In the race to find an effective treatment for Covid-19, a old drug has resurfaced from the apothecary where it accumulated dust and unleashed a worldwide madness to get hold of it growing. By the time the Ministry of Health and the regional councils began to stock up on hydroxychloroquine, the response was that "until the end of April, there are no more doses."
As this newspaper reported a month ago, hydroxychloroquine – a more modern and safer version of chloroquine phosphate – led to a resurgence when Chinese doctors who applied it in hospitals in Wuhan, Beijing or Guangzhou found out how the treatment was able to shorten the disease and improve the prognosis from the patients.
The world production of this drug is limited, despite not being a new drug. Chloroquine phosphate debuted in the fifties of the last century as a remedy against malaria, although it has been in disuse for decades, since the protozoan that causes the disease (Plasmodium falciparum) began to develop resistance, so it was replaced by antimalarials. based on another active principle, artemisinin. Only in some areas of Central America is it still used for this purpose, although the compound has also been shown to be effective for rheumatoid arthritis or lupus.
Without a doubt, the enormous international madness that there is right now to get boxes of this medicine has a sole responsibility.
No it's not Donald Trump. Neither Elon Musk nor all the celebrities who have joined a 'hype' that has caused the global depletion of reserves. The person in charge is a French virologist named Didier Raoult who is currently part of the Covid-19 scientific council that advises the Government of Emmanuel Macron. Raoult led the study that was published March 4 in the 'International Journal of Antimicrobial Agents' and subsequently the clinical trial conducted in Marseille and featuring a cocktail of hydroxychloroquine and azithromycin, an antibiotic, as the fatal combo against SARS -CoV-2.
The clinical trial ended on March 16, was uploaded on the Internet on the 17th and published on the 20th in the same journal. That is, with little time for reviews. By the time criticisms from other scientists have emerged, both from the evidence of the drug's 'in vitro' effectiveness and from the multiple procedural flaws of the Marseille clinical trial, Spain was rushing to store 390,000 doses of hydroxychloroquine provided by the pharmaceutical company Teva and the presidents of half the world were engaged in a geopolitical cold war to stock up on the product. This is how things work in these rare times.
We speak —from our respective home isolates— with Elena Gómez Díaz, researcher at the Institute of Parasitology and Biomedicine of the CSIC in Granada. For her studies with the epigenomics of malaria, Gómez Díaz, awarded with a Leonardo scholarship from the BBVA Foundation, is a perfect connoisseur of hydroxychloroquine, its mechanisms … and, especially in this case, its limitations.
QUESTION. These drugs, in their main use against malaria, were already practically discontinued, right?
REPLY. Yes, chloroquine and hydroxychloroquine, which is an improved and slightly less toxic derivative, have been among the main antimalarial drugs since the 1950s. It is manufactured very easily and is very cheap, so for developing countries, which is where malaria mainly occurs, it has allowed a very wide distribution and massive use. What has happened is that precisely because of this, over time, the malaria parasite has developed resistance to this drug, so that in most places it is no longer used because it is not effective.
Q. Where exactly is chloroquine extracted from?
A. Its origin is natural, it is from the group of quinolones. Its history dates back to Peru, where indigenous people extracted the bark of cinchona trees and used the extract — Cinchona officinalis — to combat chills and fever in the 17th century. In 1633, this herbal medicine was introduced in Europe, where it was given the same use and also began to be used against malaria. Hans Andersag and his team discovered chloroquine in 1934 at Bayer laboratories in Elberfeld, giving it the name Resochin.
Q. When you heard that chloroquine could be effective against Covid-19, were you surprised, given that malaria is caused by a parasite and this disease by a virus?
A. What chloroquine does for Plasmodium is that when it infects the red blood cell, it uses hemoglobin to get essential amino acids out. In this process of using hemoglobin, it releases a molecule called heme, but the parasite needs to metabolize that heme because it is toxic to it. What chloroquine does is block that transformation, so that this toxic product accumulates in the cell and the parasite ends up dying.
The antiviral properties of hydroxychloroquine have been known for a long time, they have been seen with SARS, MERS and even the Zika virus.
In the case of coronaviruses, the mechanism of action is different. What chloroquine does is that it lowers the pH inside the cell and that drop makes that fusion process between the virus and the cell less effective. And the other thing that chloroquine does is that, to enter the cell, the virus binds to receptors on the cell's membrane. These receptors are proteins with a certain sugar composition that allows this binding to occur. And what this medicine does is change the composition of those sugars, which prevents the recognition and binding of the virus to the receptor. This has already been seen in other previous coronaviruses, such as MERS, SARS, or even Zika virus. The antiviral properties of hydroxychloroquine have long been known.
Q. What is the point of combining hydroxychloroquine with azithromycin, which is an antibiotic, when trying to fight a virus?
R. This is the study of a French group, carried out in a hospital in Marseille. It is the first study to deal with this, but it has been published very quickly – the results were presented last week and the article was published after two days – and it is somewhat controversial, because the number of patients who have entered the The clinical trial was very small, there is controversy as to how the data has been treated, what is considered positive and what is not, how the patients have progressed clinically and also that it was a trial in which the patients did not they chose randomly, which is necessary in a clinical trial, and finally they excluded patients without giving an explanation why.
We still do not know how effective or safe hydroxychloroquine is, that is the reality today
There are a series of parameters that are essential for a study to be rigorous and the results to be conclusive and comparable that have not been met. You have to be very careful with that study and the entire scientific community is reacting in the same way. Although hydroxychloroquine is a promising drug because in 'in vitro' studies, in cells on Petri dishes, it has worked in that it reduces the multiplication of the virus and the entry of the virus into the cell, we do not have sufficient evidence animal models or clinical trials. The only published clinical trial is inconclusive. Yes, there are others that are being carried out in multiple countries. In China, there are 16 using that compound, and here in Barcelona there are six hospitals that have started trials using the same drug, but we still don't know how effective it is and how safe it is. That is the reality today.
What there is is potential, that is why the WHO has launched a clinical mega-trial with different countries, including Spain, where different promising drugs are used, including hydroxychloroquine and remdesivir, which is also used in the study that Oriol Mitjà is wearing at the Trías i Pujol Hospital in Badalona.
Q. Just in that study I think they use hydroxychloroquine not as a main drug but as prophylaxis for close contacts, in the style of what is done with malaria.
A. Well, what you are trying to avoid is infection of the cells, as prevention. Just as it is used as a prevention for malaria, in the case of the coronavirus, it is tried, by lowering the pH inside the cells, to prevent viruses from entering, so that it would lower the viral load of people who are already infected, from so that they transmit less and develop the disease to a lesser extent.
P. In summary, it is promising but at the same time tremendous that without knowing for sure whether the governments of half the world have started to supply themselves with hydroxychloroquine. Is the urge to find a cure ahead of the scientific evidence?
A. Yes, it is a big mistake, because if there are procedures, it is because they need to exist. Any drug has to fulfill two conditions: to be effective and to be safe and non-toxic. The two go hand in hand, you cannot throw something without being 100% sure that the remedy will not be worse than the disease. Although using drugs that are already on the market and have a long history of study, such as hydroxychloroquine, we save time, we do not know the behavior of these drugs in the context of Covid-19 disease.
While we need a quick fix, science needs your time to provide the right answers.
While we need a quick fix, science needs its time to provide the right answers. If we do not give you that time, the answer will not be adequate. All the advances and all the scientific potential that we are seeing now are thanks to research that started long ago, are groups that have already been doing a lot of research on coronavirus and other viral diseases.