The cure Covid-19: list of drugs and conditions of their application

In the last two weeks the flow of news about the discovery of drugs for the treatment of coronavirus infection, the early clinical trials of new drugs or even the use of drugs outside the studies (ie, without proven efficiency) is infinitely increased, according Meduza.

Чем лечат Covid-19: список препаратов и условий их применения

Photo: shutterstock

Much of the discussion was provoked by the statements of the US President Donald trump about an old anti-malarial drug hydroxyquinoline as a substance capable of becoming “one of the greatest discoveries in the history of medicine.” A few days after the statements trump the head of the Federal medico-biological Agency Veronika Skvortsova announced the start of trials in Russia, another anti-malaria substance mefloquine. And on Wednesday, April 1, American management under the control over foodstuff and medicines (FDA) issued a permit for the use of antimalarial drugs outside of clinical trials.

First of all, read this short Chapter. Self-medication can be deadly!

Before discussing how to treat this news, which is evidence of the effectiveness of these drugs based on what their mechanism of work and other challenging and interesting topics, very important again to say the most mundane things against the backdrop of loud background information is constantly forgotten.

  • On March 31, 2020 there is no specific antiviral drug against COVID-19, the effectiveness of which has been proven in clinical studies and which would be recommended for use by the world health organization (who).
  • Evidence-based medicine requires clinical trials of interventions for safety and effectiveness, and it takes time: depending on the phase of research — a few months or even a couple of years. The epidemic of coronavirus is actively developing only three months.
  • If a drug, device, or therapy involved in the study, this does not mean that they really work and are safe: study for, and you need to set, like it or not.
  • Clinical studies sometimes fail. More precisely, this: clinical studies often fail than not fail.
  • In a situation when in severe disease there is no specific medications, physicians may use drugs that seem appropriate based on the General concepts of the mechanism of disease development and operation of medicines. Every decision can be a mistake — but know this will be possible only after conducting full-fledged clinical trials.
  • The vast majority of substances that are discussed in this text, it is impossible to buy in Russia.
  • Therapy (if required) must appoint a physician.
  • Most drugs are poisons.
  • Self-medication can be very dangerous. Trying to “prevent” COVID-19 have already died a few people.

Only if we bear all this in mind, you can fully discuss the potential routes of exposure to the virus, its life cycle, differences in the mechanism of the antiviral drugs and other topics that represent purely academic, but not practical interest for the vast majority of readers.

What is happening with the therapy COVID-19 — clinical guidelines

In the treatment of patients with coronavirus doctors focus not primarily on scientific publications or the results of clinical trials (although that counts too), and who recommendations and national clinical guidelines.

The first temporary recommendations from the Russian Ministry of health released 29 January 2020, they are among the possible antiviral drugs addressed the following substances (read more about them below): ribavirin — antiviral drug used in the treatment of severe acute respiratory syndrome SARS/SARS; the HIV protease inhibitors lopinavir and ritonavir; and immunomodulator — interferon is recombinant IFN-β1b.

The last (fourth) version of this document (i.e. interim Ministry of health recommendations), updated 27 March, no mention of ribavirin, but considers in addition to the already mentioned anti-malarial drugs chloroquine and hydroxychloroquine, as well as talisman — a drug based on antibodies. The authors emphasize that there is no objective evidence for the efficacy of all these drugs in COVID-19, therefore, the appointment treatment “must be accompanied with the receipt of voluntary informed consent of the patient.”

Who in their clinical recommendations regarding COVID-19 also recognizes that “now there is no evidence to recommend any specific treatment”. However, employees of the organization continually monitor experimental therapies and conduct updated list of drugs that are used within the organization — both within clinical trials and beyond.

In addition to the above-mentioned substances and their combinations in this list who also have corticosteroids, other antiretroviral drugs (antiretroviral protease inhibitor darunavir and reverts inhibitors emtricitabine and tenofovir), cytostatics (rukolaine and builtins), immunosuppressants, other types of interferons, antiviral drugs licensed for treatment of influenza (balaclavas, marbocyl, favipiravir, Arbidol/umifenovir) and many other substances.

To give a comprehensive description of each of the substances, and even of all groups on the mechanism of action is unlikely to succeed. If you want a deeper dive into the topic in the end of the article there are links where you can study all available public information for all therapeutic options — and a table of the most large-scale clinical trials.

Further we will talk only about the most high-profile drugs, which, on the one hand, who are considered sufficiently promising to be included in an international study — but on the other hand, has received wide media coverage. This receiver, Kaletra (lopinavir + ritonavir) and, of course, anti-malarial drugs — chloroquine and its analogues.

The Solidarity program under the leadership of who: four kinds of therapy, four drug

On March 18 the next meeting of the who on the situation of the coronavirus, the head of the organization Tedros Ghebreyesus announced the start of large-scale international project of clinical research under the name Solidarity (Solidarnost’), in which the infrastructure for the collection of data on clinical trials against COVID-19 in different countries.

The idea of the project is to simplify the research: in the collection of information will be able to participate not even the most advanced medical centers under emergency load. Paperwork for registration of patients will be minimized.

According to the description, which leads the journal Science, will be sufficient to enter patient information on the who website to inform about the available in hospital drugs and to send an electronic copy of the informed consent. The system then randomly allocate the patient in the experimental group or the placebo group (drugs, of course, needs to be in the hospital — they who will not bring), and doctors will only report the final results of treatment: time of discharge and the possible need for an artificial lung ventilation (ALV).

18 March it became known that “Solidarity” has been joined by Argentina, Bahrain, Canada, France, Iran, Norway, South Africa, Spain, Switzerland and Thailand. Will Russian hospitals to participate in the program, not officially reported. The Ministry of health of Russia at the time of publication of the material did not respond to a request for “Medusa”.

It is important to note that the program Soldarity participate in all four therapies:

  • rendezesi
  • chloroquine or hydroxychloroquine
  • lopinavir + ritonavir
  • lopinavir + ritonavir + β-interferon (IFN-β1b)

They considered who the most promising.

Chloroquine, hydroxychloroquine and other anti-malarial drugs

What is it? Chloroquine — similar to the natural substance quinine a synthetic antimalarial drug, discovered in 1934 by German chemist Hans Andersson. Hydroxychloroquine — a very similar substance, which differs from chloroquine only two atoms (hydroxyl group OH) and approved for medical use by the American FDA in 1955. Mefloquine — forprostate on the same structural basis as all other quinolines, but significantly different from that of chloroquine and hydroxychloroquine; developed by the U.S. military in the 1970s, was used as an analogue of quinoline — after to spread drug resistance. As antimalarial remedies these drugs are quite old, but can still be recommended for use.

What is the mechanism of action? All these tools are made to combat malaria, however, around the early 2000s, scientists began to discuss the two side-views of activity: wide anti-virus effect and impact on the immune system. In 2003, in the midst of the SARS outbreak, the Italian scientists led by Roberto Cauda suggested the use of chloroquine to combat coronaviruses and described a possible mechanism of antiviral activity.

Briefly, it is that chloroquine penetrates the endosome membrane vesicles, which are formed inside the cells and changes their pH (in malaria there is the same, but with the cells of the parasite — the malaria parasite). After that, the enzymes that worked in endosome and require a strictly defined level of acidity, are inactivated.

Some viruses enter a cell this way, through education endosome, therefore, chloroquine can theoretically block the penetration of such a broad spectrum of viruses, inactivating essential for viral penetration enzymes. However, at the molecular level the mechanism of antiviral activity of all these substances is not installed. In addition, understanding this process is complicated by their impact on the immune system during viral infection, especially when complications like acute respiratory distress syndrome (when required ventilator), plays a key role.

Why could work? Chloroquine — simple and cheap substance that can be taken in tablet form (as opposed, for example, receiver). It is not without side effects, but is generally considered quite safe. Chloroquine blocks a good entry into the cell viruses SARS-CoV-1, MERS, and SARS-CoV-2 in vitro, i.e. in cell cultures. Previously, such results were shown for Chikugunya virus and Dengue.

Why wouldn’t it work? Antiviral effect requires a fairly high concentration of the substance. In addition, in vivo experiments on model animals, and randomized clinical trials Chikugunya and Dengue have not yielded any positive effect. In the experiments with SARS-CoV in special lines of mice that suffer from analogue middle East respiratory syndrome MERS, the use of chloroquine showed small positive results, but the concentration of virus in the blood is not decreased. In human studies, which are now being discussed, the situation was the opposite: the concentration of the virus fell, while significant clinical differences between the groups for a short time research has been found.

What else is important to know? After the speeches, trump about the use of antimalarial drugs for the treatment of COVID-19 among specialists turned heated discussion about how justified the statements now about the effectiveness. According to the journal Science, the position of the American President primarily affect a small French study of a group of renowned virologist Didier Raul (he is known by the discovery of huge mimivirus and original anticarcinoma).

In the work, preceded by several quite small for Chinese studies, the observation of 42 patients, half of whom were given hydroxychloroquine in combination with azithromycin for six days was measured by the concentration of the virus in smears from the nose. The researchers conclude that the drug inhibits the replication of the virus and proved its effectiveness, but this study, many scientists have questions.

First, they noticed that it is not a blind study in which doctors and patients knew what they are getting. Moreover, study participants chose to get them in the experimental group or control — and this decision, as you know, is affected by the severity of the condition. Second, the size of the control and experimental groups was very small. Third, the fence material with the help of a smear may not be quantitative and the concentration of the virus in it may be the result of random factors. Finally, the decrease in the concentration of the virus is not in itself a guarantee of healing; especially such diseases, the lethality associated with disruption of the immune system in acute respiratory syndrome. Read more about the claims this work can be read here, here, here and here.

The arguments for and against the use of hydroxychloroquine who had dedicated ad hoc expert meeting, the results of which the document was created, where it is summarized the current status of research material. The solution, as mentioned above, it is customary for the inclusion of substances in the study of Solidarity.

Short and clear: Proven efficacy against COVID-19 there is no need to wait for the results of large scale clinical trials.

“Kaletra” (lopinavir + ritonavir) with optional interferon

What is it? Two protease inhibitor that used in antiretroviral therapy for HIV. Approved for this purpose in the United States in 2000.

What is the mechanism of action? Lopinavir inhibits one protease (3CLpro), which is necessary for the virus to cut a large propeptide, which already produces other viral proteins, including those necessary for reproduction (replication) of the virus. Lopinavir itself is rapidly destroyed by proteases in human liver, so it is used in combination with another inhibitor with ritonavir.

Why could work? Lopinavir inhibits replication of the SARS and MERS coronaviruses in vitro and in animal models. Lopinavir alone or in combination with interferon improved clinical outcomes in experiments involving monkeys and some patients with MERS.

Why wouldn’t it work? Lopinavir has already failed in a relatively large clinical study conducted in China. It was attended by 199 patients with COVID-19; members of the experimental group was given 400 mg of lopinavir and 100 mg ritonavir for two weeks, but no improvement in comparison with the control group was found. In addition, a significant number of people were recorded side effects.

Short and clear: Proven efficacy against COVID-19 there is no need to wait for the results of large scale clinical trials.

Receiver

What is it? Analogue one of the “letters” of RNA, synthesized by chemists from the pharmaceutical company Gilead in 2012.

What is the mechanism of action? Substance refers to the large class of nucleotide analogues, among which are often looking for specific antiviral agents. The substance can include the viral enzymes in the synthesis of new RNA, however, due to the fact that it is not “real” nucleotide after its incorporation into RNA is the open circuit — and the virus, thus, cannot reproduce.

Why could work? Receiver works in vitro against many a very broad spectrum of RNA viruses, including the new coronavirus and Ebola virus. Group Ralph Baric, one of the most famous experts on coronaviruses in the world, have demonstrated the effectiveness of receiver in animal models of MERS even before the current pandemic.

Why wouldn’t it work? Receiver is a patented drug of Gilead, and its use outside the US is difficult — especially now, when the matter came high demand, and the company is under pressure from the public. Gilead has had to abandon its monopoly on the production of receiver.

The second difficulty with receivera is that it is given in injection form and can not be preformed. This creates difficulties for preventive use, although the most effective receiver in the early stages of the disease.

There are other problems: coronaviruses, in contrast to the influenza virus and many other viruses are RNA polymerases that can correct their mistakes. In such circumstances, the use of only one nucleotide analogues, without additional suppression of this ability can lead to quick formation of resistance.

Short and clear: Proven efficacy against COVID-19 there is no need to wait for the results of large scale clinical trials.

Alternative therapies

At the end of March in the international database ClinicalTrials.gov it was 260 clinical studies of drugs or other therapy against COVID-19. Approximately the number of studies was in China, on the relevant national website. Among all these experimental interventions have and cell therapy, and the well-known poison colchicine and popular in Russia, Arbidol, and the transfusion of the serum had been ill, and, of course, all of the above antiviral drugs included in the who study.

To give an adequate description of each of these potential drugs is impossible.

As reported ForumDaily:

  • A new virus was discovered in the Chinese city of Wuhan in December 2019. In 2020 it covers all continents except Antarctica. On 11 March, the President of the United States Donald trump has imposed a ban on entry into the United States from the EU. The ban came into force on Friday, March 13, and will last at least 30 days. In particular, it will affect people visiting the Schengen area for the last 14 days.
  • On 13 March, the tramp of coronavirus introduced in the U.S. nationwide state of emergency.
  • March 11, the who declared the situation with coronavirus pandemic, covering more than 110 countries. With symptoms COVID-19 caused by a coronavirus, can be found here.
  • The virologist’s advice on how to protect themselves from infection — the link.
  • Using the panic in the society because of the epidemic, the scammers have come up with several schemes to get victims ‘ personal data and money. The most common ones can be found here.
  • Panicked due to emergency, Americans are buying up large quantities of toilet paper, but can’t explain why it during an outbreak.
  • Trump has signed a law granting paid leave due to the coronavirus. Who can count on paid holidays, please click here.
  • All the news about the coronavirus please refer to our special projects.

IN THE UNITED STATES

treatment

coronavirus

Special projects

antimalarial препаратFacebookVkontakte

bookmark