Colchicine-The Divine Medicine against COVID-19

Abstract

Colchicine has a number of effects that suggest it may be useful in the treatment of COVID-19. Myeloid cells are a major source of dysregulated inflammation in COVID-19. The hyperactivation of the NLRP3 inflammasome and the subsequent cytokine storm take place precisely inside them and can lead to multiorgan damage and death. NLRP3 inflammasome inhibition has been assessed at micromolar colchicine concentrations which cannot be achieved in serum. However, colchicine has remarkable ability to accumulate intensively in leukocytes, where the cytokine storm is generated. Over 50 observational studies and randomized clinical trials, small randomized non-controlled trials, and retrospective cohort studies were initiated to test its healing effect in vivo, leading to conflicting, rather disappointing results. The WHO gives a "Strong recommendation against" the use of colchicine for COVID-19 treatment. This is because low doses of colchicine are always used, where the concentrations required to inhibit the NLRP3 inflammasome in leukocytes cannot be reached. Considering this, from March 2020, we started the administration of higher doses of colchicine. Our assumption was that a safe increase in colchicine doses to reach micromolar concentrations in leukocytes will result in NLRP3 inflammasome/cytokine storm inhibition. We demonstrated that in 785 inpatients treated with increasing doses of colchicine, mortality fell between two and seven times. Our data, including a large number of COVID-19 outpatients, showed that nearly 100% of the patients treated with this therapeutic regimen escaped hospitalization. In addition, post-COVID-19 symptoms in those treated with colchicine were significantly rarer. As a large number of viruses can overactivate the NLRP3 inflammasome (like seasonal influenza), we are convinced that higher colchicine doses would be useful in these cases as well.

Keywords: COVID-19; NLRP3 inflammasome; colchicine doses; colchicine toxicity; cytokine storm.

Figure 1

Colchicine effects. (A) Colchicine has one stereocenter located at carbon 7 and its natural configuration is S. The molecule also contains one chiral axis, whose natural configuration is aS. Colchicine has four stereoisomers, but the only one found in nature is the aS, 7s configuration. Colchicine accumulates in white blood cells, decreasing their motility, mobilization (especially chemotaxis), adhesion, and, very important in the case of COVID-19 pathophysiology, it inhibits the NLRP3 inflammasome. (B) The stimulating effects of colchicine. (C) The inhibitory effects of colchicine. Green color—stimulation; red color—inhibition; P2X2, P2X7—Purinergic Receptors; ROCK—Rho-associated protein kinase; ROS—Reactive oxygen species; NO—Nitric Oxide; PLA2—Phospholipase A2; NOX2—NADPH oxidase 2; RSA59—Isogenic recombinant demyelinating strain of mouse hepatitis virus (MHV); RSV—Respiratory Syncytial Virus; MMP9—Matrix metalloproteinase-9; NET—Neutrophil Extracellular Traps; TGF-β1—transforming growth factor beta 1; VEGF—vascular endothelial growth factor; TNFa—tumor necrosis factor alpha. For references see [14,23,24,25].

Figure 2

Doses of colchicine in different pathological situations. 1. For cardio protection, colchicine doses of 0.5/0.6 mg daily for 6 months are recommended [19]; for stroke prevention, 0.5–1 mg once daily [30]; and for vascular inflammation prevention, 0.5 mg once daily for 60 months [31]. 2. For ccute coronary syndrome, coronary artery disease, pericarditis, or atrial fibrillation, a dose of 0.5 mg twice daily for 1 month to 1 year or 0.5 mg once daily for a median of 3 years is recommended [31]. 3. For Behçet’s syndrome, a dose of 1–2 mg daily for 3 months is recommended [31]. 4. For acute gout, a dose of 1.8 mg total is recommended [32]. 5. The highest recommended doses for FMF are up to 2.4 mg. Interestingly, in cases where there is no effect, they are recommended “the maximum tolerated dose” [33]. 6. For COVID-19, a loading dose of up to 5 mg is recommended [24]. (Green bars represent low doses, yellow—medium, red—high. Diagonal stripes show varying therapeutic dosage).

Figure 3

The theoretical basis of high-dose colchicine treatment in COVID-19. Mortality in COVID-19 is due to a cytokine storm triggered directly and indirectly by SARS-CoV-2, which hyperactivates the NLRP3 inflammasome in myeloid cells. It is inhibited by micromolar concentrations of colchicine. As colchicine has a remarkable ability to accumulate intensively in leukocytes, its increasing doses can lead to such an accumulation in macrophages, neutrophils, and monocytes that is sufficient to inhibit the NLRP3 inflammasome and, accordingly, the cytokine storm. (A) Direct and indirect stimulation of NLRP3 inflammasome by SARS-CoV-2 can lead to its hyperactivation, cytokine storm, multiorgan failure, and death. (B) Low doses of colchicine are not sufficient for NLRP3 inflammasome/cytokine storm inhibition. (C) High doses of colchicine are capable of inhibiting the NLRP3 inflammasome, interrupting the cytokine storm. (Red NLRP3—hyperactivation; green NLRP3—normal function).

Figure 4

The effects of high-dose colchicine on the course of COVID-19. A high dose of colchicine inhibited the NLRP3 inflammasome and, accordingly, the cytokine storm; outpatients did not develop complications and avoided hospitalization; the mortality of hospitalized patients decreased up to seven-fold; and post-COVID-19 symptoms decreased sharply. A high dose of colchicine should also be effective in other infectious conditions associated with hyperactivation of the NLRP3 inflammasome (Red—hyperactivation; green—normal function).