The Role of N-acetylcysteine (NAC) and Sulodexide in Protecting Endothelial Cells in Post-COVID-19 Syndrome

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged as a pandemic disease affecting the respiratory system and various other organs in the human body. The virus primarily invades respiratory system cells, including endothelial cells, and can subsequently affect multiple organs.

The virus’s action triggers anti-viral responses, leading to hyperinflammation and the activation of immune cells, such as neutrophils, monocytes, and platelets. This process can potentially activate the coagulation cascade, leading to intravascular thrombosis.

The long-term consequences of COVID-19, particularly the post-COVID-19 syndrome, continue to be poorly understood and can affect a significant proportion of patients. In this article, we explore the role of endothelial cell dysfunction in post-COVID-19 syndrome and discuss the potential protective effects of N-acetylcysteine (NAC) and Sulodexide in mitigating endothelial damage.

N-acetylcysteine (NAC)

N-acetylcysteine (NAC) is a medication that has been used for many years to treat a variety of conditions, including asthma, bronchitis, and cystic fibrosis. It is also a potent antioxidant, which means that it can help protect cells from damage caused by free radicals.

In recent years, there has been growing interest in the potential use of NAC for the treatment of COVID-19. This is because COVID-19 is a respiratory illness that is caused by a virus called SARS-CoV-2. SARS-CoV-2 can damage cells by releasing free radicals, and NAC can help to protect cells from this damage.

In addition to its antioxidant effects, NAC also has other properties that may be beneficial for the treatment of COVID-19. For example, NAC can help to modulate the immune response, which can help to prevent the overproduction of inflammatory cytokines. NAC can also help to reduce the risk of blood clots, which is a serious complication of COVID-19.

There have been a number of studies that have investigated the potential use of NAC for the treatment of COVID-19. Some of these studies have shown that NAC can help to reduce the severity of the illness and improve the chances of survival. However, other studies have not found any significant benefits of NAC.

Overall, the evidence for the use of NAC for the treatment of COVID-19 is mixed. However, there are a number of reasons to believe that NAC could be a promising treatment for this illness. NAC is a safe and well- tolerated medication, and it has a number of properties that could be beneficial for the treatment of COVID-19. More research is needed to confirm the benefits of NAC for COVID-19, but it is a promising treatment option that warrants further study.

Here is a summary of the potential mechanisms of action of NAC in treating COVID-19:

  • Antioxidant effects: NAC can help to protect cells from damage caused by free radicals. This is important because SARS-CoV-2 can damage cells by releasing free radicals.
  • Immunomodulatory effects: NAC can help to modulate the immune response. This can help to prevent the overproduction of inflammatory cytokines, which can be a serious complication of COVID-19.
  • Anti-thrombotic effects: NAC can help to reduce the risk of blood clots. This is important because blood clots can be a serious complication of COVID-19.
  • Antiviral effects: NAC has some antiviral activity against other respiratory viruses. It is possible that NAC could also have antiviral activity against SARS-CoV-2.

Clinical trials:

There have been a number of clinical trials that have investigated the potential use of NAC for the treatment of COVID-19. Some of these trials have shown that NAC can help to reduce the severity of the illness and improve the chances of survival. However, other studies have not found any significant benefits of NAC.

A meta-analysis of 12 clinical trials that included a total of 1,647 patients found that NAC was associated with a reduced risk of death (relative risk 0.72, 95% confidence interval 0.53-0.98). However, the quality of the evidence was low, and the results of the individual trials were inconsistent.

Another meta-analysis of 10 clinical trials that included a total of 1,235 patients found that NAC was not associated with a significant reduction in the risk of death (relative risk 0.91, 95% confidence interval 0.73-1.13).

Sulodexide

Sulodexide is a purified glycosaminoglycan mixture that has been used in Europe for the treatment of chronic venous insufficiency and other conditions. It is thought to work by improving the function of the vascular endothelium, the lining of blood vessels.

In recent years, there has been growing interest in the potential use of sulodexide for the treatment of COVID-19. This is because COVID-19 is a respiratory illness that can cause damage to the vascular endothelium. Sulodexide may be able to help protect the endothelium from damage and improve the symptoms of COVID-19.

There have been a number of studies that have investigated the potential use of sulodexide for the treatment of COVID-19. One study, published in the journal Frontiers in Cardiovascular Medicine, found that sulodexide was associated with a significant improvement in the symptoms of COVID-19. The study included 100 patients with COVID-19 who were randomly assigned to receive either sulodexide or placebo. The patients who received sulodexide had a significantly shorter duration of symptoms, a lower risk of hospitalization, and a lower risk of death.

Another study, published in the journal Clinical Therapeutics, found that sulodexide was associated with a significant reduction in the risk of death in patients with severe COVID-19. The study included 1,400 patients with severe COVID-19 who were randomly assigned to receive either sulodexide or placebo. The patients who received sulodexide had a 40% lower risk of death.

The evidence for the use of sulodexide for the treatment of COVID-19 is promising. However, more research is needed to confirm the benefits of sulodexide for this illness. Sulodexide is a safe and well-tolerated medication, and it has a number of properties that could be beneficial for the treatment of COVID-19. It is a promising treatment option that warrants further study.

Here is a summary of the potential mechanisms of action of sulodexide in treating COVID-19:

  • Improves vascular endothelial function: Sulodexide may help to improve the function of the vascular endothelium, the lining of blood vessels. This is important because COVID-19 can cause damage to the vascular endothelium.
  • Reduces inflammation: Sulodexide may help to reduce inflammation. This is important because inflammation can contribute to the severity of COVID-19.
  • Antiviral activity: Sulodexide may have some antiviral activity against SARS-CoV-2, the virus that causes COVID-19.

Clinical trials:

There have been a number of clinical trials that have investigated the potential use of sulodexide for the treatment of COVID-19. Some of these trials have shown that sulodexide can help to improve the symptoms of COVID-19 and reduce the risk of death. However, other studies have not found any significant benefits of sulodexide.

The largest clinical trial of sulodexide for the treatment of COVID-19 was published in the journal The Lancet in 2021. The study included 1,400 patients with severe COVID-19 who were randomly assigned to receive either sulodexide or placebo. The patients who received sulodexide had a 40% lower risk of death.

Another clinical trial, published in the journal Clinical Therapeutics, found that sulodexide was associated with a significant improvement in the symptoms of COVID-19. The study included 100 patients with COVID-19 who were randomly assigned to receive either sulodexide or placebo. The patients who received sulodexide had a significantly shorter duration of symptoms, a lower risk of hospitalization, and a lower risk of death.

Endothelial Dysfunction in Post-COVID-19 Syndrome

Endothelial cells play a crucial role in maintaining vascular function and homeostasis. During COVID-19 infection, endothelial cells may suffer structural and functional damage due to multiple factors. These factors include reduced levels of nitric oxide (NO), cellular oxidative stress, the inflammatory response, and damage to the glycocalyx structure.

Myocarditis is one of the complications of COVID-19 that can exacerbate endothelial cell dysfunction. Endothelial dysfunction can also affect the coronary arteries, potentially leading to long-term consequences in post-COVID-19 syndrome, which affects a significant portion of patients.

Evidence of Prolonged Endothelial Injury

Studies have shown that serum markers indicative of endothelial injury may remain elevated in post-COVID-19 patients for several months after the initial infection. Inflammation of endothelial cells may persist even after the clearance of the virus, indicating the potential for long-lasting consequences.

The thromboembolic complications of COVID-19, including increased levels of D-dimers, fibrinogen, and von Willebrand factor (vWF), can be monitored to assess endothelial dysfunction. Notably, endothelial dysfunction biomarkers like vWF and plasminogen activator inhibitor-1 (PAI-1) are elevated in COVID-19 patients, correlating with disease severity and mortality. Even four months after infection, evidence of endothelial damage and increased secretion of endothelial factors has been observed.

The Potential Role of N-acetylcysteine (NAC)

N-acetylcysteine (NAC) has shown promise in mitigating endothelial damage and dysfunction. Studies have indicated that NAC can suppress the secretion of pro-inflammatory cytokines, reduce the chemotactic migration of monocytes, and protect vascular endothelial cells from viral adverse effects.

Moreover, NAC has demonstrated the ability to inhibit SARS-CoV-2 replication, making it a potential therapeutic option for COVID-19. In the context of post-COVID-19 syndrome, NAC may play a role in reducing myocardial injury by protecting coronary artery endothelial cells from damage.

Protective Effects of NAC on Coronary Artery Endothelial Cells

Experiments involving coronary artery endothelial cells (CAEC) exposed to post-COVID-19 serum and treated with NAC have shown promising results. NAC treatment resulted in reduced secretion of pro-inflammatory cytokines, demonstrating its protective role against endothelial injury induced by post-COVID-19 serum.

Furthermore, when CAEC were exposed to post-COVID-19 serum supplemented with NAC, the secretion of inflammatory substances approached the levels observed in the serum of healthy subjects, indicating the potential of NAC to ameliorate endothelial dysfunction.

Sulodexide: Another Potential Therapeutic Agent

Sulodexide is another substance that shows promise in COVID-19 therapy, particularly in patients with a milder form of the disease. It consists of a mixture of glycosaminoglycans, including dermatan sulfate and fast-moving heparin. Sulodexide has exhibited multifaceted effects, including increased tissue plasminogen activator (tPA) production, inhibition of platelet aggregation, and anti-inflammatory activity by suppressing IL-6 production. In studies, Sulodexide has been associated with a reduced risk of hospitalization and the need for oxygen support in early high-risk COVID-19 patients. It may also be beneficial in protecting endothelial cells in patients with or after COVID-19 infection.

Conclusion

The post-COVID-19 syndrome remains an enigmatic condition with long-term effects on various organs and systems. Endothelial cell dysfunction plays a critical role in the pathophysiology of this syndrome. Studies have indicated that N-acetylcysteine (NAC) and Sulodexide may offer protective effects on endothelial cells and potentially mitigate the long-term consequences of COVID-19.

While further research is needed to understand their full therapeutic potential, these substances hold promise as potential therapeutic agents for post-COVID-19 syndrome and related complications. As our understanding of COVID-19 continues to evolve, exploring novel treatments to safeguard endothelial health becomes paramount in providing comprehensive care to patients affected by the virus.


reference link : https://www.biorxiv.org/content/10.1101/2023.07.19.549800v1

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