Since the COVID-19 pandemic began, they are searching “desperately”, and against the clock, not only an effective vaccine against SARS-CoV-2, but also drugs that allow to defeat the virus. Or, failing that, reduce mortality or the symptoms that accompany this infection. Among these drugs are quinine derivatives (chloroquine and hydroxychloroquine), which have generated great controversy after several heads of state have recommended, without justified clinical criteria, their massive use. Among them, Donald Trump.
The president of the United States announced on May 19 that he had taken hydroxychloroquine for two weeks, about which he had heard “a lot of good things.” His justification: that “he has nothing to lose.”
For his part, the president of Brazil, Jair Bolsonaro, insists on recommending that the Brazilian population consume hydroxychloroquine, even in the presence of mild symptoms of the infection. This decision has led to the resignation of two Health Ministers in less than a month: Henrique Mandetta, in April, and Nelson Teich, a week ago. Both refused to include the drug in the treatment protocols for COVID-19, concerned about its health risks.
But what are these drugs and where do they come from?
To understand the history of these drugs we have to go back to the seventeenth century. It was at the beginning of this century when the fourth wife of the Count of Chinchón, Ana de Osorio, fell ill with malaria shortly after arriving in Lima, Peru. The governor of the city had been treated recently, so he offered the bark of the cinchona tree to the countess.
In this way, it is believed that it was she, along with her doctor, Dr. Juan de Vega, who brought the bark of this tree to Europe. The countess was healed “miraculously”, and in gratitude extended the antimalarial remedy to all the needy and sick, making it known in Spain and the rest of Europe. Quinine was the only effective treatment for malaria for 300 years.
However, it took more than two centuries for the English physician JF Payne, in 1894, to describe the healing of lupus skin lesions after the administration of quinine.
During World War II, four million Allied soldiers took this drug for three years to prevent malaria in the Pacific and North Africa. This situation made it possible to advance significantly in the knowledge of its pharmacological properties and its usefulness in improving patients with arthritis and lupus.
After the war, they looked for derivatives of quinine that were better tolerated. This is how chloroquine began to be used in 1943, and hydroxychloroquine in 1955. But as its use became popular, its toxicity also became evident , its use declining until the 1980s.
How does hydroxychloroquine work?
As antimalarial agents, these drugs are highly effective. At the moment it is not known in detail what their mechanism of action is, although it is known that they increase the pH inside the parasites. They appear to only act on parasites within red blood cells, inducing lysosomal degradation of hemoglobin and destruction of the parasite (a protozoan of the genus Plasmodium ).
Similarly, although its exact mechanism of action is unknown, quinine and its derivatives have anti-inflammatory, immunosuppressive and immune response modulating effects. This makes them effective in rheumatic and systemic autoimmune diseases, such as rheumatoid arthritis or lupus.
Its mechanism of action against SARS-Cov-2 has not been elucidated either . Everything indicates that it makes it difficult for the virus to enter cells (by a mechanism similar to its antimalarial action). Another option is to alter the ability of the virus to bind to the outside of a host cell.
In addition, there are its subtle effects on a wide variety of cells and processes of the immune system, which would stimulate the body’s ability to fight the coronavirus.
Hypothetical benefits …
Really, what is the rationale for using hydroxychloroquine in COVID-19 positive patients? First, it was used, alone or in combination, because it was known to inhibit SARS-CoV-1 infection. Furthermore, the sequence and structure homologies between SARS-CoV-1 and SARS-CoV-2 suggested that chloroquine could reduce the infectivity of the recent coronavirus.
Following the dissemination of the encouraging results of a study carried out in France with 80 patients affected by COVID-19, several groups of scientists set out to investigate the efficacy of the combination of hydroxychloroquine with azithromycin, a broad-spectrum antibiotic, to treat separately or in combination to patients affected by SARS-CoV-2.
However, although the data seemed encouraging, the lack of a control group, as well as design flaws in the study (mainly patient selection biases), have left the scientific community baffled.
As if that were not enough, an observational study with more than 96,000 patients published in The Lancet not only found no benefit in the use of these drugs, but it seems that the risk of arrhythmia and death is higher in those treated with hydroxychloroquine.
At present, we can affirm that there is no tangible evidence on the efficacy of hydroxychloroquine as a treatment in patients with COVID-19, nor as a prophylaxis against this disease. For this reason, scientific societies and regulatory authorities, such as the FDA, the agency that controls drugs in the United States, and the European Medicines Agency (EMA), recommend conducting more clinical studies that confirm or deny their effectiveness, and, Currently, more than 80 studies are underway on the use of this drug for the treatment and / or prevention of SARS-CoV-2 infection.
But voices have also emerged questioning the drug’s efficacy in this disease. In fact, a recent article in the British Medical Journal indicates that hydroxychloroquine does not significantly reduce intensive care admission or death in hospitalized patients with pneumonia due to COVID-19.
… or unacceptable risks
On the other hand, it must be borne in mind that this group of drugs has a dark side, such as its safety problems, such as digestive disorders (nausea, vomiting and diarrhea), ocular (reversible after stopping treatment early), cardiac ( arrhythmias) and neuropsychiatric (psychosis and suicidal ideation), as well as loss of appetite and weight, etc.
Among the serious adverse effects, noteworthy are cardiac, such as QT prolongation (an alteration of the electrocardiogram) and other arrhythmias, as well as retinopathy and severe psychiatric effects. These adverse effects can even be fatal when the drug is consumed at high doses or without medical supervision, some cases having occurred with doses lower than 4 grams of hydroxychloroquine.
These adverse effects, especially cardiac ones, can be especially serious if hydroxychloroquine is combined with other medications , such as azithromycin, included in many treatment protocols for this disease.
To top it all, comorbidities in the most severe COVID-19 infected patients, such as hypokalemia (potassium deficiency), hypomagnesemia (magnesium deficiency), or fever, can increase the risk of arrhythmias if chloroquine and its derivatives are used. In this regard, the FDA has reported nearly 500 cases of cardiac arrest suspected of being caused by the individual administration of chloroquine , hydroxychloroquine, lopinavir / ritonavir, and azithromycin.
Neuropsychiatric disorders, such as acute psychotic conditions, suicide attempts or completed suicides, have also been reported in patients who received an initial dose of 800 mg of hydroxychloroquine on the first day, followed by a dose of 400 mg daily.
Due to these safety concerns, both the FDA and the EMA have issued recommendations to closely monitor the occurrence of adverse reactions in patients with COVID-19 infection treated with chloroquine / hydroxychloroquine.
Be cautious until you have more data
So what stance should we take? Above all, one must be cautious. It seems clear that, before choosing to recklessly self-medicate, it is advisable to wait for a greater body of scientific evidence. In this way, it will be possible to prevent other people from following the counterproductive advice of illustrious leaders.
Although it is frustrating not being able to treat people who are suffering, with the data currently available we cannot conclude that the benefits of hydroxychloroquine outweigh the risks.
The “friendly” relationship between hydroxychloroquine and COVID-19 is not clear at this time and we must wait to confirm whether we are dealing with “close friends or enemies”.
Francisco López-Muñoz, Associate Professor of Pharmacology and Vice-Rector for Research and Science, 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.
