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During the autumn-winter months, influenza circulates more often, also contributes to a greater proportion of flu-like diseases, and sometimes it comes to serious epidemics (seasonal). the incidence of infection depends on the basic immunity of the population. it should be noted that influenza viruses are constantly changing every year their antigenic structure (jefferson t.). fda offers two main classes of anti-flu drugs for use: m2 protein inhibitors (this includes remantadine) and neuraminidase inhibitors (zanamivir and oseltamivir). however, increasing resistance to existing antiviral drugs among influenza viruses, which are constantly changing, underlines the need to develop alternative interventions for influenza prevention and / or therapy. flu is an acute respiratory illness that can be caused by the influenza viruses a and b. complications due to the disease can occur, especially among children and the elderly.
Rimantadine (alpha-methyl-1-adamantane-methylamine hydrochloride) was approved for use in the United States in 1993, in the former USSR since 1969. It is intended for the prevention and treatment of influenza A in adults and for the prevention of children over 1 year old. Remantadine is an M2 ion channel inhibitor that inhibits the replication of influenza A virus, mainly blocking the ion channel of the M2 protein, thereby preventing the fusion of the virus and host cell membranes and the release of viral RNA into the cytoplasm of infected cells.
Influenza is most often caused by a group A virus. The classification of influenza viruses as A or B is determined by nucleoprotein and matrix proteins, which are part of the viral envelope. Influenza A has 3 subtypes. Influenza is still associated with significant morbidity and mortality. People with chronic lung or heart disease are at higher flu mortality; and 80–90% of deaths occurred in people 65 years of age or older. The most common signs and symptoms of influenza include a sudden increase in body temperature, sore throat, myalgia, an unproductive cough, and sometimes several days of severe malaise. Flu-related complications and mortality most often occur due to pulmonary complications in the elderly or in patients with other concomitant diseases. Pneumonia is either primary viral pneumonia associated with high mortality, or, more often, secondary bacterial pneumonia after an acute flu episode. Mixed viral and bacterial pneumonia can also occur due to flu. In geriatric patients, acute pneumonia can aggravate congestive heart failure or accelerate the development of myocardial infarction. Other serious complications include myositis, pericarditis, encephalitis, transverse myelitis, and sometimes Reyes syndrome (in children) or renal failure.
Despite the availability of effective vaccines, only about 20% of patients with a high risk of morbidity receive vaccinations annually. In addition, the flu vaccine does not fully protect against all strains of the disease, and protection may decrease several months after vaccination. For HIV-positive patients, even those with minimal or no symptoms, the risk is increased due to a reduced antibody response to influenza vaccines. Only vaccination of 70–80% of the population will be effective, and this will help to reduce the prevalence of the disease and the associated mortality. Antiviral drugs do not prevent disease. In older people, the process of generating antibodies against vaccination in optimal concentrations can take up to 6 weeks. Remantadine may provide protection during this interim period. The effectiveness of vaccination does not decrease with the simultaneous use of rimantadine; actually the effect is additive. Remantadine did not have an adverse effect.This effect on antibody production has been determined in several studies in adults or older adults on the effects of influenza A. Remantadine therapy for influenza A has accelerated clinical recovery, improving pulmonary function and, as a rule, reducing subsequent transmission of the virus. In a pediatric study, the virus release decreased during the first 2 days of therapy, but after its termination, the proportion of patients secreting the virus increased compared with the continuous use of the drug. Possible explanations for the increased release of the virus after cessation of rimantadine administration include interference with the cellular immune response or a delayed or altered response of the host cell that controls the release of the virus caused by the administration of rimantadine. The elderly treatment study showed a rapid quantitative decrease in viral titers in the first 24 hours, but titers were comparable in the placebo group on day 3. No increase in virus secretion was detected during therapy and when monitoring more than 7 days. The presence of drug-resistant influenza A viruses for rimantadine has been recognized since 1965, but no reduction in the clinical efficacy of drugs has been reported to date. Rimantadine licensing was delayed in 1989 due to the emergence of drug-resistant influenza A virus during prevention and treatment. However, no naturally-occurring drug-resistant viruses have been identified. One of the strategies used to reduce the development of drug resistance of strains may include a shorter duration of therapy (1-3 days) and the use of rimantadine only in high-risk populations. Using combination antiviral therapies may be the second strategy. And besides this, as one of the options, isolation of patients with a known drug-resistant virus can prevent the transmission of the virus.
Remantadine it is slowly and well absorbed in the digestive tract, and maximum concentrations are reached after about 6 hours. It has a large distribution volume and a long half-life. In healthy adults, half-lives range from 13 to 65 hours (25.4 hours on average) and from 20 to 65 hours (32 hours on average) in people aged 70 years or more. Binding to plasma proteins of rimantadine is about 40%. The drug in the liver is extensively metabolized, with ↓ 25% of the dose excreted unchanged in the urine; about 75% is excreted within 72 hours as hydroxylated metabolites. In severe renal or hepatic insufficiency, the half-life is approximately doubled, which requires a dose reduction.
The pediatric population is especially important for study, since the child contributes to the transmission of infection both within the family and in society as a whole. Two independent outbreaks of influenza A occurred when rimantadine was studied for prophylactic use. Thus, rimantadine determined the infection rate in the family at 73% and the incidence of influenza-like disease at 78%. So, rimantadine was more effective than placebo in the prevention of influenza A. The drug is also more effective in preventing infection. Remantadine should not be used for postexposure. Thus, rimantadine appears to be more effective than placebo in the treatment of influenza A virus in the early stages of the infection process. Pharmacokinetics of a single dose of rimantadine in adolescents and children. Single doses of rimantadine were given to children and young people to evaluate the safety and pharmacokinetics of this antiviral compound. The half-life of rimantadine in young people was 27.7 ± 4.9 hours for tablets and 27.8 ± 8.0 hours for drugs in the form of a syrup. A total of 10 children aged 5 to 8 years received rimantadine syrup. The half-life of rimantadine in children was 24.8 ± 9.4 hours. A single dose of rimantadine was well tolerated by young adults and children (Anderson E.L., Van Voris L.P., Bartram J., Hoffman H.E., Belshe R.B., 1987).
For antiviral agents to be effective, they must be taken within 48 hours of the onset of flu symptoms. Antiviral drugs shorten the duration of the disease by reducing the severity of certain symptoms. Using Remantadina it is advisable if the disease is of a viral nature and the drug affects the virus. For optimal treatment, patients with influenza symptoms should receive antiviral drugs in the early stages (as early as possible), and family doctors should accurately and quickly diagnose the disease.
Remantadine causes a low incidence of side effects. The most common side effects in all age groups were associated with damage to the central nervous system or gastrointestinal tract, including insomnia, headache, nervousness, nausea, and abdominal pain. Concentration difficulties, psychomotor dysfunction, and neuropsychic side effects have not been reported. This makes Remantadine an attractive choice for treatment / prevention of influenza A. Convulsions have been reported, so patients with epilepsy should be given rimantadine with caution.
Due to its pharmacokinetic profile, Remantadine may be useful for patients with mild or moderate renal failure. Dosage reduction is recommended only for patients with creatinine clearance of 0.17 ml / s or less. Dose adjustment is not recommended in patients with mild or moderate renal failure. However, patients should be monitored for side effects to monitor the accumulation of rimantadine and its metabolites. Remantadine is approved for prevention, but not for the treatment of influenza A infections in children. Remantadine Approved for administration twice a day, but has a pharmacokinetic profile that will allow you to dose once a day. The clinical significance of the drug-resistant influenza virus should be further explored (Wintermeyer S.M., Nahata M.C.).
Recently, an experimental alternative strategy has been developed based on the anti-influenza synergistic combination of inhibitors with different modes of action. This approach overcomes the barrier of drug resistance, increases the effectiveness and reduces the severity of adverse reactions of the drug by reducing the dose (Govorkov A.I., Webster, 2010). Several types of influenza virus are susceptible to various drugs. And therefore, depending on the strain of the virus, combined treatment with oseltamivir and rimantadine is recommended as an acceptable alternative (Simeonova L., Gegova G., Galabov A.S., 2012). Extensive research and optimistic data from preclinical and clinical studies with new compounds strongly support the idea that influenza infection will be prevented and treated much more successfully in subsequent years with a significant reduction in morbidity, severity and mortality. However, no matter how effective a particular monotherapy is, the risk of drug resistance still exists. Monitoring of viral drug resistance and alternative approaches to counteracting resistance should be applied worldwide (Simeonova L., Gegova G., Galabov A.S., 2006).