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Diabetes is a worldwide prevalent disease and diabetic retinopathy (DR) is one of the common complications, which is vision threatening and even leading to blindness.The current management of DR includes laser retina photocoagulation, vitrectomy, and frequent intravitreal anti-vascular endothelial growth factor (VEGF) agents.However, these measures do not target the root cause and their efficacy is limited.Fenofibrate is a blood lipid lowering therapeutics and its metabolite, fenofibric acid, is responsible for the pharmacology effect.Two large clinical trials (FIELD and ACCORD-Eye) have demonstrated oral fenofibrate retarded progression of DR and the needs for laser retinopexy.The animal and cell researches have revealed that fenofibric acid attenuated overexpression of basement membrane and VEGF, protected the tight junctions of endothelial cells and vascular permeability, as well as inhibited cells migration and neovascularization via suppression of inflammatory cytokines.These pharmacological effects might be materialized through several pathways, such as PPAR-α, MAPK and nuclear factor-κB (NF-кB). Blood-ocular barrier is a significant limiting factor for therapeutics reaching retina after systemic administration.Local ocular application of fenofibric acid may achieve better efficacy through improving therapeutic concentration in the eye.This drug may be delivered either by eye drop formulation or a sustained delivery device under conjunctiva or sub-Tenon.
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A 22-year-old male patient visited the Department of Dermatology of the First Affiliated I Iospital of Zbengzhou University on October 31,2016 due to dark red papules,nodules,pustules and cysts on the face,neck,back and in the axillary and inguinal regions for 6 years,and multiple dark purple plaques and ulcers on bilateral lower limbs for 1 year.Six years ago,the patient was diagnosed with acne in other hospital,and no treatment was given.One year ago,multiple purple plaques occurred on the bilateral lower limbs,which then ruptured and progressed into ulcers with diameters of 1-12 cm.On May 9,2002,the patient visited the Department of Pediatric Medicine of the First Affiliated Hospital of Zhengzhou University due to the left knee joint swelling and pain for half a year.Laboratory examination showed negative rheumatoid factor,and smear examination of the left knee joint effusions revealed that there were neutrophils and a small amount of lymphocytes and monocytes in the joint effusions,and no abnormal cells were observed.Then,the patient was diagnosed with pyogenic arthritis of the left knee.Physical examination at admission showed poor general condition,walking difficulty,slightly increased blood pressure of 142/92 mmHg (1 mmHg =0.133 kPa),multiple purple plaques on the bilateral lower limbs with central ulcer formation.Histopathological examination of ulcer margin on the lower limbs showed ulceration,intercellular edema and infiltrating neutrophils in the epidermis,and edema,focal erythrocyte extravasation,diffuse infiltration of neutrophils,lymphocytes and histiocytes in the superficial and middle dermis.Clinical manifestations and pathological features confirmed a diagnosis of pyoderma gangrenosum.There were extensive inflammatory papules,pustules,abscesses and cysts on the face,neck,waist and back,and a small amount of dark red nodules on the axillary and inguinal regions,which were consistent with cystic acne and hidradenitis suppurativa.As PSTPIP1 gene sequencing showed,no mutations were found in exon fragments,while compound heterozygous mutations c.36 + 68 G ＞ A,c.137 + 47 G ＞ C and c.562 + 114 C ＞ G her were found in intron fragments.Among 100 healthy controls,45 carried the same mutations.So,these mutation sites were considered to be polymorphic sites,and the pathogenicity of these mutations was still unclear.Finally,the patient was diagnosed with PAPASH syndrome.The patient was treated with methylprednisolone,cefminox,isotretinoin and thalidomide,and the lesions were markedly improved after 2 weeks.Now the patient was still followed up.
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The human sclera accounts for 95％ of the surface of the eyeball,providing ample contact area which is suitable for targeted trans-scleral ocular drug delivery.Currently there are several tans-scleral sustained-release strategies,including intra-scleral delivery,episcleral delivery,as well as tans-scleral iontophoresis.Different devices and methods have their own advantages and disadvantages,for example,intrascleral delivery is somehow invasive,and episcleral delivery device needs to be made thin to prevent erosion of conjunctiva,iontophoresis needs to be frequently repeated as of its short-term effect.With the development of bio-material engineering technology,episcleral microfilm could become an ideal drug delivery route for posterior segment ocular diseases.
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The suprachoroidal space (SCS) is the potential space between the sclera and choroid.Drugs delivered through SCS can bypass the sclera,avoiding clearance by conjunctival and scleral blood vessels and lymphatic circulation,so that more drugs can reach the disease tissues such as choroid and retina.SCS drug delivery does not disrupt the ocular integrity,is safer than the intravitreal drug injection and more effective than trans-scleral drug delivery.In addition,SCS delivery only needs a very small volume of drug,which makes it possible to be carried out in multiple parts of the sclera,and the specific disease area can be more precisely targeted.SCS drug delivery is suitable for the treatment of choroidal and retinal diseases.However,currently SCS drug delivery is still a novel field and many aspects need to be more in-depth studied,including its safety,delivery methods,drug formulation and effectiveness.
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Background Dimethyl sulfoxide(DMSO) is a commonly used adjuvant to promote testing drug solubility to prepare multi-levels testing drug concentrations.DMSO is cell type-dependent cytotoxic and its toxicity can interfere the testing drug evaluation.Determining its safe concentration on commonly used cell types is important for ocular drug development.Objective This study was to determine the minimal toxic concentration of DMSO for in vitro ocular cell lines in a simulated drug screening setting.Methods Retinal pigment epithelial (RPE) cells were isolated from one pigmented rabbit and primarily cultured.Human RPE cell strain (ARPE19),scleral fibroblasts line (S75-Fron),human Müller cell line (MIO-M1),human lens epithelial cell line (HLEC),human choroidal melanoma cell line (OCM-1),human umbilical endothelial cell (HUVEC) and human HeLa cell line (HELA) were cultured.Different concentrations of DMSO (1.6％,1.0％,0.8％,0.4％,0.2％ and 0.1％) were prepared with 160 μl DMSO solution and 9.84 ml RPMI1640 (or DMEM/F12 or DMEM) containing 2％ fetal bovine serum.Different concentrations of DMSO were added in medium for 96 hours,and the and viability (absorbance) of the cells was detected using MTS to evaluate the cytotoxicity of DMSO.Results Rabbit primary RPE cells showed the yellow-green fluorescence for cytokeratin(CK) and HMB45 red fluorescence for S100.The viability of the cells was gradually declined as the increase of DMSO dose,showing significant differences in ARPE19,S75-Fron,HLEC,OCM-1,HUVEC and primary RPE cells (all at P＜0.05),and when DMSO concentrations were ≥ 0.8％,the cell viabilities were significantly lower.But no significant difference was found in MIO-M1 cells among different doses of DMSO (F=0.830,P=0.547).The minimal toxic concentration of DMSO for ARPE19,HUVEC,HELA,HLEC,MIO-M1,OCM-1,primary RPE cells and S75-Fron was 0.8％,0.1％,0.8％,＞1.6％,＞1.6％,0.2％,0.2％,0.2％,respectively,and HUVEC was more sensitive to the cytotoxicity of DMSO (P=0.02),and MIO-M1 was the least sensitive to DMSO (P =0.39).The viability of HUVEC and primary RPE cells went down with the increase of DMSO dose,and S75-Fron viability started to decline in 0.1％ DMSO and then stabilize with the higher concentrations until 1.6％ DMSO at which the viability showed further decline.Conclusions The tolerability of ocular cells in vitro to DMSO varies depending on the cell types.The minimal toxic concentration ranged from 0.1％ to 1.6％.The result suggests that a concurrent DMSO control should be set up along with the testing compound.
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· Heterochromia was observed in a six-month-old Dutch pigmented rabbit and the rabbit was examined for general and eye anomalies. The rabbit showed a blue eye with fundus hypochromia on the right and a brown eye with partial fundus hypochromia on the left. White fur (white forelock) was present, but deafness was not apparent although no objective audiologic examination was performed. Histology studies of both eyes revealed that significantly fewer pigment cells in iris stroma and less pigmentation in retinal pigment epithelium and choroid in the right eye than in the left eye.