RESUMO
The emergence of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) in China, reported to the World Health Organization on December 31, 2019, has led to a large global pandemic and is a major public health issue. As a result, there are more than 200 clinical trials of COVID-19 treatments or vaccines that are either ongoing or recruiting patients. One potential therapy that has garnered international attention is hydroxychloroquine; a potent immunomodulatory agent FDA-approved for the treatment of numerous inflammatory and autoimmune conditions, including malaria, lupus, and rheumatoid arthritis. Hydroxychloroquine has demonstrated promise in vitro and is currently under investigation in clinical trials for the treatment of COVID-19. Despite an abundance of empirical data, the mechanism(s) involved in the immunomodulatory activity of hydroxychloroquine have not been characterized. Using the unbiased chemical similarity ensemble approach (SEA), we identified C-C chemokine receptor type 4 (CCR4) as an immunomodulatory target of hydroxychloroquine. The crystal structure of CCR4 was selected for molecular docking studies using the SwissDock modeling software. In silico, hydroxychloroquine interacts with Thr-189 within the CCR4 active site, presumably blocking endogenous ligand binding. However, the CCR4 antagonists compound 18a and K777 outperformed hydroxychloroquine in silico, demonstrating energetically favorable binding characteristics. Hydroxychloroquine may subject COVID-19 patients to QT-prolongation, increasing the risk of sudden cardiac death. The FDA-approved CCR4 antagonist mogalizumab is not known to increase the risk of QT prolongation and may serve as a viable alternative to hydroxychloroquine. Results from this report introduce additional FDA-approved drugs that warrant investigation for therapeutic use in the treatment of COVID-19.
RESUMO
PURPOSE: To evaluate and compare biomechanical properties in normal and keratoconic eyes using a dynamic ultra-high-speed Scheimpflug camera equipped with a non-contact tonometer (Corvis ST; Oculus Optikgeräte GmbH, Wetzlar, Germany). METHODS: This retrospective study evaluated 89 eyes (47 normal, 42 keratoconic) and a validation arm of 72 eyes (33 normal, 39 keratoconic) using the Corvis ST. A diagnosis of keratoconus was established by clinical findings confirmed by topography and tomography. Dynamic corneal response parameters collected by the Corvis ST (A1 velocity, deformation amplitude [DA], DA Ratio Max 1mm, and Max Inverse Radius) and a stiffness parameter at first applanation (SP-A1) were incorporated into a novel logistic regression equation (DCR index). Area under the receiver operating curve (AUC) was used to assess the sensitivity and specificity of the DCR index. RESULTS: DA, DA Ratio Max 1mm, Max Inverse Radius, and SP-A1 were each found to be statistically significantly different between normal and keratoconic eyes (Mann-Whitney test [independent samples]; P = .0077, < .0001, < .0001, and < .0001, respectively; significance level: P < .05). DCR index demonstrated high sensitivity, specificity, and overall correct detection rate (92.9%, 95.7%, and 94.4%, respectively; AUC = 98.5). The sensitivity and overall correct detection rate improved when eyes with Topographical Keratoconus Classification grades (TKC) greater than 0 were reevaluated (from 92.9% to 96.6% and from 94.4% to 96.1%, respectively). CONCLUSIONS: Combining multiple biomechanical parameters (A1 velocity, DA, DA Ratio Max 1mm, Max Inverse Radius, and SP-A1) into a logistic regression equation allows for high sensitivity and specificity for distinguishing keratoconic from normal eyes. [J Refract Surg. 2017;33(9):625-631.].