after corneal debridement. RESULTS: Combination of TTX and PPC resulted in corneal anesthesia that was 8 to 10 times longer in duration than that from either drug administered alone, whereas OTAB did not prolong anesthesia. The rate of corneal healing was moderately delayed after coadministration of TTX and PPC. CONCLUSIONS: Coadministration of TTX and PPC significantly prolonged corneal anesthesia, but in view of delayed corneal reepithelialization, caution is suggested in the use of the drug combination.
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Anestesia Local/métodos , Anestésicos Locais/farmacologia , Córnea/efeitos dos fármacos , Propoxicaína/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia , Anestésicos Combinados , Animais , Linhagem Celular , Química Farmacêutica , Córnea/fisiologia , Ceratócitos da Córnea/efeitos dos fármacos , Epitélio Corneano/efeitos dos fármacos , Humanos , Masculino , Compostos de Amônio Quaternário/farmacologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Cicatrização/efeitos dos fármacosRESUMO
We have developed a drug delivery system for prolonged trans-tympanic antibiotic delivery from a single dose administration. Increased permeability to ciprofloxacin of the intact tympanic membrane (TM) was achieved by chemical permeation enhancers (CPEs--bupivacaine, limonene, sodium dodecyl sulfate); this was also seen by CPEs contained within a hydrogel (poloxamer 407) to maintain the formulation at the TM. The CPE-hydrogel formulation had minimal effects on auditory thresholds and tissue response in vivo. CPE-hydrogel formulations have potential for ototopical delivery of ciprofloxacin for the treatment of acute otitis media (AOM) and other middle ear diseases.
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Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Ciprofloxacina/administração & dosagem , Ciprofloxacina/farmacocinética , Nanocápsulas/administração & dosagem , Otite Média/tratamento farmacológico , Membrana Timpânica/metabolismo , Animais , Chinchila , Ciprofloxacina/química , Composição de Medicamentos/métodos , Masculino , Nanocápsulas/químicaRESUMO
AIMS: To evaluate the clinical outcomes following Moscow Eye Microsurgery Complex in Russia keratoprosthesis (MICOF KPro) implantation in end-stage autoimmune dry eyes. METHODS: A retrospective observational case series. Fourteen patients with end-stage autoimmune dry eyes underwent MICOF KPro surgery by one surgeon (YH) in the Chinese PLA General Hospital between 2000 and 2009. Retention of the prosthesis and vision were recorded and postoperative complications were analysed. RESULTS: Preoperative diagnosis included Stevens-Johnson syndrome (n=7), ocular cicatricial pemphigoid (n=4) and Sjogren's syndrome (n=3). The mean follow-up period was 3.9 years (range 10 months-7.8 years). After surgery, 13 eyes (93%) showed a visual acuity of 20/200 or better and 6 eyes (43%) achieved excellent vision of 20/40 or better. At last visit, 69% of the eyes (9/13) maintained a visual acuity of at least 20/200. The first case retained a visual acuity of 20/80 7.8 years after the operation. The most common complication was stromal melting that threatened anatomical success. Seven of the first eight patients showed tissue melting, and four of them had leakage. All of these were repaired successfully. The latter six cases received prophylactic autologous auricular cartilage implantation to reinforce the anterior surface of recipient's cornea at either stage 1 or 2. Other causes of vision loss included pre-existing glaucoma (n=6), sterile vitritis (n=5), cylinder loosening (n=1) and retroprosthetic membrane (n=4). CONCLUSION: MICOF KPro provided useful vision for the end stage of autoimmune dry eyes in our study. Anatomical stability of KPro was achieved in all cases using repair and reinforcing surgery.
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Doenças Autoimunes/patologia , Doenças Autoimunes/cirurgia , Síndromes do Olho Seco/patologia , Síndromes do Olho Seco/cirurgia , Cartilagem da Orelha/transplante , Próteses e Implantes , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Substância Própria/patologia , Substância Própria/cirurgia , Seguimentos , Glaucoma/patologia , Humanos , Pessoa de Meia-Idade , Penfigoide Mucomembranoso Benigno/patologia , Penfigoide Mucomembranoso Benigno/cirurgia , Próteses e Implantes/efeitos adversos , Falha de Prótese , Reoperação , Estudos Retrospectivos , Síndrome de Sjogren/patologia , Síndrome de Sjogren/cirurgia , Síndrome de Stevens-Johnson/patologia , Síndrome de Stevens-Johnson/cirurgia , Infecção da Ferida Cirúrgica/patologia , Tempo , Acuidade VisualRESUMO
BACKGROUND AND OBJECTIVES: Quaternary lidocaine derivatives (QLDs) have recently received much attention because of their potential application in prolonged or sensory-selective local anesthesia. However, associated tissue toxicity is an impeding factor that makes QLDs unfavorable for clinical use. Based on the proposed intracellular site of action, we hypothesized that nerve blocks obtained from lower concentrations of QLDs would be enhanced by the coapplication of extracellularly acting site 1 sodium-channel blocker, resulting in prolonged block duration but with minimal tissue toxicity. METHODS: Quaternary lidocaine derivatives (QX-314 or QX-222), site 1 sodium-channel blockers (tetrodotoxin [30 µM] or saxitoxin [12.5 µM]), or both were injected in the vicinity of the sciatic nerve. Thermal nociceptive block was assessed using a modified hot plate test; motor block by a weight-bearing test. Tissue from the site of injection was harvested for histological assessment. RESULTS: Coapplication of 25 mM QX-314 or 100 mM QX-222 with site 1 sodium-channel blockers produced an 8- to 10- fold increase in the duration of nerve blocks (P < 0.05), compared with QLDs or site 1 blockers alone. Quaternary lidocaine derivatives elicited severe myotoxicity; this was not exacerbated by coinjection of the site 1 sodium-channel blockers. CONCLUSIONS: Coadministration of site 1 sodium-channel blockers and QLDs greatly prolongs the duration of peripheral nerve block without enhancing local tissue injury, but minimal myotoxicity still persists. It is not clear that the risks of QLDs are outweighed by the benefits in providing prolonged nerve blockade.