Leonardo Tannus Malki

Dry Eye Disease Treatment: A Systematic Review of Published Trials and a Critical Appraisal of Therapeutic Strategies

Dry eye disease (DED) treatment is an area of increasing complexity, with the emergence of several new treatment agents in recent years. Evaluation of the efficacy of these agents is limited by heterogeneity in outcomes definition and the small number of comparative studies. We provide a systematic review of clinical trials (CTs) related to DED treatment and a critical appraisal of CT public databases. CT reports obtained from eight databases were reviewed, as well as public free-access electronic databases for CT registration. Data evaluation was based on endpoints such as symptoms, Schirmer test, ocular surface staining scores, recruitment of patients, type and efficacy of the drug, and the design and site of performance of the study. Forty-nine CTs were evaluated involving 5,189 patients receiving DED treatment. Heterogeneity in study design prevented meta-analysis from yielding meaningful results, and a descriptive analysis of these studies was conducted. The most frequent categories of drugs for DED in these studies were artificial tears, followed by anti-inflammatory drugs and secretagogues. Although 116 studies have been completed, according to the registration database for clinical trials, only 17 of them (15.5%) were published. Out of 185 registered CTs related to DED, 72% were performed in the USA. The pharmaceutical industry sponsored 78% of them. The identification of effective DED treatment strategies is hindered by the lack of an accepted set of definitive criteria for evaluating disease severity.

A New Method to Predict the Epidemiology of Fungal Keratitis by Monitoring the Sales Distribution of Antifungal Eye Drops in Brazil

Purpose Fungi are a major cause of keratitis, although few medications are licensed for their treatment. The aim of this study is to observe the variation in commercialisation of antifungal eye drops, and to predict the seasonal distribution of fungal keratitis in Brazil. Methods Data from a retrospective study of antifungal eye drops sales from the only pharmaceutical ophthalmologic laboratory, authorized to dispense them in Brazil (Opthalmos) were gathered. These data were correlated with geographic and seasonal distribution of fungal keratitis in Brazil between July 2002 and June 2008. Results A total of 26,087 antifungal eye drop units were sold, with a mean of 2.3 per patient. There was significant variation in antifungal sales during the year (p<0.01). A linear regression model displayed a significant association between reduced relative humidity and antifungal drug sales (R2 = 0.17,p<0.01). Conclusions Antifungal eye drops sales suggest that there is a seasonal distribution of fungal keratitis. A possible interpretation is that the third quarter of the year (a period when the climate is drier), when agricultural activity is more intense in Brazil, suggests a correlation with a higher incidence of fungal keratitis. A similar model could be applied to other diseases, that are managed with unique, or few, and monitorable medications to predict epidemiological aspects.

The Role of Dyslipidemia on Ocular Surface, Lacrimal and Meibomian Gland Structure and Function

Purpose: Dyslipidemia is characterized by high lipid blood levels that are risk factors for cardiovascular diseases, which are leading causes of death. However, it is unclear whether dyslipidemia is a cause of the dry eye syndrome (DES). Therefore we determined in transgenic mice models of dyslipidemia, whether there is an association with DES development. Methods: Dyslipidemic models included male and female adult mice overexpressing apolipoprotein CIII (Apo CIII), LDL receptor knockout (LDLR-KO) and ApoE knockout (ApoE-KO). They were compared with age- and gender-matched C57BL/6 mice. Ocular health was evaluated based on corneal slit lamp assessment, phenol red thread test (PRT) and impression cytology. Blood lipid profiles and histology of meibomian and lacrimal glands were also evaluated. Effects of high-fat diet and aging were observed in LDLR-KO and ApoCIII strains, respectively. Results: Body weight and lacrimal gland weight were significantly higher in male mice compared to females of the same strain (P < 0.05). Body weight was significantly lower in LDLRKO mice receiving high lipid diet compared to their controls (P = 0.0043). ApoE-KO were hypercholesterolemic and ApoCIII hypertriglyceridemic while LDLR-KO showed increases in both parameters. The PRT test was lower in male LDLR-KO mice with high-fat diet than control mice with standard diet (P = 0.0273). Aging did not affect lacrimal structural or functional parameters of ApoCIII strain. Conclusions: DES development is not solely dependent on dyslipidemia in relevant mice models promoting this condition. On the other hand, lacrimal gland structure and function are differentially impacted by lipid profile changes in male and female mice. This dissociation suggests that other factors beside dyslipidemia impact on tear film dysfunction and DES development.

Insulin replacement restores the vesicular secretory apparatus in the diabetic rat lacrimal gland

PURPOSE In the lacrimal gland (LG) acinar cells, signaling regulates the release of secretory vesicles through specific Rab and SNARE exocytotic proteins. In diabetes mellitus (DM), the LGs are dysfunctional. The aim of this work was to determine if secretory apparatus changes were associated with any effects on the secretory vesicles (SV) in diabetic rats as well as the expression levels of constituent Rab and members of the SNARE family, and if insulin supplementation reversed those changes. METHODS DM was induced in male Wistar rats with an intravenous dose of streptozotocin (60 mg/kg). One of the two diabetic groups was then treated every other day with insulin (1 IU). A third control group was injected with vehicle. After 10 weeks, Western blotting and RT-PCR were used to compared the Rab and SNARE secretory factor levels in the LGs. Transmission electron microscopy evaluated acinar cell SV density and integrity. RESULTS In the diabetes mellitus group, there were fewer and enlarged SV. The Rab 27b, Rab 3d, and syntaxin-1 protein expression declined in the rats with diabetes mellitus. Insulin treatment restored the SV density and the Rab 27b and syntaxin expression to their control protein levels, whereas the Vamp 2 mRNA expression increased above the control levels. CONCLUSIONS Diabetes mellitus LG changes were associated with the declines in protein expression levels that were involved in supporting exocytosis and vesicular formation. They were partially reversed by insulin replacement therapy. These findings may help to improve therapeutic management of dry eye in diabetes mellitus.

Buphthalmos development in adult: case report

To report a case of extensive globe enlargement due to secondary glaucoma in a young adult suffering from ocular surface disorders related to hypohidrotic ectodermal dysplasia. To the best of our knowledge, this is the first report of buphthalmos in the adulthood.

Lacrimal gland primary acinar cell culture: the role of insulin.

PURPOSE The goal of the present study was to establish a protocol for primary culture of lacrimal gland acinar cells (LGACs) and to assess the effect of adding insulin to the culture media. METHODS LGACs were isolated and cultured from lacrimal glands of Wistar male rats. The study outcomes included cell number, viability, and peroxidase release over time and in response to three concentrations of insulin (0.5, 5.0, and 50.0 μg/mL). RESULTS In LGAC primary culture, cells started to form clusters by day 3. There was a time-response pattern of peroxidase release, which rose by day 6, in response to carbachol. Culture viability lasted for 12 days. An insulin concentration of 5.0 μg/mL in the culture medium resulted in higher viability and secretory capacity. CONCLUSIONS The present method simplifies the isolation and culture of LGACs. The data confirmed the relevance of adding insulin to maintain LGACs in culture.