Combined Therapy of Influenza with Antiviral Drugs with a Different Mechanism of Action in Comparison with Monotherapy
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Aleksandr Fyodorovich Popov et al /J. Pharm. Sci. & Res. Vol. 10(2), 2018, 357-360 Combined therapy of influenza with antiviral drugs with a different mechanism of action in comparison with monotherapy Aleksandr Fyodorovich Popov, Pacific State Medical University, 690600 Russia, Vladivostok, prosp. Ostryakova, 2 Mihail Yur'evich Shchelkanov, Far Eastern Federal University, 690600 Russia, Vladivostok, Sukhanova St., 8 Kseniya Aleksandrovna Dmitrenko, Pacific State Medical University, 690600 Russia, Vladivostok, prosp. Ostryakova, 2 Anna Ivanovna Simakova, Pacific State Medical University, 690600 Russia, Vladivostok, prosp. Ostryakova, 2 Abstract Increasing of drug-resistance in influenza virus is a new serious challenge for global healthcare. Existing antiviral therapy is incompletely effective and there is a need for improving the efficacy of current treatment strategies. One of the possible ways to overcome the resistance of influenza virus is to combine the use of antiviral drugs with various mechanisms of action. To assess the efficacy of influenza А (Н1N1) pdm09 monotherapy with antiviral drugs (oseltamivir or umifenovir) versus combination of two antiviral drugs with different mechanism of action (oseltamivir+kagocel and umifenovir+kagocel), an open comparative study was conducted. All 200 patients with confirmed by RT-PCR analysis diagnosis influenza А (Н1N1) pdm09 were randomly sorted to four group of 50 persons. Group 1 received monotherapy with an influenza virus fusion inhibitor umifenovir (Arbidol); Group 2 - monotherapy with a competitive inhibitor of influenza´s neuraminidase enzyme oseltamivir (Tamiflu); Group 3 - an influenza virus fusion inhibitor umifenovir (Arbidol) in combination with an interferons inductor Kagocel; Group 4 - a competitive inhibitor of influenza´s neuraminidase enzyme oseltamivir (Tamiflu) in combination with an interferons inductor Kagocel. The clinical efficacy of antiviral therapy was assessed in dynamic with the following parameters: the time of temperature normalization, the time of intoxication and catarrhal symptoms reducing, the frequency of the main clinical manifestations and the incidence of complications. The end point in the duration of symptoms assessing was the absence of symptoms of the disease within 24 hours. All therapy was within the limits of registered medical use for the drugs. Patients groups were equivalent in terms of admission to hospital, age, sex, and the length of treatment from the onset of the disease. The study demonstrated that the combination of drugs oseltamivir (Tamiflu) and umifenovir (Arbidol) with the antiviral agent Kagocel significantly increases the therapeutic efficacy compared with the corresponding monotherapy. Efficiency was proved with reducing the incidence of major clinical manifestations of indicators, reducing the duration of clinical symptoms and a decrease in the frequency of aggravations. Keywords: influenza, А (Н1N1) pdm09, resistance, combined therapy, monotherapy, kagocel, umifenovir, oseltamivir INTRODUCTION selection of the virus escape mutants ("genetic drift") occurs, so Influenza and other acute respiratory viral infections are the most that by the end of the current epidemic season influenza viruses mass socially significant diseases. In recent years, epidemics may differ markedly from their predecessors at the beginning of caused by respiratory viruses have been characterized by a severe the same epidemic season. Fifth, as a result of the genetic course of the disease and a high mortality rate from these reassortment and adaptation of zoonotic influenza viruses to infections worldwide. According to the World Health mammalian cells, new subtypes of the virus with a pandemic Organization, in spite of the mass vaccination against influenza in potential may occur. The most epidemic and pandemic potential developed countries, 3–5 million people every year become ill belongs to type A influenza virus, which circulates both in human only with severe forms of influenza in the world. In the Russian and in animal population (wild birds and poultry, pigs, bats) in the Federation, the incidence of influenza and other ARVI is 20–40 form of various subtypes. In recent decades, it has become million people per year, including 40–60 % of children. Influenza apparent that overcoming the species barrier for these viruses is infection (caused by Influenzavirus, B and C genus of the not a rare phenomenon [4–5]. Development of vaccines against Orthomyxoviridae family) plays an important role in exacerbating new strains of influenza virus would require a certain amount of chronic diseases and developing complications, which are often time, financial costs; and chemotherapy will be the only means to the cause of patient’s death: it has been shown that the presence of restrict the spread of the disease. chronic cardiovascular or lung diseases increases tenfold the risk Etiotropic drugs are the basis of antiviral influenza chemotherapy. of death due to influenza [1–3]. However, their widespread use in clinical practice leads to the Given the epidemiological relevance, WHO recommends emergence and rapid increase of resistant viral strains. Therefore, vaccination against influenza. However, there is a number of the issue of finding new and optimizing use of existing antiviral factors that put in doubt the vaccination as the only method of drugs remains relevant [6–10]. According to experts, one of the influenza prevention. First, incomplete population coverage by possible ways to overcome the development of resistance is the vaccination. Second, vaccines cannot completely eliminate the use of combinations of two or more antiviral drugs with different incidence of influenza, but reduce the risk of severe forms of mechanisms of action. The advantages of monotherapy in this disease, complications and fatal outcome. Third, the epidemic case may include not only a synergy of action, but first of all the process can be caused by various variants of influenza viruses, complexity of the formation of a genetic barrier for the emergence and the strain of vaccines, which is recommended by WHO twice of resistance, which in this case requires multiple mutations in the a year, does not always correspond to the current circulating genetic structure of the virus. epidemic strains. Fourth, under the action of collective immunity, 357 Aleksandr Fyodorovich Popov et al /J. Pharm. Sci. & Res. Vol. 10(2), 2018, 357-360 The purpose of this work is to compare the therapeutic efficacy of onset of the disease 2.0 ± 0.5 days) received monotherapy with oseltamivir (Tamiflu®) and umifenovir (Arbidol®) in the umifenovir; group 2 (23 men, 27 women, 29.2 ± 3.1 years, 2.7 ± monotherapy and in combination with an antiviral drug, widely 0.8 days) – monotherapy with oseltamivir; group 3 (26 men, 24 used in Russia and in a number of other countries, in the women, 23.6 ± 2.9 years, 1.9 ± 0.6 days) – combined therapy with composition of etiotropic ARVI and influenza therapy, namely an umifenovir and kagocel; group 4 (21 men, 29 women, 26.8 ± 3.0 inducer of interferons Kagocel ® [11]. years, 1.7 ± 0.6 days) – therapy with oseltamivir and kagocel. The control group was not formed for ethical reasons. METHODS Clinical efficacy criteria for antiviral drugs: An Scientific and research work was carried out from December 2013 assessment/analysis of the term of temperature normalization, to March 2016 by the staff of the Department of Infectious reduction of intoxication, catarrhal symptoms, frequency of the Diseases, located on the basis of Regional Clinical Hospital No. 2 main clinical manifestations and frequency of complications after of Vladivostok. The study included 200 adult patients admitted to the end of treatment compared with the condition before the start the hospital with a preliminary diagnosis of "moderate influenza". of treatment. For the assessment of the duration of symptoms, the Of 200 patients aged from 21 to 60 years (26.54.6 years), 100 end point was considered to be their absence within 24 hours. (50 %) were men (21–60 years old, 31.2 4.2 years), 100 (50 % ) Statistical processing of the obtained results was carried out – women (23–60 years old, 34.34.3 years). Influenza-infected using the methods of the empirical (calculating mean values and pregnant women were not included in the study. All patients had standard deviations) and parametric (Student’s t-test) approaches no history of influenza vaccination over the current epidemic using STATISTICA 6.0 software package (StatSoft, USA). period. The presence of influenza A infection was confirmed by a nasopharyngeal swab test using real-time reverse transcription RESULTS polymerase chain reaction (RT-PCR). Patients were hospitalized The severity of the disease was average in all patient groups and at various periods from the disease onset: from several hours to 3 was characterized by typical clinical manifestations of influenza days. [3–7]. The clinic was characterized by acute onset (100 %), rapid Therapy: All schemes of antiviral drugs use were prescribed rise of temperature to subfebrile (34.5 %) or febrile (65.5 %) strictly according to the instructions for the drugs use. Umifenovir values. In the acute period of the disease before the start of (Arbidol, Pharmstandard, Russia) is an inhibitor of influenza treatment, patients had symptoms of general intoxication: virus fusion and endosome membranes. It was used in the form of weakness (100 %), headache (70 %), myalgia (61 %), loss of tablets (100 mg) in the monotherapy