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1.
Infektsionnye Bolezni ; 20(3):104-112, 2022.
Article in Russian | EMBASE | ID: covidwho-2274927

ABSTRACT

The aim of this study was to analyze the efficacy and safety of using etiotropic therapy with favipiravir and molnupiravir that can selectively bind and inhibit not only SARS-CoV-2 proteins but also other RNA-containing pathogens of acute respiratory diseases. High transmission of pathogens, the risk of becoming chronic, frequent complications, cases of co-infection with several pathogens, which can lead to a more severe course of the disease, insufficient vaccination effectiveness, all this requires additional strategies for both prevention and treatment of acute respiratory viral infections. RNA-dependent RNA polymerase (RdRp), which has no equivalent in human cells, is involved in RNA synthesis and is an excellent therapeutic target for diseases caused by RNA viruses, including SARS-CoV-2. The long process of drug development and the "reuse" of drugs approved for other indications or successfully tested in terms of safety and tolerability pose the challenge of rapid establishment of an effective drug, including for the treatment of severe cases of COVID-19.Copyright © 2022, Dynasty Publishing House.

2.
Drug Development and Registration ; 12(1):215-226, 2023.
Article in Russian | Scopus | ID: covidwho-2266947

ABSTRACT

Introduction. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus (severe acute respiratory syndrome-related coronavirus 2). COVID-19 is now expected to stay with us for many years as a recurring disease. Molnupiravir and favipiravir are oral antiviral drugs with anti-RNA polymerase activity. The Russian Health Ministry has approved molnupiravir and favipiravir for the treatment of COVID-19. The study describes development and validation of high-performance liquid chromatography – tandem mass spectrometry (HPLC-MS/MS) method for the simultaneous determination of β-D-N4-Hydroxycytidine and favipiravir in human blood plasma. The method could be applied in pharmacokinetic study of molnupiravir and favipiravir. Aim. The aim of this study is to develop and validate a HPLC-MS/MS bioanalytical method for the determination of β-D-N4-Hydroxycytidine and favipiravir in human plasma. Materials and methods. The determination of β-D-N4-Hydroxycytidine and favipiravir in human plasma by HPLC-MS/MS. The samples were processed by 0.1 % formic acid in acetonitrile. Internal standard: promethazine. Mobile phase: 0.01 mol/L Ammonium formate buffer solution (Eluent A), 0.1 % formic acid and 0.08 % aqueous ammonia in water/acetonitrile 10: 90 (Eluent B). Column: Shim-pack GWS C18, 150 × 4.6 mm, 5 μm. Analytical range: 50.00–10000.00 ng/mL for β-D-N4-Hydroxycytidine, 250.00–20000.00 ng/mL for favipiravir in human plasma. Ionization source: electrospray ionization. Detection conditions: 260.00 m/z → 82.10 m/z, 260.00 m/z → 111.00 m/z, 260.00 m/z → 127.95 m/z (β-D-N4-Hydroxycytidine);156.15 m/z → 65.95 m/z, 156.15 m/z → 85.00 m/z, 156.15 m/z → 113.10 m/z (favipiravir);285.05 m/z → 198.05 m/z (promethazine). Results and discussion. This method was validated by selectivity, suitability of reference standard, matrix effect, calibration curve, accuracy, precision, spike recovery, the lower limit of quantification, carry-over effect and stability. Conclusion. The HPLC-MS/MS method for quantitative determination of β-D-N4-Hydroxycytidine and favipiravir in human plasma was developed and validated. The analytical range was 50.00–10000.00 ng/mL for β-D-N4-Hydroxycytidine, 250.00–20000.00 ng/mL for favipiravir in human plasma. This method was applied to investigate the pharmacokinetics of molnupiravir and favipiravir. © Komarov T. N., Karnakova P. K., Archakova O. A., Shchelgacheva D. S., Bagaeva N. S., Shohin I. E., Zaslavskaya K. Ya., Bely P. A., 2023.

3.
Farmatsiya i Farmakologiya ; 10(6):573-588, 2022.
Article in English | EMBASE | ID: covidwho-2251079

ABSTRACT

Currently, there are data that that make it possible to speak about a high clinical efficacy of the use of succinic salt of tyrosylD-alanyl-glycyl-phenylalanyl-leucyl-arginine (hexapeptide succinate) for the COVID-19 treatment. This article is devoted to the results of clinical trials of the original Russian drug based on it. The aim of the study was to evaluate a clinical efficacy, safety and tolerability of intramuscular and inhalation use of hexapeptide succinate in complex therapy in comparison with standard therapy in patients with moderate COVID-19. Materials and methods. The research was conducted from February 28, 2022 to November 22, 2022 based on 10 research centers in the Russian Federation. The study included hospitalized patients (n=312) over 18 years of age with moderate COVID-19 who had undergone a screening procedure and were randomized into 3 groups: group 1 received standard therapy in accordance with the Interim Guidelines in force at the time of the study, within 10 days;group 2 received hexapeptide succinate (Ambervin Pulmo) intramuscularly at the dose of 1 mg once a day for 10 days;group 3 received hexapeptide succinate (Ambervin Pulmo) 10 mg once a day by inhalation for 10 days. Results. According to the results of the study, therapy with the drug hexapeptide succinate, both intramuscular and inhaled, provided an acceleration of recovery up to the complete absence of the disease signs in more than 80% of hospitalized COVID-19 patients. By the end of the therapy course with the drug, more than 60% of patients had met the criteria for discharge from hospital and could continue the treatment on an outpatient basis. About 70% of patients in the inhalation group and 80% in the intramuscular hexapeptide succinate injection group had concomitant diseases (hypertension - 28%, obesity - 14%), which indicates the effectiveness of this drug use in comorbid patients. The use of the drug contributed to the restoration of damaged lung tissues, normalization of oxygenation, the disappearance of shortness of breath and a decrease in the duration of the disease symptoms compared with standard therapy. As a result of a comparative analysis of adverse events in terms of their presence, severity, causal relationship with the therapy and outcome, there were no statistically significant differences between the treatment groups. Conclusion. Thus, the results of the clinical study of the succinate hexapeptide efficacy and safety showed the feasibility of using the drug in pathogenetic therapy COVID-19 regimens.Copyright © 2022 Volgograd State Medical University, Pyatigorsk Medical and Pharmaceutical Institute. All rights reserved.

4.
Infektsionnye Bolezni ; 20(3):104-112, 2022.
Article in Russian | EMBASE | ID: covidwho-2233983

ABSTRACT

The aim of this study was to analyze the efficacy and safety of using etiotropic therapy with favipiravir and molnupiravir that can selectively bind and inhibit not only SARS-CoV-2 proteins but also other RNA-containing pathogens of acute respiratory diseases. High transmission of pathogens, the risk of becoming chronic, frequent complications, cases of co-infection with several pathogens, which can lead to a more severe course of the disease, insufficient vaccination effectiveness, all this requires additional strategies for both prevention and treatment of acute respiratory viral infections. RNA-dependent RNA polymerase (RdRp), which has no equivalent in human cells, is involved in RNA synthesis and is an excellent therapeutic target for diseases caused by RNA viruses, including SARS-CoV-2. The long process of drug development and the "reuse" of drugs approved for other indications or successfully tested in terms of safety and tolerability pose the challenge of rapid establishment of an effective drug, including for the treatment of severe cases of COVID-19. Copyright © 2022, Dynasty Publishing House.

5.
Infektsionnye Bolezni ; 20(3):104-112, 2022.
Article in Russian | EMBASE | ID: covidwho-2217851

ABSTRACT

The aim of this study was to analyze the efficacy and safety of using etiotropic therapy with favipiravir and molnupiravir that can selectively bind and inhibit not only SARS-CoV-2 proteins but also other RNA-containing pathogens of acute respiratory diseases. High transmission of pathogens, the risk of becoming chronic, frequent complications, cases of co-infection with several pathogens, which can lead to a more severe course of the disease, insufficient vaccination effectiveness, all this requires additional strategies for both prevention and treatment of acute respiratory viral infections. RNA-dependent RNA polymerase (RdRp), which has no equivalent in human cells, is involved in RNA synthesis and is an excellent therapeutic target for diseases caused by RNA viruses, including SARS-CoV-2. The long process of drug development and the "reuse" of drugs approved for other indications or successfully tested in terms of safety and tolerability pose the challenge of rapid establishment of an effective drug, including for the treatment of severe cases of COVID-19. Copyright © 2022, Dynasty Publishing House.

6.
Farmatsiya i Farmakologiya ; 10(5):432-445, 2022.
Article in English | EMBASE | ID: covidwho-2217824

ABSTRACT

Since the beginning of the pandemic, repeated attempts have been made to develop etiotropic therapy for a novel coronavirus infection. Hydroxychloroquine, lopinavir/ritonavir, etc. derivatives were used as antiviral agents, however, they demonstrated a low efficiency and an insufficient safety. In this connection, other groups of drugs with a more effective and safe pharmacological profile are currently being actively used. The aim of the study was to analyze the literature references on the efficacy and safety of antiviral drugs for the COVID-19 treatment. Materials and methods. When searching for the materials for the review article writing, such databases as PubMed, Google Scholar, e-Library were used. The search was carried out on publications for the period from January 2020 to September 2022. The key queries were: COVID-19, etiotropic therapy;immunological drugs;antiviral drugs;interferons. Results. Currently, there are various degrees of effective etiotropic drugs for the treatment of COVID-19 patients. The review has considered a few groups of drugs that are of interest from the point of view of etiotropic therapy: immunological drugs (anticovid plasma, the drugs based on antiviral antibodies, the drugs of recombinant interferons-alpha2 and -beta1, as well as interferon inducers, i.e., the drugs based on double-stranded RNA sodium salt, and others);drugs that block the penetration of the virus into the cell (umifenovir);the drugs that disrupt the process of the viral replication (favipiravir, remdesivir, molnupiravir, nirmatrelvir/ritonavir). Conclusion. Synthetic antivirals, in particular favipiravir, molnupiravir, remdesivir, and nirmatrelvir/ritonavir, have the largest evidence base for their efficacy and safety. The search for new effective and safe etiotropic drugs for the treatment of COVID-19, as well as the collection and analysis of post-registration data on the drugs already used in clinical practice, continues. Copyright © 2022 Volgograd State Medical University, Pyatigorsk Medical and Pharmaceutical Institute. All rights reserved.

7.
Farmatsiya i Farmakologiya ; 10(4):371-386, 2022.
Article in English | EMBASE | ID: covidwho-2155963

ABSTRACT

The article presents the data from an open, two-stage, multicenter study on the efficacy and safety evaluation of a combined drug (a fixed combination of nirmatrelvir 300 mg and ritonavir 100 mg) in the complex therapy in COVID-19 patients. The aim of the study was to assess the safety, tolerability and pharmacokinetic parameters of the fixed combination of nirmatrelvir 300 mg and ritonavir 100 mg in healthy volunteers, the efficacy and safety assessment of the drug in the combination therapy compared with the standard therapy in COVID-19 patients. Material and methods. An open two-stage multicenter clinical study to assess the main pharmacokinetic parameters, safety, and efficacy against COVID-19 of the drug nirmatrelvir 300 mg and ritonavir 100 mg combination (Skyvira PROMOMED RUS LLC, Russia) in the adult population, included 2 stages. At stage 1, safety, tolerability and pharmacokinetic parameters were evaluated in healthy volunteers (over 18 years of age) in order to confirm their comparability with the literature data known for a set of active substances. Phase 2 assessed efficacy and safety in COVID-19 patients. As a part of the second stage, the study involved 264 patients (men and women aged 18 to 80 years), who had been divided into two groups. The first group patients (n=132) received the study drugs (nirmatrelvir 300 mg and ritonavir 100 mg) - 1 tablet twice a day with an interval of 12+/-2 hours for 5 days in combination with pathogenetic and symptomatic therapy. The second group patients (n=132) received standard therapy in accordance with the approved Temporary Guidelines for the Prevention and Treatment of Novel Coronavirus Infection (Version 15 dated February 22, 2022). Results. During the study, none of the patients from the (nirmatrelvir + ritonavir) group experienced a transition of the COVID-19 course to a heavier severity level, in contrast to the patients in the standard therapy group. The study participants included patients with comorbidities (68% of the general population), with risk factors for COVID-19 progression to a heavier severity level and the risk of hospitalization (75% of the general population). There were no cases of COVID-19 progression Copyright © 2022 Volgograd State Medical University, Pyatigorsk Medical and Pharmaceutical Institute. All rights reserved.

8.
Drug Development and Registration ; 11(3):220-229, 2022.
Article in Russian | Scopus | ID: covidwho-2057050

ABSTRACT

Introduction. Coronavirus disease (COVID-19) is an acute infectious disease caused by SARS-CoV-2 (severe acute respiratory syndrome-related coronavirus 2). Favipiravir is a synthetic prodrug with antiviral activity used for the treatment of COVID-19. There are oral and parenteral dosage forms of favipiravir. Compared with oral administration, parenteral administration has some advantages. Developing a method for the determination of favipiravir in human blood plasma is necessary for performing the analytical part of clinical studies of favipiravir for parenteral administration as an infusion, studying pharmacokinetics, and choosing the optimal dosage of the drug. Aim. The aim of this study is to develop and validate a method for quantitative determination of favipiravir in human plasma by high-performance liquid chromatography with ultraviolet detection (HPLC-UV) for pharmacokinetic studies. Materials and methods. Determination of favipiravir in human plasma by HPLC-UV. The UV detection was set at 323 ± 2 nm. The samples were processed by methanol protein precipitation. Internal standard: raltegravir. Mobile phase: 0.1 % formic acid in water with 0.08 % aqueous ammonia (eluent A), 0.1 % formic acid in acetonitrile with 0.08 % aqueous ammonia (eluent B). Column: Phenomenex Kinetex®, C18, 150 × 4.6 mm, 5 μm. Analytical range: 0.25–200.00 μg/mL. Results and discussion. This method was validated by selectivity, calibration curve, accuracy, precision, spike recovery, the lower limit of quantification, carry-over effect and stability. Conclusion. We developed and validated the method of quantitative determination of favipiravir in human plasma by HPLC-UV. The analytical range was 0.25–200.00 μg/mL in human plasma. The method could be applied in pharmacokinetics studies of favipiravir. © Komarov T. N., Karnakova P. K., Archakova O. A., Shchelgacheva D. S., Bagaeva N. S., Shohin I. E., Zaslavskaya K. Ya., Bely P. A., 2022.

9.
Farmatsiya i Farmakologiya ; 10(2):217-228, 2022.
Article in English | Scopus | ID: covidwho-1912455

ABSTRACT

The article presents modern scientific data on long-term clinical and pathogenetic effects of the antiviral drug Areplivir (Favipiravir) in patients with metabolic syndrome in the post-COVID period. The aim of the article is to study long-term cytokine-mediated (IL-6/sIL6r and LIF/sLIFr) pathogenetic effects of the favipiravir (Areplivir®) based drug on the incidence of complications in patients with metabolic syndrome in the post-COVID period. Material and methods. With the approval of the local ethics committee at the N.P. Ogarevs Mordovia State University (Protocol No. 5 dated May 17, 2020) “An open prospective comparative study of the Areplivir® (Favipiravir) drug effectiveness in reducing the risk of complications in the post-COVID period in patients with metabolic syndrome” in the Republic of Mordovia was carried out. The study included 190 metabolic syndrome patients who received the outpatient treatment for COVID-19 at Saransk polyclinics from February 2021 to March 2021. The case of COVID-19 was diagnosed in accordance with the current Temporary Guidelines for the prevention, diagnosis and treatment of the new coronavirus infection. Results. The analysis of the metabolic syndrome patients' follow-up within 1 year after undergoing COVID-19, revealed significant differences in the incidence of complications depending on the intake of the favipiravir based drug. The patients who were administrated with favipiravir at the early stage of infection, were characterized by lower serum levels of four members of the interleukin 6 family - IL-6 (IL-6, sIL6r and LIF, sLIFr) 10, 30 and 180 days after a clinical and laboratory recovery (p<0.001). The average statistical changes in the IL-6/sIL6r system of the group administrated with favipiravir, were 90%, and they were higher than in the group not administrated with antiviral drugs. In the group of the patients administrated with favipiravir, there was a significant (p<0.001) positive dynamic of the sLIFr indicator, while in the comparison group, there was an increase in this indicator. A protective effect of the early favipiravir use was characterized by a decrease in the frequency of cardiovascular complications, a 2.66-fold decrease in the risk of a stroke and the ACS in the post-COVID period. Conclusion. The areplivir therapy in the acute period of coronavirus infection made it possible to timely reduce the viral load. It helps to correct the pro-inflammatory vector of the immune response at the post-COVID stage and, accordingly, reduces the risk of progression of atherosclerosis, transient cerebrovascular accidents with a cognitive decline, an endothelial dysfunction, and can be considered a secondary prevention of life-threatening cardiovascular complications. © 2022 Volgograd State Medical University, Pyatigorsk Medical and Pharmaceutical Institute. All rights reserved.

10.
Farmatsiya i Farmakologiya ; 10(1):113-126, 2022.
Article in English | EMBASE | ID: covidwho-1887390

ABSTRACT

Research in the development of new therapeutic agents with a wide spectrum of the antiviral activity and a low ability to develop resistance remains the main dimension in combating the global threat to public health. The need for a parenteral form of favipiravir was dictated by the necessity to increase the efficacy of therapy in COVID-19 inpatients. This dosage form has expanded the possibilities of drug therapy in the inpatients, for whom a therapeutic effect acceleration and a high safety profile of the drugs used are especially important. The aim of the article is the evaluation of the efficacy and safety of a medicinal product containing favipiravir for the parenteral administration against the background of pathogenetic and symptomatic therapy, in comparison with standard therapy in hospitalized COVID-19 patients. Materials and methods. An open, randomized, multicenter comparative study was conducted in 6 research centers in the Russian Federation to evaluate the efficacy and safety of favipiravir, a lyophilisate for the preparation of a concentrate for the infusion solution administrated to the patients hospitalized with COVID-19. Screening procedures and randomization were completed in 217 patients, 209 of which had completed the study in accordance with the protocol. Results. Between the study groups, statistically significant differences have been found out, making it possible to consider the hypothesis of the drug Areplivir (favipiravir) superiority for the parenteral administration over the standard therapy, which included favipiravir (p. o.) and remdesivir. A comparative analysis has shown that a course of therapy with the parenteral favipiravir drug leads to a significant improvement in the condition of patients with COVID-19, significant benefits in terms of the speed and frequency of improvement in the clinical status of patients, as well as a reduction in the hospital stay length. It has been proven that therapy with a drug containing favipiravir for the parenteral administration does not adversely affect the parameters of clinical and biochemical blood tests, urinalysis, coagulograms, vital signs and ECG, which indicates the therapy safety. The study drug is characterized by a high safety profile and tolerability. Conclusion. The versatility and resistance to mutations of RNA-dependent RNA polymerase make it possible to consider it as the main target for combating the most common RNA viruses that cause ARVI, that determines the need further studies of favipiravir to expand the range of its indications.

11.
Infektsionnye Bolezni ; 18(3):30-40, 2020.
Article in Russian | Scopus | ID: covidwho-1000751

ABSTRACT

Objective. Тo evaluate the efficacy and safety of favipiravir (Areplivir) in patients with coronavirus disease 2019 (COVID-19) and compare it with recommended standard therapy. Patients and methods. Two hundred men and women aged between 18 and 80 years with COVID-19 were randomized into this study. The experimental group included patients who received favipiravir, whereas the control group comprised patients who received causal therapy in accordance with the latest version of the temporary methodical recommendations of the Ministry of Health of Russia ‘Prevention, diagnosis, and treatment of coronavirus infection (COVID-19).’ The efficacy and safety of therapy were evaluated by assessing clinical improvement using the WHO Ordinal Scale for Clinical Improvement, clinical and laboratory parameters, findings of chest computed tomography (CT), and elimination of SARS-CoV-2. We also analyzed the frequency and type of adverse events, need for invasive and non-invasive ventilation, and death rates. Results. Our analysis has demonstrated significant benefits of favipiravir over standard therapy in terms of the time to clinical improvement (in the experimental group it was 4 days shorter on average), time to recovery, frequency of recovery after 10 days (44% of patients from the experimental group and 10% of patients from the control group had no clinical signs of the disease at this time-point), and frequency of virus elimination by day 10 of therapy. Treatment with favipiravir was associated with a significant improvement in the lung condition (according to CT), normalization of laboratory parameters, and saturation level. Favipiravir has demonstrated a good safety profile similar to that of standard therapy. There was no difference in the frequency of adverse events between the experimental and control groups. Conclusion. The use of favipiravir for the treatment of SARS-CoV-2 infection reduced the time to clinical improvement by 4 days on average compared to standard therapy, ensured improvement of the lung condition (according to CT scans), and facilitated virus elimination in more than 90% of patients, thereby promoting faster recovery. Favipiravir had a good safety profile and was well tolerated by patients. This treatment regimen was shown to be effective, sufficient, and clinically reasonable to achieve good outcomes. Timely initiation of therapy with favipiravir (Areplivir) improves disease prognosis and reduces the global socioeconomic burden of the current pandemic. © 2020, Dynasty Publishing House. All rights reserved.

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