between danger and miracle drug, opinions differ

CHLOROQUIN. Chloroquine creates as much hope as mistrust in the fight against the coronavirus. It became in a few days a highly political subject, which divides doctors as much as politicians.

[Mise à jour le 26 mars 2020 à 12h19] Chloroquine still crystallizes hope and caution. Danger for some, miracle drug against coronavirus for others, difficult to see clearly in this ocean of contradictory statements, coming both from political figures and from members of the medical world. One thing is certain, the government’s position: we treat the most serious cases of coronavirus with chloroquine and we await the results of clinical trials for the rest. The distrust of this molecule usually used against malaria should not obscure the fact that other patients are undergoing regular treatment with chloroquine, whose recent interest is causing the rupture of various drugs in which it is present. “The recent craze for chloroquine should not prevent patients who usually need these treatments from having access to them,” warned Jérôme Salomon, the director general of health, on Wednesday evening in his daily point on Covid-19. Community pharmacists will now be forced to dispense these drugs only on medical prescription, he added.

Chloroquine, or hydroxychloroquine, has been the subject of fierce debate among doctors and politicians since Professor Didier Raoult, French specialist in infectious diseases, working in the faculty of medicine of the University of Aix- Marseille and the IHU Méditerranée Infection, published the results of its first tests on 24 patients with coronavirus. The latter has multiplied since speaking on the supposed benefits of the molecule. Didier Raoult even went so far as to offer patients feeling coronavirus symptoms to come to the CHU in Marseille for testing and possibly treatment, which caused a large queue outside the Timone hospital on Monday . However, the World Health Organization (WHO) calls for caution regarding chloroquine. For now, the tests carried out with the molecule concern only too few patients, which prevents them from making it a reliable drug against Covid-19.

In France, the government, via the Minister of Health Olivier Véran, said it was in favor of more extensive clinical trials and currently underway on a European scale, in at least 7 countries, since March 22. In the meantime, the High Council of Public Health issued an opinion this Monday, March 23, indicating that chloroquine could certainly be administered to patients suffering from “serious forms” of coronavirus, but only in a strict medical protocol and on “collegial decision of the doctors”. It cannot be marketed and used on a larger scale, for “less severe” forms.

Olivier Véran has indicated that he will sign a decree to this effect. The latter will regulate the use of chloroquine for “hospital medical teams who wish”, but will prevent “any prescription” of chloroquine “in the general population”. Guest of the TF1 8:00 pm Monday March 23, Prime Minister Edouard Philippe nevertheless indicated that “from today, more than 800 patients will be able to enter a series of tests for this molecule and others” .

The Analysis, Research and Expertise Committee (Care), set up on Tuesday March 24 to advise Emmanuel Macron, is to provide opinions on the fight against Covid-19 and on treatments in the coming weeks. And the very new president of Care, Françoise Barré-Sinoussi, virologist and Nobel Prize in medicine in 2008, has already given her feeling, very decided on the question: it is necessary to wait “a study on a sufficient number of patients in conditions of extremely rigorous methodology to have reliable data “on chloroquine before generalizing its use. For this pioneer of HIV research, “there are very preliminary results, and we must ensure that there are no deleterious effects. There can be serious side effects including heart problems “. While many invoke the urgency to act and to generalize the use of chloroquine, she therefore also recommends at this stage to await the results of clinical trials currently conducted at European level.

Little known to the general public until recently, chloroquine is a molecule used in medicine in antimalarial treatments. In other words, it is used as a preventative before going to countries at risk, as in curative once malaria is contracted. Hydroxychloroquine is the most commonly administered substance by mouth. Chloroquine then has a hydroxyl group (the OH entity comprising a bonded oxygen and hydrogen atom). We speak most often of “hydroxychloroquine sulfate”.

Nivaquine and Plaquenil are the other terms often used for a few days about a potential treatment for coronavirus. These are actually the names behind which the molecules of chloroquine and hydroxychloroquine are marketed. Nivaquine is a brand of Sanofi that presents chloroquine in the form of a 100 mg scored tablet. Plaquenil, from the same pharmaceutical group, is composed of hydroxychloroquine sulfate in the form of 200 mg tablets. Chloroquine or hydroxychloroquine are also found under the brands Axemal, Dolquine and Quensyl. All these treatments are also used in the treatment of rheumatoid arthritis and lupus. In France, the only French manufacturer of chloroquine (Sanofi – NDLR) is currently working to be able to supply the establishments carrying out tests.

Taking chloroquine is not without risk for patients. The molecule is considered a “narrow therapeutic margin” drug, which means that the therapeutic effective dose is close to the toxic dose. Among the effects of chloroquine, the main ones concern cardiovascular disorders which can occur suddenly during treatment. A study by the Toulouse University Hospital going back to 2011 also evokes long-term effects on the retina, in other words after 5 to 7 years of treatment at 6.5 mg / kg / day. “The risk then increases further with the continued use of the drug,” wrote the CHU. Risks which explain in particular the very precise dosages used during the tests carried out in Marseille by Professor Raoult.

Monday, March 23, we learned that an Arizona resident had died, died after ingesting chloroquine phosphate, a product used in particular … to clean aquariums. This American in his sixties was notably inspired by the words of President Donald Trump, who praised the merits of chloroquine as a remedy against the coronavirus. The American head of state allowed himself to be convinced by Professor Didier Raoult, as much criticized as glorified for his tests considered positive, but also limited. The victim’s wife was also hospitalized.

If you consult the instructions for Plaquenil or Nivaquine, the list of undesirable effects and counter-indications is very long. Chloroquine should be avoided in case of allergy to hydroxychloroquine or its derivatives, of course, but also in case of retinopathy (retinal disease), deficiency in “Glucose-6-Phosphate Dehydrogenase” or porphyria (diseases of the blood), severe liver or kidney disease, or intolerance to certain sugars. It is also not recommended in case of pregnancy or breastfeeding or must at least be the subject of a medical opinion. Chloroquine is also incompatible with other treatments such as anxiety remedies (citalopram, escitalopram, hydroxyzine), depression (tricyclic antidepressants), psychiatric disorders (antipsychotics), vomiting (domperidone), bacterial or other antimalarial infections (for example, halofantrine or piperaquine). A cocktail with other drugs known to affect the heart rate can also be very dangerous.

As with many drugs, side effects are very numerous and sometimes frightening, although some are considered to be uncommon. They range from heart rhythm disturbances in some patients, to a risk of hemolysis (destruction of red blood cells) or a decrease in blood sugar levels, passing by an acute attack of porphyria, visual disturbances (visual acuity, color vision …), worsening of lesions in case of psoriasis, muscle stiffness, abnormal movements, tremors, nausea, stomach pain, diarrhea, vomiting, loss of appetite, itching, hives or sudden swelling in case of allergy, a rash of pimples or a “slate color of the skin or mucous membranes” or even rash of bubbles or detachment of the skin, discoloration or even hair loss, headache, buzzing ears to deafness, dizziness, convulsions, progressive muscle weakness or even muscle atrophy (myopathy), hepatitis in more rare cases … “This medication should only be taken under medical supervision “, still warn the notices that we have consulted. A complete ophthalmological assessment is sometimes recommended before treatment.

In France, Professor Raoult unveiled the results of his first tests on March 16 in a video shot at the IHU in Marseille with his staff. In summary, his clinical trials, conducted on 24 patients with coronavirus, would lead to the cure of three quarters of them after six days. The treatment consists of taking 600 mg of chloroquine per day for ten days “.” I am not an outsider, I am ahead “, said Didier Raoult at La Provence these last days, absolutely certain to have found the remedy against the coronavirus, annoying the passage of a few skeptical voices and the time lost according to him by the authorities. This is what led him from this Monday, March 23 to ensure the screening of coronavirus in all “feverish” people coming to the Institut hospitalo universitaire Méditerranée Infection, even if the regional health agencies (ARS), including that of the PACA region, ensure that screening tests are no longer intended to be Raoult and his teams want to start chloroquine treatment for positive patients. In the press release accompanying this campaign, the signatory doctors indicate that all patients with Covid-19, “don t many who are not very symptomatic have lung lesions on CT scan “, are treated. The treatment combines hydroxychloroquine, a derivative of chloroquine, and azithromycin, an antibiotic.

According to Professor Philippe Parola, head of the infectious diseases department of the Marseille IHU, linked to the team of Didier Raoult, “this combination of chloroquine and azithromycin meant that the number of patients who had received no longer had a detectable virus, that is, they were no longer contagious “on the first test. He denies being a “sorcerer”. “You don’t have to wait for patients to get worse and come to intensive care to see what my colleagues in intensive care are going through, that is to say a massive influx of patients who are often elderly and at a very advanced stage of the disease”, he told franceinfo. Philippe Parola also assures that other “clinical trials will be useful”. “But I don’t know when they will be available,” he regrets.

Professor Raoult extensively cited experiments carried out in China on the molecule, from which he was inspired: “The fact of ignoring what the Chinese said about chloroquine is delusional. They were the ones who had the patients to experiment , not us, “he said in an interview to Marianne. Several hospitals in China tested the molecule on their patients at the start of the epidemic, with the publication of some studies even going back to the beginning of January. But they did not provide a clear answer on chloroquine.

An article written by a team of pharmacologists from Qingdao University Hospital, published on February 19 and reported in the Japanese online scientific journal J-STAGE, states that “a lot of effort has been made to find effective drugs against virus in China “. And the conclusion is clear: “it has been shown that chloroquine phosphate, an old drug for the treatment of malaria, has apparent efficacy and acceptable safety against pneumonia associated with Covid-19”. To establish this observation, the authors rely on in vitro studies, then on the experience of 10 hospitals in Wuhan, Jingzhou, Guangzhou, Beijing, Shanghai, Chongqing and Ningbo. “The results of more than 100 patients have shown that chloroquine phosphate is superior to other treatments for inhibiting the exacerbation of pneumonia”, all “without serious adverse effects”. It is also pointed out that the anti-viral and anti-inflammatory potential of chloroquine may explain its “powerful efficacy” in the treatment of patients with Covid-19. A conference organized on February 15, 2020 with government experts approved the use of chloroquine in the treatment of pneumonia and its recommendation by the Chinese National Health Commission, said the text.

But another study, published on March 3 on the website of ZheJiang University, south of Shanghai, gave results more difficult to interpret. This involved (only) 30 patients in a still mild condition, half being treated with chloroquine, the other without the molecule. On arrival, 86.7% of the “chloroquine group” were negative for the coronavirus after 7 days of treatment, ie 13 patients. But in the same period 93.3% of the patients in the other group, or 14 patients, were also negative. All patients were considered to be cured after 14 days. Hydroxychloroquine therefore did not give any significant results, but the sample proved to be too thin to really assess its effects by “randomizing” the doses, the power of the treatment and by evaluating the relevance of choloroquine according to the severity cases.

On February 25 the Marseille IHU will already publish a video entitled “Towards a way out of the crisis?” highlighting Chinese advances. Two Chinese publications are cited there, which emphasize the value of chloroquine, “to accelerate the healing of patients” affected by the coronavirus. But the results of these tests would be unclear: this Monday, March 23, Philippe Klein, French doctor in Wuhan, epicenter of the global epidemic of Covid-19, assured on LCI that the tests conducted in China and having started well before those of Marseille had produced “no significant results” so far. Studies have also been carried out in Iran, South Korea and Saudi Arabia.

To get everyone to agree and to follow a strict protocol, a European clinical trial called “Discovery” was launched on March 22, 2020 in at least seven countries, including France. Four experimental treatments against the coronavirus will be tested on a total sample of 3,200 patients, including 800 in France. These four treatments are the combination of the anti-viral and anti-infectious agents remdesivir, lopinavir and ritonavir, other combinations of these three treatments with or without beta interferon, used against multiple sclerosis, and finally the treatment based on hydroxychloroquine. . Inserm, the organization that oversees medical research in France, indicates that five French hospitals are participating in the trials, but not the IHU Mediterranean. In France, Director General of Health Jérôme Salomon praised this approach, considering it essential to produce “all, all together, urgent scientific knowledge in good conditions so that solutions appear quickly, whether negative or positive” . The results should be available 15 days after the start of treatment, that is, in the first week of April.

Pending the results of clinical trials, chloroquine is causing debate among scientists, some believing that it should be generalized, others believing that the molecule must continue to follow clinical tests according to the conventional protocol before d be used more massively. Other medical professionals place the cursor in the middle: they are not against tests, but they wait to see to decide whether or not to favor chloroquine as a remedy for coronavirus. This is the case of François Bricaire, infectiologist and former head of department at the Pitié-Salpêtrière hospital in Paris. “The advantage is a known product (…) We don’t take a lot of risk using it,” he reacted on March 23, when asked about the LCI antenna. It is notably on the basis of this argument that the Marseille IHU conducts its tests directly on patients, even before the publication of the results of the European clinical trial.

Among politicians too, the molecule arouses enthusiasm on the one hand, distrust on the other. Among the most convinced, we find the current mayor of Nice Christian Estrosi, himself struck by the coronavirus and who considers himself cured after being treated with chloroquine. “We don’t have time to experiment on mice,” said the former interior minister. The deputy LR Valérie Boyer, also contaminated and treated with the treatment of Didier Raoult, says to “trust this professor and his teams”. “I would like to thank them for the hope they give us in front of the Covid-19,” she said on Twitter. Bruno Retailleau, chairman of the LR group in the Senate, urged the government not to “fall behind” on the issue. Seven LR deputies also wrote to Emmanuel Macron asking him to speed up on chloroquine, according to the letter that Le Figaro obtained. On the left, however, we are cautious.

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