Multiple studies have established that hyperinflammatory response induced by SARS CoV-2 is a main cause of complications and death in infected subjects. Such dysfunctional immune response has been described as a dysregulated and exacerbated production of cytokines and chemokines that attracts and activates inflammatory cells, which start and sustain pulmonary and systemic damage, thus causing complications that lead to multi organ failure and death. Therefore, we suggest that blocking key inflammation receptors could help to reduce migration and activation of T cells, monocytes/macrophages and neutrophils, thus mitigating the cytokine dysregulation and averting severe complications and death. Importantly, the optimum treatment for COVID-19 severe patients should combine a modulator of the immune response plus a direct antiviral drug against SARS-CoV-2, in order to address both the hyperinflammatory effects of the immune dysregulation and the viral load. Methods: Maraviroc (MVC), a CCR5 antagonist, and Favipiravir (FPV), an antiviral, will be evaluated single and combined, added to the treatment currently used at the Hospital General de México Dr. Eduardo Liceaga for severe COVID-19 patients. One hundred patients will be allocated in four arms [Current treatment only (CT), CT+MVC, CT+FPV, CT+MVC+FPV]. Percentage of patients free of mechanical ventilation or death at day 28, immunophenotyping and viral load will be compared between groups. Discussion: New immune focused therapies are targeting strong inflammation mediators such as IL-6 and IL1-β; nevertheless, to our best knowledge, only one study explores chemotaxis control. The use of a drug therapy that addresses both the regulation of the immune response and the inhibition of viral replication could at the same time, help to alleviate the hyperinflammatory condition and reduce the time of the viral clearance process, therefore improving treatment outcomes.
Multiple studies have established that hyperinflammatory response induced by SARS CoV-2 is a main cause of complications and death in infected subjects. Such dysfunctional immune response has been described as a dysregulated and exacerbated production of cytokines and chemokines that attracts and activates inflammatory cells, which start and sustain pulmonary and systemic damage, thus causing complications that lead to multi organ failure and death. Therefore, we suggest that blocking key inflammation receptors could help to reduce migration and activation of T cells, monocytes/macrophages and neutrophils, thus mitigating the cytokine dysregulation and averting severe complications and death. Importantly, the optimum treatment for COVID-19 severe patients should combine a modulator of the immune response plus a direct antiviral drug against SARS-CoV-2, in order to address both the hyperinflammatory effects of the immune dysregulation and the viral load. Methods: Maraviroc (MVC), a CCR5 antagonist, and Favipiravir (FPV), an antiviral, will be evaluated single and combined, added to the treatment currently used at the Hospital General de México Dr. Eduardo Liceaga for severe COVID-19 patients. One hundred patients will be allocated in four arms [Current treatment only (CT), CT+MVC, CT+FPV, CT+MVC+FPV]. Percentage of patients free of mechanical ventilation or death at day 28, immunophenotyping and viral load will be compared between groups. Discussion: New immune focused therapies are targeting strong inflammation mediators such as IL-6 and IL1-β; nevertheless, to our best knowledge, only one study explores chemotaxis control. The use of a drug therapy that addresses both the regulation of the immune response and the inhibition of viral replication could at the same time, help to alleviate the hyperinflammatory condition and reduce the time of the viral clearance process, therefore improving treatment outcomes.
Multiple studies have established that hyperinflammatory response induced by SARS CoV-2 is a main cause of complications and death in infected subjects. Such dysfunctional immune response has been described as a dysregulated and exacerbated production of cytokines and chemokines that attracts and activates inflammatory cells, which start and sustain pulmonary and systemic damage, thus causing complications that lead to multi organ failure and death. Therefore, we suggest that blocking key inflammation receptors could help to reduce migration and activation of T cells, monocytes/macrophages and neutrophils, thus mitigating the cytokine dysregulation and averting severe complications and death. Importantly, the optimum treatment for COVID-19 severe patients should combine a modulator of the immune response plus a direct antiviral drug against SARS-CoV-2, in order to address both the hyperinflammatory effects of the immune dysregulation and the viral load. Methods: Maraviroc (MVC), a CCR5 antagonist, and Favipiravir (FPV), an antiviral, will be evaluated single and combined, added to the treatment currently used at the Hospital General de México Dr. Eduardo Liceaga for severe COVID-19 patients. One hundred patients will be allocated in four arms [Current treatment only (CT), CT+MVC, CT+FPV, CT+MVC+FPV]. Percentage of patients free of mechanical ventilation or death at day 28, immunophenotyping and viral load will be compared between groups. Discussion: New immune focused therapies are targeting strong inflammation mediators such as IL-6 and IL1-β; nevertheless, to our best knowledge, only one study explores chemotaxis control. The use of a drug therapy that addresses both the regulation of the immune response and the inhibition of viral replication could at the same time, help to alleviate the hyperinflammatory condition and reduce the time of the viral clearance process, therefore improving treatment outcomes.
Objective: Both cardiac diastolic dysfunction (DD) and arterial stiffness are early manifestations of obesity-associated prediabetes and serve as risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Since the incidence of DD and arterial stiffness are increasing worldwide due to exponential growth in obesity, an effective treatment is urgently needed to blunt their development and progression. Here we investigated whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses DD and arterial stiffness in an animal model of prediabetes more effectively than valsartan monotherapy.Methods: Sixteen week-old male Zucker Obese rats (ZO; n=64) were assigned randomly to 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val; 68 mg•kg-1•day-1; ZOSV); Group 3: valsartan (31 mg•kg-1•day-1; ZOV) and Group 4: hydralazine, an anti-hypertensive drug (30 mg•kg-1•day-1; ZOH). Six Zucker Lean (ZL) rats that received saline only (Group 5) served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage.Results: Sac/val improved echocardiographic parameters of impaired left ventricular (LV) stiffness in untreated ZO rats, without altering the amount of food consumed or body weight gained. In addition to improving DD, sac/val also decreased aortic stiffness and reversed impairment of nitric oxide-induced vascular relaxation seen in ZO rats. However, sac/val had no impact on LV hypertrophy. Notably, sac/val was more effective at ameliorating DD compared to val. Although, hydralazine was as effective as sac/val in improving these parameters, it adversely affected LV mass index. Further, proteomics revealed distinct effects of sac/val, including marked suppression of Notch-1 by both valsartan and sac/val suggesting that cardiovascular protection afforded by both share some common mechanisms; however, sac/val increased IL-4 which is increasingly been recognized for its cardiovascular protection, possibly contributing, in part, to more favorable effects of sac/val over val alone in improving obesity associated DD.Conclusions: These studies suggest that sac/val is superior to val in reversing obesity-associated DD. It is an effective drug combination to blunt progression of asymptomatic DD and vascular stiffness to HFpEF development in a preclinical model of obesity-associated prediabetes.
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