Efficacy of Sildenafil in Patients with Severe COVID-19 and Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is common in severe coronavirus disease 2019 (COVID-19) and worsens the prognosis. Sildenafil, a phosphodiesterase-5 inhibitor, is approved for PAH treatment but little is known about its efficacy in cases of severe COVID-19 with PAH. This study aimed to investigate the clinical efficacy of sildenafil in patients with severe COVID-19 and PAH. Intensive care unit (ICU) patients were randomly assigned to receive sildenafil or a placebo, with 75 participants in each group. Sildenafil was administered orally at 0.25 mg/kg t.i.d. for one week in a placebo-controlled, double-blind manner as an add-on therapy alongside the patient's routine treatment. The primary endpoint was one-week mortality, and the secondary endpoints were the one-week intubation rate and duration of ICU stay. The mortality rate was 4% vs. 13.3% (p = 0.078), the intubation rate was 8% and 18.7% (p = 0.09), and the length of ICU stay was 15 vs. 19 days (p < 0.001) for the sildenafil and placebo groups, respectively. If adjusted for PAH, sildenafil treatment significantly reduced mortality and intubation risks: OR = 0.21 (95% CI: 0.05-0.89) and OR = 0.26 (95% CI: 0.08-0.86), respectively. Sildenafil demonstrated some clinical efficacy in patients with severe COVID-19 and PAH and should be considered as an add-on therapy in these patients.

Impaired ß 2 -adrenergic endothelium-dependent vasodilation in patients previously hospitalized with coronavirus disease 2019.

AIM: The pulse wave response to salbutamol (PWRS) - change in augmentation index (AIx) - provides a means to assess endothelial vasodilator function in vivo . Endothelial dysfunction plays a relevant role in the pathogenesis of hypertension and cardiovascular disease and appears to underlie many of the complications of coronavirus disease 2019 (COVID-19). However, to what degree this persists after recovery is unknown. METHODS: Individuals previously hospitalized with COVID-19, those recovered from mild symptoms and seronegative controls with well known risk factors for endothelial dysfunction were studied. To assess the involvement of nitric oxide-cyclic guanosine monophosphate pathway (NO-cGMP) on PWRS, sildenafil was also administrated in a subsample. RESULTS: One hundred and one participants (60 men) aged 47.8 ±â€Š14.1 (mean ±â€ŠSD) years of whom 33 were previously hospitalized with COVID-19 were recruited. Salbutamol had minimal effect on haemodynamics including blood pressure and heart rate. It reduced AIx in controls ( n  = 34) and those recovered from mild symptoms of COVID-19 ( n  = 34) but produced an increase in AIx in those previously hospitalized: mean change [95% confidence interval] -2.85 [-5.52, -0.188] %, -2.32 [-5.17,0.54] %, and 3.03 [0.06, 6.00] % for controls, those recovered from mild symptoms and those previously hospitalized, respectively ( P  = 0.001). In a sub-sample ( n  = 22), sildenafil enhanced PWRS (change in AIx 0.05 [-2.15,2.24] vs. -3.96 [-7.01. -2.18], P  = 0.006) with no significant difference between hospitalized ( n  = 12) and nonhospitalized participants ( n  = 10). CONCLUSIONS: In patients previously hospitalized with COVID-19, there is long-lasting impairment of endothelial function as measured by the salbutamol-induced stimulation of the NO-cGMP pathway that may contribute to cardiovascular complications.

The war against the SARS-CoV2 infection: Is it better to fight or mitigate it?

In trying to understand the biochemical mechanism involved in the recent pandemic COVID-19, there is currently growing interest in angiotensin-converting enzyme II (ACE2). Nevertheless, the attempts to counteract COVID-19 interference with this enzymatic cascade are frustrating, and the results have thus far been inconclusive. Let's start again by considering the involved factors in an alternative way: we could postulate that COVID-19 could be more aggressive/fatal due to a high level of "basal" inflammation with low Nitric Oxide (NO) levels in hypertensive, diabetic and obese patients. Interestingly, the "protective" effects of several factors (such as estrogens) may play a role by increasing the formation of endogenous NO. From a therapeutic point of view, phosphodiesterase type 5 inhibitors such as oral Tadalafil, could be used in order to increase the basal NO levels. In this way, we don't fight the virus, but we may be able to mitigate its effects.

COVID-19 in a Patient with ß-Thalassemia Major and Severe Pulmonary Arterial Hypertension.

We here report the successful recovery from coronavirus disease-19 (COVID-19) pneumonia in a patient with ß-thalassemia major (ß-TM) and severe pulmonary arterial hypertension (PAH), focusing on the patient's comorbidities, therapeutic course and drug interaction.

Three novel prevention, diagnostic, and treatment options for COVID-19 urgently necessitating controlled randomized trials.

PURPOSE: Asymptomatic or minimally symptomatic infection with COVID-19 can result in silent transmission to large numbers of individuals, resulting in expansion of the pandemic with a global increase in morbidity and mortality. New ways of screening the general population for COVID-19 are urgently needed along with novel effective prevention and treatment strategies. HYPOTHESIS: A hypothetical three-part prevention, diagnostic, and treatment approach based on an up-to-date scientific literature review for COVID-19 is proposed. Regarding diagnosis, a validated screening questionnaire and digital app for COVID-19 could help identify individuals who are at risk of transmitting the disease, as well as those at highest risk for poor clinical outcomes. Global implementation and online tracking of vital signs and scored questionnaires that are statistically validated would help health authorities properly allocate essential health care resources to test and isolate those at highest risk for transmission and poor outcomes. Second, regarding prevention, no validated protocols except for physical distancing, hand washing, and isolation exist, and recently ivermectin has been published to have anti-viral properties against COVID-19. A randomized trial of ivermectin, and/or nutraceuticals that have been published to support immune function including glutathione, vitamin C, zinc, and immunomodulatory supplements (3,6 Beta glucan) could be beneficial in preventing transmission or lessening symptomatology but requires statistical validation. Third, concerning treatment, COVID-19 induced inflammation and "cytokine storm syndrome" with hemophagocytic lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) have resulted in extreme morbidity and mortality in those with certain comorbidities, secondary to "acute respiratory distress syndrome" (ARDS) and multiorgan dysfunction with disseminated intravascular coagulation (DIC). Deficiency in red blood cell, serum and alveolar glutathione has been published in the medical literature for ARDS, as well as viral and bacterial pneumonias, resulting from increased levels of free radical/oxidative stress. A randomized controlled trial of blocking NF-κB and cytokine formation using glutathione precursors (N-acetyl-cysteine [NAC] and alpha lipoic acid) and PO/IV glutathione with associated anti-viral effects should be performed, along with an evaluation of Nrf2 activators (curcumin, sulforaphane glucosinolate) which have been scientifically proven to lower inflammation. Since high mortality rates from sepsis induced DIC due to COVID-19 infection has also been associated with thrombotic events and elevated levels of D-dimer, randomized controlled trials of using anticoagulant therapy with heparin is urgently required. This is especially important in patients on ventilators who have met certain sepsis induced coagulopathy (SIC) criteria. The use of acetazolamide with or without sildenafil also needs to be explored with or without heparin, since increased oxygen delivery to vital organs through prevention of thrombosis/pulmonary emboli along with carbonic anhydrase inhibition may help increase oxygenation and prevent adverse clinical outcomes. CONCLUSION AND IMPLICATIONS: A three-part prevention, diagnostic, and treatment plan is proposed for addressing the severe complications of COVID-19. Digital monitoring of symptoms to clinically diagnose early exposure and response to treatment; prevention with ivermectin as well as nutritional therapies that support a healthy immune response; treatment with anti-inflammatory therapies that block NF-κB and activate Nrf2 pathways, as well as novel therapies that address COVID-19 pneumonia and ARDS with DIC including anticoagulation and/or novel respiratory therapies with or without acetazolamide and sildenafil. These three broad-based interventions urgently need to be subjected to randomized, controlled trials.