Last week a press release was published by an Institute linked to the University of Montreal (Canada) in which the positive therapeutic effect of a classic anti-inflammatory drug: colchicine was indicated in patients with covid-19. Other anti-inflammatory agents, so-called steroids, such as dexamethasone, have also been tested against the coronavirus.
This way of reporting on the results of the research, through press releases, instead of through scientific articles published in prestigious magazines, is reminiscent of the recent case that occurred this week in Spain with plitidepsin, in relation to the trivialization of technical information by part of many media, with headlines that promise “hope” against covid-19.
With this new press release, colchicine joins drugs such as remdesivir, dexamettosan, hydroxychloroquine, bamlanivimab, baricitinib, melatonin or lopinavir, among others, which have been tested with very disparate therapeutic results. Although none show a powerful antiviral action against SARS-CoV-2 in humans, they can help treatment in different specific cases and improve the clinical evolution of some patients.
Colchicine is a classic drug associated with the treatment of acute attacks of gout, a disease known since ancient times, and which is due to an excess of uric acid levels (hyperuricemia). In fact, this disease is already mentioned in the famous Egyptian papyrus of Ebers, dated around 1550 BC, a document that collects much of the knowledge of the ancient Egyptians in the field of human physiology, pathology and therapy.
The source of colchicine, the colchicum root (Colchicum autumnale), appears as a therapeutic remedy for the relief of pain and inflammation of certain patients already on the Sumerian clay tablets from Nippur, dated towards the end of the third millennium B.C. But it would be in 1820, when the French chemists Pierre Joseph Pelletier and Joseph Bienaimé Caventou obtained the main analgesic and anti-inflammatory active principle from the root of this plant, which they called colchicine. Today, in addition to gout, it is also used in inflammatory arthritis and in certain cases of pericarditis.
The anti-inflammatory mechanism of action of colchicine
Currently, colchicine is a second-line treatment for acute gout attacks, when the administration of other anti-inflammatory drugs, such as corticosteroids, is contraindicated or insufficient.
Due to its ability to bind to tubulin and interfere with the assembly of microtubules in phagocytes, colchicine is a substance that inhibits mitosis, phagocytosis, and leukocyte migration after the deposition of urate crystals in the joints. Furthermore, it also leads to a decrease in the production of leukocyte lactic acid. This causes less crystal genesis, by reducing the acidic pH.
Although the anti-inflammatory mechanism of action of colchicine is not fully elucidated, it appears that this substance interferes with several signals from the biochemical cascades of the inflammatory process. The end result is that the inflammatory response is attenuated. In particular, colchicine inhibits the release of interleukin-1 beta and the expression of other important pro-inflammatory cytokines and interleukins, such as interleukin-6.
Precisely these mechanisms would be responsible for interfering with the inflammatory process generated by SARS-CoV-2, the famous “cytokine storm”, as shown in the figure:
What evidence does the use of colchicine have against covid-19?
The press release briefly describes the results of a study started in March last year and suspended early, with only 75% of patients analyzed, due to its apparent good results.
This study corresponds to the Colchicine Coronavirus SARS-CoV2 Trial (COLCORONA study) of which, yesterday, a preprint was made public. It is a multicenter, controlled, phase III clinical trial with a randomized and double-blind design, in which centers from Canada, the United States, Spain, South Africa, Brazil and Greece have participated. The objective was to evaluate the efficacy and safety of colchicine in adult patients diagnosed with covid-19 and who presented at least one high-risk criterion such as hypertension, obesity, diabetes or some heart disease.
According to the press release, 4488 patients were included in this study, part of whom received a 0.5 mg / day dose of colchicine, compared to another group of patients controlled with placebo, for 30 days. According to this statement, the use of colchicine in outpatients with covid-19 was able to reduce hospitalizations by 25%, the need for mechanical ventilation by 50% and deaths by 44%.
However, although the reported data seem encouraging, these results have not yet been published in any scientific journal, and the preprint should be evaluated by specialist reviewers. The study indicates that the benefits of colchicine appear to be more marked in patients with diabetes and in the group of men, although no statistically significant differences were obtained. In addition, the evolution of persistent symptoms of covid-19, nor the effects of treatment with clochicine in the long term, were not evaluated.
A very recently published meta-analysis also suggests a benefit, in terms of mortality reduction, with colchicine-based treatment in patients with covid-19, although the authors of the same point out that more studies are needed to confirm and demonstrate definitely this benefit.
In this sense, in Spain there are currently nine clinical studies authorized by the Spanish Agency for Medicines and Health Products (AEMPS) to evaluate the efficacy of colchicine in the treatment of patients with covid-19, six of them in the that the effect of the administration of colchicine alone is evaluated.
The problem of colchicine toxicity
The main problem with colchicine is its safety profile, which results in a narrow therapeutic window. In 2010, the AEMPS already issued an informative note after receiving notifications of cases of poisoning with this drug. It stated that due to this narrow margin, colchicine is a highly toxic drug.
At low doses (0.5 mg / day), the most common adverse events observed are gastrointestinal in nature, such as diarrhea and nausea. This is shown by the new study, with a diarrhea rate of 13.7%. Other serious adverse events such as a higher incidence of infection (2.2% vs. 1.6% in the placebo group) and pneumonia (0.9% vs. 0.4% in the placebo group) have also been observed in different studies. placebo group).
Colchicine is contraindicated in patients with kidney disease, due to the risk of accumulation and toxicity. Its use together with many other drugs is discouraged due to the high risk of drug interactions. This is the case of drugs that inhibit certain liver enzymes (CYP3A4) and P-glycoprotein inhibitors. In these circumstances, simultaneous use can raise colchicine plasma levels, facilitating its toxicity.
To the list of dangerous combinations must be added some very commonly used antibiotics, such as clarithromycin and erythromycin; antifungals, such as ketoconazole, itraconazole, fluconazole; antivirals, such as indinavir, atazanavir, nelfinavir, ritonavir, saquinavir, amprenavir, fosamprenavir; other drugs, such as diltiazem, cyclosporine, and verapamil; and even grapefruit juice and other bitter citrus fruits. In these cases, the colchicine dose must be readjusted.
In the event of intoxication or overdose, the lethal dose can range from 0.5-0.8 mg / kg of body weight and symptoms can take hours to appear, so patients who have ingested an overdose of colchicine require immediate evaluation medical.
These conditions are initially characterized by the appearance of gastrointestinal symptoms (diarrhea, nausea, vomiting and abdominal pain), the subsequent development of multiorgan failure, with hypotension, cardiogenic shock, respiratory distress, kidney failure, liver damage, system involvement central nervous system, hypocalcemia and spinal cord suppression, with high morbidity and mortality. Finally, in a third phase, if the patient recovers, rebound leukocytosis, stomatitis, and hair loss may appear.
You have to be extremely cautious
As has happened on other occasions, the way to communicate the results of the investigation, especially in a pathology as mediatic as Covid-19, does not seem the most appropriate, regardless of the absence of underlying economic interests.
Contrasting technical evidence must come from published scientific articles, and therefore reproducible, and not from press releases that seek to achieve “a minute of glory” in the media. Press releases, to inform the public, should always come after the full publication of results.
This issue is extremely important, because in the ten months that we have been in the pandemic there have been examples of “very promising” drugs that, finally, have not been able to scientifically demonstrate their effectiveness. The first studies (and therefore the first communications to the media) were carried out without a solid scientific basis. Such is the case of hydroxychloroquine, so praised by political leaders such as Trump and Bolsonaro, or ivermectin, which has been used and continues to be used widely, despite its efficacy and possible benefits not being scientifically proven.
Burning ships without following a correct communication protocol can be counterproductive. Especially in a case as compromised as colchicine. Even the finest data that can be extracted from the preprint, in the absence of the decision of the reviewers and editors, show statistically very narrow differences with placebo in some of the parameters evaluated. This could make it difficult to incorporate this drug into the therapeutic guidelines for the treatment of covid-19.
As it is a drug with almost two centuries old, relatively used, consumed orally and with a very low price, citizens could be tempted to resort to it, following the “great benefits” proclaimed by some headlines of press, without the corresponding optional controls. This could be a huge mistake, with a fatal outcome, due to the high toxicity of the drug.
We must insist on avoiding self-medication with colchicine, be cautious with the information provided and wait for the final results of the studies that are underway, properly published in prestigious scientific journals. It is evident that the global situation generated by the pandemic is dramatic and that any therapeutic help to infected patients is always welcome. Pharmacological research is advancing in this field in a very important way, incorporating new and classic agents, and perhaps colchicine also has its place. But in all this, proven scientific criteria and, of course, patient safety must always prevail.
Francisco López-Muñoz, Professor of Pharmacology and Vice-rector for Research and Science at the Camilo José Cela University, Camilo José Cela University and Jose Antonio Guerra Guirao, Professor of Pharmacology and Toxicology. Pharmacy faculty. Complutense University of Madrid., Complutense University of Madrid
This article was originally published on The Conversation. Read the original.
