The effect of reparixin on survival in patients at high risk for in-hospital mortality: a meta-analysis of randomized trials

Abstract

IntroductionA great number of anti-inflammatory drugs have been suggested in the treatment of SARS-CoV-2 infection. Reparixin, a non-competitive allosteric inhibitor of the CXCL8 (IL-8) receptors C-X-C chemokine receptor type 1 (CXCR1) and C-X-C chemokine receptor type 2 (CXCR2), has already been tried out as a treatment in different critical settings. Due to the contrasting existing literature, we decided to perform the present meta-analysis of randomized controlled trials (RCTs) to investigate the effect of the use of reparixin on survival in patients at high risk for in-hospital mortality.MethodsWe created a search strategy to include any human RCTs performed with reparixin utilization in patients at high risk for in-hospital mortality, excluding oncological patients. Two trained, independent authors searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) for appropriate studies. Furthermore, references of review articles and included RCTs were screened to identify more studies. No language restrictions were enforced. To assess the risk of bias of included trials, the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) was used.ResultsOverall, six studies were included and involved 406 patients (220 received reparixin and 186 received the comparator). The all-cause mortality in the reparixin group was significantly lower than that in the control group [5/220 (2.3%) in the reparixin group vs. 12/186 (6.5%) in the control group, odds ratio = 0.33 (95% confidence interval 0.12 to 0.96), p-value for effect 0.04, p for heterogeneity 0.20, I2 = 36%]. In addition, no difference in the rate of pneumonia, sepsis, or non-serious infections was shown between the two groups.ConclusionOur meta-analysis of randomized trials suggests that short-term inhibition of CXCL8 activity improved survival in patients at high risk for in-hospital mortality without increasing the risk of infection.Meta-analysis registrationPROSPERO, identifier CRD42021254467.

NETosis Induced by Serum of Patients with COVID-19 is Reduced with Reparixin or Antibodies Against DEK and IL-8

“…NETosis is correlated with the progression and severity of COVID-19, and the search for new drugs or clinical trials of existing drugs targeting NETosis is ongoing [21,22]. Treatment modalities such as direct inhibition of cytokines IL-1β, IL-6, and IL-8 or blocking the CXCR1/CXCR2 receptors with drugs like reparixin offer promising results [22][23][24][25][26].…”

Bidirectional causal associations between type 2 diabetes and COVID‐19

“…Along with the ( TNF )‐encoded cytokine Tumor necrosis factor (TNF‐α), IL‐8 orchestrates a notorious “cytokine storm” afflicting many hospitalized patients with COVID‐19. 49 Inhibitors of IL‐8 50 and TNF‐α‐dependent 51 pathways have been utilized for attenuating disease progression in severe SARS‐CoV‐2 infection.…”

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…This site is formed by TM1, TM3, TM6, and TM7. Currently, Reparixin and its analogues are considered as drugs that can reduce or prevent inflammatory and autoimmune processes, as well as suppress the development and metastasis of tumors [197,202]. Ladarixin, a potent allosteric inhibitor of CXCR1 and CXCR2, is highly effective (IC50 of about 0.1 nM) in preventing damage to pancreatic islets caused by proinflammatory factors and autoimmune reactions, indicating its potential antidiabetic activity [203,204].…”

“…Reparixin, a non-competitive allosteric inhibitor of CXCR1 and CXCR2, suppresses the stimulatory effects of interleukin-8 (IL-8) on these receptors, to the greatest extent in the case of CXCR1, but does not affect their affinity for this agonist [206,207]. Reparixin has now been shown to be clinically successful as an anti-inflammatory drug, including in the treatment of patients with severe pneumonia caused by COVID19, and Reparixin treatment has not been associated with an increased risk of secondary infections [202].…”

“…the immunoprecipitation of autoantibodies to β1-AR in patients with different forms of cardiomyopathy, it was found that immunogenic epitopes in all cases were localized in ECL2 of β1-AR. In cardiomyopathy in patients with Chagas disease, the epitope included the region 201-205, in postpartum cardiomyopathy the epitope corresponded to the region 200-210, and in dilated cardiomyopathy, the epitopes were located in overlapping regions[197][198][199][200][201][202][206][207][208][209][210][211][212] including TM4 …”