Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Drug generations that combat influenza A virus infection

Drug generations that combat influenza A virus infection Influenza viruses are significant human respiratory pathogens that cause infections and unpredictable pandemic outbreaks. M2 ion-channel protein, participating in the transmission of viral genetic materials into infected cells, is considered to be the crucial target for old-generation drugs such as rimantadine and amantadine. Neuraminidase protein, which is responsible for the replication of the influenza virus, is affected by the new generation of drugs, including oseltamivir (Tamiflu) and zanamivir (Relenza). The virus mutations that cause oseltamivir resistance are also described. This review presents the details concerning the treatment of influenza neuraminidase inhibitors against the H5N1 strain. It also describes virus mutations that cause resistance to oseltamivir and presents a new drug, peramivir, which is a neuraminidase inhibitor that was introduced against the H1N1 epidemic. This work specifies the details of the pharmacokinetics, dosing, toxicity, , and efficiency of the drugs being used against influenza A virus infections. Keywords: amantadine; M2 ion-channel protein; neuraminidase; oseltamivir; peramivir; rimantadine; zanamivir. Introduction For the treatment of influenza A virus, the new generation of drugs known as inhibitors of neuraminidase and the oldgeneration drugs that inhibit M2 ion-channel protein are administered. Neuraminidase inhibitors were introduced into medicine in 1999 as the followers of natural sialic acid substrate for neuraminidase [1]. They have greater *Corresponding author: Gabriela aroffe, Department of Molecular Biology, Faculty of Biological Sciences, University of Zielona Góra, Zielona Góra, Poland, E-mail: gzaroffe@gmail.com Jacek Leluk, Agata yniewska and Rafal Filip: Department of Molecular Biology, Faculty of Biological Sciences, University of Zielona Góra, Zielona Góra, Poland specificity and affinity for enzyme activity by complementing actions. Neuraminidase binds N-acetyl neuraminic acid located in the recesses, which are present on the top of each unit. Blocking reduces the spread of viral neuraminidase in the body. Inhibiting the neuraminidase activity prevents the release of progeny virions from cells infected with influenza virus and the sialic acid fragments are removed. The neuraminidase of the influenza A virus is a tetramer in the form of mushroom-shaped spikes on the virus surface and constitutes 5% to 10% of the viral proteins (Figure 1). It consists of four identical subunits, each composed of 469 amino acid residues. Neuraminidase combines with the N-acetyl neuraminic acid in the recesses, occurring on the peak of each unit; such inhibiting reduces the spread of viral neuraminidase in the organism. Influenza is widespread and there is no person who has not encountered by the virus. Every year, several million people come down with the flu. There is a small percentage of dying due to severe complications. Scientists are still working on drugs that largely reduce nuisance of the disease. The disease is transmitted through droplets. The largest number of cases occurs during seasonal epidemics at the end of the month of November to March. Virions are generally of spherical shape with a diameter of 80 to 120 nm [2] and appear as filamentous forms. The virus induces the morphological differentiation gene encoding a membrane protein M and genes encoding hemagglutinin and a nucleoprotein. The virion is surrounded by a double lipid envelope derived from the host cell (Figure 2). The genetic material of the virus is comprised of a single ribonucleic acid RNA with negative polarity. RNA virions A and B is in the form of eight segments, Type C is seven segments. The segments are associated with the nucleoprotein and polymerase PB2, PB1, PA form a ribonucleoprotein complex, which constitutes the core of the virion influenza. The core is surrounded by a protein membrane M1. The coating is a lipid-anchored membrane protein M2 together with the glycoproteins hemagglutinin and neuraminidase. Envelope glycoproteins on the surface protrusions form a rod shape [2]. Virus subtypes are isolated depending on the type occurring hemagglutinin and neuraminidase. There 2G. aroffe et al.: Drugs on influenza A virus infection M2 ion-channel proteins are sensitive to the old-generation drugs, including rimantadine and amantadine. M2 is situated in an envelope of influenza virus and creates a specific M2 ion channel. As a homotetramer, the channel is constructed out of four identical transmembrane domains with -helix conformations (Figure 3). Tetramerization is stabilized by intermolecular contact between C-terminal amphipathic helices. Inside the M2 ion channel, His37 acts as a pH sensor, whereas Trp41 plays a role in the gateway channel. This ion channel is activated by a low pH surrounding environment, where it is located due to the protonation of His37. The flow of protons through the M2 ion channel leads to the acidification of the virus interior. Allowing the dissociation of the channel protein from the viral nucleoprotein matrix, the viral genome is unlocked. A new generation of drugs, in comparison to older-generation drugs, has a lower number of adverse reactions, exhibits greater activity toward influenza types A and B, and causes less risk of the emergence of drug resistance in the strains. Figure 1:Neuraminidase tetramer. are 16 hemagglutinin subtypes (H1­H16) and 9 neuraminidase subtypes (N1­N9) distinguished. All of subtypes are present in waterfowl. There are subtypes H1 and H3 in equines, H3 and H7 in pigs and there are three subtypes H1, H2, H3 and two subtypes N1 and N2 in humans. There was also a statement of human infection by viruses that occur only in birds, which were subtyped A (H5N1), A (H9N2), A (H7N7), A (H7N3). Oseltamivir Oseltamivir is a new-generation drug [1] with the trade name Tamiflu, which was developed by C.U. Kim, W. Lew, Figure 2:Construction of the influenza virus. https://www.cdc.gov/flu/images/h1n1/3D_Influenza_black_key_pieslice_lrg.jpg G. aroffe et al.: Drugs on influenza A virus infection3 with the digestive system, such as nausea and vomiting. In some cases, of which the reliability has not been confirmed, the of the medicine also appear in the form of a rash, swelling on the face and tongue, hepatitis and wrong functional tests, abnormal heart rhythm, relapse of diabetes, mental confusion, and depressive bursts. The medicine cannot be administered to pregnant and breastfeeding women. Oseltamivir is a prodrug; its complete reaction develops after the metabolism changes in the body. Before the transformation, the drug is practically not active. Due to ethyl ester, it requires hydrolysis to accept the active form of carboxylate [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Figure 4). This discovery was possible using the techniques of drug development and investigating the X-rays of crystal structures in sialic acid and neuraminidase activity [4]. During the development of the drug, oseltamivir alone and its active metabolite were synonymously identified as GS4104 and Ro64-0796 and GS4071 and Ro64-0802. Figure 3:M2 ion-channel protein. The medicine is applied orally or in slime form at a dose of 75 mg twice daily for 5 days. Oseltamivir is readily and X. Chen in cooperation with the U.S. pharmaceutical company Gilead Science. Oseltamivir's influence involves the binding of viral influenza to the host cell, thus limiting the infection of penetrating in mucous membranes and reducing the infectivity of virus. Oseltamivir alleviates disease symptoms, fever, muscle pain, and headache on average from 0.7 to 1.5 days [1]. The medicine is applied in the case of prevention and uncomplicated treatment of acute influenza to humans who are 1 year or older when the disease symptoms have been identified within 2 days. The treatment is effective in approximately 60% to 70%. In humans with diagnosed disease before the end of 36 h, 38% of the symptoms are reduced by 1.5 days. If treatment is started within 12 h of the onset of fever time diseases reduced by 3 days. When treatment within 12 h of the onset of fever is initiated, the duration of the disease is reduced by 3 days. Oseltamivir is an effective drug that is tolerated by people in high-risk groups who suffer from cardiovascular disease and respiratory system disorders [3]. Oseltamivir is clinically well-tolerated medicine [3]. Adverse reactions that appear approximately after 2 days of its administration include disturbances connected Figure 4:Oseltamivir (atom colors: blue, nitrogen; red, oxygen; gray, carbon). 4G. aroffe et al.: Drugs on influenza A virus infection absorbed from the gastrointestinal tract and reaches the liver, whereas the active metabolite is created through the bloodstream and distributed throughout the organism, concentrating to a large extent in the upper respiratory tract [5]. Oral use of the drug leads to the activities of the main metabolites up to 80%; the maximum concentration in the organism is obtained after 3 to 4 h. The half-life phase inside the human body is from 6 to 10 h, with 3% plasma protein binding. In the elderly, the activity of the major metabolite is 25% stronger than in young adults [6]. There is no need for dosage adjustment for age because the drug is rapidly excreted by the kidneys due to glomerular filtration and active tubular secretion without further metabolism. The drug's metabolism does not influence liver functions. Children between 1 and 12 years old remove active metabolites from the body faster than older people. Infants above 1 year old actively metabolize and excrete the drug. The drug is not advised for infants below 1 year old [7]. and wild-type viruses retained their genotypic traits. These studies are not fully documented, so researchers are still working to gain more relevant and reliable results. Oseltamivir, which is known as a neuraminidase inhibitor during treatment, may cause the drug resistance of viruses. After the clinical research, three known mutations were defined in the neuraminidase gene of viral influenza type A as being less susceptible to exposure to the drug. R292K mutation (arginine lysine) substitution occurs at the site functional N2 neuraminidase. E119V mutation (glutamic acid valine) substitution occurs at the site of N2 neuraminidase. H274Y mutation (histidine tyrosine) substitution occurs within the N1 neuraminidase and interacts with the functionality of site. The research on viral point mutations can have a disturbed contagiousness and an ability to transfer operation in comparison to the wild-type virus. The changing degree can develop based on the mutations. Oseltamivir is a new-generation drug and suppresses the influenza A virus strain during replication. The medicine, when applied preventively as well as in the course of falling ill, effectively reduces the viral pathogenic effects. The medicine is given orally, and there is no significant contraindication for the age groups in which it is applicable. As opposed to older-generation medicines, it triggers fewer adverse effects, which additionally has good influence on weakened organisms due to illness. Clinical tests with naturally occurring strains performed in the laboratory confirm the effective action of the drug. The viral resistance to the drug is weak; so far, there are only three known mutations that affect the sensitivity of viral drug exposure. Oseltamivir is a promising drug in influenza A virus treatment until more effective and less resistant drugs are discovered. Drug resistance in the viral world is an extremely big problem because of the numerous mutations and gene-pool exchange between strains. Infections by this virus caused six deaths from those 18 infected. The virulence of the H9N2 strain A/ Hong/1074 was also studied [9]. The research was carried out in mice and humans who fell ill. The mice were divided into two control groups infected with viruses. One control group had been given drugs in doses of 1 and 10 mg/kg; the other control group was infected with the H5N1 virus of avian influenza A/Hong Kong/156/97. Oseltamivir inhibited the mortality in mice and kept them alive. Research on drug resistance The research team from St. Jude Children's Research Hospital in Memphis-Lauderdale acting on the virus strain H5N1 of avian influenza A/Hong Kong/156/97 investigated the effectiveness of the A/Hong Kong/ G1/97 (H9N2) and people infected with the influenza type A/Hong Kong/1074/99 (H9N2). A reduction of the virus' presence in the lungs and proliferation inside body was reported. Delaying therapy for 36 h increases the mortality rate of mice in comparison to the control sample. The oral application of oseltamivir at a dose of 0.1 mg/kg/day in combination with rimantadine (1 mg/ kg/day) effectively reduces and prevents the number of deaths in mice. The performed studies confirm the efficiency of the drug in the treatment of infections caused by H5N1 and H9N2 in mice. As a result of the research on the resistance of the virus to oseltamivir, Herlocher et al. isolated three type A viruses, each of them having a mutation in the gene responsible for neuraminidase and its resistance to the drug [8]. The research was carried out on ferrets. In earlier studies, the R292K virus mutation A (H3N2) is not transferred to another organism unlike the wild-type virus [8]. This model was used to examine whether the E119V mutant A (H3N2) virus and H274Y mutant A (H1N1) virus would be transferred under similar conditions. Both mutant viruses were carried, but the H274Y mutant required more than 100 times viral particles to infect ferrets and attacked the immune system much more slowly than the wild-type virus. The mutant Zanamivir Zanamivir is a medicine that is used in influenza virus infection in 19 countries [10]. It is a neuraminidase inhibitor G. aroffe et al.: Drugs on influenza A virus infection5 Figure 5:Zanamivir (atom colors: blue, nitrogen; red, oxygen; gray, carbon). ailments. It appears on the airway epithelium within 10 s of application. During clinical trials, the concomitant use of zanamivir combined with the influenza vaccines does not influence the production of antibodies. Zanamivir, when administered within 48 h of the onset of influenza symptoms, reduces the average disease duration by up to 2.5 days. It is indicated for the treatment of people above 50 years old who are at high risk of complications and patients suffering from cardiovascular disease, asthma, and diabetes. The prophylactic drug use in a dose of 10 mg/day for 4 weeks efficiently prevents the disease (67%) and the fever (84%). Zanamivir also can be used for children. During inhalation, the drug of active substance (10­20%) directly reaches the lungs [12]. The remaining dose is absorbed systematically from the throat with a frequency of 4% to 17%. A dose of 10 mg peak plasma concentration is reached after 1 to 2 h. Drug binding protein is below 10%. The half-life period lasts in the body from 2.5 to 5.1 h. Zanamivir is not metabolized in the body. It is excreted by the kidneys in unchanged form. In patients with kidney disease, dose modification is not required as this drug does not interfere with kidney function. In difficult cases, the drug can be administered intravenously and transported directly to the respiratory mucosa [13]. that efficiently inhibits the replication of the influenza A virus (Figure 5). Drug testing in mice has revealed effectiveness in the treatment of avian influenza H9N2, H6N1, and H5N1. The drug does not interact with other specifics. Its chemical structure is similar to the one of sialic acid; hence, it can fit into the substrate binding pockets without the necessity of conformational change [3]. Drug interactions with the participation of the guanidine group in the neuraminidase-active site relate to glutamic acid residues (Glu199 and Glu227), and glycerol hydroxyl groups bind to glutamic acid (Glu276). Arginine residue (Arg152), isoleucine at position 222, and tryptophan at position 178 participate in the process of drug binding pathway. However, the development of drug resistance is rare. Zanamivir triggers the adverse effects to a low extent [14]. Dosage recommended by doctors does not adversely affect lung function. Vesicle shrinkage and loss of body function were observed only in people suffering from asthma or other chronic lung diseases. Allergic reactions, swelling of the mouth and throat, and skin itching are uncommon . In some cases, dizziness, headaches, and problems with the digestive system were also observed. The liver enzyme level rises during long-term drug use. In a group of children between 5 and 12 years old, only some cases suffered from irritated pharyngeal cavity and a cough. The drug is not recommended for use in breastfeeding mothers because of the penetration of the drug into the milk. Studies in pregnant rats did not prove that zanamivir might trigger the development of birth defects in offspring. Zanamivir is an easy-to-use medicine due to its powder form, which is absorbed within 10 s after inhalation [14]. The drug works directly in the penetration of the virus into the body. It induces few adverse effects and may be used without any major contraindications in humans. Zanamivir is not metabolized in the body and excreted by the kidneys in unchanged form. This is a big advantage, The drug is applied by inhalation from a diskhaler in dry powder form [11]. The recommended dose for children above 7 years old and adults is 10 mg twice daily. On the first day of treatment, the next dose should be taken with at least 2 h time interval. Patients who have pulmonary diseases should preventively take bronchodilators. Due to the good tolerability of the drug, there is no need to adjust the dose for patients suffering from kidney 6G. aroffe et al.: Drugs on influenza A virus infection as it does not affect the liver. The medicine is applied in the treatment and prevention of influenza A virus. It effectively reduces the incidence and symptoms in case of illness. The quick action of the drug is especially needed in the treatment of groups of individuals who are more than 50 years old, as the overall immunity of the organism is much weaker and complications can be tougher in the course. and in patients undergoing hemodialysis. In patients with renal impairment, the recommended dose should be reduced to 600 mg. During clinical trials, the drug was not used in people below 18 years old. The dosage of the drug requires modification for adults. In October 2009, the U.S. FDA permitted the administration of the drug in cases of suspicion or substantiated illness with H1N1. The condition was drug resistance to other antiviral drugs used during an existing disease. The drug can be administered at a dose of not more than 600 mg/24 h in adults and children above 6 years old. In case of children below 6 years old, the dose should be adjusted according to body weight and used with precisely specified rules. The treatment should be carried out within 5 to 10 days. Longer treatment is provided only in case of continuous release of infectious virus strain and in critical situations. Peramivir Peramivir, an antiviral drug, is a neuraminidase inhibitor developed by BioCryst Pharmaceuticals, USA (www. biocryst.com). The drug is in the fourth phase of its clinical trials. On December 19, 2014, the U.S. Food and Drug Administration (FDA) approved RAPIVAB (peramivir injection), an intravenous neuraminidase inhibitor, for the treatment of acute uncomplicated influenza in patients 18 years and older who have been symptomatic for no more than 2 days. Peramivir, as a cyclopentane analog, binds to the active site of the neuraminidase of influenza virus strains A and B. The drug works on swine flu virus H1N1. RAPIVAB's approval was supported by data from more than 2700 subjects treated with peramivir in 27 clinical trials. The recommended dose of RAPIVAB in adult patients 18 years or older with acute uncomplicated influenza is a single 600 mg dose that is administered via intravenous infusion for 15 to 30 min. Peramivir is not recommended for use in pregnant or breastfeeding women or people suffering from severe mental disorders or kidney failure. This medicine should not be used by patients with Reye's syndrome. This drug should not be used in newborns, infants, and children. People who experience allergic reactions to other neuraminidase inhibitors or other ingredients should not take pharmaceuticals. Precautions should be taken in the event of serious bacterial infections. Patients should be constantly monitored. The drug is excreted by the kidneys in patients with renal impairment and the dose should be adjusted for the patient's conditions. Additionally, associated with the drug include dizziness, headaches, depression, anxiety and internal distraction, delirium, insomnia, and problems with the digestive system such as nausea, diarrhea, and vomiting. can be hematuria, cystitis, hypertension, abnormal liver enzyme activity, and anorexia. It is applied intravenously and quickly gets to the infected sites. It should not be given intramuscularly. The drug is delivered in the form of 200 mg in 20 mL vials. This medicine does not contain any preservatives. There is no bacteriostatic effect. To obtain the dilution, 0.9% or 0.45% sodium chloride is commonly used. RAPIVAB injection is compatible with 5% dextrose or lactated Ringers. It is diluted with the compounds that may contain glucose or other electrolytes. It cannot be administered with other drugs. It binds to plasma proteins (<30%). The drug is not completely metabolized in the liver and is excreted by the kidney; the half-life in the body in people without kidney problems ranges from 7.7 to 20.8 h. Renal clearance accounts for about 90% of the total clearance. There was no drug accumulation after repeated doses. Peramivir has been evaluated in terms of pharmacokinetics in healthy subjects with mild, moderate, or severe renal impairment Neuraminidase inhibitors in the treatment and prophylaxis of avian influenza By June 18, 2008, the World Health Organization (WHO) recorded 385 cases of individuals who were infected with bird (H5N1) influenza (www.who.int/csr/disease/avian_ influenza/guidelines/clinicalmanage07/en/); in 243 G. aroffe et al.: Drugs on influenza A virus infection7 cases, the infection ended with death. The mortality rate amounted to 61.5%. To prevent death and cure the illness, the WHO recommended oseltamivir, fast diagnoses of the virus, and treatment with medicine. In the case of avian influenza, oseltamivir treatment should be independent of the duration of influenza symptoms. According to an experiment conducted on animals, in case of H5N1 treatment, one should apply a 150 mg dose twice daily and extend the time of patient treatment to 7 to 10 days unlike the standard illness with seasonal influenza. The term extension of drug exposure [15] is based on the duration of viral replication, which is 15 to 17 days after the appearance of infection symptoms. Viral excretion from the organism can take up to 3 weeks. In patients infected by H5N1 with symptoms of diarrhea and vomiting, the administration of oseltamivir may be restricted, the dose should be modified, and ancillary drugs are also used. Neuraminidase inhibitors (zanamivir and peramivir or a combination therapy) can be administered intravenously by adding a neuraminidase inhibitor to amantadine or rimantadine. Before attempting treatment, health-care providers should confirm that the strain causing the infection is sensitive to the effects of these drugs. During clinical trials, it has been found that combination therapy and antiviral activity can reduce the risk of developing drug resistance. Animal experiments [16] also show that it is a good method to cure a sick patient. At present, virus resistance to amantadine and rimantadine is a fairly common problem and these drugs are ineffective against the H5N1 virus. When treating H5N1 infection [13], the development of the virus in the body should be monitored by taking samples of biological materials, such as throat swabs or tracheal aspirates, before starting the treatment, at 4 to 5 days on the therapy and 7 to 8 days after its commencement. Through research, we can identify the time to stop the replication of the virus in the body and determine whether the virus is excreted from the body and to diagnose whether it is a drug-resistant strain. Neuraminidase inhibitors [13] are drugs used in postexposure prophylaxis in patients exposed to the H5N1 virus. One should apply the pharmacological prevention with patients in groups of average and greater risk. The high-risk group includes people who have very close contact with individuals who are sick or infected with a virus from a dead animal and who have participated in decontaminating a contaminated environment. The medium-risk group includes people who have had direct contact with a single infected animal, a patient suspected of infection, medical personnel, and laboratory staff that lack appropriate personal protective equipment. Prophylactic treatment should coincide with the duration of exposure; for example, those involved in eliminating infected poultry should take medication 7 to 10 days after exposure to the virus. Zanamivir may be an alternative drug for the prophylaxis of oseltamivir applied after exposure to the virus. Old-generation drugs used to treat influenza Old-generation drugs used in the treatment of influenza A cause various and exhibit significant drug resistance [17]. The old-generation drugs that were used to treat influenza A virus include rimantadine and amantadine. Rimantadine Rimantadine belongs to flu medicines of the older generation, with the commercial name flumadina (Figure 6). It was discovered and patented in 1963 in the USA by William W. Richard with Du Pont & Co. [17]. Rimantadine is an inhibitor of the M2 ion-channel protein, as it inhibits the replication of the influenza A virus by blocking the ion channel through which the virus penetrates the cells. In the case of infection with influenza virus, it enters the host cell via receptor-mediated endocytosis. The drug is effective against all subtypes of influenza A [18], which previously caused infections in humans (H1N1, H2N2, and H3N2). It is not effective against Figure 6:Rimantadine (atom colors: blue, amino group; gray, carbon). 8G. aroffe et al.: Drugs on influenza A virus infection type B viruses because the M2 protein is unique to virus type A. It was also found that the drug is active against avian influenza H5N1. According to Clover, rimantadine has no impact on the amount of antibodies occurring in the body having defensive reactions to the virus. Tested samples proved that the presence of IgA antibodies in nasal secretions was reduced. In the study of influenza virus resistance to rimantadine and amantadine [19], more than 7000 viral strains in the interval from 1994 to 2005 were taken into account. The drug resistance increased from 0.4% to 12.3% among the viruses collected in South Korea (15%), Taiwan (23%), Hong Kong (70%), and China (74%) [9]. In a study conducted by the U.S. Centers for Disease Control and Prevention [20], 109 of 120 (91%) samples of H3N2 influenza viruses isolated from patients in the USA contained the amino acid at position 31 (asparagine) M2 protein, which confirms resistance to rimantadine and amantadine. This phenomenon is due to the point mutation in the M gene and leads to a change of amino acids in M2 protein. Mutants that cause resistance to the drugs are edible and can easily move to a wild strain of the virus and cause a typical flu. Paracetamol reduces the effectiveness of rimantadine by 11% and acetylsalicylic acid by 10% (bazalekow. mp.pl/leki/doctor_subst.html?id=4735). The simultaneous use of an intranasal trivalent vaccine with twp attenuated live virus strains of type A and B may affect the immunogenicity of the vaccine's weakening of the type A virus. Rimantadine treatment should be discontinued at least 48 h before vaccination and continue for 14 days after vaccination. Until now, there was no report of interactions with inactivated influenza vaccines. Treatment should be started within 24 to 48 h after the first symptoms of influenza (bazalekow.mp.pl/leki/ doctor_subst.html?id=4735) and continue for 5 days or until 24 to 48 h after cessation of symptoms. Adults and children above 14 years old should receive a dose of 100 mg twice daily, children between 11 and 14 years old 50 mg thrice daily, and children between 7 and 10 years old 50 mg twice daily. Among children between 1 and 6 years old, the drug may be applied after an analysis of ailments' benefits and under strict medical supervision. In patients above 65 years old with hepatic impairment suffer from renal insufficiency, the drug is used at a dose of 100 mg/day. The drug is given orally in the form of tablets or syrup, and it has a maximum plasma concentration after 6 h [21]. A dose's half-life is about 30 h in adults and children. Rimantadine is metabolized in the liver and less than 25% of the dose is excreted in the urine. In the elderly, rimantadine metabolism is prolonged 20% longer than in adults. In patients with chronic liver disease [22], the pharmacokinetics does not significantly change; in severe cases, the elimination half-life of the body is heightened. In case of severe renal failure [23], a rimantadine dose should be reduced due to metabolite problems. Hemodialysis would not remove rimantadine from the body. Particular cautions should be exercised in treating patients with epilepsy. In the event that seizures worsen, therapy should be discontinued immediately. Rimantadine effectively shortens the duration of fever and influences the inhibition of virus replication in the body. Among the patients infected with H3N2, a 200 mg/24 dose treatment for 5 days resulted in a decrease of secretion of the droplet by the virus and the fever lasted, on average, less than 37 h [24]. The drug is active against avian influenza but only effective in the classic cases of influenza A; unfortunately, a high percentage of adverse reactions may result in a reluctance to use the drug. Among the most frequent undesirable symptoms [17], there are gastroenteric manifestations. During clinical research, nausea, vomiting, anorexia, dry mouth, insomnia, giddiness, and increased nervousness was observed in less than 3% of the cases. Security-related research and long-term prophylactic use of the drug carried out in the group receiving the drug and placebo presented no important differences from the gastrointestinal tract and nervous system. Adverse reactions from 0.3% to 1% are diarrhea, indigestion, impaired concentration, ataxia, somnolence, agitation, depression, tinnitus, dyspnea, and skin rash. In a small degree, heart palpitations, cardiac insufficiency, heart blockage, hypertension, disorders of the cerebral vessels, and bronchospasms were also stated. Rimantadine should not be administered to pregnant or breastfeeding women because of the that have been observed in rats' experiments. It is also unchecked for women's safety in the aforementioned states. It has been proven that it permeates the placenta and milk. Rimantadine has been available in the pharmaceutical industry for more than 40 years. The drug acts on the M2 ion-channel protein to effectively block the proton flow. It is an effective method for fighting the virus. For 40 years, viruses acquired drug resistance, so rimantadine G. aroffe et al.: Drugs on influenza A virus infection9 is not fully effective against all influenza A viruses. The drug causes a number of , which additionally reduced the efficiency of the organism. Dose modifications should be carried out in children and elderly. The symptoms among the patients need to be monitored. Nevertheless, during the 40 years in which drug-resistant viruses have appeared, it is one of the most effective medications for influenza treatment. Rimantadine weakens other medicines applicable at colds. The illness should be reliably diagnosed and then, if necessary, other supportive medicines should be excluded from the treatment. The drug should not be coadministered with vaccines for influenza as it reduces their effectiveness. At the same time, ask yourself whether vaccination with the influenza virus makes any sense because vaccines are composed of several years of delay despite the fact that viruses mutate very quickly. We are unable to get vaccinated for a virus that is attacking at the moment. drug that is significantly less expensive than rimantadine and oseltamivir. The use of the drug is associated with a very quick emergence of resistant strains to the fully infectious stable. In immunocompromised patients, viruses may be propagated for long periods. The administration of influenza prevention or treatment (www.bazalekow) in children for a period longer than 3 to 4 days increases the risk of drug resistance. The drug is applied orally [26] and is very well absorbed. In patients without any symptoms of the disease, peak plasma concentrations are attained after 2 to 8 h, and the half-life in young people is 11.8 h, in the elderly about 28.9 h half-life in renal failure may extend two or three times, and in patients undergoing dialysis for 8 days. Amantadine is not removed by hemodialysis. It is excreted without change in the urine. This applies to 90% of the drug. When the pH is acidic, the urine excretion of amantadine is significantly increased. In the case of experiments with 15 people [25] exposed to the virus, amantadine prevented 61% from falling ill; in 25%, it alleviated other connected symptoms. The duration of fever was reduced by about 1 day and the drug had no effect on the secretion of virus by respiratory droplets. The use of drugs that simultaneously prolong the QT interval in the ECG is also contraindicated. Amantadine increases the effects of drugs that stimulate the central nervous system and carries the risk of cardiac arrhythmias, nervousness, and insomnia. In case of the simultaneous use of anticholinergic drugs, symptoms such as confusion and hallucinations can also be increased. Memantine is a drug that enhances the effect of amantadine and its adverse effects. Increasing concentrations of amantadine in the blood serum may be due to the use of diuretics, comprising in its composition triamterene with hydrochlorothiazide. The results showed no interaction with the influenza vaccine. There is an increased risk of adverse anticholinergic symptoms associated with the concomitant use of antihistamines, antidepressants, and antidiskinetic agents. Amantadine increases the sedative effects of alcohol. People should not operate machinery or drive under the influence of the drug. In the case of influenza type A, the dose is 100 to 200 mg once daily or 100 mg twice daily for adults and 100 mg once daily for the elderly above 65 years old; similarly, the dose is 100 mg once daily for children between 5 and 9 years old and 100 mg dose twice daily for children Amantadine Amantadine [25] is an antiviral drug used in the treatment and prevention of the influenza A virus but has no effect on type B. It is available in tablet or syrup form. Amantadine is a synthetic tricyclic amine that can inhibit the release of viral genetic materials into the host cell's nucleocapsid and combat its replication (Figure 7). It is also a medicine that is used to treat Parkinson's disease. It can be effective with additive interferon therapy when applied in patients with chronic hepatitis C [26]. It is effective against all types of influenza A virus that have caused disease in humans (H1N1, H2N2, and H3N2). In contrast with the case of avian influenza H5N1, it is not an active drug. Amantadine is a Figure 7:Amantadine (atom colors: blue, amino group; gray, carbon). 10G. aroffe et al.: Drugs on influenza A virus infection between 9 and 12 years old. In patients with renal impairment, the dose must be individualized. to the risk of birth defects. Due to various , newgeneration drugs are replacing older-generation drugs. Humanity has a big problem because viruses continue to mutate. Working on improving drug therapy is an urgent problem that focuses on the effectiveness of treatment. The main [26] during treatment are gastrointestinal symptoms including nausea, vomiting, diarrhea, constipation, and loss of appetite. Other commonly observed symptoms are sleep disorders, dizziness, agitation, marbled cyanosis, swelling in the legs, orthostatic hypotension, nervousness, anxiety, insomnia, and profuse sweating. The symptoms that rarely occur within the dosing period include slurred speech or vision, disorientation, seizures, rashes, urinary incontinence, and increased liver enzymes. Rare symptoms include arrhythmia, photosensitivity, thrombocytopenia, peripheral nerve disorders, and leukocytopenia. Amantadine can be overdosed. The symptoms of drug's excess in the body are neuromuscular disorders, psychosis, restlessness, seizures, hallucinations, hyperventilation, respiratory failure, pulmonary edema, renal, cardiac arrhythmias, nausea, and vomiting. There is no specific antidote for overdose. Doctors use gastric lavage to enhance diuresis and introduce symptomatic treatment. The occurrences of adverse reactions largely depend on dose and especially affect elderly people. usually worsen after 2 days of initiating treatment and disappear after the cessation of treatment. Amantadine is contraindicated in patients with epilepsy. It may cause mydriasis. It should not be administered to patients with glaucoma or pregnant women because of the risk of birth defects. It should not be used also during breastfeeding. Amantadine and rimantadine are well-known inhibitors of the M2 ion-channel protein. The drugs are active not only in treatment of influenza but also in secondary treatment as they are strong antiviral drugs and are able to destroy the hepatitis C virus. They are also used in the treatment for Parkinson's disease. They belong to oldgeneration drug classes in connection with the viruses, including genetic mutations responsible for drug resistance. However, a combined treatment with new-generation drugs can be applied effectively to give better results in the treatment. The drugs are cheap, so they are accessible to a larger audience. Before starting treatment, it is important to consider the relevant benefits of treatment as the medicine can cause a number of that do not always stop upon the cessation of treatment. The oldergeneration drugs are contraindicated because of their on children and elderly people. Additionally, these drugs should not be administered to pregnant women due Conclusions New generation drugs, that is, the neuraminidase inhibitors in comparison with amantadine and rimantadine are characterized by fewer , less risk of emergence of drug resistance, and activity against virus type A and B. Drugs of the old generation are characterized by the following features: they are active against virus type A, cause many and cause a large drug resistance of viruses. To benefit a quick diagnosis needs to be carried out. Influenza virus strains mutate very quickly and you should pay attention to whether the treatment will be effective. One can also use combination therapy involving the neuraminidase inhibitor addition to amantadine and rimantadine, but you need to check whether the strain causing the infection is sensitive to these drugs. In our test trials, the combination therapy provides a reduction in antiviral activity and the risk of developing drug resistance. Continuous mutation of the virus is a major challenge for scientists and involves constant work. In the design of new drugs one should pay special attention to the number of mutations and the positions correlated with them. Knowledge of correlated mutations is currently an important aspect for drug design, since the linked sites exhibit high activity within a protein which functions on the drug. Author contributions: The authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. Research funding: None declared. Employment or leadership: None declared. Honorarium: None declared. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Bio-Algorithms and Med-Systems de Gruyter

Drug generations that combat influenza A virus infection

Download PDF
11 pages

Loading next page...
 
/lp/de-gruyter/drug-generations-that-combat-influenza-a-virus-infection-7bzsE3hLfd

References (27)

Publisher
de Gruyter
Copyright
Copyright © 2017 by the
ISSN
1895-9091
eISSN
1896-530X
DOI
10.1515/bams-2016-0027
Publisher site
See Article on Publisher Site

Abstract

Influenza viruses are significant human respiratory pathogens that cause infections and unpredictable pandemic outbreaks. M2 ion-channel protein, participating in the transmission of viral genetic materials into infected cells, is considered to be the crucial target for old-generation drugs such as rimantadine and amantadine. Neuraminidase protein, which is responsible for the replication of the influenza virus, is affected by the new generation of drugs, including oseltamivir (Tamiflu) and zanamivir (Relenza). The virus mutations that cause oseltamivir resistance are also described. This review presents the details concerning the treatment of influenza neuraminidase inhibitors against the H5N1 strain. It also describes virus mutations that cause resistance to oseltamivir and presents a new drug, peramivir, which is a neuraminidase inhibitor that was introduced against the H1N1 epidemic. This work specifies the details of the pharmacokinetics, dosing, toxicity, , and efficiency of the drugs being used against influenza A virus infections. Keywords: amantadine; M2 ion-channel protein; neuraminidase; oseltamivir; peramivir; rimantadine; zanamivir. Introduction For the treatment of influenza A virus, the new generation of drugs known as inhibitors of neuraminidase and the oldgeneration drugs that inhibit M2 ion-channel protein are administered. Neuraminidase inhibitors were introduced into medicine in 1999 as the followers of natural sialic acid substrate for neuraminidase [1]. They have greater *Corresponding author: Gabriela aroffe, Department of Molecular Biology, Faculty of Biological Sciences, University of Zielona Góra, Zielona Góra, Poland, E-mail: gzaroffe@gmail.com Jacek Leluk, Agata yniewska and Rafal Filip: Department of Molecular Biology, Faculty of Biological Sciences, University of Zielona Góra, Zielona Góra, Poland specificity and affinity for enzyme activity by complementing actions. Neuraminidase binds N-acetyl neuraminic acid located in the recesses, which are present on the top of each unit. Blocking reduces the spread of viral neuraminidase in the body. Inhibiting the neuraminidase activity prevents the release of progeny virions from cells infected with influenza virus and the sialic acid fragments are removed. The neuraminidase of the influenza A virus is a tetramer in the form of mushroom-shaped spikes on the virus surface and constitutes 5% to 10% of the viral proteins (Figure 1). It consists of four identical subunits, each composed of 469 amino acid residues. Neuraminidase combines with the N-acetyl neuraminic acid in the recesses, occurring on the peak of each unit; such inhibiting reduces the spread of viral neuraminidase in the organism. Influenza is widespread and there is no person who has not encountered by the virus. Every year, several million people come down with the flu. There is a small percentage of dying due to severe complications. Scientists are still working on drugs that largely reduce nuisance of the disease. The disease is transmitted through droplets. The largest number of cases occurs during seasonal epidemics at the end of the month of November to March. Virions are generally of spherical shape with a diameter of 80 to 120 nm [2] and appear as filamentous forms. The virus induces the morphological differentiation gene encoding a membrane protein M and genes encoding hemagglutinin and a nucleoprotein. The virion is surrounded by a double lipid envelope derived from the host cell (Figure 2). The genetic material of the virus is comprised of a single ribonucleic acid RNA with negative polarity. RNA virions A and B is in the form of eight segments, Type C is seven segments. The segments are associated with the nucleoprotein and polymerase PB2, PB1, PA form a ribonucleoprotein complex, which constitutes the core of the virion influenza. The core is surrounded by a protein membrane M1. The coating is a lipid-anchored membrane protein M2 together with the glycoproteins hemagglutinin and neuraminidase. Envelope glycoproteins on the surface protrusions form a rod shape [2]. Virus subtypes are isolated depending on the type occurring hemagglutinin and neuraminidase. There 2G. aroffe et al.: Drugs on influenza A virus infection M2 ion-channel proteins are sensitive to the old-generation drugs, including rimantadine and amantadine. M2 is situated in an envelope of influenza virus and creates a specific M2 ion channel. As a homotetramer, the channel is constructed out of four identical transmembrane domains with -helix conformations (Figure 3). Tetramerization is stabilized by intermolecular contact between C-terminal amphipathic helices. Inside the M2 ion channel, His37 acts as a pH sensor, whereas Trp41 plays a role in the gateway channel. This ion channel is activated by a low pH surrounding environment, where it is located due to the protonation of His37. The flow of protons through the M2 ion channel leads to the acidification of the virus interior. Allowing the dissociation of the channel protein from the viral nucleoprotein matrix, the viral genome is unlocked. A new generation of drugs, in comparison to older-generation drugs, has a lower number of adverse reactions, exhibits greater activity toward influenza types A and B, and causes less risk of the emergence of drug resistance in the strains. Figure 1:Neuraminidase tetramer. are 16 hemagglutinin subtypes (H1­H16) and 9 neuraminidase subtypes (N1­N9) distinguished. All of subtypes are present in waterfowl. There are subtypes H1 and H3 in equines, H3 and H7 in pigs and there are three subtypes H1, H2, H3 and two subtypes N1 and N2 in humans. There was also a statement of human infection by viruses that occur only in birds, which were subtyped A (H5N1), A (H9N2), A (H7N7), A (H7N3). Oseltamivir Oseltamivir is a new-generation drug [1] with the trade name Tamiflu, which was developed by C.U. Kim, W. Lew, Figure 2:Construction of the influenza virus. https://www.cdc.gov/flu/images/h1n1/3D_Influenza_black_key_pieslice_lrg.jpg G. aroffe et al.: Drugs on influenza A virus infection3 with the digestive system, such as nausea and vomiting. In some cases, of which the reliability has not been confirmed, the of the medicine also appear in the form of a rash, swelling on the face and tongue, hepatitis and wrong functional tests, abnormal heart rhythm, relapse of diabetes, mental confusion, and depressive bursts. The medicine cannot be administered to pregnant and breastfeeding women. Oseltamivir is a prodrug; its complete reaction develops after the metabolism changes in the body. Before the transformation, the drug is practically not active. Due to ethyl ester, it requires hydrolysis to accept the active form of carboxylate [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Figure 4). This discovery was possible using the techniques of drug development and investigating the X-rays of crystal structures in sialic acid and neuraminidase activity [4]. During the development of the drug, oseltamivir alone and its active metabolite were synonymously identified as GS4104 and Ro64-0796 and GS4071 and Ro64-0802. Figure 3:M2 ion-channel protein. The medicine is applied orally or in slime form at a dose of 75 mg twice daily for 5 days. Oseltamivir is readily and X. Chen in cooperation with the U.S. pharmaceutical company Gilead Science. Oseltamivir's influence involves the binding of viral influenza to the host cell, thus limiting the infection of penetrating in mucous membranes and reducing the infectivity of virus. Oseltamivir alleviates disease symptoms, fever, muscle pain, and headache on average from 0.7 to 1.5 days [1]. The medicine is applied in the case of prevention and uncomplicated treatment of acute influenza to humans who are 1 year or older when the disease symptoms have been identified within 2 days. The treatment is effective in approximately 60% to 70%. In humans with diagnosed disease before the end of 36 h, 38% of the symptoms are reduced by 1.5 days. If treatment is started within 12 h of the onset of fever time diseases reduced by 3 days. When treatment within 12 h of the onset of fever is initiated, the duration of the disease is reduced by 3 days. Oseltamivir is an effective drug that is tolerated by people in high-risk groups who suffer from cardiovascular disease and respiratory system disorders [3]. Oseltamivir is clinically well-tolerated medicine [3]. Adverse reactions that appear approximately after 2 days of its administration include disturbances connected Figure 4:Oseltamivir (atom colors: blue, nitrogen; red, oxygen; gray, carbon). 4G. aroffe et al.: Drugs on influenza A virus infection absorbed from the gastrointestinal tract and reaches the liver, whereas the active metabolite is created through the bloodstream and distributed throughout the organism, concentrating to a large extent in the upper respiratory tract [5]. Oral use of the drug leads to the activities of the main metabolites up to 80%; the maximum concentration in the organism is obtained after 3 to 4 h. The half-life phase inside the human body is from 6 to 10 h, with 3% plasma protein binding. In the elderly, the activity of the major metabolite is 25% stronger than in young adults [6]. There is no need for dosage adjustment for age because the drug is rapidly excreted by the kidneys due to glomerular filtration and active tubular secretion without further metabolism. The drug's metabolism does not influence liver functions. Children between 1 and 12 years old remove active metabolites from the body faster than older people. Infants above 1 year old actively metabolize and excrete the drug. The drug is not advised for infants below 1 year old [7]. and wild-type viruses retained their genotypic traits. These studies are not fully documented, so researchers are still working to gain more relevant and reliable results. Oseltamivir, which is known as a neuraminidase inhibitor during treatment, may cause the drug resistance of viruses. After the clinical research, three known mutations were defined in the neuraminidase gene of viral influenza type A as being less susceptible to exposure to the drug. R292K mutation (arginine lysine) substitution occurs at the site functional N2 neuraminidase. E119V mutation (glutamic acid valine) substitution occurs at the site of N2 neuraminidase. H274Y mutation (histidine tyrosine) substitution occurs within the N1 neuraminidase and interacts with the functionality of site. The research on viral point mutations can have a disturbed contagiousness and an ability to transfer operation in comparison to the wild-type virus. The changing degree can develop based on the mutations. Oseltamivir is a new-generation drug and suppresses the influenza A virus strain during replication. The medicine, when applied preventively as well as in the course of falling ill, effectively reduces the viral pathogenic effects. The medicine is given orally, and there is no significant contraindication for the age groups in which it is applicable. As opposed to older-generation medicines, it triggers fewer adverse effects, which additionally has good influence on weakened organisms due to illness. Clinical tests with naturally occurring strains performed in the laboratory confirm the effective action of the drug. The viral resistance to the drug is weak; so far, there are only three known mutations that affect the sensitivity of viral drug exposure. Oseltamivir is a promising drug in influenza A virus treatment until more effective and less resistant drugs are discovered. Drug resistance in the viral world is an extremely big problem because of the numerous mutations and gene-pool exchange between strains. Infections by this virus caused six deaths from those 18 infected. The virulence of the H9N2 strain A/ Hong/1074 was also studied [9]. The research was carried out in mice and humans who fell ill. The mice were divided into two control groups infected with viruses. One control group had been given drugs in doses of 1 and 10 mg/kg; the other control group was infected with the H5N1 virus of avian influenza A/Hong Kong/156/97. Oseltamivir inhibited the mortality in mice and kept them alive. Research on drug resistance The research team from St. Jude Children's Research Hospital in Memphis-Lauderdale acting on the virus strain H5N1 of avian influenza A/Hong Kong/156/97 investigated the effectiveness of the A/Hong Kong/ G1/97 (H9N2) and people infected with the influenza type A/Hong Kong/1074/99 (H9N2). A reduction of the virus' presence in the lungs and proliferation inside body was reported. Delaying therapy for 36 h increases the mortality rate of mice in comparison to the control sample. The oral application of oseltamivir at a dose of 0.1 mg/kg/day in combination with rimantadine (1 mg/ kg/day) effectively reduces and prevents the number of deaths in mice. The performed studies confirm the efficiency of the drug in the treatment of infections caused by H5N1 and H9N2 in mice. As a result of the research on the resistance of the virus to oseltamivir, Herlocher et al. isolated three type A viruses, each of them having a mutation in the gene responsible for neuraminidase and its resistance to the drug [8]. The research was carried out on ferrets. In earlier studies, the R292K virus mutation A (H3N2) is not transferred to another organism unlike the wild-type virus [8]. This model was used to examine whether the E119V mutant A (H3N2) virus and H274Y mutant A (H1N1) virus would be transferred under similar conditions. Both mutant viruses were carried, but the H274Y mutant required more than 100 times viral particles to infect ferrets and attacked the immune system much more slowly than the wild-type virus. The mutant Zanamivir Zanamivir is a medicine that is used in influenza virus infection in 19 countries [10]. It is a neuraminidase inhibitor G. aroffe et al.: Drugs on influenza A virus infection5 Figure 5:Zanamivir (atom colors: blue, nitrogen; red, oxygen; gray, carbon). ailments. It appears on the airway epithelium within 10 s of application. During clinical trials, the concomitant use of zanamivir combined with the influenza vaccines does not influence the production of antibodies. Zanamivir, when administered within 48 h of the onset of influenza symptoms, reduces the average disease duration by up to 2.5 days. It is indicated for the treatment of people above 50 years old who are at high risk of complications and patients suffering from cardiovascular disease, asthma, and diabetes. The prophylactic drug use in a dose of 10 mg/day for 4 weeks efficiently prevents the disease (67%) and the fever (84%). Zanamivir also can be used for children. During inhalation, the drug of active substance (10­20%) directly reaches the lungs [12]. The remaining dose is absorbed systematically from the throat with a frequency of 4% to 17%. A dose of 10 mg peak plasma concentration is reached after 1 to 2 h. Drug binding protein is below 10%. The half-life period lasts in the body from 2.5 to 5.1 h. Zanamivir is not metabolized in the body. It is excreted by the kidneys in unchanged form. In patients with kidney disease, dose modification is not required as this drug does not interfere with kidney function. In difficult cases, the drug can be administered intravenously and transported directly to the respiratory mucosa [13]. that efficiently inhibits the replication of the influenza A virus (Figure 5). Drug testing in mice has revealed effectiveness in the treatment of avian influenza H9N2, H6N1, and H5N1. The drug does not interact with other specifics. Its chemical structure is similar to the one of sialic acid; hence, it can fit into the substrate binding pockets without the necessity of conformational change [3]. Drug interactions with the participation of the guanidine group in the neuraminidase-active site relate to glutamic acid residues (Glu199 and Glu227), and glycerol hydroxyl groups bind to glutamic acid (Glu276). Arginine residue (Arg152), isoleucine at position 222, and tryptophan at position 178 participate in the process of drug binding pathway. However, the development of drug resistance is rare. Zanamivir triggers the adverse effects to a low extent [14]. Dosage recommended by doctors does not adversely affect lung function. Vesicle shrinkage and loss of body function were observed only in people suffering from asthma or other chronic lung diseases. Allergic reactions, swelling of the mouth and throat, and skin itching are uncommon . In some cases, dizziness, headaches, and problems with the digestive system were also observed. The liver enzyme level rises during long-term drug use. In a group of children between 5 and 12 years old, only some cases suffered from irritated pharyngeal cavity and a cough. The drug is not recommended for use in breastfeeding mothers because of the penetration of the drug into the milk. Studies in pregnant rats did not prove that zanamivir might trigger the development of birth defects in offspring. Zanamivir is an easy-to-use medicine due to its powder form, which is absorbed within 10 s after inhalation [14]. The drug works directly in the penetration of the virus into the body. It induces few adverse effects and may be used without any major contraindications in humans. Zanamivir is not metabolized in the body and excreted by the kidneys in unchanged form. This is a big advantage, The drug is applied by inhalation from a diskhaler in dry powder form [11]. The recommended dose for children above 7 years old and adults is 10 mg twice daily. On the first day of treatment, the next dose should be taken with at least 2 h time interval. Patients who have pulmonary diseases should preventively take bronchodilators. Due to the good tolerability of the drug, there is no need to adjust the dose for patients suffering from kidney 6G. aroffe et al.: Drugs on influenza A virus infection as it does not affect the liver. The medicine is applied in the treatment and prevention of influenza A virus. It effectively reduces the incidence and symptoms in case of illness. The quick action of the drug is especially needed in the treatment of groups of individuals who are more than 50 years old, as the overall immunity of the organism is much weaker and complications can be tougher in the course. and in patients undergoing hemodialysis. In patients with renal impairment, the recommended dose should be reduced to 600 mg. During clinical trials, the drug was not used in people below 18 years old. The dosage of the drug requires modification for adults. In October 2009, the U.S. FDA permitted the administration of the drug in cases of suspicion or substantiated illness with H1N1. The condition was drug resistance to other antiviral drugs used during an existing disease. The drug can be administered at a dose of not more than 600 mg/24 h in adults and children above 6 years old. In case of children below 6 years old, the dose should be adjusted according to body weight and used with precisely specified rules. The treatment should be carried out within 5 to 10 days. Longer treatment is provided only in case of continuous release of infectious virus strain and in critical situations. Peramivir Peramivir, an antiviral drug, is a neuraminidase inhibitor developed by BioCryst Pharmaceuticals, USA (www. biocryst.com). The drug is in the fourth phase of its clinical trials. On December 19, 2014, the U.S. Food and Drug Administration (FDA) approved RAPIVAB (peramivir injection), an intravenous neuraminidase inhibitor, for the treatment of acute uncomplicated influenza in patients 18 years and older who have been symptomatic for no more than 2 days. Peramivir, as a cyclopentane analog, binds to the active site of the neuraminidase of influenza virus strains A and B. The drug works on swine flu virus H1N1. RAPIVAB's approval was supported by data from more than 2700 subjects treated with peramivir in 27 clinical trials. The recommended dose of RAPIVAB in adult patients 18 years or older with acute uncomplicated influenza is a single 600 mg dose that is administered via intravenous infusion for 15 to 30 min. Peramivir is not recommended for use in pregnant or breastfeeding women or people suffering from severe mental disorders or kidney failure. This medicine should not be used by patients with Reye's syndrome. This drug should not be used in newborns, infants, and children. People who experience allergic reactions to other neuraminidase inhibitors or other ingredients should not take pharmaceuticals. Precautions should be taken in the event of serious bacterial infections. Patients should be constantly monitored. The drug is excreted by the kidneys in patients with renal impairment and the dose should be adjusted for the patient's conditions. Additionally, associated with the drug include dizziness, headaches, depression, anxiety and internal distraction, delirium, insomnia, and problems with the digestive system such as nausea, diarrhea, and vomiting. can be hematuria, cystitis, hypertension, abnormal liver enzyme activity, and anorexia. It is applied intravenously and quickly gets to the infected sites. It should not be given intramuscularly. The drug is delivered in the form of 200 mg in 20 mL vials. This medicine does not contain any preservatives. There is no bacteriostatic effect. To obtain the dilution, 0.9% or 0.45% sodium chloride is commonly used. RAPIVAB injection is compatible with 5% dextrose or lactated Ringers. It is diluted with the compounds that may contain glucose or other electrolytes. It cannot be administered with other drugs. It binds to plasma proteins (<30%). The drug is not completely metabolized in the liver and is excreted by the kidney; the half-life in the body in people without kidney problems ranges from 7.7 to 20.8 h. Renal clearance accounts for about 90% of the total clearance. There was no drug accumulation after repeated doses. Peramivir has been evaluated in terms of pharmacokinetics in healthy subjects with mild, moderate, or severe renal impairment Neuraminidase inhibitors in the treatment and prophylaxis of avian influenza By June 18, 2008, the World Health Organization (WHO) recorded 385 cases of individuals who were infected with bird (H5N1) influenza (www.who.int/csr/disease/avian_ influenza/guidelines/clinicalmanage07/en/); in 243 G. aroffe et al.: Drugs on influenza A virus infection7 cases, the infection ended with death. The mortality rate amounted to 61.5%. To prevent death and cure the illness, the WHO recommended oseltamivir, fast diagnoses of the virus, and treatment with medicine. In the case of avian influenza, oseltamivir treatment should be independent of the duration of influenza symptoms. According to an experiment conducted on animals, in case of H5N1 treatment, one should apply a 150 mg dose twice daily and extend the time of patient treatment to 7 to 10 days unlike the standard illness with seasonal influenza. The term extension of drug exposure [15] is based on the duration of viral replication, which is 15 to 17 days after the appearance of infection symptoms. Viral excretion from the organism can take up to 3 weeks. In patients infected by H5N1 with symptoms of diarrhea and vomiting, the administration of oseltamivir may be restricted, the dose should be modified, and ancillary drugs are also used. Neuraminidase inhibitors (zanamivir and peramivir or a combination therapy) can be administered intravenously by adding a neuraminidase inhibitor to amantadine or rimantadine. Before attempting treatment, health-care providers should confirm that the strain causing the infection is sensitive to the effects of these drugs. During clinical trials, it has been found that combination therapy and antiviral activity can reduce the risk of developing drug resistance. Animal experiments [16] also show that it is a good method to cure a sick patient. At present, virus resistance to amantadine and rimantadine is a fairly common problem and these drugs are ineffective against the H5N1 virus. When treating H5N1 infection [13], the development of the virus in the body should be monitored by taking samples of biological materials, such as throat swabs or tracheal aspirates, before starting the treatment, at 4 to 5 days on the therapy and 7 to 8 days after its commencement. Through research, we can identify the time to stop the replication of the virus in the body and determine whether the virus is excreted from the body and to diagnose whether it is a drug-resistant strain. Neuraminidase inhibitors [13] are drugs used in postexposure prophylaxis in patients exposed to the H5N1 virus. One should apply the pharmacological prevention with patients in groups of average and greater risk. The high-risk group includes people who have very close contact with individuals who are sick or infected with a virus from a dead animal and who have participated in decontaminating a contaminated environment. The medium-risk group includes people who have had direct contact with a single infected animal, a patient suspected of infection, medical personnel, and laboratory staff that lack appropriate personal protective equipment. Prophylactic treatment should coincide with the duration of exposure; for example, those involved in eliminating infected poultry should take medication 7 to 10 days after exposure to the virus. Zanamivir may be an alternative drug for the prophylaxis of oseltamivir applied after exposure to the virus. Old-generation drugs used to treat influenza Old-generation drugs used in the treatment of influenza A cause various and exhibit significant drug resistance [17]. The old-generation drugs that were used to treat influenza A virus include rimantadine and amantadine. Rimantadine Rimantadine belongs to flu medicines of the older generation, with the commercial name flumadina (Figure 6). It was discovered and patented in 1963 in the USA by William W. Richard with Du Pont & Co. [17]. Rimantadine is an inhibitor of the M2 ion-channel protein, as it inhibits the replication of the influenza A virus by blocking the ion channel through which the virus penetrates the cells. In the case of infection with influenza virus, it enters the host cell via receptor-mediated endocytosis. The drug is effective against all subtypes of influenza A [18], which previously caused infections in humans (H1N1, H2N2, and H3N2). It is not effective against Figure 6:Rimantadine (atom colors: blue, amino group; gray, carbon). 8G. aroffe et al.: Drugs on influenza A virus infection type B viruses because the M2 protein is unique to virus type A. It was also found that the drug is active against avian influenza H5N1. According to Clover, rimantadine has no impact on the amount of antibodies occurring in the body having defensive reactions to the virus. Tested samples proved that the presence of IgA antibodies in nasal secretions was reduced. In the study of influenza virus resistance to rimantadine and amantadine [19], more than 7000 viral strains in the interval from 1994 to 2005 were taken into account. The drug resistance increased from 0.4% to 12.3% among the viruses collected in South Korea (15%), Taiwan (23%), Hong Kong (70%), and China (74%) [9]. In a study conducted by the U.S. Centers for Disease Control and Prevention [20], 109 of 120 (91%) samples of H3N2 influenza viruses isolated from patients in the USA contained the amino acid at position 31 (asparagine) M2 protein, which confirms resistance to rimantadine and amantadine. This phenomenon is due to the point mutation in the M gene and leads to a change of amino acids in M2 protein. Mutants that cause resistance to the drugs are edible and can easily move to a wild strain of the virus and cause a typical flu. Paracetamol reduces the effectiveness of rimantadine by 11% and acetylsalicylic acid by 10% (bazalekow. mp.pl/leki/doctor_subst.html?id=4735). The simultaneous use of an intranasal trivalent vaccine with twp attenuated live virus strains of type A and B may affect the immunogenicity of the vaccine's weakening of the type A virus. Rimantadine treatment should be discontinued at least 48 h before vaccination and continue for 14 days after vaccination. Until now, there was no report of interactions with inactivated influenza vaccines. Treatment should be started within 24 to 48 h after the first symptoms of influenza (bazalekow.mp.pl/leki/ doctor_subst.html?id=4735) and continue for 5 days or until 24 to 48 h after cessation of symptoms. Adults and children above 14 years old should receive a dose of 100 mg twice daily, children between 11 and 14 years old 50 mg thrice daily, and children between 7 and 10 years old 50 mg twice daily. Among children between 1 and 6 years old, the drug may be applied after an analysis of ailments' benefits and under strict medical supervision. In patients above 65 years old with hepatic impairment suffer from renal insufficiency, the drug is used at a dose of 100 mg/day. The drug is given orally in the form of tablets or syrup, and it has a maximum plasma concentration after 6 h [21]. A dose's half-life is about 30 h in adults and children. Rimantadine is metabolized in the liver and less than 25% of the dose is excreted in the urine. In the elderly, rimantadine metabolism is prolonged 20% longer than in adults. In patients with chronic liver disease [22], the pharmacokinetics does not significantly change; in severe cases, the elimination half-life of the body is heightened. In case of severe renal failure [23], a rimantadine dose should be reduced due to metabolite problems. Hemodialysis would not remove rimantadine from the body. Particular cautions should be exercised in treating patients with epilepsy. In the event that seizures worsen, therapy should be discontinued immediately. Rimantadine effectively shortens the duration of fever and influences the inhibition of virus replication in the body. Among the patients infected with H3N2, a 200 mg/24 dose treatment for 5 days resulted in a decrease of secretion of the droplet by the virus and the fever lasted, on average, less than 37 h [24]. The drug is active against avian influenza but only effective in the classic cases of influenza A; unfortunately, a high percentage of adverse reactions may result in a reluctance to use the drug. Among the most frequent undesirable symptoms [17], there are gastroenteric manifestations. During clinical research, nausea, vomiting, anorexia, dry mouth, insomnia, giddiness, and increased nervousness was observed in less than 3% of the cases. Security-related research and long-term prophylactic use of the drug carried out in the group receiving the drug and placebo presented no important differences from the gastrointestinal tract and nervous system. Adverse reactions from 0.3% to 1% are diarrhea, indigestion, impaired concentration, ataxia, somnolence, agitation, depression, tinnitus, dyspnea, and skin rash. In a small degree, heart palpitations, cardiac insufficiency, heart blockage, hypertension, disorders of the cerebral vessels, and bronchospasms were also stated. Rimantadine should not be administered to pregnant or breastfeeding women because of the that have been observed in rats' experiments. It is also unchecked for women's safety in the aforementioned states. It has been proven that it permeates the placenta and milk. Rimantadine has been available in the pharmaceutical industry for more than 40 years. The drug acts on the M2 ion-channel protein to effectively block the proton flow. It is an effective method for fighting the virus. For 40 years, viruses acquired drug resistance, so rimantadine G. aroffe et al.: Drugs on influenza A virus infection9 is not fully effective against all influenza A viruses. The drug causes a number of , which additionally reduced the efficiency of the organism. Dose modifications should be carried out in children and elderly. The symptoms among the patients need to be monitored. Nevertheless, during the 40 years in which drug-resistant viruses have appeared, it is one of the most effective medications for influenza treatment. Rimantadine weakens other medicines applicable at colds. The illness should be reliably diagnosed and then, if necessary, other supportive medicines should be excluded from the treatment. The drug should not be coadministered with vaccines for influenza as it reduces their effectiveness. At the same time, ask yourself whether vaccination with the influenza virus makes any sense because vaccines are composed of several years of delay despite the fact that viruses mutate very quickly. We are unable to get vaccinated for a virus that is attacking at the moment. drug that is significantly less expensive than rimantadine and oseltamivir. The use of the drug is associated with a very quick emergence of resistant strains to the fully infectious stable. In immunocompromised patients, viruses may be propagated for long periods. The administration of influenza prevention or treatment (www.bazalekow) in children for a period longer than 3 to 4 days increases the risk of drug resistance. The drug is applied orally [26] and is very well absorbed. In patients without any symptoms of the disease, peak plasma concentrations are attained after 2 to 8 h, and the half-life in young people is 11.8 h, in the elderly about 28.9 h half-life in renal failure may extend two or three times, and in patients undergoing dialysis for 8 days. Amantadine is not removed by hemodialysis. It is excreted without change in the urine. This applies to 90% of the drug. When the pH is acidic, the urine excretion of amantadine is significantly increased. In the case of experiments with 15 people [25] exposed to the virus, amantadine prevented 61% from falling ill; in 25%, it alleviated other connected symptoms. The duration of fever was reduced by about 1 day and the drug had no effect on the secretion of virus by respiratory droplets. The use of drugs that simultaneously prolong the QT interval in the ECG is also contraindicated. Amantadine increases the effects of drugs that stimulate the central nervous system and carries the risk of cardiac arrhythmias, nervousness, and insomnia. In case of the simultaneous use of anticholinergic drugs, symptoms such as confusion and hallucinations can also be increased. Memantine is a drug that enhances the effect of amantadine and its adverse effects. Increasing concentrations of amantadine in the blood serum may be due to the use of diuretics, comprising in its composition triamterene with hydrochlorothiazide. The results showed no interaction with the influenza vaccine. There is an increased risk of adverse anticholinergic symptoms associated with the concomitant use of antihistamines, antidepressants, and antidiskinetic agents. Amantadine increases the sedative effects of alcohol. People should not operate machinery or drive under the influence of the drug. In the case of influenza type A, the dose is 100 to 200 mg once daily or 100 mg twice daily for adults and 100 mg once daily for the elderly above 65 years old; similarly, the dose is 100 mg once daily for children between 5 and 9 years old and 100 mg dose twice daily for children Amantadine Amantadine [25] is an antiviral drug used in the treatment and prevention of the influenza A virus but has no effect on type B. It is available in tablet or syrup form. Amantadine is a synthetic tricyclic amine that can inhibit the release of viral genetic materials into the host cell's nucleocapsid and combat its replication (Figure 7). It is also a medicine that is used to treat Parkinson's disease. It can be effective with additive interferon therapy when applied in patients with chronic hepatitis C [26]. It is effective against all types of influenza A virus that have caused disease in humans (H1N1, H2N2, and H3N2). In contrast with the case of avian influenza H5N1, it is not an active drug. Amantadine is a Figure 7:Amantadine (atom colors: blue, amino group; gray, carbon). 10G. aroffe et al.: Drugs on influenza A virus infection between 9 and 12 years old. In patients with renal impairment, the dose must be individualized. to the risk of birth defects. Due to various , newgeneration drugs are replacing older-generation drugs. Humanity has a big problem because viruses continue to mutate. Working on improving drug therapy is an urgent problem that focuses on the effectiveness of treatment. The main [26] during treatment are gastrointestinal symptoms including nausea, vomiting, diarrhea, constipation, and loss of appetite. Other commonly observed symptoms are sleep disorders, dizziness, agitation, marbled cyanosis, swelling in the legs, orthostatic hypotension, nervousness, anxiety, insomnia, and profuse sweating. The symptoms that rarely occur within the dosing period include slurred speech or vision, disorientation, seizures, rashes, urinary incontinence, and increased liver enzymes. Rare symptoms include arrhythmia, photosensitivity, thrombocytopenia, peripheral nerve disorders, and leukocytopenia. Amantadine can be overdosed. The symptoms of drug's excess in the body are neuromuscular disorders, psychosis, restlessness, seizures, hallucinations, hyperventilation, respiratory failure, pulmonary edema, renal, cardiac arrhythmias, nausea, and vomiting. There is no specific antidote for overdose. Doctors use gastric lavage to enhance diuresis and introduce symptomatic treatment. The occurrences of adverse reactions largely depend on dose and especially affect elderly people. usually worsen after 2 days of initiating treatment and disappear after the cessation of treatment. Amantadine is contraindicated in patients with epilepsy. It may cause mydriasis. It should not be administered to patients with glaucoma or pregnant women because of the risk of birth defects. It should not be used also during breastfeeding. Amantadine and rimantadine are well-known inhibitors of the M2 ion-channel protein. The drugs are active not only in treatment of influenza but also in secondary treatment as they are strong antiviral drugs and are able to destroy the hepatitis C virus. They are also used in the treatment for Parkinson's disease. They belong to oldgeneration drug classes in connection with the viruses, including genetic mutations responsible for drug resistance. However, a combined treatment with new-generation drugs can be applied effectively to give better results in the treatment. The drugs are cheap, so they are accessible to a larger audience. Before starting treatment, it is important to consider the relevant benefits of treatment as the medicine can cause a number of that do not always stop upon the cessation of treatment. The oldergeneration drugs are contraindicated because of their on children and elderly people. Additionally, these drugs should not be administered to pregnant women due Conclusions New generation drugs, that is, the neuraminidase inhibitors in comparison with amantadine and rimantadine are characterized by fewer , less risk of emergence of drug resistance, and activity against virus type A and B. Drugs of the old generation are characterized by the following features: they are active against virus type A, cause many and cause a large drug resistance of viruses. To benefit a quick diagnosis needs to be carried out. Influenza virus strains mutate very quickly and you should pay attention to whether the treatment will be effective. One can also use combination therapy involving the neuraminidase inhibitor addition to amantadine and rimantadine, but you need to check whether the strain causing the infection is sensitive to these drugs. In our test trials, the combination therapy provides a reduction in antiviral activity and the risk of developing drug resistance. Continuous mutation of the virus is a major challenge for scientists and involves constant work. In the design of new drugs one should pay special attention to the number of mutations and the positions correlated with them. Knowledge of correlated mutations is currently an important aspect for drug design, since the linked sites exhibit high activity within a protein which functions on the drug. Author contributions: The authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. Research funding: None declared. Employment or leadership: None declared. Honorarium: None declared. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Journal

Bio-Algorithms and Med-Systems – de Gruyter

Published: Mar 1, 2017

There are no references for this article.