Six ways in which fluvoxamine can work to prevent severe Covid-19
Six ways in which fluvoxamine can work to prevent severe Covid-19

Six ways in which fluvoxamine can work to prevent severe Covid-19

One recently meta-analysis of a small number of fluvoxamine efficacy trials enrolling just over 2,000 patients found that fluvoxamine reduces the chances of serious hospitalization by up to 95%. If this effect is maintained in larger studies, fluvoxamine may be an important component of the Test-to-Treat strategy that the United States is rolling out.

Fluvoxamine was not developed as an anti-COVID drug. It has long been used as a mood-stabilizing selective serotonin reuptake inhibitor (SSRI) and is now available as an inexpensive generic drug worldwide.

Characteristics of severe Covid

The apparent effectiveness of fluvoxamine raises the question of how it can work independently of its use as a mood stabilizer. The following review of Sukhatme et al. provides details on the potential mechanisms by which fluvoxamine has the potential to interfere with the most serious consequences of COVID 19 infection, including cytokine storms, coagulation, and hyperinflammation.

There are six known mechanisms, potentially several, by which fluvoxamine may act to treat Covid in the late stages and prevent sequelae in the late stages: reduction of platelet aggregation, decreased mast cell degranulation, interference with endolysosomal viral trafficking and membrane binding, sigma-1 receptor activity increased melatonin levels.

Inhibition of Cytokine Storm: Decreased mast cell degranulation

The cytokine storm is a life-threatening systemic inflammatory syndrome involving elevated levels of circulating cytokines and immune cell hyperactivation. Basically, this is the alarm bell in your immune system when a dangerous pathogen is detected, which sends the immune system to fight the attacker and results in severe symptoms.

One of the primary triggers of the cytokine storm is the interaction between SARS-CoV-2 and human mast cells, which are often viral reservoirs for RNA viruses. Lung tissue in the lungs of deceased Covid patients is often associated with activated mast cells, which are degranulated by viruses upon infection.

Fluvoxamine also interacts with mast cells, lowering mRNA levels of protease-1, promoting mucosal permeability in intestinal allergic hypersensitivity reactions. This is likely to affect the efficacy of interaction between virus and mast cells, leading to less severe cytokine storm reactions and symptoms. Therefore, fluvoxamine has the potential to reduce the cytokine pathway in severe SARS-CoV-2 infection.

Inhibition of coagulation: Reduction of platelet aggregation

Coagulation is the thickening of the blood as a result of platelets accumulating. This can lead to bloodstream problems such as hypertension. Although platelets do not produce serotonin, they absorb and contain the high concentrations of the chemical. When platelets collect in the bloodstream, they release serotonin to ease hemostasis.

Fluvoxamine inhibits the uptake of serotonin from platelets and therefore inhibits platelet aggregation. Fluvoxamine is a serotonin reuptake inhibitor and inhibits platelet serotonin levels before clot formation. ONE 2011 survey showed that patients taking SSRIs measured lower coagulation levels than those not taking the drug. Fluvoxamine therefore has the potential to reduce the coagulation pathway in severe SARS-CoV-2 infection.

Inhibition of hyperinflammation: Sigma-1 receptor activity

Hyperinflammation after coagulation causes a number of health problems, including joint pain, gastrointestinal problems and in some cases brain damage. A player in inflammation is the sigma-1 receptor, which regulates endoplasmic reticulum mitochondrial calcium ion signaling, resulting in pro-inflammatory responses at higher concentrations.

Fluvoxamine upregulates interleukin-10 (IL-10), which is an anti-inflammatory protein. The sigma-1 receptor downregulates other interleukins, such as IL-6 and IL-8, but not IL-10. Therefore, high levels of IL-10 can inhibit the sigma-1 receptor and its hyperinflammatory processes. In other words, fluvoxamine may reduce Covid-related hyperinflammation.

Indirect mechanisms: Endolysosomal viral trade and membrane binding

SARS-CoV-2, along with other beta-coronaviruses, uses lysosomal trafficking to escape infected cells. Lysosomes degrade worn cell structures in a process called apoptosis, which the virus uses as a means to leave one infected cell to find another.

Basic SSRIs like fluvoxamine actually inhibit lysosomes by disrupting their charge and reducing their membrane crossing efficiency. This may not affect the virus itself, but it does inhibit one of its main escape routes, resulting in antiviral effects that can make long-term infections more difficult.

We also note that lysosomotropic drugs also affect the viral entry of SARS-CoV-2. Although fluvoxamine has not been specifically tested for this function, it has an anti-lysosome function, which means that it can also affect viral entry.

Inhibition of hyperinflammation: Elevated melatonin levels

Fluvoxamine raises melatonin levels by inhibiting the enzyme CYP1A2, which is involved in the metabolism of polyunsaturated fatty acids. Some CYP1A2 reactions result in high blood pressure and foreign inflammatory reactions. Melatonin reduces inflammation from the NLRP3 pathway, a common tool for SARS-CoV-2. Fluvoxamine may therefore reduce Covid-related hyperinflammation.

Although it is still early days, given the relatively limited trials, fluvoxamine has been shown to prevent severe COVID, the results already look promising. Moreover, the study of Sukhatme et al. finds that there are many independent biochemical pathways that can explain how these drugs, given earlier in infection, can prevent serious illness. Although fluvoxamine does not appear to have a direct antiviral effect beyond effective endosomal viral entry into the cell, it does have a number of activities that randomly inhibit the very pathways that are characteristic of the most severe forms of COVID-19. We can only hope that these promising results stand up to further investigation.

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