A group of French scientists published in the International Journal of Antimicrobial Agents the results of a clinical study of the effect of a combination of two drugs - based on hydroxychloroquine and azithromycin - against the new coronavirus. According to preliminary data, such therapy may be effective in the treatment of COVID-2019.
What kind of coronavirus vaccines are being developed in Russia? More details
Pharmacodynamics and pharmacokinetics
The drug Chloroquine inhibits the synthesis of deoxyribonucleic acid (DNA) and leads to the death of asexual erythrocyte forms of plasmodium and dysenteric amoeba. The substance has the ability to bind free radicals and stabilize subcellular and cellular membranes.
Chloroquine preparations also inhibit the intensity of production of lysosomal enzymes, suppress chemotaxis and reactivity of lymphocytes, and inhibit neutral protease and collagenase . Reduce the intensity of platelet aggregation in capillaries.
Due to the ability of the substance to actively bind to nucleic acids , it has a pronounced cytotoxic effect, and it is this mechanism that underlies the nonspecific anti-inflammatory and immunosuppressive effect of the drug. Chloroquine also reduces the production and release of lymphokines, which suppresses allergic processes and the inflammation that accompanies them. The substance also has a beneficial effect on the excitability of the heart, reduces it, which causes an antiarrhythmic effect.
After entering the digestive tract, the drug is quickly metabolized, the maximum concentration in the blood is reached after 2-5 hours. Approximately half of the drug binds to albumin in the blood. The substance is well distributed throughout tissues and organs, especially large concentrations can be found in the liver, kidneys, spleen and lungs.
A stable and sustained concentration in the body is achieved after 7 days of administration. Chloroquine drugs penetrate well through the blood-brain barrier and placenta. About a quarter of the dose taken is metabolized in the body, the rest is gradually excreted unchanged. 3 days after the end of treatment, the concentration of lek. funds in the blood decreases by 50%. The drug is excreted through the kidneys. In case of kidney failure, problems may arise with the elimination of the drug, as it accumulates in the body. T1/2 is 1-2 months. The speed and intensity of the process depends on the pH of the urine; acidification speeds up the process, alkalization slows it down.
The medicine is quite effective in the fight against Plasmodium vivax, Plasmodium malariae, erythrocyte forms of many strains of Plasmodium falciparum and tissue forms of dysenteric amoeba.
Indications for use of Chloroquine
The medicine is used:
- for the treatment and prevention of all types of malaria ;
- with non-intestinal amoebiasis ;
- in patients with amoebic liver abscess ;
- for chronic and subacute forms of systemic lupus erythematosus ;
- in patients with all types of scleroderma ;
- for rheumatoid arthritis ;
- for photodermatosis and porphyria .
What kind of drug is chloroquine?
Chloroquine (lat. Chloroquinum) is a drug from the group of 4-aminoquinoline derivatives. Belongs to the group of quinolines - antimalarial drugs (the same group includes, in particular, hydroxychloroquine, quinine, quinidine, mefloquine and primaquine). According to the Russian Medicines Register, chloroquine is a white or off-white crystalline powder with a slight creamy tint and has a bitter taste. Easily soluble in water, slightly soluble in alcohol.
According to the World Health Organization, chloroquine was previously used as part of a therapy to treat tropical malaria. However, it is currently used more limitedly due to the development of resistance to the pathogen in most malaria-endemic regions: Africa, Southeast Asia, India and South America.
Medicines from the quinoline group also have antiamoebic and anti-inflammatory effects. They can be used as an antirheumatic agent, in the treatment of extraintestinal (hepatic) amebiasis, systemic lupus erythematosus, and also for photodermatitis.
Side effects
The medicine may cause unwanted reactions:
- nausea, vomiting, abdominal pain, lack of appetite;
- headaches , insomnia or drowsiness , dizziness , psychosis , convulsions ;
- myocardial diseases and changes in the electrocardiogram;
- thrombocytopenia , leukopenia , low blood pressure;
- allergic dermatitis , sun sensitivity;
- arthralgia , myalgia , hair loss, changes in hair and skin color.
With long-term treatment with the drug, the following may occur:
- corneal clouding, vision problems, retinal damage, noise and ringing in the ears.
Instructions for use (Method and dosage)
Orally or intravenously. Depending on the goal and the disease being treated with Chloroquine, different dosages and methods of administration are used.
Standard dosage for the prevention of malaria : 500 mg, 2 times a week, then 1 time on the same day of the week.
For amebiasis , use 1.5 grams of the substance per day, divided into 3 doses, one week. For the next week, the drug is taken at 750 mg per day, 3 times.
Then, from 2 to 6 months, drink 750 mg of the drug twice a week.
Rheumatoid arthritis - tablets take 0.25 g twice a day, one week. For the next year, take 250 mg every day.
Treatment of systemic lupus erythematosus - from 250 mg to 0.5 g of the drug is taken every day.
Publications in the media
(Chloroquinum) INN
Synonyms. Delagil, Rezokhin, Khingamin.
Composition and release form. Chloroquine tablets 0.25 g; 5% solution in ampoules of 5 ml.
Indications. Prevention and treatment of malaria; rheumatoid arthritis, systemic lupus erythematosus, scleroderma.
Pharmachologic effect. Causes the death of asexual erythrocyte forms of all types of plasmodia as a result of binding and changing the properties of their DNA. It also has a gamontocidal effect. Has a moderate immunosuppressive effect. Inhibits the synthesis of nucleic acids, the activity of some enzymes, immunological processes, inhibits the production of rheumatoid factor. Accumulates in white blood cells, stabilizes lysosomal membranes and inhibits the activity of many enzymes, including collagenase and proteases, which cause the destruction of cartilage tissue.
Pharmacokinetics The drug is quickly and almost completely absorbed from the gastrointestinal tract into the blood. Bioavailability - 89%. Peak plasma concentrations after oral administration are achieved within 3.5 hours. Communication with plasma proteins - 50%. The concentration of the drug in erythrocytes is 2-5 times higher than in blood plasma. Metabolized in the liver to form the active metabolite - desethylchloroquine. It is excreted slowly in the urine unchanged (47%) and in the form of metabolites; excretion increases with acidic urine. The drug may be present in the urine for months or even years after treatment is stopped.
Side effects. Dermatitis; abdominal pain, loss of appetite, weight loss; dizziness; nausea, vomiting; noise in ears; disturbance of accommodation, retinopathy; leukopenia; pigment deposition in the cornea; liver dysfunction; graying of hair; dystrophic changes in the myocardium.
Contraindications . Severe heart disease, impaired renal and liver function; diseases of the hematopoietic organs; severe neurological disorders; psoriasis; porphyria.
Adverse reactions when interacting with other drugs . Salicylates, corticosteroids and penicillamine enhance skin lesions caused by chloroquine.
Information for the patient. For the treatment of malaria, 2-2.5 g are prescribed per course of treatment. The course of treatment is 3-5 days. The drug is taken after meals. For the treatment of rheumatoid arthritis and connective tissue diseases, 0.25 g is prescribed once a day after dinner, 2-3 hours before bedtime. The course of treatment is 3-6 months. Missed dose: Take the missed dose as soon as possible; do not take it at all if there is almost no time left before the next dose; do not take double doses.
Overdose
- headache;
- disturbances of consciousness;
- vomit;
- vision problems;
- collapse;
- convulsions.
In case of severe overdose, respiratory depression occurs after 2 hours, which can be fatal.
In case of overdose, it is recommended to rinse the stomach and drink activated carbon in a dosage 5 times higher than the dose taken. The use of emetics is allowed. Your doctor may prescribe peritoneal dialysis and plasmapheresis .
Interaction
Prescribed with caution with cytostatics, Betamethasone , Phenylbutazone , prednisone , cyclophosphamide , Isoniazid , bromelain , Dexamethasone , with drugs containing gold, CGS, with Levamisole , with MAO inhibitors and other antimalarials, with valproic acid , penicillamine .
Antacids interfere with the absorption of the drug.
Caution should be exercised when using insulin , as Chloroquine enhances its hypoglycemic effect.
Combined use with cardiac glycosides can lead to glycoside intoxication.
The combination of algeldrate + magnesium hydroxide may reduce the absorption of chloroquine in the digestive tract. It is recommended to maintain a 2-hour interval between these drugs.
The medicine cannot be combined with Amiodarone , ribociclib . The drug reduces the anticonvulsant effect of Carbamazepine and the concentration of praziquantel in the blood plasma.
Lek. the product enhances the hepatotoxicity of ethyl alcohol.
Treatment of coronavirus with Chloroquine, effectiveness study
Along with other drugs ( favipiravir , remdesivir and others), Chloroquine is being tried to treat the COVID-19 coronavirus , the pandemic of which began in March 2021. The drug has good performance in the treatment of COVID-19 as an experimental agent. Clinical trials have already begun in China. However, a case of self-medication was recorded, which led to the death of the patient.
The drug is recommended in South Korea, China and Italy for the treatment of COVID-19. But it is noted that the product has an extensive list of side effects and cannot be used for patients with heart disease and diabetes . The studies also note that the substance hydroxychloroquine showed higher effectiveness and fewer adverse reactions.
Chloroquine/hydroxychloroquine in the treatment of patients with COVID-19
Doctors all over the world are currently searching for drugs to effectively treat patients with COVID-19. On April 21, during “Scientific Tuesday”, which was traditionally held online, clinical data on the use of two actively discussed drugs in drug therapy: chloroquine and hydroxychloroquine were presented to the research staff of the Federal State Budgetary Institution “National Medical Research Center for TPM” of the Ministry of Health of Russia. The report was made by a senior researcher at the Department of Clinical Cardiology of the National Medical Research Center for Therapy and Preventive Medicine, Ph.D. Yu.V. Mareev.
According to in vitro (test tube) studies, chloroquine and hydroxychloroquine suppressed the effect of the SARS-CoV-2 virus, which causes COVID-19. The possibility of using the drug in the treatment of COVID-19 was actively discussed after the publication of the work of P. Gautret et al. [1], which showed that on the 6th day of treatment, among patients who were given hydroxychloroquine, compared with those who were not given it, there were fewer virus-positive patients (according to PCR tests). And among the patients who were given a combination of hydroxychloroquine and azithromycin, there was not a single virus-positive patient on the 6th day of treatment. At the same time, this study has a number of limitations. First of all, it is necessary to note its small size (42 patients). Also, there was no randomization in the work, which means the results could be due to differences in patient characteristics rather than the actual effect of the drugs. In addition, it is worth noting that 6 patients were excluded from the hydroxychloroquine group, as well as the fact that clinical outcomes were not analyzed.
In addition, two more randomized studies were done in China. In the first study involving 30 people [2], there was no difference in the number of patients in whom the virus was absent on the 7th day of treatment according to PCR tests. The groups also did not differ in the time it took for body temperature to normalize. In a second study involving 62 people [3], the hydroxychlorine group showed faster normalization of body temperature and cough, as well as more pronounced positive dynamics according to lung CT.
It is obvious that the first clinical studies on the use of hydroxychloroquine, conducted in France and China, do not provide a definitive answer about the drug’s place in the treatment of COVID-19. Therefore, a number of randomized controlled trials have now been launched that will study the role of hydroxychloroquine and chloroquine both in the treatment of patients with COVID-19 and in the prevention of infection in medical personnel involved in the treatment of such patients. In this case, an important issue is both determining the feasibility of using drugs in general and finding optimal doses. Confirmation of the importance of the latter are the results of the ChloroCOVID-19 study [4], which was originally planned to compare the effectiveness of high and low doses of chloroquine, but after a trend towards an increased risk of death with a high dose of the drug was recorded, this part of the study was completed ahead of schedule.
As noted, speaking in the discussion, the head of the department of preventive pharmacotherapy, MD, Professor S.Yu. Martsevich, “in this case we saw randomized studies, the quality of which was very low; they did not meet the most basic requirements for such studies. Therefore, the evidentiary value of these randomized trials is low. However, according to him, there is an opinion that in exceptional cases the effectiveness of the drug can be confirmed without conducting an RCT. However, for this to happen, two conditions must be met: the evidence of the drug’s effects and the presence of competent studies of a lesser degree of evidence, namely, observational studies. Now, according to Sergei Yuryevich, the results of a large French observational study [5], based on a register of patients in four clinics, are being prepared for publication. This study showed a complete lack of effect of hydroxychloroquine.
Regarding the prevention of COVID-19 using this drug, its use is undesirable given the lack of convincing data and potential side effects. According to Professor S.Yu. Martsevich, this especially applies to patients with cardiovascular diseases.
Update: After the meeting, another observational study with hydroxychloroquine was published on medrxiv.org. This work assessed the risk of death and the need for mechanical ventilation (ALV) in 368 COVID 19 patients observed in veterans' clinics in the United States[6]. The work compared patients receiving hydroxychloroquine, a combination of hydroxychloroquine and azithromycin, and patients not receiving hydroxychloroquine. It should be noted that this is not a randomized trial, but a retrospective analysis of data. Patients receiving hydroxychloroquine or a combination of hydroxychloroquine and azithromycin had more severe disease, so the authors performed statistical analyzes to account for these differences. According to the work, the risk of death of patients was higher in patients receiving hydroxychloroquine compared to patients who did not receive it, but the risk of death in patients receiving a combination of hydroxychloroquine and azithromycin did not differ from those who did not receive hydroxychloroquine. The risk of mechanical ventilation did not differ between groups. The results of the work should be treated with caution (which was also indicated by the authors of the article), since any statistical analysis has its limitations, and statistical analysis cannot take into account differences in characteristics that were not included in the database. Thus, only the results of large RCTs will answer the question of the effectiveness and safety of hydroxychloroquine in patients with COVID 19.
Links:
[1] P. Gautret et al., “Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial,” Int. J. Antimicrob. Agents, p. 105949, Mar. 2020.
[2] J. CHEN et al., “A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19),” J Zhejiang Univ (Med Sci), vol. 49, no. February, pp. 1–10, Mar. 2021.
[3] Z. Chen et al., “Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial,” medRxiv, p. 2020.03.22.20040758, Apr. 2021.
[4] MGS Borba et al., “Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded , phase IIb clinical trial (CloroCovid-19 Study),” medRxiv, p. 2021.04.07.20056424, Apr. 2021.
[5] M. Mahevas et al., “No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial,” medRxiv, p. 2020.04.10.20060699, Apr. 2021.
[6] J. Magagnoli et al., “Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19,” medRxiv, p. 2020.04.16.20065920, Apr. 2021.
Reviews
The drug is often taken as a preventive measure before traveling to countries with low incidence of malaria.
Some reviews of Chloroquine drugs:
- “... I took this drug with my wife as a preventative measure. We drank the entire course. I did not notice any changes or adverse reactions. But when we arrived home from vacation, we were calm that everything was in order”;
- “...I was getting ready to go on a trip far abroad. While I was taking the course, I felt nauseous and dizzy. But I decided that it was better than getting sick”;
- “... I’ve been taking pills for a month now, treating amoebiasis. After 7 days of taking it I felt much better. It’s true that my vision has gone bad and I feel constant nausea.”
Can chloroquine be used as a treatment against coronavirus?
On March 20, a group of French scientists published the results of a clinical study of the effect of a combination of two drugs - hydroxychloroquine and azithromycin - against the new coronavirus SARS-CoV-2. Scientists studied the effectiveness of using hydroxychloroquine alone, as well as in combination with the antibiotic azithromycin.
The studies were carried out at the Méditerranée Infection Hospital of the University Hospital of the University of Marseille. They involved 36 adult patients, both with and without symptoms of COVID-19, who were confirmed to have the SARS-CoV-2 virus in a nasopharyngeal sample.
The patients were divided into two groups. The first included 16 people who were prescribed symptomatic treatment and antibiotics to prevent bacterial superinfection. The second group included 14 patients who took oral hydroxychloroquine sulfate for ten days. Six of them also received azithromycin to prevent superinfection. Doctors gave them daily electrocardiograms to check for side effects on their hearts.
On the fifth day, all six patients from the second group who received combination treatment tested negative for coronavirus; repeated testing also did not reveal the infection. Scientists note that the test group was very small and larger clinical studies are needed to confirm the results.
What kind of coronavirus vaccine is being tested in the USA? More details
US President Donald Trump said that chloroquine could be effective in treating coronavirus . “It may work, or it may not work... I have a good feeling about it,” the American president assured. In turn, the head of the Institute of Allergy and Infectious Diseases of the National Institutes of Health (USA), Anthony Fauci , commenting on Trump’s words, did not rule out that this drug can be used to treat the new coronavirus, but clinical trials are required.
