Abstract
Currently there are no specific treatments available for acute dengue infection. We considered that rupatadine, a platelet-activating factor receptor inhibitor, might modulate dengue-associated vascular leak. The effects of rupatadine were assessed in vitro, and in a dengue model, which showed that rupatadine significantly reduced endothelial permeability by dengue sera in vitro, and significantly inhibited the increased haematocrit in dengue-infected mice with dose-dependency. We conducted a randomised, placebo-controlled trial in 183 adult patients in Sri Lanka with acute dengue, which showed that rupatadine up to 40 mg daily appeared safe and well-tolerated with similar proportions of adverse events with rupatadine and placebo. Although the primary end-point of a significant reduction in fluid leakage (development of pleural effusions or ascites) was not met, post-hoc analyses revealed small but significant differences in several parameters on individual illness days - higher platelet counts and lower aspartate-aminotransferase levels on day 7 in the rupatadine group compared to the placebo group, and smaller effusions on day 8 in the subgroup of patients with pleural effusions. However, due to the small sample size and range of recruitment time, the potential beneficial effects of rupatadine require further evaluation in large studies focused on recruitment during the early febrile phase.
Highlights
We found that sera from patients with acute dengue significantly reduced the expression of tight junction protein ZO-1, and reduced trans-endothelial resistance (TEER) in endothelial cells, which were both significantly improved by platelet activating factor (PAF) receptor blockade[8]
We have previously shown that PAF receptor blockade inhibited the effects of acute dengue sera on endothelial permeability in vitro using a high affinity inhibitor (1-(N,N-Dimethylcarbamoyl)-4-ethynyl-3-(3-fluoro-4-((1H-2-methylimidazo[4,5-c] pyridin-1-yl)methyl)benzoyl)-indole, HCl)[8]
In order to investigate whether a licensed human medication with known PAF receptor blockade activity could affect dengue sera-induced vascular permeability, human umbilical vein derived endothelial cell lines (HUVEC) were incubated with PAF and/or acute dengue sera in the presence or absence of rupatadine
Summary
Objectives and outcomesThere were two primary objectives in this study, which were to evaluate the safety of rupatadine up to 40 mg/day in acute dengue infection and its effect in preventing or reducing fluid leak. In order to determine if rupatadine prevented fluid leakage, we assessed if there was a reduction in the proportion of individuals who developed fluid leakage (those who developed pleural effusions or ascites) in the treatment arm compared to the placebo. As we wished to assess if rupatadine, reduced the extent of leakage, the quantity of pleural effusion or ascites, were measured in whom fluid was detected in pleural or peritoneal cavities. For evaluation of reduction in the pleural fluid leakage, the maximum height of the pleural effusion was assessed daily in all patients, throughout the course of the illness. As all patients who had pleural effusions, invariably had some degree of ascites, the presence of ascites was used for analysis of fluid leakage, when evaluating the primary end point
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