laninamivir and Influenza--Human

The influenza virus remains a major health concern for mankind because it tends to mutate frequently and cause high morbidity. Influenza prevention and treatment are greatly aided by the use of antivirals. One such class of antivirals is neuraminidase inhibitors (NAIs), effective against influenza viruses. A neuraminidase on the virus's surface serves a vital function in viral propogation by assisting in the release of viruses from infected host cells. Neuraminidase inhibitors are the backbone in stoping such virus propagation thus helps in the treatment of influenza viruses infections. Two NAI medicines are licensed globally: Oseltamivir (Tamiflu™) and Zanamivir (Relanza™). There are two molecules that have acquired Japanese approval recently: Peramivir and Laninamivir, whereas Laninamivir octanoate is in Phase III clinical trials. The need for novel NAIs is due to frequent mutations in viruses and the rise in resistance against existing medication. The NA inhibitors (NAIs) are designed to have (oxa)cyclohexene scaffolds (a sugar scaffold) to mimic the oxonium transition state in the enzymatic cleavage of sialic acid. This review discusses in details and comprises all such conformationally locked (oxa)cyclohexene scaffolds and their analogues which have been recently designed and synthesized as potential neuraminidase inhibitors, thus as antiviral molecules. The structure-activity relationship of such diverese molecules has also been discussed in this review.

Topics: Antiviral Agents; Cyclohexenes; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza, Human; Neuraminidase; Orthomyxoviridae; Oseltamivir; Zanamivir

Laninamivir octanoate is a recently developed inhaled neuraminidase inhibitor for treating influenza virus infection. We performed meta-analyses to clarify the efficacy of laninamivir octanoate on influenza treatment and prevention.. MEDLINE and CENTRAL were searched to identify eligible studies. The log median time to event ratios (logMRs) and log odds ratios (logORs) were combined with meta-analysis.. Nine studies in treatment settings and three studies in prophylaxis settings were eligible for this meta-analysis. There was no significant difference between laninamivir octanoate and oseltamivir (8 studies, logMR 0.04, 95% CI [-0.05, 0.14]; P=0.36) or zanamivir (4 studies, logMR -0.01, 95% CI [-0.12, 0.11]; P=0.93) in alleviating fever. However, laninamivir octanoate was associated with significantly longer fever duration in treating H3N2 influenza as compared to oseltamivir (4 studies, logMR 0.29, 95% CI [0.00, 0.59]; P=0.047). Laninamivir octanoate was associated with significantly longer duration of fever as compared to peramivir (4 studies, logMR 0.46, 95% CI [0.14, 0.77]; P=0.004). Laninamivir octanoate significantly reduced the incidence of clinical influenza in post-exposure settings (3 studies, logOR -1.17, 95% CI [-1.72, -0.62]; P<0.001).. Overall, the efficacy of laninamivir octanoate in treating influenza was comparable to that of oseltamivir or zanamivir, but it should be noted that laninamivir octanoate was associated with significantly longer fever duration in treating influenza H3N2 as compared to oseltamivir and oseltamivir-resistant mutations in seasonal influenza H1N1 might have affected the results. Peramivir may be superior to laninamivir in treating influenza. Laninamivir octanoate is effective in preventing influenza in post-exposure settings as compared to placebo.

Topics: Administration, Inhalation; Antiviral Agents; Betainfluenzavirus; Disease Management; Drug Therapy, Combination; Guanidines; Humans; Influenza A virus; Influenza, Human; Post-Exposure Prophylaxis; Pyrans; Sialic Acids; Treatment Outcome; Zanamivir

Influenza is an important cause of annual epidemics of respiratory viral infection associated with significant morbidity and mortality. Three classes of drugs, the M2 ion channel, neuraminidase and RNA-dependent RNA polymerase inhibitors, are approved for the prevention and treatment of influenza. Due to widespread resistance to the class, the M2 ion channel inhibitors are not recommended currently for therapy. The only polymerase inhibitor, favipiravir, is approved only in Japan and its use is highly restricted. Despite significant data to support the early use of the neuraminidase inhibitors, their use in all patient populations is suboptimal. The data to support the early use of neuraminidase inhibitors will be reviewed, as will current data on the utilization rates in ambulatory and hospitalized populations.

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A virus; Influenza, Human; Neuraminidase; Oseltamivir; Pyrans; RNA-Dependent RNA Polymerase; Sialic Acids; Viral Matrix Proteins; Viral Proteins; Zanamivir

Influenza is a major cause of substantial morbidity and mortality in humans every year. Vaccination is the main strategy to prevent influenza infection, but antiviral agents also play an important role in the control of both seasonal and pandemic influenza. During the influenza A/H1N1 pandemic in 2009, early prompt antiviral therapy may have reduced the severity of the influenza outcomes including pneumonia, hospitalization and mortality in the Republic of Korea. Since the 2009 H1N1 pandemic, there have been increasing usages of antiviral agents for the treatment of patients with seasonal influenza. Although currently rare, antiviral resistance among influenza viruses may emerge and increase with increased use of neuraminidase inhibitors. New agents with different modes of action are under investigation, including favipiravir, DAS181, nitazoxanide and broad-spectrum neutralizing monoclonal antibodies. Data are limited with respect to high-dose and combination antiviral therapies. So, clinical trials are warranted to evaluate diverse antiviral combinations that may be synergistic and less likely to induce breakthrough resistance.

Topics: Acids, Carbocyclic; Amides; Antiviral Agents; Clinical Trials as Topic; Cyclopentanes; Drug Resistance, Viral; Guanidines; Hospitalization; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Oseltamivir; Pyrans; Pyrazines; Republic of Korea; Sialic Acids; Zanamivir

Influenza A and B viruses cause significant morbidity and mortality worldwide each year. The neuraminidase inhibitors (NAIs) are the most commonly used class of influenza antiviral drugs for the treatment of infected patients. In vitro studies have shown that influenza B viruses are significantly less susceptible to oseltamivir and other neuraminidase inhibitors compared with influenza A viruses. Following analysis of published clinical studies, we show that oseltamivir does appear to have lower effectiveness in patients infected with influenza B virus compared with influenza A infected patients, but due to insufficient studies on zanamivir, laninamivir or peramivir, it was not possible to conclude the relative effectiveness of these drugs against influenza A virus compared with B virus.

Topics: Antiviral Agents; Guanidines; Humans; Influenza A virus; Influenza B virus; Influenza, Human; Microbial Sensitivity Tests; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Zanamivir

During epidemics, influenza attack rates in children may exceed 40%. Options for prevention and treatment currently include the neuraminidase inhibitors zanamivir and oseltamivir. Laninamivir octanoate, the prodrug of laninamivir, is currently being developed.. To assess the efficacy, safety and tolerability of neuraminidase inhibitors in the treatment and prevention of influenza in children.. For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1) which includes the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to January week 2, 2011) and EMBASE (January 2010 to January 2011).. Double-blind, randomised controlled trials (RCTs) comparing neuraminidase inhibitors with placebo or other antiviral drugs in children aged up to and including 12 years. We also included safety and tolerability data from other types of studies.. Four review authors selected studies, assessed study quality and extracted data for the current and previous versions of this review. We analysed data separately for oseltamivir versus placebo, zanamivir versus placebo and laninamivir octanoate versus oseltamivir.. Six treatment trials involving 1906 children with clinical influenza and 450 children with influenza diagnosed on rapid near-patient influenza testing were included. Of these 2356 children, 1255 had laboratory-confirmed influenza. Three prophylaxis trials involving 863 children exposed to influenza were also included. In children with laboratory-confirmed influenza oseltamivir reduced median duration of illness by 36 hours (26%, P < 0.001). One trial of oseltamivir in children with asthma who had laboratory-confirmed influenza showed only a small reduction in illness duration (10.4 hours, 8%), which was not statistically significant (P = 0.542). Laninamivir octanoate 20 mg reduced symptom duration by 2.8 days (60%, P < 0.001) in children with oseltamivir-resistant influenza A/H1N1. Zanamivir reduced median duration of illness by 1.3 days (24%, P < 0.001). Oseltamivir significantly reduced acute otitis media in children aged one to five years with laboratory-confirmed influenza (risk difference (RD) -0.14, 95% confidence interval (CI) -0.24 to -0.04). Prophylaxis with either zanamivir or oseltamivir was associated with an 8% absolute reduction in developing influenza after the introduction of a case into a household (RD -0.08, 95% CI -0.12 to -0.05, P < 0.001). The adverse event profile of zanamivir was no worse than placebo but vomiting was more commonly associated with oseltamivir (number needed to harm = 17, 95% CI 10 to 34). The adverse event profiles of laninamivir octanoate and oseltamivir were similar.. Oseltamivir and zanamivir appear to have modest benefit in reducing duration of illness in children with influenza. However, our analysis was limited by small sample sizes and an inability to pool data from different studies. Oseltamivir reduces the incidence of acute otitis media in children aged one to five years but is associated with a significantly increased risk of vomiting. One study demonstrated that laninamivir octanoate was more effective than oseltamivir in shortening duration of illness in children with oseltamivir-resistant influenza A/H1N1. The benefit of oseltamivir and zanamivir in preventing the transmission of influenza in households is modest and based on weak evidence. However, the clinical efficacy of neuraminidase inhibitors in 'at risk' children is still uncertain. Larger high-quality trials are needed with sufficient power to determine the efficacy of neuraminidase inhibitors in preventing serious complications of influenza (such as pneumonia or hospital admission), particularly in 'at risk' groups.

Topics: Acetamides; Antiviral Agents; Child; Enzyme Inhibitors; Guanidines; Humans; Influenza, Human; Neuraminidase; Oseltamivir; Pyrans; Randomized Controlled Trials as Topic; Sialic Acids; Zanamivir

During epidemics, influenza attack rates in children may exceed 40%. Options for prevention and treatment currently include the neuraminidase inhibitors zanamivir and oseltamivir. Laninamivir octanoate, the prodrug of laninamivir, is currently being developed.. To assess the efficacy, safety and tolerability of neuraminidase inhibitors in the treatment and prevention of influenza in children.. For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1) which includes the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to January week 2, 2011) and EMBASE (January 2010 to January 2011).. Double-blind, randomised controlled trials (RCTs) comparing neuraminidase inhibitors with placebo or other antiviral drugs in children aged up to and including 12 years. We also included safety and tolerability data from other types of studies.. Four review authors selected studies, assessed study quality and extracted data for the current and previous versions of this review. We analysed data separately for oseltamivir versus placebo, zanamivir versus placebo and laninamivir octanoate versus oseltamivir.. Six treatment trials involving 1906 children with clinical influenza and 450 children with influenza diagnosed on rapid near-patient influenza testing were included. Of these 2356 children, 1255 had laboratory-confirmed influenza. Three prophylaxis trials involving 863 children exposed to influenza were also included. In children with laboratory-confirmed influenza oseltamivir reduced median duration of illness by 36 hours (26%, P < 0.001). One trial of oseltamivir in children with asthma who had laboratory-confirmed influenza showed only a small reduction in illness duration (10.4 hours, 8%), which was not statistically significant (P = 0.542). Laninamivir octanoate 20 mg reduced symptom duration by 2.8 days (60%, P < 0.001) in children with oseltamivir-resistant influenza A/H1N1. Zanamivir reduced median duration of illness by 1.3 days (24%, P < 0.001). Oseltamivir significantly reduced acute otitis media in children aged one to five years with laboratory-confirmed influenza (risk difference (RD) -0.14, 95% confidence interval (CI) -0.24 to -0.04). Prophylaxis with either zanamivir or oseltamivir was associated with an 8% absolute reduction in developing influenza after the introduction of a case into a household (RD -0.08, 95% CI -0.12 to -0.05, P < 0.001). The adverse event profile of zanamivir was no worse than placebo but vomiting was more commonly associated with oseltamivir (number needed to harm = 17, 95% CI 10 to 34). The adverse event profiles of laninamivir octanoate and oseltamivir were similar.. Oseltamivir and zanamivir appear to have modest benefit in reducing duration of illness in children with influenza. However, our analysis was limited by small sample sizes and an inability to pool data from different studies. In addition, the inclusion of data from published trials only may have resulted in significant publication bias. Based on published trial data, oseltamivir reduces the incidence of acute otitis media in children aged one to five years but is associated with a significantly increased risk of vomiting. One study demonstrated that laninamivir octanoate was more effective than oseltamivir in shortening duration of illness in children with oseltamivir-resistant influenza A/H1N1. The benefit of oseltamivir and zanamivir in preventing the transmission of influenza in households is modest and based on weak evidence. However, the clinical efficacy of neuraminidase inhibitors in 'at risk' children is still uncertain. Larger high-quality trials are needed with sufficient power to determine the efficacy of neuraminidase inhibitors in preventing serious complications of influenza (such as pneumonia or hospital admission), particularly in 'at risk' groups.

Topics: Antiviral Agents; Child; Child, Preschool; Enzyme Inhibitors; Guanidines; Humans; Infant; Influenza, Human; Neuraminidase; Oseltamivir; Pyrans; Randomized Controlled Trials as Topic; Sialic Acids; Zanamivir

Oseltamivir and zanamivir are well-established and well-researched drugs for the treatment of influenza in Japan and the rest of the world. A new neuraminidase inhibitor, laninamivir octanoate, has been approved for use in Japanese clinics. Laninamivir octanoate is an inhaled drug with unique characteristics. The inhaled laninamivir octanoate is converted into its active form, laninamivir, in the lungs where a high concentration persists for a long period of time. The concentration of laninamivir exceeds the level necessary for influenza virus replication inhibition for at least 5 days, thus influenza can be treated with a single administration. The drug is delivered using one device requiring four inhalations for children and two devices requiring eight inhalations for adults. Clinical trials have shown comparable efficacy for laninamivir octanoate and oseltamivir. Laninamivir octanoate also displayed a sufficient antiviral effect to treat infection with H275Y-mutated oseltamivir-resistant virus. Laninamivir octanoate has displayed clinical efficacy comparable to that of oseltamivir and zanamivir against the H1N1 pandemic influenza strain from 2009, seasonal H3N2 influenza and influenza B viruses. The prophylactic efficacy of laninamivir octanoate has been shown in animal models. The effectiveness of laninamivir against the highly pathogenic avian influenza virus H5N1 has also been shown in vitro and in animal models. A major clinical benefit of this drug is that the single administration is very convenient for both the patient and doctor, which leads to improved compliance. Furthermore, this drug shows promise for the treatment of influenza in future pandemics.

Topics: Administration, Inhalation; Adult; Animals; Antiviral Agents; Birds; Caprylates; Child; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza B virus; Influenza in Birds; Influenza, Human; Japan; Neuraminidase; Oseltamivir; Prodrugs; Pyrans; Sialic Acids; Viral Proteins; Virus Replication; Zanamivir

Human infections with avian influenza A (H5N1) are relatively rare but are associated with high mortality. As of July 5, 2010 there had been 500 cases and 296 fatalities. The influenza virus readily undergoes mutation and reassortment, and there are concerns that an H5N1 variant could be responsible for a future pandemic. The influenza neuraminidase inhibitors zanamivir and oseltamivir are approved for the treatment and prophylaxis of influenza. Oseltamivir is being used to treat H5N1 infections and the case has been made for a role for zanamivir; however, there are no case reports for the latter. Zanamivir is a potent inhibitor of H5N1, attains high lung concentrations immediately on administration, distributes into plasma at antiviral concentrations, has a low propensity for generating resistant virus, and retains activity against H275Y oseltamivir-resistant virus. There have been several reports of oseltamivir-resistant H5N1 arising during treatment with oseltamivir, and zanamivir retains effectiveness (in vitro or in vivo) against these isolates. Compassionate use of intravenous zanamivir for the treatment of seriously ill patients, including those with H275Y H1N1 infections, has also shown promising results. It is concluded that there is a role for zanamivir in treating H5N1 infections either as the approved, inhaled formulation in patients capable of using the Diskhaler, or as the intravenous formulation if compassionate use is warranted. The relatively small number of patients with these infections remains an obstacle to completion of clinical trials. Evidence is therefore likely to be based on carefully documented case reports, ideally in patients treated early in the course of the infection.

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Disease Outbreaks; Drug Resistance, Viral; Guanidines; Humans; Immunocompromised Host; Influenza A Virus, H5N1 Subtype; Influenza, Human; Oseltamivir; Pneumonia, Viral; Pyrans; Severity of Illness Index; Sialic Acids; Zanamivir

Oseltamivir and zanamivir are currently licensed worldwide for influenza treatment and chemoprophylaxis. Both drugs require twice-daily administration for 5 days for treatment. A new influenza drug, laninamivir (code name R-125489), and its prodrug form, CS-8958 (laninamivir octanoate or laninamivir prodrug), which are long-acting neuraminidase inhibitors, are introduced in this review. Laninamivir potently inhibited the neuraminidase activities of various influenza A and B viruses, including subtypes N1-N9, pandemic (2009) H1N1 virus, highly pathogenic avian influenza (HPAI) H5N1 viruses and oseltamivir-resistant viruses. Because of the long retention of laninamivir in mouse lungs after an intranasal administration of CS-8958, therapeutic administration of a single dose of CS-8958 showed superior efficacy to repeated administrations of zanamivir or oseltamivir in animal infection models for influenza A and B viruses. These include pandemic (2009) H1N1 virus and HPAI H5N1 virus. Prophylactic single administration of CS-8958, as early as 7 days prior to infection, also showed superior efficacy. Finally, the potential of a single inhalation of CS-8958 for influenza patients was demonstrated by clinical studies, and CS-8958 has been approved and is commercially available as Inavir(®) (Daiichi Sankyo Co., Ltd, Tokyo) in Japan.

Topics: Animals; Antiviral Agents; Disease Models, Animal; Drug Administration Routes; Drug Administration Schedule; Guanidines; Humans; Influenza, Human; Mice; Neuraminidase; Orthomyxoviridae; Oseltamivir; Pandemics; Prodrugs; Pyrans; Rats; Sialic Acids; Zanamivir

Neuraminidase inhibitors (NAIs) reduce influenza symptoms but clear evidence of relationships between viral titer reduction and symptom alleviation is lacking. This open-label, randomized study evaluated differences in viral dynamics between NAIs, and relationships between viral dynamics and influenza symptoms (trial registration number: UMIN000012670).. Patients (n = 123) aged 4-12 years with influenza A virus infection were randomized to intravenous peramivir, oral oseltamivir, inhaled zanamivir, or inhaled laninamivir. Patients received regular viral assessments of nasal discharge, at least until rapid antigen tests were negative. Time to virus clearance, based on influenza virus titer, was the primary endpoint.. Peramivir recipients had a significantly shorter time to virus clearance than oseltamivir recipients (adjusted p = 0.035). Comparisons between the peramivir group and other NAI groups were not significant. There were no significant inter-group differences in other clinical efficacy endpoints (time to resolution of fever, time to alleviation of symptoms). However, the peramivir group showed a smaller numerical proportion of relapses with fever or positive virus than the other groups.. The time to virus clearance was significantly shorter with peramivir than with oseltamivir. Although no clear relationship between virus dynamics and symptoms was observed, ongoing studies should clarify the situation.

Topics: Acids, Carbocyclic; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Female; Guanidines; Humans; Influenza A virus; Influenza, Human; Japan; Male; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Time Factors; Treatment Outcome; Zanamivir

The duration of fever and symptoms after laninamivir octanoate hydrate (laninamivir) inhalation were investigated in the Japanese 2015/16 influenza season, and the results were compared with those of the 2011/12 to 2014/15 seasons. A total of 1068 patients were evaluated for the duration of fever and symptoms in the five studied seasons. The influenza types/subtypes were 125 A(H1N1)pdm09 (62.2%), 17 A(H3N2) (8.5%), and 59 B (29.4%) in the 2015/16 season. The median durations of fever were 40.0, 41.0, and 47.0 h, and the median durations of symptoms were 87.0, 76.0, and 93.0 h for A(H1N1)pdm09, A(H3N2), and B, respectively, with no significant difference. The median durations of fever were 52.0 and 46.0 h and the median durations of symptoms 93.0 and 88.0 h for the Victoria and Yamagata B lineages, respectively, with no significant difference. Fever resolution after laninamivir inhalation by the A(H1N1)pdm09 patients was similar in the 2013/14 and 2015/16 seasons. Fever resolution after laninamivir inhalation was similar in all comparisons of the 2011/12 to 2015/16 seasons for both A(H3N2) and B, with no significant difference among the five seasons. Over the seasons tested, eight adverse drug reactions (ADRs) were reported for 1128 patients. The most frequent ADR was diarrhea, and all ADRs were resolved and not serious. These results indicate the continuing clinical effectiveness of laninamivir against influenza A(H1N1)pdm09, A(H3N2), and B, with no safety issues.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Antiviral Agents; Child; Enzyme Inhibitors; Female; Fever; Guanidines; Humans; Influenza, Human; Male; Middle Aged; Neuraminidase; Pregnancy; Product Surveillance, Postmarketing; Pyrans; Sialic Acids; Treatment Outcome; Young Adult; Zanamivir

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Cyclopentanes; Female; Guanidines; Humans; Influenza, Human; Japan; Male; Middle Aged; Oseltamivir; Pyrans; Sialic Acids; Treatment Outcome; Zanamivir

A single administration of laninamivir octanoate, a long-acting neuraminidase inhibitor, has been proven to be effective in the treatment of influenza but not for post-exposure prophylaxis.. We conducted a double-blind, multicenter, randomized, placebo-controlled study to determine if a single administration of laninamivir octanoate 40 mg was superior to placebo for post-exposure prophylaxis. Eligible participants who had cohabited with an influenza patient within 48 hours of symptom onset were randomly assigned (1:1:1) to 1 of 3 groups: 40 mg of laninamivir octanoate single administration (LO-40SD), 20 mg of laninamivir octanoate once daily for 2 days (LO-20TD), or placebo. The primary efficacy endpoint was the proportion of participants who developed clinical influenza (defined as influenza virus positive, an axillary temperature >37.5°C, and at least 2 symptoms) over a 10-day period.. A total of 803 participants were enrolled, with 801 included in the primary analysis. The proportions of participants with clinical influenza were 4.5% (12/267), 4.5% (13/269), and 12.1% (32/265) in the LO-40SD, LO-20TD, and placebo groups, respectively. A single administration of laninamivir octanoate 40 mg significantly reduced the development of influenza compared with placebo (P = .001). The relative risk reductions compared with the placebo group were 62.8% and 63.1% for the LO-40SD and LO-20TD groups, respectively. The incidence of adverse events in the LO-40SD group was similar to that of the LO-20TD and placebo groups.. A single administration of laninamivir octanoate was effective and well tolerated as post-exposure prophylaxis to prevent the development of influenza.. JapicCTI-142679.

Topics: Administration, Inhalation; Adolescent; Adult; Antiviral Agents; Child; Double-Blind Method; Enzyme Inhibitors; Family Characteristics; Female; Guanidines; Humans; Influenza, Human; Male; Middle Aged; Neuraminidase; Post-Exposure Prophylaxis; Pyrans; Sialic Acids; Young Adult; Zanamivir

A single 20-mg dose of inhaled laninamivir octanoate is an effective treatment of influenza. However, the efficacy of laninamivir octanoate for the prevention of influenza in children <10 years of age has not yet been established.. We conducted a double-blind, multicenter, randomized, placebo-controlled study to determine whether the efficacy of a single 20-mg dose of inhaled laninamivir octanoate to prevent the development of influenza was superior to that of placebo as prophylaxis for influenza in pediatric (<10 years) household members of index cases. Eligible subjects without influenza, in contact with an influenza-infected index case living in the same household, were blindly randomly assigned in a 1:1 ratio to receive 20 mg of laninamivir octanoate or placebo. The primary end point was the proportion of subjects who developed clinical influenza during a 10-day period.. A total of 343 subjects were randomly assigned, with 341 subjects included in the full analysis set for the primary analysis. The proportions of subjects who developed clinical influenza were 11% (18/171) in the laninamivir octanoate group and 19% (33/170) in the placebo group (P = .02). The relative risk reduction was 45.8% (95% confidence interval, 7.5% to 68.2%). The incidence of adverse events was similar in both groups.. A single 20-mg dose of inhaled laninamivir octanoate was effective and well tolerated as prophylaxis for influenza.

Topics: Administration, Inhalation; Age Factors; Antiviral Agents; Child; Child, Preschool; Communicable Disease Control; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Family Characteristics; Follow-Up Studies; Guanidines; Humans; Influenza, Human; Japan; Monitoring, Physiologic; Pyrans; Risk Assessment; Sialic Acids; Treatment Outcome; Zanamivir

The clinical outcome of laninamivir octanoate hydrate (laninamivir) in the Japanese 2013-2014 influenza season was investigated. A total of 235 patients were enrolled, of whom 222 were evaluated for the duration of fever and other symptoms. The types/subtypes were 101 A(H1N1)pdm09 (45.5%), 37 A(H3N2) (16.7%), and 84 B (37.8%). The median durations of fever were 32.0, 41.0, and 50.0 h, and the median durations of symptoms were 74.5, 85.0, and 95.0 h for A(H1N1)pdm09, A(H3N2), and B, respectively. The differences among the three groups were not statistically significant. There was no significant difference in the duration of fever or symptoms between patients under 10 and 10 years or over. The median durations of fever were 46.0 and 58.0 h and the median durations of symptoms were 95.0 and 77.0 h for the Yamagata and Victoria lineages, respectively. The virus positive rates at day 5 were significantly different at 31.5% (28/89), 12.1% (4/33), and 34.7% (26/75) for the three type/subtypes, respectively. The virus positive rates for A(H1N1)pdm09 and B were significantly higher for the patients under 10 years than for the patients 10 years or older. (p = 0.0379 and 0.0320, respectively). No significant increase was found between the IC(50) of days 1 and 5. No adverse drug reactions associated with laninamivir were reported. These results indicate the continuing clinical utility of laninamivir against influenza, irrespective of the virus type/subtype or lineage, and that it is unlikely that the clinical use of laninamivir will lead to selection of resistant virus.

Topics: Antiviral Agents; Child; Female; Guanidines; Humans; Influenza A virus; Influenza, Human; Inhibitory Concentration 50; Male; Pyrans; Sialic Acids; Zanamivir

Laninamivir octanoate hydrate (laninamivir) is a long-acting, single inhalation neuraminidase inhibitor that was approved in Japan in 2010 for the treatment of influenza A and B virus infection. We investigated the duration of fever and other symptoms after the initiation of laninamivir in the Japanese 2011-2012 influenza season. Virus isolation was done and the 50% inhibitory concentration (IC₅₀) was measured for the virus isolates at days 1 and 5. For 211 patients (A(H3N2): 190, B: 21), the median durations of fever of A(H3N2) and B patients were 33.0 and 50.0 h, respectively (p = 0.0989). Fever was resolved within 72 h after inhalation by 89.7% of the A(H3N2) patients and by 81.0% of the patients with B. The median durations of symptoms for A(H3N2) and B patients were 89.0 and 94.0 h, respectively (p = 0.5809). On day 5, the influenza virus-positive rates for A(H3N2) and B patients were significantly different: 25.8% (40/155) and 70.6% (12/17), respectively (p < 0.0001). No significant change in IC₅₀ value was found between day 1 and day 5 for any of the four tested neuraminidase inhibitors, and no IC₅₀ value exceeded 50 nM. The incidence of adverse drug reactions was 1.3% (3/234), with no serious reactions reported. These results show that laninamivir was effective for the treatment of both influenza A(H3N2) and B in this study, with no safety issues. The clinical effectiveness of laninamivir for A(H3N2) was superior to that for B.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Child; Child, Preschool; Female; Fever; Guanidines; Humans; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Inhibitory Concentration 50; Male; Middle Aged; Pyrans; Sialic Acids; Young Adult; Zanamivir

The clinical effectiveness of Laninamivir octanoate hydrate (laninamivir) was investigated in the Japanese 2012-2013 influenza season for comparison with that of the Japanese 2011-2012 influenza season. A total of 235 patients were enrolled, of whom 210 were evaluated for the duration of fever and other symptoms. The median durations of fever for A(H3N2) were 32.0 and 38.0 h and the median durations of symptoms for the A(H3N2) were 102.0 and 84.0 h for patients aged under 10 and 10 years or older, respectively. All four influenza B patients were 10 years or older, and their median duration of fever was 43.0 h and the median duration of symptoms was 71.0 h. There was no significant difference in the duration of fever or symptoms between the two seasons. The rates of patients A(H3N2) virus positive at day 5 were 37.2% (16/43) and 12.8% (18/141) for those aged under 10 years and 10 years or older, respectively. The virus positive rate was significantly higher for the patients under 10 years than for the patients aged 10 years or older (p < 0.0001). No significant change in IC50 value was found between days 1 and 5. Adverse drug reactions were reported by 2 of the 231 patients (0.87%), but neither was serious. These results suggest that laninamivir continued to be effective against influenza A(H3N2) with no safety issues and that it is unlikely that the clinical use of laninamivir will lead to virus resistance.

Topics: Antiviral Agents; Child; Disease Outbreaks; Female; Guanidines; Humans; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Japan; Male; Microbial Sensitivity Tests; Pyrans; Sialic Acids; Treatment Outcome; Zanamivir

Laninamivir octanoate, a long-acting neuraminidase inhibitor, is an effective treatment for influenza. However, its effectiveness for the prevention of influenza has not yet been demonstrated. We conducted a double-blind, multicenter, randomized, placebo-controlled trial to determine whether laninamivir octanoate was superior to a placebo for post-exposure prophylaxis of influenza in household contacts. Eligible participants, who were household members who did not have influenza and were in contact with an influenza-infected index patient, were randomly assigned (1:1:1) to one of three groups: 20 mg of laninamivir octanoate once daily for 2 days (LO-2), 20 mg of laninamivir octanoate once daily for 3 days (LO-3), or a placebo. The primary endpoint was the proportion of participants who developed clinical influenza during a 10-day period. A total of 1711 participants were enrolled, and 1451 participants were included in the primary analysis. The proportion of participants with clinical influenza was 3.9 % (19/487) in the LO-2 group, 3.7 % (18/486) in the LO-3 group, and 16.9 % (81/478) in the placebo group (P < 0.001 for each of the laninamivir octanoate group). The relative risk reductions, compared with the placebo group, were 77.0 % [95 % confidence interval (CI) 62.7-85.8] and 78.1 % (95 % CI 64.1-86.7 %) for the LO-2 and LO-3 groups, respectively. The incidences of adverse events in the laninamivir octanoate groups were similar to that in the placebo group. The inhalation of 20 mg of laninamivir octanoate once daily for 2 or 3 days was well tolerated and effectively prevented the development of influenza in household contacts.

Topics: Administration, Inhalation; Adolescent; Adult; Antiviral Agents; Child; Child, Preschool; Disease Transmission, Infectious; Double-Blind Method; Family Characteristics; Female; Guanidines; Humans; Infant; Influenza, Human; Male; Middle Aged; Placebos; Post-Exposure Prophylaxis; Pyrans; Sialic Acids; Zanamivir

The neuraminidase inhibitors (NAIs) oseltamivir, zanamivir, laninamivir and peramivir are available in Japan. However, the selective use of NAIs for treating outpatients with influenza has not been clearly defined.. We assigned 191 patients with influenza to 4 groups, each treated with a different NAI, and then compared how long it took to alleviate fever and other symptoms and to eliminate the virus.. Alleviation of fever occurred significantly sooner with peramivir than with either zanamivir (p = 0.0002) or oseltamivir (p = 0.0059), but was not significantly different from that with laninamivir (p = 0.0457; p < 0.0083). Other symptoms were also alleviated sooner by peramivir than by the other 3 NAIs.. The ability of each NAI to alleviate influenza symptoms and fever varied. The appropriate use of NAIs requires further study.

Topics: Acids, Carbocyclic; Adult; Aged; Aged, 80 and over; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Enzyme Inhibitors; Female; Guanidines; Humans; Infant; Influenza, Human; Japan; Male; Middle Aged; Neuraminidase; Oseltamivir; Outpatients; Pyrans; Sialic Acids; Time Factors; Treatment Outcome; Young Adult; Zanamivir

Influenza infection tends to be severe in patients with chronic underlying diseases. This study evaluated the efficacy and safety of laninamivir octanoate, an inhaled neuraminidase inhibitor, for the treatment of influenza patients with chronic respiratory diseases; we conducted a double-blind, randomized controlled trial to compare the efficacy and safety of laninamivir octanoate and oseltamivir for the treatment of influenza in these patients. A total of 203 patients aged ≥20 years were randomized to receive either laninamivir octanoate or oseltamivir. The primary efficacy endpoint was the time to illness alleviation. This study is registered with JapicCTI; the registration number is JapicCTI-090940. The full analysis set (FAS) included a total of 201 patients (laninamivir group, n = 101; oseltamivir group, n = 100). Most patients had underlying bronchial asthma and 170 patients were infected with influenza A(H1N1)2009. The median time to illness alleviation was 64.7 h in the laninamivir group and 59.7 h in the oseltamivir group, with a difference of 5.0 h between the two groups (95 % confidence interval, -13.6 to 16.1 h). No adverse events specific to laninamivir octanoate were observed, and adverse events such as bronchospasm, which has been reported to be observed with other inhaled drugs related to laninamivir octanoate, did not occur. Laninamivir octanoate showed similar efficacy and safety to oseltamivir in the treatment of influenza, including that caused by influenza A(H1N1)2009, in patients with chronic respiratory diseases.

Topics: Adult; Aged; Antiviral Agents; Asthma; Chronic Disease; Double-Blind Method; Enzyme Inhibitors; Female; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Treatment Outcome; Zanamivir

The purpose of this study was to compare the efficiency and safety of a new neuraminidase inhibitor, laninamivir octanoate (LO), with zanamivir (ZN) in pediatric patients with influenza.. One hundred twelve pediatric patients ≤ 15 years, diagnosed with a rapid diagnostic test as having influenza from January to May 2011, were randomly assigned to the LO group or the ZN group, and their parents were asked to complete a questionnaire during the recovery at home. The LO group was instructed to inhale LO once (20 or 40 mg depending on age), and the ZN group was instructed to inhale ZN (20 mg) twice daily for 5 days.. The LO group (n = 55) and the ZN group (n = 57) were well balanced. Finally, 44 patients in the LO group and 41 patients in the ZN group could be evaluated. Median times to fever resolution after initial treatment were 36 hours in the LO group and 37 hours in the ZN group. No differences were observed between the 2 groups with respect to the frequencies of asthmatic symptoms, pneumonia, gastrointestinal symptoms, or abnormal behaviors. Six younger children could not inhale LO well for technical reasons.. Our data suggest that the efficiency and safety of LO are the same as those of ZN in pediatric patients with influenza but that LO may be more convenient than ZN because it requires only a single inhalation. However, younger patients may not inhale LO efficiently.

Topics: Administration, Inhalation; Adolescent; Child; Child, Preschool; Female; Fever; Guanidines; Humans; Influenza, Human; Male; Neuraminidase; Pyrans; Sialic Acids; Surveys and Questionnaires; Treatment Outcome; Zanamivir

A single administration of laninamivir octanoate, a long-acting neuraminidase inhibitor, against influenza infection has been proven effective in nonclinical studies. This study evaluated the clinical efficacy of laninamivir octanoate for the treatment of adult influenza patients.. A double-blind, randomized controlled trial examined whether laninamivir octanoate was noninferior to oseltamivir. A total of 1003 patients aged ≥ 20 years with febrile influenza symptoms for no more than 36 h were randomized to receive either 40 mg of laninamivir octanoate, 20 mg of laninamivir octanoate, or oseltamivir. Laninamivir octanoate was inhaled once on day 1, and oseltamivir (75 mg) was administered orally twice daily for 5 days. The primary end point was the time to illness alleviation.. A total of 996 patients were included in the primary analysis (40-mg laninamivir octanoate, n = 334; 20-mg laninamivir octanoate, n = 326; and oseltamivir, n = 336). The median time to illness alleviation in the 40-mg laninamivir octanoate, 20-mg laninamivir octanoate, and oseltamivir groups was 73.0, 85.8, and 73.6 h, respectively. The difference between laninamivir octanoate and oseltamivir was -0.6 h (95% confidence interval, -9.9 to 6.9 h) for the 40-mg group and 12.2 h (95% confidence interval, -1.5 to 17.2 h) for the 20-mg group. The upper limits of the 95% confidence intervals were less than the prespecified noninferiority margin (18 h). The proportion of patients shedding virus at day 3 was significantly lower in the 40-mg laninamivir octanoate group than in the oseltamivir group (P = .006).. A single inhalation of laninamivir octanoate is effective for the treatment of seasonal influenza, including that caused by oseltamivir-resistant virus, in adults.. NCT00803595.

Topics: Administration, Inhalation; Administration, Oral; Adult; Aged; Antiviral Agents; Drug Administration Schedule; Female; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Male; Middle Aged; Oseltamivir; Pyrans; Sialic Acids; Viral Load; Zanamivir

This study assessed the differences in daily virus reduction and the residual infectivity after the recommended home stay period in Japan in patients infected with influenza and treated with baloxavir (BA), laninamivir (LA), oseltamivir (OS), and zanamivir (ZA).. We conducted an observational study on children and adults at 13 outpatient clinics in 11 prefectures in Japan during seven influenza seasons from 2013/2014 to 2019/2020. Virus samples were collected twice from influenza rapid test-positive patients at the first and second visit 4-5 days after the start of treatment. The viral RNA shedding was quantified using quantitative RT-PCR. Neuraminidase (NA) and polymerase acidic (PA) variant viruses that reduce susceptibility to NA inhibitors and BA, respectively, were screened using RT-PCR and genetic sequencing. Daily estimated viral reduction was evaluated using univariate and multivariate analyses for the factors such as age, treatment, vaccination status, or the emergence of PA or NA variants. The potential infectivity of the viral RNA shedding at the second visit samples was determined using the Receiver Operator Curve based on the positivity of virus isolation.. Among 518 patients, 465 (80.0%) and 116 (20.0%) were infected with influenza A (189 with BA, 58 with LA, 181 with OS, 37 with ZA) and influenza B (39 with BA, 10 with LA, 52 with OS, 15 with ZA). The emergence of 21 PA variants in influenza A was detected after BA treatment, but NA variants were not detected after NAIs treatment. Multiple linear regression analysis showed that the daily viral RNA shedding reduction in patients was slower in the two NAIs (OS and LA) than in BA, influenza B infection, aged 0-5 years, or the emergence of PA variants. The residual viral RNA shedding potentially infectious was detected in approximately 10-30% of the patients aged 6-18 years after five days of onset.. Viral clearance differed by age, type of influenza, choice of treatment, and susceptibility to BA. Additionally, the recommended homestay period in Japan seemed insufficient, but reduced viral spread to some extent since most school-age patients became non-infectious after 5 days of onset.

Topics: Adult; Antiviral Agents; Child; Enzyme Inhibitors; Humans; Influenza, Human; Japan; Neuraminidase; Oseltamivir; Outpatients; RNA, Viral; Seasons; Zanamivir

Large scale investigation of the clinical effectiveness of neuraminidase inhibitors for circulating influenza viruses are important along with the surveillance of virus susceptibility in vitro.. The duration of fever and other influenza symptoms as markers of the clinical effectiveness of laninamivir octanoate hydrate (laninamivir) were investigated in the Japanese 2017/18 and 2018/19 influenza seasons and compared with the results of the previous six seasons.. Influenza A(H1N1)pdm09, A(H3N2), and B were found in 14, 45, and 52 patients in the 2017/18 season and in 22, 62, and 0 in the 2018/19 season, respectively. The median duration of fever for B was significantly longer than for A(H1N1)pdm09 and A(H3N2) in the 2017/18 season (p = 0.0461) and for A(H3N2) than for A(H1N1)pdm09 in the 2018/19 season (p = 0.0290). However, the differences were subtle in both seasons for other symptoms, with no significant differences in their median duration in comparison of the circulating types/subtypes. Over the eight seasons with the previous six seasons added, the median durations of fever were consistently longer for B than for A, but the relation between the A subtypes was inconsistent. The median durations of fever were comparable over the eight seasons for the virus types/subtypes, as were the median durations of other symptoms. The percentage of febrile patients decreased in a similar pattern over the eight seasons for each type/subtype.. The results confirmed that laninamivir has continued to be clinically effective against all types/subtypes of influenza viruses, with no safety issues.

Topics: Antiviral Agents; Fever; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza, Human; Japan; Neuraminidase; Pyrans; Seasons; Sialic Acids; Zanamivir

Baloxavir marboxil (baloxavir) is a new oral antiviral for influenza types A and B.. To determine the cost-effectiveness of baloxavir versus laninamivir in otherwise healthy (OwH) adults in Japan.. A decision tree was utilized to describe the course of influenza and predict associated costs and quality-adjusted life-years (QALYs) over one year by antiviral. Costs were valued from the public healthcare payer perspective, including influenza test, antiviral acquisition, other medications, physician visits, other outpatient costs associated with influenza or drug-related adverse events (DRAEs), and hospitalizations. Resource utilization and unit costs were obtained from the analysis of the JammNet claims database. Health state utilities were obtained from a clinical trial of baloxavir and previous models, and were driven by influenza symptoms, DRAEs, and complications caused by influenza. Sensitivity analyses were also performed.. The total payer expenditure per patient for baloxavir versus laninamivir was ¥9383 versus ¥9132. The additional acquisition costs of baloxavir were partly offset by the DRAE costs avoided. Baloxavir showed a small gain in QALYs versus laninamivir and the incremental cost per QALY gained (¥2,231,260) was lower than the considered willingness-to-pay threshold (¥5,000,000/QALY). Key model drivers were the probability of DRAEs and the duration of symptoms. The probability of baloxavir being cost-effective was 64%.. This cost-effectiveness study on baloxavir suggests that it would be cost-effective compared to laninamivir in OwH adults in Japan. Further studies are needed in different settings such as high-risk population and with different comparators.

Topics: Adult; Cost-Benefit Analysis; Dibenzothiepins; Guanidines; Humans; Influenza, Human; Japan; Morpholines; Pyrans; Pyridones; Sialic Acids; Triazines

Baloxavir marboxil (baloxavir) is a single-dose antiviral which was previously found to be a cost-effective alternative to laninamivir in otherwise healthy adults in Japan. This study aimed at investigating the cost-effectiveness of baloxavir versus laninamivir in patients with influenza at high risk for complications.. A decision tree was utilized to estimate costs and health gains associated with the use of antivirals. A lifetime horizon was applied to capture the long-term impact of influenza complications, and other events with associated costs and health outcomes were accounted for one influenza season. The study population was stratified into three categories: adolescents and non-elderly adults with high-risk conditions (HRC), elderly without other HRC, and elderly with other HRC. The cost-effectiveness was assessed from a public healthcare payer's perspective. The duration of influenza symptoms, probabilities of complications and probabilities of adverse events were obtained from a clinical trial and network meta-analysis. The costs of influenza and adverse events management were derived from the JammNet claims database. Utility values were informed by the clinical trial data and literature. Sensitivity analyses were also performed.. The baloxavir strategy was associated with higher costs (+¥144) and higher quality-adjusted life-years (QALYs) in adults with HRC, elderly without HRC and elderly with HRC (+0.00078, +0.00183 and +0.00350 respectively). The overall incremental cost/QALY for baloxavir versus laninamivir was ¥68,855, which was below the willingness-to-pay threshold of ¥5 million/QALY gained. Key drivers of the model results were the probability of pneumonia and bronchitis. The probability of baloxavir being cost-effective was 72%.. This study suggests that influenza treatment with baloxavir is cost-effective compared with laninamivir in the adult high-risk population in Japan.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Cost-Benefit Analysis; Dibenzothiepins; Guanidines; Humans; Influenza, Human; Japan; Middle Aged; Morpholines; Pyrans; Pyridones; Sialic Acids; Triazines

We conducted a post-marketing surveillance of laninamivir octanoate hydrate for Inhalation Suspension Set in patients under the age of 5 infected with the influenza virus to evaluate safety and efficacy of the drug.. Subjects enrolled by the centralized enrollment system were administered laninamivir once using a nebulizer based on the package insert.. Safety was evaluated in 1104 patients. The incidence of ADRs was 1.00% (11/1104). Compared to the incidence of ADRs of 2.04% (9/441) in the clinical trials for development, no increase in the frequency of ADRs was noted. Serious ADRs were noted in 3 patients (5 cases): 2 cases of convulsive attack, each 1 case of muscular weakness, a depressed level of consciousness, and pain in extremities. Excluding 2 patients with unknown outcomes, all of the patients recovered or their symptoms were alleviated. To detect risk factors for the occurrence of ADRs, 16 attributes were examined, and none of them were found to be significant. Efficacy was evaluated in 881 patients. The median time (95% CI) to fever resolution was 37.0 (33.0-39.0) h in type A virus (785 patients), 45.0 (34.0-56.0) h in type B virus (95 patients), and 22.0 h (1 patient) in the mixed type. This was similar to the time to fever resolution in the clinical trials.. The results of this surveillance verified that there are no noticeable problems with the safety or efficacy of laninamivir for children under the age of 5 infected with the influenza A and B viruses.

Topics: Administration, Inhalation; Antiviral Agents; Child, Preschool; Guanidines; Humans; Influenza, Human; Neuraminidase; Product Surveillance, Postmarketing; Pyrans; Sialic Acids; Zanamivir

We aimed to investigate the association between anaphylaxis and anti-influenza drug use using the Japanese Adverse Drug Event Report (JADER) database, a national spontaneous reporting database in Japan. We surveyed registered cases from the JADER database between April 2004 and November 2019. The target drugs were five anti-influenza drugs, namely oseltamivir, zanamivir, peramivir, laninamivir, and baloxavir. Adverse events associated with anaphylaxis, "anaphylactic reaction," "anaphylactic shock," "anaphylactoid reaction," and "anaphylactoid shock," were evaluated. The association between anaphylaxis and anti-influenza drug use was assessed by calculating the reporting odds ratio (ROR) and information component (IC) as a measure of disproportionality. Signals were considered positive if the lower limit of the 95% confidence interval (CI) of ROR was > 1, and that of IC was > 0. The number of anaphylaxis cases associated with anti-influenza drug use was 199 (0.9%). Signals were detected for inhaled laninamivir (ROR: 4.24 [95% CI: 3.06-5.88], IC: 1.83 [1.35-2.30]), intravenous peramivir (ROR: 2.97 [2.11-4.17], IC: 1.40 [0.90-1.89]), and oral baloxavir (ROR: 3.05 [2.22-4.18], IC: 1.44 [0.98-1.90]). Conversely, signals were not detected for oral oseltamivir or inhaled zanamivir. Although zanamivir and laninamivir were used as dry powder inhalers containing lactose as an additive, they differed in terms of signal detection. Our analysis indicated that the signal of anaphylaxis may varies based on the main component or dosage form of each anti-influenza drug. Appropriate use of these drugs is essential to prevent anaphylaxis and improve health status.

Topics: Acids, Carbocyclic; Adult; Adverse Drug Reaction Reporting Systems; Anaphylaxis; Antiviral Agents; Databases, Factual; Dibenzothiepins; Female; Guanidines; Humans; Influenza, Human; Japan; Male; Middle Aged; Morpholines; Pyrans; Pyridones; Sialic Acids; Triazines; Young Adult

The recommended antiviral drugs available for the treatment and prevention of influenza are neuraminidase inhibitors (NAIs). The aim of this study was to evaluate age-related clinical manifestations of adverse events (AEs) related to NAIs. FAERS and WebMD data were downloaded. The available NAIs selected for the analysis were oseltamivir, peramivir, zanamivir, and laninamivir. Disproportionality was analyzed using the proportional reporting ratio (PRR), the reporting odds ratio (ROR), and the information component (IC) methods. In total, 16729 AEs from 4598 patients and 575 AEs from 440 patients in the FAERS and WebMD, respectively, were included in the analysis. In the FAERS, AEs were more common among those who were younger (<19 years) for zanamivir, while for those who were older (>65 years) for peramivir. A disproportionality analysis showed that signals for vomiting and hallucinations were detected in younger patients given oseltamivir, while an abnormal hepatic function, cardiac failure, shock, and cardio-respiratory arrest were detected in older patients given peramivir. Psychiatric disorders were most common in younger and older patients, while gastrointestinal disorders were most common in adult given oseltamivir in the WebMD. Adverse symptoms related to NAIs varied and depended on the drugs used and the age of the patient.

Topics: Acids, Carbocyclic; Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Antiviral Agents; Child; Child, Preschool; Female; Guanidines; Humans; Infant; Infant, Newborn; Influenza, Human; Internet; Male; Middle Aged; Neuraminidase; Odds Ratio; Oseltamivir; Patient Participation; Pyrans; Risk Factors; Sialic Acids; United States; United States Food and Drug Administration; Young Adult; Zanamivir

Our earlier study investigated the incidence of severe abnormal behavior associated with neuraminidase inhibitors (NIs), but some studies have specifically examined the association of oseltamivir use and moderately abnormal behavior. Therefore, this study was undertaken to assess associations between moderately abnormal behavior and administered drugs. All cases of patients with influenza who exhibited moderately abnormal behavior were reported to us by physicians of all sentinel clinics and hospitals for influenza throughout Japan. Open Data of the National Database of Electronic Medical Claims include the numbers of patients diagnosed as having influenza who were prescribed NI. Incidence by NI was tested using Fisher's exact test. We received 518 moderately abnormal cases in 5-9-year-olds and 207 moderately abnormal behavior cases in 10-19-year-olds. The incidence among NI ranged from 193 per one million influenza patients in laninamivir among 10-19-year-olds to 1021 for peramivir among 5-9-year-olds. Estimation results revealed the order of risk among NIs as peramivir, oseltamivir, zanamivir and laninamivir in moderate abnormal behavior. Because of data limitations, risk among patients with and without NI cannot be compared.

Topics: Acids, Carbocyclic; Adolescent; Antiviral Agents; Child; Cyclopentanes; Enzyme Inhibitors; Guanidines; Humans; Illness Behavior; Influenza, Human; Japan; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Young Adult; Zanamivir

Topics: Antiviral Agents; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Interferons; Neuraminidase; Pyrans; Sialic Acids; Zanamivir

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Dibenzothiepins; Drug Resistance, Viral; Guanidines; Humans; Indonesia; Influenza B virus; Influenza, Human; Japan; Male; Microbial Sensitivity Tests; Morpholines; Mutation; Neuraminidase; Pyrans; Pyridones; Sialic Acids; Triazines; Zanamivir

Even though abnormal behavior related with influenza and neuraminidase inhibitors (NI) has been discussed, the risks of acetaminophen and co-administration of NI and acetaminophen have not been examined. This study assesses those risks.. All cases of patients with influenza who present with severe abnormal behavior are reported by physicians of all clinics and hospitals throughout Japan. The numbers of people diagnosed as having influenza, whether prescribed NI and acetaminophen or not, were extracted from the National Database of Electronic Medical Claims (NDBEMC). The study period was from September 2009 to March 2016.. We found two consistent results among four combinations of age class and severity. The one was that patients who did not use NI or acetaminophen showed significantly higher incidence of abnormal behavior than zanamivir with acetaminophen, another one was that patients with oseltamivir only has higher incidence than zanamivir with acetaminophen. Concerning about acetaminophen, the use of it significantly decrease risk for severe and the most severe instances in 5-9-year-old patients with laninamivir and the severe instances in 10-19-year-old patients with zanamivir.. We also demonstrated that acetaminophen alone or co-administered with NI does not seem to raise the risk of abnormal behavior in influenza patients.

Topics: Acetaminophen; Adolescent; Age Factors; Antiviral Agents; Behavioral Symptoms; Child; Drug Therapy, Combination; Enzyme Inhibitors; Female; Guanidines; Humans; Incidence; Influenza, Human; Japan; Male; Neuraminidase; Oseltamivir; Pyrans; Risk Factors; Sialic Acids; Zanamivir

We herein report the first case of immune-mediated drug-induced liver injury that may have been caused by laninamivir. A 15-year-old girl was diagnosed with influenza and prescribed 40 mg laninamivir. Six weeks later, she was admitted to our hospital because of jaundice and fatigue. Laboratory examinations revealed elevated levels of hepatobiliary enzymes, and acute liver injury was suspected. Laboratory examinations and histological findings were characteristic of autoimmune hepatitis. Steroid treatment was ineffective, and azathioprine was added to the treatment. Twenty-two months after the onset, a second biopsy revealed the absence of inflammatory infiltrations, and the drugs were withdrawn. Liver function tests remained normal nine months after withdrawal.

Topics: Adolescent; Antiviral Agents; Azathioprine; Chemical and Drug Induced Liver Injury; Female; Guanidines; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Influenza A virus; Influenza, Human; Jaundice; Pyrans; Sialic Acids; Zanamivir

Laninamivir, a neuraminidase inhibitor (NAI), has been used for the treatment and prophylaxis of influenza A/B. To date, pneumonia has not been reported as an adverse effect of NAIs. Here, we report the first 2 cases of drug-induced pneumonitis after the administration of laninamivir octanoate (LO), a pro-drug of laninamivir. Case 1 reports a 20-year-old healthy woman presenting with LO-induced pneumonitis so severe that it was necessary for endotracheal intubation and administration of mechanical ventilator support. Steroids were used for the treatment of pneumonitis and rapid improvement was observed. Case 2 reports a 35-year-old healthy woman presenting with less severe LO-induced pneumonitis that improved without any treatment. In both cases, drug-induced lymphocyte stimulation tests (DLSTs) were positive. In the bronchoalveolar lavage (BAL) fluid, the proportion of eosinophils to lymphocytes was higher in Case 1. Conversely, the proportion of lymphocytes to eosinophils was higher in Case 2. Collectively, we determined 3 clinical issues: (1) LO could cause pneumonia; (2) BAL and DLST could be helpful in the diagnosis of LO-induced pneumonitis; and (3) LO-induced pneumonia could become severe, though steroids were effective in improving it.

Topics: Administration, Inhalation; Adult; Antiviral Agents; Bronchoalveolar Lavage; Female; Glucocorticoids; Guanidines; Humans; Influenza A virus; Influenza, Human; Lung; Neuraminidase; Pneumonia; Pyrans; Respiration, Artificial; Sialic Acids; Tomography, X-Ray Computed; Treatment Outcome; Viral Proteins; Young Adult; Zanamivir

The clinical effectiveness of four neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir, and peramivir) for children aged 0 months to 18 years with influenza A and B were investigated in the 2014-2015 to 2016-2017 influenza seasons in Japan. A total of 1207 patients (747 with influenza A and 460 with influenza B) were enrolled. The Cox proportional-hazards model using all of the patients showed that the duration of fever after administration of the first dose of the NAI was shorter in older patients (hazard ratio = 1.06 per 1 year of age, p < 0.001) and that the duration of fever after administration of the first dose of the NAI was shorter in patients with influenza A infection than in patients with influenza B infection (hazard ratio = 2.21, p < 0.001). A logistic regression model showed that the number of biphasic fever episodes was 2.99-times greater for influenza B-infected patients than for influenza A-infected patients (p < 0.001). The number of biphasic fever episodes in influenza A- or B-infected patients aged 0-4 years was 2.89-times greater than that in patients aged 10-18 years (p = 0.010), and the number of episodes in influenza A- or B-infected patients aged 5-9 years was 2.13-times greater than that in patients aged 10-18 years (p = 0.012).

Topics: Acids, Carbocyclic; Adolescent; Betainfluenzavirus; Child; Child, Preschool; Cyclopentanes; Enzyme Inhibitors; Female; Guanidines; Humans; Infant; Infant, Newborn; Influenza A virus; Influenza, Human; Japan; Male; Neuraminidase; Oseltamivir; Pyrans; Seasons; Sialic Acids; Treatment Outcome; Zanamivir

Neuraminidase inhibitors are recommended for children hospitalized with influenza-related respiratory infections, and oseltamivir is the first choice of treatment in most situations. However, little is known regarding the recent trend in using neuraminidase inhibitors and their difference in health economy. The aim of this study was to reveal recent trends in neuraminidase inhibitor use and compare hospitalization costs across different treatment regimens.. We retrospectively obtained the hospital discharge records of inpatients under 18 years of age with a diagnosis of influenza-related respiratory infections using a national inpatient database in Japan. We excluded patients with chronic medical conditions from the analyses. Multivariable mixed effects regression models were used to investigate the recent treatment trends and healthcare costs.. We identified 27 771 inpatients with influenza-related respiratory infections. The proportions of neuraminidase inhibitor use increased from 62.6% in 2010 to 71.8% in2014 (P. We observed an increasing trend in peramivir use and decreasing trends in use of oseltamivir and zanamivir. Treatment with peramivir required higher hospitalization costs.

Topics: Acids, Carbocyclic; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Drug Utilization; Enzyme Inhibitors; Female; Guanidines; Hospitalization; Humans; Infant; Influenza, Human; Japan; Male; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Zanamivir

The duration of fever and symptoms after laninamivir octanoate hydrate (laninamivir) inhalation were investigated in the Japanese 2016/17 influenza season and the results were compared with those of the 2011/12 to 2015/16 seasons. A total of 1278 patients were evaluated for the duration of fever and symptoms in the six studied seasons. In the 2016/17 season, the influenza types/subtypes of the patients were 6 A (H1N1)pdm09 (2.9%), 183 A (H3N2) (87.6%), and 20 B (9.6%). The respective median durations of fever for A (H1N1)pdm09, A (H3N2), and B were 38.0, 33.0, and 38.5 h, without significant difference (p = 0.9201), and the median durations of symptoms were 86.5, 73.0, and 99.0 h, with significant difference (p = 0.0342). The median durations of fever and symptoms after laninamivir inhalation were quite consistent for the six studied seasons for A (H1N1)pdm09, A (H3N2), and B, without any significant differences. The percentage of patients with unresolved fever patients displayed a similar pattern through the six studied seasons for all these virus types. There was no significant difference in the duration of fever or symptoms between the Victoria and Yamagata lineages in the 2016/17 season and those of the previous studied seasons. Over the seasons tested, ten adverse drug reactions (ADRs) were reported from 1341 patients. The most frequent ADR was diarrhea and all ADRs were self-resolving and not serious. These results indicate the continuing clinical effectiveness of laninamivir against influenza A (H1N1)pdm09, A (H3N2), and B, with no safety issues.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Child; Female; Fever; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza, Human; Inhibitory Concentration 50; Male; Middle Aged; Pyrans; Seasons; Sialic Acids; Young Adult; Zanamivir

Topics: Acids, Carbocyclic; Amino Acid Substitution; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Epidemiological Monitoring; Global Health; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza B virus; Influenza, Human; Inhibitory Concentration 50; Microbial Sensitivity Tests; Neuraminidase; Oseltamivir; Pyrans; Seasons; Sialic Acids; World Health Organization; Zanamivir

Neuraminidase (NA) inhibitors are the recommended antiviral medications for influenza treatment. However, their therapeutic efficacy can be compromised by NA changes that emerge naturally and/or following antiviral treatment. Knowledge of which molecular changes confer drug resistance of influenza A(H7N9) viruses (group 2NA) remains sparse.. Fourteen amino acid substitutions were introduced into the NA of A/Shanghai/2/2013(H7N9). Recombinant N9 (recN9) proteins were expressed in a baculovirus system in insect cells and tested using the Centers for Disease Control and Prevention standardized NA inhibition (NI) assay with oseltamivir, zanamivir, peramivir, and laninamivir. The wild-type N9 crystal structure was determined in complex with oseltamivir, zanamivir, or sialic acid, and structural analysis was performed.. All substitutions conferred either reduced or highly reduced inhibition by at least 1 NA inhibitor; half of them caused reduced inhibition or highly reduced inhibition by all NA inhibitors. R292K conferred the highest increase in oseltamivir half-maximal inhibitory concentration (IC50), and E119D conferred the highest zanamivir IC50. Unlike N2 (another group 2NA), H274Y conferred highly reduced inhibition by oseltamivir. Additionally, R152K, a naturally occurring variation at the NA catalytic residue of A(H7N9) viruses, conferred reduced inhibition by laninamivir.. The recNA method is a valuable tool for assessing the effect of NA changes on drug susceptibility of emerging influenza viruses.

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Databases, Genetic; Drug Resistance, Multiple, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A Virus, H7N9 Subtype; Influenza, Human; Inhibitory Concentration 50; Neuraminidase; Oseltamivir; Protein Conformation; Pyrans; Recombinant Proteins; Sialic Acids; Viral Proteins; Zanamivir

We evaluated the environmental fate of new three anti-influenza drugs, favipiravir (FAV), peramivir (PER), and laninamivir (LAN), and an active prodrug of LAN, laninamivir octanoate (LANO), in comparison with four conventional drugs, oseltamivir (OS), oseltamivir carboxylate (OC), amantadine (AMN), and zanamivir (ZAN) by photodegradation, biodegradation, and sorption to river sediments. In addition, we conducted 9-month survey of urban rivers in the Yodo River basin from 2015 to 2016 (including the influenza season) to investigate the current status of occurrence of these drugs in the river environment. The results clearly showed that FAV and LAN rapidly disappeared through photodegradation (half-lives 1 and 8 h, respectively), followed by LANO which gradually disappeared through biodegradation (half-life, 2 days). The remained PER and conventional drugs were, however, persistent and transported from upstream to downstream sites. Rates of their sorption to river sediments were negligibly small. Detected levels remained were in the range from N.D. to 89 ng/L for the river waters and from N.D. to 906 ng/L in sewage effluent. However, all of the remained drugs were effectively removed by ozonation after chlorination at a sewage treatment plant. These findings suggest the importance of introducing ozonation for reduction of pollution loads in rivers, helping to keep river environments safe. To the best of our knowledge, this is the first evaluation of the removal effects of natural sunlight, biodegradation, and sorption to river sediments on FAV, PER, LAN, LANO, and a conventional drug, AMN.

Topics: Acids, Carbocyclic; Amides; Antiviral Agents; Biodegradation, Environmental; Cyclopentanes; Environmental Monitoring; Fresh Water; Guanidines; Half-Life; Humans; Influenza, Human; Japan; Prodrugs; Pyrans; Pyrazines; Rivers; Seasons; Sewage; Sialic Acids; Water Pollutants, Chemical; Zanamivir

Background In Japan, four neuraminidase inhibitors (NAIs) are currently prescribed to patients with influenza A and B. To know the backgrounds and clinical courses of patients with influenza who were treated with NAIs is important in the selection of appropriate medications. Methods We conducted a multicenter observational study in Osaka with postcard questionnaires. Patients who were prescribed NAIs were provided postcard questionnaires containing questions on their backgrounds, body temperatures, and durations of other influenza symptoms. We analyzed the factors that were associated with early fever alleviation using a logistic regression model. Results The postcard response rate was 31% (326 of 1050), and 307 patients were enrolled in this study [150 patients who were under 10 years old (type A, 118; and type B, 32) and 157 patients who were 10 or older (type A, 114; and type B, 43)]. In the patients under 10, the multivariate analysis showed that influenza type (Type B vs Type A; Odds Ratio, 0.13; 95% Confidence Interval: 0.04-0.38) was associated with early fever alleviation. However, NAIs were not related to early fever alleviation. Laninamivir tended to contribute more to early fever alleviation compared to oseltamivir in patients under 10 (Odds Ratio, 2.50;$95% Confidence Interval: 0.90-7.80). Conclusions The types,of prescibed NAIs were not significantly related to early fever alleviation. However, the fever durations of the patients under 10 who were prescribed laninamivir were shorter than those of patients under 10 who were prescribed oseltamivir or zanamivir.

Topics: Acids, Carbocyclic; Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Disease Outbreaks; Enzyme Inhibitors; Female; Guanidines; Humans; Infant; Influenza, Human; Japan; Male; Middle Aged; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Surveys and Questionnaires; Treatment Outcome; Zanamivir

Viral fitness of a laninamivir-selected influenza A/Brisbane/10/2007-like (H3N2) isolate (LRVp9) containing a 237-amino acid neuraminidase deletion and a P194L hemagglutinin mutation was evaluated in vitro and in ferrets. LRVp9 and the wild-type (WT) virus showed comparable replication kinetics in MDCK-ST6GalI cells. Cultured virus was recovered between days 2 and 5 post-infection in nasal washes (NW) from the 4 WT-infected ferrets whereas no virus was recovered from the LRVp9-infected animals. There was a ≥1 log reduction in viral RNA copies/μl of NW for LRVp9 compared to WT at most time points. The large neuraminidase deletion compromises viral infectivity in vivo.

Topics: Animals; Antiviral Agents; Drug Resistance, Viral; Ferrets; Gene Deletion; Genetic Fitness; Guanidines; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Influenza A Virus, H3N2 Subtype; Influenza, Human; Mutation; Neuraminidase; Orthomyxoviridae Infections; Pyrans; RNA, Viral; Sialic Acids; Virus Replication; Zanamivir

The current School Health and Safety Act in Japan states that children with influenza infection should stay home until day 6(th) after symptoms onset. This was an amendment of a previous version recommending school return on day 3 after defervescence. Here, we investigated the duration of fever and virus shedding after laninamivir treatment in 7 children infected with influenza A(H3N2) virus and 21 children with influenza B virus in relation to the school return timing recommended by the School Health and Safety Act during the 2011-2012 influenza season. Nasal discharge was collected on the first, second, and third hospital visits and virus titers were assessed by virus culture and real-time PCR. Duration of fever after laninamivir treatment was 1 day longer for influenza B than for influenza A(H3N2). Virus detection rates with 50% tissue culture infectious dose and viral RNA were highest at the first visit and gradually decreased at subsequent visits. Virus positivity rates were detectable at the time of defervescence in less than half of the enrolled patients (14.3-42.9%). Virus shedding rates were similarly low (0.0-19.0%) on day 3 or later from defervescence and on day 6 or later from fever onset (school return dates per the old and current School Health and Safety Act) regardless of the influenza type. In conclusion, despite the higher efficacy of laninamivir against A(H3N2) viruses than B viruses, viral shedding is low after return to school for both types, regardless of the version of the School Health and Safety Act.

Topics: Antiviral Agents; Child; Demography; Female; Guanidines; Health; Humans; Influenza A Virus, H3N2 Subtype; Influenza, Human; Male; Neuraminidase; Pyrans; RNA, Viral; Schools; Sialic Acids; Virus Shedding; Zanamivir

The duration of fever and other symptoms as markers of the clinical effectiveness of laninamivir octanoate hydrate (laninamivir) were investigated in the Japanese 2014-2015 influenza season and the results were compared with those of the previous three seasons, 2011-2012 to 2013-2014. From these four seasons, the data of 636 influenza A(H3N2) and 128 influenza B patients was available for analysis. No significant difference was found in their baseline characteristics. The median duration of fever for all A(H3N2) patients ranged from 32.0 to 41.0 h. The duration of fever in the 2014-2015 season was significantly shorter than that in the 2012-2013 and 2013-2014 seasons (p = 0.0204 and 0.0391, respectively), but the differences were within nine hours. The median duration of symptoms for A(H3N2) ranged from 80.0 to 89.0 h, with no significant difference among the four seasons (p = 0.2222). The median duration of fever for B patients ranged from 43.0 to 50.0 h, with no significant difference among the four seasons. The duration of the symptoms for B varied by season, but no significant difference was found among the four seasons. Over the four seasons, 44 adverse events were reported from among 921 patients, with all resolving without treatment. These results indicate the continuing effectiveness of laninamivir against influenza A(H3N2) and B, with no safety issues. It is unlikely that the clinical use of laninamivir has caused viral resistance in the currently epidemic viruses.

Topics: Administration, Inhalation; Antiviral Agents; Child; Female; Fever; Guanidines; Humans; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Japan; Kaplan-Meier Estimate; Male; Product Surveillance, Postmarketing; Proportional Hazards Models; Pyrans; Sialic Acids; Treatment Outcome; Zanamivir

Shedding of the pandemic virus during an influenza pandemic is thought to persist longer than shedding of influenza viruses during annual influenza seasons, because people have much less immunity against a pandemic influenza. A correlation is thought to exist between the length of virus shedding and the clinical severity of influenza illness.. We compared the virus isolation rates of children with pandemic A H1N1/09 influenza infection and children with A H3N2 influenza infection after the patients had been treated with one of three neuraminidase inhibitors (NAI) such as peramivir, laninamivir and oseltamivir. The clinical effectiveness of each NAI was assessed on the basis of the duration of the febrile period after the start of treatment.. Influenza viruses were isolated from 15 of the 34 patients in the A H3N2 group (mean age 6.2 years) and from 4 of the 25 patients in the A H1N1/09 (mean age 5.6 years) virus group (44.1% versus 16.0%; P<0.05). However, the differences between the duration of fever in the patients in the A H3N2 group and A H1N1/09 group after treatment with the NAIs were not significant.. The virus isolation rates after treatment with each of the NAIs were significantly lower in the A H1N1/09 group, suggesting that the pandemic A H1N1/09 virus was more sensitive to the NAIs than the seasonal A H3N2 virus was. Clinically, there were no significant differences in the effectiveness of the NAIs between the H1N1/09 infected group and H3N2 infected group.

Topics: Acids, Carbocyclic; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Enzyme Inhibitors; Female; Fever; Guanidines; Humans; Infant; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza, Human; Male; Neuraminidase; Oseltamivir; Pyrans; Severity of Illness Index; Sialic Acids; Time Factors; Treatment Outcome; Viral Proteins; Virus Shedding; Zanamivir

Prolonged treatment of an immunocompromised child with oseltamivir and zanamivir for A(H1N1)pdm09 virus infection led to the emergence of viruses carrying H275Y and/or E119G in the neuraminidase (NA). When phenotypically evaluated by NA inhibition, the dual H275Y-E119G substitution caused highly reduced inhibition by 4 NA inhibitors: oseltamivir, zanamivir, peramivir, and laninamivir.

Topics: Acids, Carbocyclic; Amino Acid Substitution; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Immunocompromised Host; Infant; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Mutation, Missense; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Viral Proteins; Zanamivir

To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC50) of neuraminidase inhibitors (NAIs) for the influenza virus isolates in the 2013-2014 influenza season and compared the results to those of the 2010-2011 to 2012-2013 influenza seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype of influenza was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 327 influenza viruses were isolated: 172 influenza A(H1N1)pdm09 (52.6%), 49 A(H3N2) (15.0%), and 106 B (32.4%). Numbers of Victoria and Yamagata lineage isolates were 36 and 70, respectively. Two A(H1N1)pdm09 isolates showed a high IC50 for oseltamivir (130 and 150 nM) exceeding by 100 times the geometric mean of the IC50 of oseltamivir for A(H1N1)pdm09 isolates (0.76 nM). No isolate showed a very high IC50 for A(H3N2) or B. The IC50 of the NAIs except for oseltamivir for A(H1N1) pdm09 were significantly higher than those of the 2010-2011 season (P < 0.05). The IC50 of all four NAIs for A(H3N2) were significantly lower than those of the 2012-2013 season (P < 0.001). The IC50 of the NAIs for B except for oseltamivir were significantly lower than those of the 2012-2013 season (P < 0.001). Although there are some isolates that show highly reduced sensitivity to oseltamivir among A(H1N1)pdm09 isolates, the currently epidemic influenza A(H1N1)pdm09, A(H3N2) and B viruses are susceptible to all four NAIs with no trend toward decreased sensitivity.

Topics: Acids, Carbocyclic; Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Cyclopentanes; Enzyme Inhibitors; Female; Guanidines; Humans; Infant; Infant, Newborn; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Inhibitory Concentration 50; Japan; Male; Middle Aged; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Time Factors; Young Adult; Zanamivir

We investigated the clinical symptoms of 206 pediatric patients with influenza virus infection and compared them among oseltamivir-treated, zanamivir-treated, and laninamivir-treated groups in 2013/2014 influenza season. The drug compliance of each neuraminidase inhibitor was good in all three groups. Although the duration of fever after administration of the first dose of each neuraminidase inhibitor were significantly prolonged in the patient with influenza B infection than in the patient with influenza A infection, no statistically significant difference in the clinical efficacy and the side effect among three groups were found. The number of biphasic fever episodes in patients treated with neuraminidase inhibitor was rare (two episodes of oseltamivir-treated group and one episode of zanamivir-treated group). In conclusion, under the good drug compliance, the efficacy of all three neuraminidase inhibitor was the same for the treatment of influenza virus infection in children.

Topics: Antiviral Agents; Child; Enzyme Inhibitors; Guanidines; Humans; Influenza, Human; Japan; Medication Adherence; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Time Factors; Zanamivir

To evaluate the clinical effectiveness of the two inhaled neuraminidase inhibitors (NAIs), zanamivir (ZN) and laninamivir octate (LO), for influenza A(H3N2) and B virus infections.. A prospective, multicenter observational study was conducted from January to April in 2012.. Outpatients aged 5-18 years who had a temperature of 37.5°C or higher and were diagnosed as having influenza based on an immunochromatographic assay were enrolled.. A total of 338 patients treated with ZN and 314 patients treated with LO were compared.. The duration of fever after administration of the first dose of each NAI was evaluated as a primary endpoint. The secondary endpoint was episodes of biphasic fever.. No statistically significant difference in the duration of fever was found between the ZN and LO groups (log-rank test, P = 0.117). A logistic regression model showed that episodes of biphasic fever increased by 1.19 times for every decrease of 1 year of age (P = 0.016) and that the number of biphasic fever episodes in patients treated with LO was 5.80-times greater than that in patients treated with ZN (P < 0.001).. Although the duration of fever in the LO group was comparable to that in the ZN group, episodes of biphasic fever were more frequent in younger children and in the LO group than in the ZN group.

Topics: Adolescent; Antiviral Agents; Child; Child, Preschool; Chromatography, Affinity; Female; Fever; Guanidines; Humans; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Male; Prospective Studies; Pyrans; Sialic Acids; Time Factors; Treatment Outcome; Zanamivir

Evidence of the effectiveness of influenza vaccination in children and elderly adults is limited, although this population has the highest risk for influenza infection.. We enrolled 4443 participants, aged 3-97 years, who had influenza-kit-positive results during seasons 2007-12, including 2135 with influenza A, 534 with A/H1N1, and 1643 with influenza B. Eligible subjects completed a questionnaire to identify past influenza infection and vaccination history. For the diagnosis of current influenza infection, subjects were examined, and pharyngeal swabs were collected and tested using the Capilia flu rapid diagnosis kit to confirm influenza infection. An interim analysis was performed using clinician-based surveillance data for the entire four seasons of influenza infection in Japan.. In 3035 adults aged 14-64 years, administration of the influenza vaccine significantly reduced the frequency of infection (P<0.01) in the 2008 and 2010 seasons, but not in the 2009 and 2011 seasons. Moreover, the vaccine did not reduce the frequency of infection in children (aged <13 years) and older adults (aged >65 years) significantly. Laninamivir, oseltamivir phosphate, zanamivir hydrate, and amantadine hydrochloride were administered to 1381, 2432, 1044, and 100 patients, respectively. They were effective in >97% of patients, with no significant differences being found. Adverse effects were few. However, the recurrence rate of influenza infection after treatment was significantly reduced in patients who received laninamivir compared with that in those who received oseltamivir and zanamivir (P<0.01). The effectiveness of laninamivirdid not decrease.. The vaccines administered had limited efficacy in reducing the frequency of influenza infection in young adults. Laninamivir significantly reduced the recurrence of influenza infection when compared with other neuraminidase inhibitors.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Child; Child, Preschool; Female; Guanidines; Humans; Influenza Vaccines; Influenza, Human; Japan; Male; Middle Aged; Neuraminidase; Orthomyxoviridae; Pyrans; Sialic Acids; Vaccination; Young Adult; Zanamivir

Influenza viruses collected from regions of Asia, Africa and Oceania between 2009 and 2012 were tested for their susceptibility to two new neuraminidase inhibitors, peramivir and laninamivir. All viruses tested had normal laninamivir inhibition. However, 3·2% (19/599) of A(H1N1)pdm09 viruses had highly reduced peramivir inhibition (due to H275Y NA mutation) and <1% (6/1238) of influenza B viruses had reduced or highly reduced peramivir inhibition, with single occurrence of variants containing I221T, A245T, K360E, A395E, D432G and a combined G145R+Y142H mutation. These data demonstrate that despite an increase in H275Y variants in 2011, there was no marked change in the frequency of peramivir- or laninamivir-resistant variants following the market release of the drugs in Japan in 2010.

Topics: Acids, Carbocyclic; Africa; Antiviral Agents; Asia; Cyclopentanes; Guanidines; Humans; Influenza A virus; Influenza B virus; Influenza, Human; Japan; Microbial Sensitivity Tests; Mutation, Missense; Neuraminidase; Oceania; Pyrans; Sialic Acids; Viral Proteins; Zanamivir

Emergence of influenza viruses with reduced susceptibility to neuraminidase inhibitors (NAIs) is sporadic, often follows exposure to NAIs, but occasionally occurs in the absence of NAI pressure. The emergence and global spread in 2007/2008 of A(H1N1) influenza viruses showing clinical resistance to oseltamivir due to neuraminidase (NA) H275Y substitution, in the absence of drug pressure, warrants continued vigilance and monitoring for similar viruses. Four World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza (WHO CCs) tested 11,387 viruses collected by WHO-recognized National Influenza Centres (NIC) between May 2012 and May 2013 to determine 50% inhibitory concentration (IC50) data for oseltamivir, zanamivir, peramivir and laninamivir. The data were evaluated using normalized IC50 fold-changes rather than raw IC50 data. Nearly 90% of the 11,387 viruses were from three WHO regions: Western Pacific, the Americas and Europe. Only 0.2% (n=27) showed highly reduced inhibition (HRI) against at least one of the four NAIs, usually oseltamivir, while 0.3% (n=39) showed reduced inhibition (RI). NA sequence data, available from the WHO CCs and from sequence databases (n=3661), were screened for amino acid substitutions associated with reduced NAI susceptibility. Those showing HRI were A(H1N1)pdm09 with NA H275Y (n=18), A(H3N2) with NA E119V (n=3) or NA R292K (n=1) and B/Victoria-lineage with NA H273Y (n=2); amino acid position numbering is A subtype and B type specific. Overall, approximately 99% of circulating viruses tested during the 2012-2013 period were sensitive to all four NAIs. Consequently, these drugs remain an appropriate choice for the treatment and prophylaxis of influenza virus infections.

Topics: Acids, Carbocyclic; Amino Acid Substitution; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A virus; Influenza, Human; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Zanamivir

The purpose of this study is to assess pregnancy outcomes of women treated with a novel neuraminidase inhibitor, laninamivir, during pregnancy.. A retrospective review of pregnancy outcomes of 112 pregnant women who were given laninamivir for treatment of influenza was performed. Possible adverse events, including miscarriages, preterm birth, foetal malformation and any neonatal morbidity requiring treatment, were assessed.. Seventeen, 39, 46 and 10 women were administered a single inhaled dose of 20 or 40 mg of laninamivir at gestational week (GW) 3-11, 12-21, 22-36 and 37 or more, respectively. One (1.8%) of 56 women with laninamivir at GW <22 experienced miscarriage at GW <12. The remaining 111 women gave birth to 111 viable infants but at preterm (GW <37) in nine (8.8%) of 102 women with laninamivir at GW <37. Three (2.7%) of the 111 newborns had malformations: forefoot varus deformity, foot polydactyly and cleft lip in one each born to a mother taking laninamivir at GW 6, 17 and 21, respectively. Five neonates (4.5%) were small for gestational age. Eleven (9.9%), five (4.5%) and no neonates required phototherapy for jaundice, transient respiratory supports for respiratory distress syndrome (n = 2) or transient tachypnoea of the newborn (n = 3), and glucose administration for hypoglycaemia, respectively.. Although this study included a small number of study women and no control women, the results suggested that maternal exposure to laninamivir did not increase the rate of adverse pregnancy and foetal outcomes.

Topics: Adolescent; Adult; Antiviral Agents; Female; Guanidines; Humans; Infant, Newborn; Influenza, Human; Japan; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Pyrans; Retrospective Studies; Sialic Acids; Young Adult; Zanamivir

To genetically characterize human influenza viruses and their susceptibilities to antivirals during two post-pandemic seasons in Lebanon.. Influenza virus was isolated from nasopharyngeal swabs that were obtained from patients with influenza-like illness during 2010-2012 and further analyzed both phenotypically and genotypically.. During the 2010-2011 season, both 2009 pandemic H1N1 (H1N1p) and B viruses co-circulated with equal prevalence, while the H3N2 virus predominated during the 2011-2012 season. All H3N2 and H1N1 viruses were resistant to amantadine. Importantly, all viruses of the influenza A and B types were susceptible to the neuraminidase (NA) inhibitors oseltamivir, zanamivir, peramivir, and laninamivir. Nonetheless, all 2011-2012 H1N1p isolates had three mutations (V241I, N369K, and N386S) in the NA gene that were suggested to be permissive of the H275Y mutation, which confers resistance to oseltamivir. We also detected one H1N1p virus during the 2010-2011 season with a 4-fold decrease in susceptibility to oseltamivir due to an NA-S247N mutation. This isolate was phylogenetically distinct from other H1N1p viruses that were isolated in other regions.. Influenza A viruses with reduced susceptibility to oseltamivir and mutations permissive for acquiring NA resistance-conferring mutation with minimal burden on their fitness were isolated in Lebanon.

Topics: Acids, Carbocyclic; Amantadine; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Lebanon; Microbial Sensitivity Tests; Mutation; Neuraminidase; Oseltamivir; Pandemics; Phylogeny; Pyrans; Sialic Acids; Zanamivir

Zanamivir, laninamivir, and CS-8958 are three neuraminidase inhibitors that have been clinically used to combat influenza. We report herein a novel organocatalytic route for preparing these agents. Only 13 steps are needed for the assembly of zanamivir and laninamivir from inexpensive D-araboascorbic acid by this synthetic route, which relies heavily on a thiourea-catalyzed enantioselective Michael addition of acetone to tert-butyl (2-nitrovinyl)carbamate and an anti-selective Henry reaction of the resulting Michael adduct with an aldehyde prepared from D-araboascorbic acid. The synthetic procedures are scalable, as evident from the preparation of more than 3.5 g of zanamivir.

Topics: Antiviral Agents; Catalysis; Guanidines; Humans; Influenza, Human; Pyrans; Sialic Acids; Zanamivir

Amino acid changes in or near the active site of neuraminidase (NA) in influenza viruses reduce the susceptibility to NA inhibitor drugs. Here, we report the recovery of three influenza B viruses with reduced susceptibilities to NA inhibitors from human patients with no history of antiviral drug treatment. The three viruses were isolated by inoculating Madin-Darby canine kidney (MDCK) cells with respiratory specimens from the patients. NA inhibition assays demonstrated that two of the three isolates showed a highly reduced susceptibility to peramivir and moderately reduced susceptibility to oseltamivir, zanamivir, and laninamivir. The remaining one isolate exhibited moderately reduced sensitivity to peramivir, zanamivir, and laninamivir but was susceptible to oseltamivir. A sequence analysis of viruses propagated in MDCK cells revealed that all three isolates contained a single mutation (Q138R, P139S, or G140R) in NA not previously associated with reduced susceptibility to NA inhibitors. However, pyrosequencing analyses showed that the Q138R and G140R mutations were below a detectable level in the original clinical specimens; the P139S mutation was detected at a very low level, suggesting that the mutant viruses may be preferably selected during propagation in MDCK cells. The NA crystallographic structure showed that these mutations were located at the interface between the two monomers of the NA tetramer, away from the NA active site. In addition to amino acid substitutions around the active site of NA, these observations suggest that alterations in the monomer-monomer interface region of NA may contribute to reduced sensitivity to NA inhibitors.

Topics: Animals; Antiviral Agents; Catalytic Domain; Dogs; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza B virus; Influenza, Human; Japan; Madin Darby Canine Kidney Cells; Models, Molecular; Mutation; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Viral Proteins; Zanamivir

Laninamivir octanoate (LO) is a new neuraminidase inhibitor for inhalation. The objectives of this study were to model the population pharmacokinetics of LO and its active metabolite laninamivir after inhaled administration of LO using a pooled population of healthy subjects, and adult and pediatric patients with influenza virus infection from 8 clinical studies, and to evaluate covariate effects on pharmacokinetics. The pharmacokinetics of LO and laninamivir in plasma and urine are well-described by structural models that consist of a 2-compartment model for LO with instantaneous bolus input and first-order elimination; and a 1-compartment model for laninamivir with formation of laninamivir via the metabolic pathway from LO in systemic circulation, entry of laninamivir from the respiratory tract compartment, and linear elimination. Creatinine clearance was identified as a covariate of apparent total clearance for LO and renal clearances for LO and laninamivir, with the largest effect on laninamivir exposure. Body weight was identified to affect distribution volumes of LO and laninamivir and the metabolic clearance of LO; however there was no notable effect on exposures across the wide body weight range evaluated. The population pharmacokinetic model also provides insight into the likely kinetics of drug disposition in the respiratory tract following inhaled administration.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Child; Child, Preschool; Enzyme Inhibitors; Female; Guanidines; Humans; Influenza, Human; Male; Middle Aged; Neuraminidase; Prodrugs; Pyrans; Sialic Acids; Zanamivir

Neuraminidase (NA) inhibitors (NAIs) are currently the only antivirals effective against influenza infections due to widespread resistance to M2 inhibitors.. Influenza A and B viruses (n = 1079) collected worldwide between April 01, 2011, and September 30, 2011, were assessed for susceptibility to FDA-approved NAIs, oseltamivir and zanamivir, and investigational peramivir, using the fluorescent-based NA-Fluor™ Influenza Neuraminidase Assay Kit. A subset of viruses (n = 98) were tested for susceptibility to the investigational NAI, laninamivir.. Influenza A(H1N1)pdm09 viruses (n = 326) were sensitive to all NAIs, except for two (0.6%) with H275Y (N1 numbering; H274Y in N2 numbering) substitution, which exhibited elevated IC50 s for oseltamivir and peramivir, and a third with previously unreported N325K substitution, exhibiting reduced susceptibility to oseltamivir. Influenza A(H3N2) viruses (n = 407) were sensitive to all NAIs. Influenza B viruses (n = 346) were sensitive to all NAIs, except two (0.6%) with H273Y (N1 numbering; H274Y in N2 numbering) substitution, exhibiting reduced susceptibility to oseltamivir and peramivir, and one with previously unreported G140R and N144K substitutions, exhibiting reduced susceptibility to oseltamivir, zanamivir, and peramivir. All influenza A and B viruses were sensitive to laninamivir. It is unknown whether substitutions N325K, G140R, and N144K were present in the virus prior to culturing because clinical specimens were unavailable for testing.. This study summarizes NAI susceptibility of influenza viruses circulating worldwide during the 2011 Southern Hemisphere (SH) season, assessed using the NA-Fluor™ Kit. Despite low resistance to NAIs among tested influenza viruses, constant surveillance of influenza virus susceptibility to NAIs should be emphasized.

Topics: Acids, Carbocyclic; Africa; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Global Health; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Neuraminidase; Oceania; Oseltamivir; Pyrans; Seasons; Sentinel Surveillance; Sialic Acids; South America; Zanamivir

Two new influenza virus neuraminidase inhibitors (NAIs), peramivir and laninamivir, were approved in 2010 which resulted to four NAIs that were used during the 2010-2011 influenza season in Japan. This study aims to monitor the susceptibility of influenza virus isolates in 2009-2010 and 2010-2011 influenza seasons in Japan to the four NAIs using the fluorescence-based 50% inhibitory concentration (IC₅₀) method. Outliers were identified using box-and-whisker plot analysis and full NA gene sequencing was performed to determine the mutations that are associated with reduction of susceptibility to NAIs. A total of 117 influenza A(H1N1)pdm09, 59 A(H3N2), and 18 type B viruses were tested before NAI treatment and eight A(H1N1)pdm09 and 1 type B viruses were examined from patients after NAI treatment in the two seasons. NA inhibition assay showed type A influenza viruses were more susceptible to NAIs than type B viruses. The peramivir and laninamivir IC₅₀ values of both type A and B viruses were significantly lower than the oseltamivir and zanamivir IC₅₀ values. Among influenza A(H1N1)pdm09 viruses, the prevalence of H274Y viruses increased from 0% in the 2009-2010 season to 3% in the 2010-2011 season. These H274Y viruses were resistant to oseltamivir and peramivir with 200-300 fold increase in IC₅₀ values but remained sensitive to zanamivir and laninamivir. Other mutations in NA, such as I222T and M241I were identified among the outliers. Among influenza A(H3N2) viruses, two outliers were identified with D151G and T148I mutations, which exhibited a reduction in susceptibility to oseltamivir and zanamivir, respectively. Among type B viruses, no outliers were identified to the four NAIs. For paired samples that were collected before and after drug treatment, three (3/11; 27.3%) H274Y viruses were identified among A(H1N1)pdm09 viruses after oseltamivir treatment but no outliers were found in the laninamivir-treatment group (n=3). Despite widespread use of NAIs in Japan, the prevalence of NAI-resistant influenza viruses is still low.

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Female; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Japan; Microbial Sensitivity Tests; Neuraminidase; Pandemics; Pyrans; Seasons; Sialic Acids; Viral Proteins; Zanamivir

Laninamivir, a potent neuraminidase (NA) inhibitor, is an active metabolite of laninamivir octanoate (code name: CS-8958) which is a long acting NA inhibitor and is commercially available under the brand name Inavir in Japan to complete the treatment of influenza by a single inhalation. It is supposed that the long acting character is provided by the long retention of laninamivir in the respiratory tract after intranasal administration of laninamivir octanoate in mice and with stable binding of laninamivir to NA of various influenza viruses such as N1, N2 subtypes and NA of B virus. Peramivir, another NA inhibitor, is also approved in Japan as a single intravenous infusion. In spite of the quick disappearance of peramivir from the blood after injection, the reason treatment can be completed by a single administration is thought to be that peramivir showed stable binding to NA with N9 subtype. Therefore, the stable binder, laninamivir is possibly effective by a single intravenous administration in the mouse model infected with influenza viruses. A single intravenous administration of laninamivir and peramivir at 30mg/kg significantly prolonged mice survival at a comparable level in the mouse lethal model infected with the A/PR/8/34 (H1N1) virus. Also, a single intravenous administration of laninamivir and peramivir significantly suppressed virus proliferation in the lungs of mice infected with influenza B virus. Thus, laninamivir may be effective by a single intravenous infusion in treating influenza, the same as peramivir.

Topics: Administration, Intravenous; Animals; Antiviral Agents; Disease Models, Animal; Female; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza B virus; Influenza, Human; Mice; Mice, Inbred BALB C; Pyrans; Sialic Acids; Zanamivir

Topics: Administration, Inhalation; Antiviral Agents; Epidemics; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Japan; Neuraminidase; Pyrans; Sialic Acids; Zanamivir

Laninamivir octanoate hydrate (laninamivir) is a long-acting neuraminidase inhibitor which requires only a single inhaled dose to fully treat infection by the influenza virus. In Japan, this drug was launched in October 2010 as a new treatment for the influenza virus. A postmarketing surveillance study was conducted in the 2010/2011 influenza season to assess the efficacy of this drug in clinical settings. For 3542 patients evaluated for efficacy (type A, n = 3179; type B, n = 342, unknown type, n = 3), including the day of drug administration, the median duration to fever resolution was three days, and the median duration to relief from influenza symptoms was four days. Based on the judgment of participating physicians, the efficacy rate was 97.6 % for type A influenza, 93.3 % for type B influenza, and 100 % in unknown types. "Treatment failure," as judged by participating physicians, was most closely correlated with the inhalation status of laninamivir. Despite laninamivir requiring only the administration of a single dose, it was confirmed to be an effective treatment in more than 90 % of patients with type A or type B influenza virus infections. This drug was considered to be useful for the treatment of influenza infections due to ease of use and its improvement of compliance. It became clear that the efficacy of laninamivir depended strongly on the status of inhalation, and thus careful and detailed instructions on the correct method of inhalation were considered to be important in order to obtain reliable therapeutic effects.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Child; Female; Fever; Guanidines; Humans; Influenza, Human; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Neuraminidase; Product Surveillance, Postmarketing; Pyrans; Sialic Acids; Treatment Outcome; Zanamivir

Abnormal behavior and delirium are common in children with influenza. While abnormal behavior and delirium are considered to be associated with influenza encephalopathy, an increased risk of such neuropsychiatric symptoms in patients receiving neuraminidase inhibitor treatment is suspected. Laninamivir octanoate hydrate, recently approved in Japan, is a long-acting neuraminidase inhibitor. It is important to establish a safety profile for laninamivir early, based on post-marketing experiences.. Spontaneous safety reports collected in the early post-marketing phase vigilance were analyzed. Adverse events of interest such as abnormal behavior/delirium, dizziness/vertigo, respiratory disorders, shock/syncope, and any other serious events were intensively reviewed by the Safety Evaluation Committee.. Abnormal behavior/delirium was a frequently reported event. Almost all the reported cases were considered to be due to influenza and not laninamivir. There were 32 cases of abnormal behavior/delirium that could lead to dangerous accidents, and these were observed more frequently in males and teenagers. Syncope probably related to the act of inhalation per se of laninamivir was reported during this survey.. This safety review revealed that the safety profile of laninamivir for abnormal behavior/delirium and syncope was similar to that of other neuraminidase inhibitors. As stated in the labeling, teenage patients inhaling laninamivir should remain under constant parental supervision for at least 2 days and should be closely monitored for behavioral changes to prevent serious accidents associated with abnormal behavior/delirium. Furthermore, to avoid syncope because of inhalation, patients should be instructed to inhale in a relaxed sitting position.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Antiviral Agents; Child; Delirium; Female; Guanidines; Humans; Influenza, Human; Male; Middle Aged; Pyrans; Sialic Acids; Syncope; Zanamivir

The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.

Topics: Acids, Carbocyclic; Animals; Cell Line; Cyclopentanes; Dogs; Enzyme Assays; Enzyme Inhibitors; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Inhibitory Concentration 50; Neuraminidase; Oseltamivir; Zanamivir

Antiviral drugs are an important option for managing infections caused by influenza viruses. This study assessed the drug susceptibility of 2009 pandemic influenza A (H1N1) viruses collected globally between April 2009 and January 2010.. Virus isolates were tested for adamantane susceptibility, using pyrosequencing to detect the S31N marker of adamantane resistance in the M2 protein and biological assays to assess viral replication in cell culture. To assess neuraminidase (NA) inhibitor (NAI) susceptibility, virus isolates were tested in chemiluminescent NA inhibition assays and by pyrosequencing to detect the H275Y (H274Y in N2 numbering) marker of oseltamivir resistance in the NA.. With the exception of three, all viruses that were tested for adamantane susceptibility (n=3,362) were resistant to this class of drugs. All viruses tested for NAI susceptibility (n=3,359) were sensitive to two US Food and Drug Administration-approved NAIs, oseltamivir (mean ±sd 50% inhibitory concentration [IC(50)] 0.25 ±0.12 nM) and zanamivir (mean IC(50) 0.29 ±0.09 nM), except 23 (0.7%), which were resistant to oseltamivir, but sensitive to zanamivir. Oseltamivir-resistant viruses had the H275Y mutation in their NA and were detected in patients exposed to the drug through prophylaxis or treatment. NA activity of all viruses was inhibited by the NAIs peramivir, laninamivir (R-125489) and A-315675, except for H275Y variants, which exhibited approximately 100-fold reduction in peramivir susceptibility.. This report provides data regarding antiviral susceptibility of 2009 pandemic influenza A (H1N1) surveillance viruses, the majority of which were resistant to adamantanes and sensitive to NAIs. These findings provide information essential for antiviral resistance monitoring and development of novel diagnostic tests for detecting influenza antiviral resistance.

Topics: Acids, Carbocyclic; Adamantane; Amino Acid Substitution; Animals; Antiviral Agents; Cell Line; Cyclopentanes; Dogs; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Microbial Sensitivity Tests; Mutation, Missense; Neuraminidase; Oseltamivir; Pyrans; Pyrrolidines; Sialic Acids; Viral Plaque Assay; Zanamivir

Two neuraminidase (NA) inhibitors, zanamivir (Relenza) and oseltamivir phosphate (Tamiflu), have been licensed for the treatment of and prophylaxis against influenza. In this paper, the new potent NA inhibitor R-125489 is reported for the first time. R-125489 inhibited the NA activities of various type A and B influenza viruses, including subtypes N1 to N9 and oseltamivir-resistant viruses. The survival effect of R-125489 was shown to be similar to that of zanamivir when administered intranasally in a mouse influenza virus A/Puerto Rico/8/34 infection model. Moreover, we found that the esterified form of R-125489 showed improved efficacy compared to R-125489 and zanamivir, depending on the acyl chain length, and that 3-(O)-octanoyl R-125489 (CS-8958) was the best compound in terms of its life-prolonging effect (P < 0.0001, compared to zanamivir) in the same infection model. A prolonged survival effect was observed after a single administration of CS-8958, even if it was given 7 days before infection. It is suggested that intranasally administered CS-8958 works as a long-acting NA inhibitor and shows in vivo efficacy as a result of a single intranasal administration.

Topics: Animals; Antiviral Agents; Cell Line; Dogs; HeLa Cells; Humans; Influenza A virus; Influenza B virus; Influenza, Human; Mice; Neuraminidase; Prodrugs; Zanamivir