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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Four neuraminidase (NA) inhibitors and an RNA synthesis inhibitor were recently approved and are currently in clinical use for influenza. Among NA inhibitors, oseltamivir phosphate (OSE, Tamiflu®) and zanamivir are approved worldwide, whereas peramivir and laninamivir octanoate (LAN, Inavir®) are regionally approved for human use. Therefore, OSE has been used to treat infections of highly pathogenic influenza viruses, such as H5N1 and H7N9, which caused epidemic in southeast Asia and Egypt, and China, respectively. Generally, OSE is administered twice daily for 5 days by oral administration, and LAN once by inhalation for completing influenza therapy. In this study, we compared the efficacy of OSE and LAN administered according to the regimens in mice infected with highly lethal influenza viruses. The drugs were administered at the early and late stages of infection, which correspond to mild and severe inflammation in the lungs, respectively. Based on the drugs' regimens for human, a single administration of LAN at both stages of inflammation showed superior efficacy to repeated administration of OSE. LAN, as in OSE, could also be efficacious in treating severe influenza in humans. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) in the viruses epidemic in the 2015–2016 influenza season in Japan, we measured the 50% inhibitory concentration (IC 50 ) of NAIs for influenza virus isolates and compared them with the results from the 2010–11 to 2014–15 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. Influenza viruses were isolated: 210 influenza A(H1N1)pdm09 (67.3%), 20 A(H3N2) (6.4%), and 82 B (26.3%), and for the Victoria and Yamagata lineages the numbers were 53 (64.6%) and 28 (34.1%), respectively, with one unknown. Two A(H1N1)pdm09 isolates showed a high IC50 for oseltamivir (130 and 150 nM). No isolate showed a very high IC50 for A(H3N2) or B. The ratios of geometric mean IC50 of the 2015–2016 influenza season to those of the 2010–2011 to 2014–2015 influenza seasons ranged from 0.62 to 1.78 for A(H1N1) pdm09. The range was 0.73–1.35 for A(H3N2) and 0.48–1.12 for B. No significant trend of increase or decrease in IC50 was found for any of the four NAIs. Although some isolates showed highly reduced sensitivity to oseltamivir among the 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC 50 ) 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 IC 50 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 IC 50 for oseltamivir (130 and 150 nM) exceeding by 100 times the geometric mean of the IC 50 of oseltamivir for A(H1N1)pdm09 isolates (0.76 nM). No isolate showed a very high IC 50 for A(H3N2) or B. The IC 50 of the NAIs except for oseltamivir for A(H1N1) pdm09 were significantly higher than those of the 2010–2011 season (P < 0.05). The IC 50 of all four NAIs for A(H3N2) were significantly lower than those of the 2012–2013 season (P < 0.001). The IC 50 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. [ABSTRACT FROM AUTHOR]

Laninamivir is a long-acting antiviral requiring only a single dose for the treatment of influenza infection, making it an attractive alternative to existing neuraminidase inhibitors that require multiple doses over many days. Like zanamivir, laninamivir is administered to patients by inhalation of dry powder. To date, studies investigating the effectiveness of laninamivir or zanamivir in a ferret model of influenza infection have administered the drug in a solubilised form. To better mimic the delivery action of laninamivir in humans, we assessed the applicability of a Dry Powder Insufflator™ (DPI) as a delivery method for laninamivir octanoate (LO) in ferrets to determine the effectiveness of this drug in reducing influenza A and B virus infections. In vitro characterisation of the DPI showed that both the small particle sized LO (0.7–6.0 μm diameter) and the large particle sized lactose carrier (20–100 μm diameter) were effectively discharged. However, LO delivered to ferrets via the DPI prior to infection with either A(H1N1)pdm09 or B viruses had a limited effect on nasal inflammation, clinical symptoms and viral shedding compared to placebo. Our preliminary findings indicate the feasibility of administering powder drugs into ferrets, but a better understanding of the pharmacokinetics and pharmacodynamics of LO in ferrets following delivery by the DPI is warranted prior to further studies. [ABSTRACT FROM AUTHOR]

The neuraminidase (NA) inhibitors oseltamivir and zanamivir are administered twice daily for 5 days for treatment of influenza. Laninamivir is a 7-methoxy derivative of zanamivir, but a single dose is effective when taken as the laninamivir octanoate prodrug. We show here in IC 50 kinetics assays and a solid phase reactivation assay that compared to zanamivir laninamivir also demonstrates slow binding to but slower dissociation from multiple wild type NAs. A D197E mutation in an influenza B and an E119G in an N9 neuraminidase which confer 15- and 150-fold resistance to laninamivir result in faster binding and dissociation. Despite similar IC 50 s our assays demonstrate more rapid dissociation of laninamivir from clade 1 compared to 2 H5N1 NAs. [ABSTRACT FROM AUTHOR]

The neuraminidase inhibitors (NAIs) oseltamivir phosphate (Tamiflu ® ), zanamivir (Relenza ® ), laninamivir octanoate (Inavir ® ), and peramivir (Rapiacta ® ) have been available for the treatment of influenza in Japan since 2010. The emergence of resistant virus to any of the NAIs is a great concern for influenza treatment. To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC 50 ) of each NAI for influenza virus isolates in the 2012–2013 influenza season and compared the results to those of the 2010–2011 and 2011–2012 influenza seasons. Viral isolation of specimens obtained prior to treatment was done using Madine-Darby canine kidney cells, and the type and subtype of influenza, A(H1N1)pdm09, A(H3N2), or influenza B, was determined by RT-PCR using type- and subtype-specific primers. The IC 50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 329 influenza viruses were isolated:5 influenza A(H1N1)pdm09 (1.5%), 316 influenza A(H3N2) (96.1%), and 8 influenza B (2.4%). No isolate showed an IC 50 value exceeding 50 nM for any of the neuraminidase inhibitors. The IC 50 values for A(H3N2) and B were similar to those of the 2010–2011 and 2011–2012 seasons. No isolate showed an increased IC 50 value for A(H1N1)pdm09. These results indicate that the currently epidemic influenza viruses are susceptible to all four neuraminidase inhibitors, with no trend for IC 50 values to increase at present. [ABSTRACT FROM AUTHOR]

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 IC 50 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. [ABSTRACT FROM AUTHOR]

The neuraminidase inhibitors oseltamivir phosphate (Tamiflu®), zanamivir (Relenza®), laninamivir octanoate (Inavir®), and peramivir (Rapiacta®) have been available for the treatment of influenza in Japan since 2010. To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC50) of each drug for influenza virus isolates from the 2011-2012 influenza season. Specimens were obtained from patients prior to treatment. Viral isolation was done using Madine-Darby canine kidney cells, and the type and subtype of influenza A(H1N1)pdm09, A(H3N2), or influenza B were determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. The lineage of influenza B virus was determined by direct sequencing of the hemagglutinin gene. Influenza A(H3N2) and influenza B viruses were isolated in 283 and 42 patients, respectively, while no influenza A(H1N1)pdm09 virus was isolated. No isolate showed an IC50 value exceeding 50 nM for any of the neuraminidase inhibitors. IC50 values for A(H3N2) were similar between the 2010-2011 and 2011-2012 seasons. In contrast, the IC50 values for influenza B viruses in the 2011-2012 season to the four drugs were significantly lower than those found in the 2010-2011 season. These results indicate that the currently epidemic influenza viruses are susceptible to all four neuraminidase inhibitors, with no trend for IC50 values to increase in Japan at present. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Highlights: [•] All NA inhibitors were administered once intravenously to examine in vivo efficacy. [•] The efficacy was assessed in an influenza A and B viruses infection mouse model. [•] Laninamivir tended to reduce the viral load compared to peramivir. [•] Laninamivir could be enough to treat influenza by a single injection like peramivir. [Copyright &y& Elsevier]

Highlights: [•] Susceptibility of influenza viruses to all four NAIs was determined by IC50 method. [•] Prevalence of oseltamivir-resistant A(H1N1)pdm09 viruses increased to 3%. [•] A novel I222T mutation in NA showed a reduction in susceptibility to all four NAIs. [•] No NAI resistance was found among influenza A(H3N2) and B viruses in this study. [ABSTRACT FROM AUTHOR]

Abstract: Laninamivir octanoate hydrate (laninamivir) is a long-acting neuraminidase inhibitor (NAI) that completes treatment with only a single inhalation. It was launched in Japan in October 2010 as an anti-influenza agent. A post-marketing surveillance study was conducted in the 2010/2011 influenza season to assess the safety of this drug in clinical settings. Adverse drug reactions (ADRs) were observed in 50 patients (59 events) out of 3542 patients subjected to safety evaluation (incidence 1.41%). Commonly reported ADRs were psychiatric disorders (abnormal behaviour, etc.), gastrointestinal disorders (diarrhoea, nausea, etc.) and nervous system disorders (dizziness, etc.), with incidences of 0.48% (n =17), 0.45% (n =16) and 0.17% (n =6), respectively. No serious ADRs occurred. ADRs usually emerged on the day on which laninamivir was inhaled (52.5%) and ADRs emerged within 3 days after inhalation in >90% of adversely affected patients. ADRs resolved or improved within 3 days in >85% of patients. The incidence of adverse events involving abnormal behaviour was 3.1% (30/959) among patients <10 years of age, 0.7% (8/1088) among patients aged 10–19 years, 0.1% (2/1431) among adult patients aged 20–64 years and 0.0% (0/64) among patients aged ≥65 years. It was confirmed that laninamivir is unlikely to cause delayed ADRs or a prolonged duration of ADRs despite this drug being a long-acting NAI. Furthermore, the incidence of ADRs was not found to have increased compared with that observed during clinical trials, and the types of ADR observed during this study were similar to those previously observed. Thus, laninamivir octanoate hydrate was confirmed to have no noticeable problem with safety. [Copyright &y& Elsevier]

Abstract: Influenza A H5N1 and pH1N1 viruses have broadly emerged and become widespread in various countries around the world. Oseltamivir, the most commonly used antiviral drug against the seasonal and pandemic influenza viruses, is targeted at the viral neuraminidase (NA), but some isolates of this virus have become highly resistant to this drug. The novel long-acting drug, laninamivir, was recently developed to inhibit influenza A and B viruses of either the wild-type (WT) or the oseltamivir resistant mutant of NA. To understand the high efficiency of laninamivir, all-atom molecular dynamics simulations were performed on the WT and H274Y mutant of H5N1 and pH1N1 NAs with laninamivir bound. As a result, the novel drug was found to directly interact with 11 binding residues mainly through salt bridge and hydrogen bond formation (as also seen by electrostatic contribution). These are comprised of 7 of the catalytic residues (R118, D151, R152, R224, E276, R292 and R371), and 4 of the framework residues (E119, W178, E227 and E277). Laninamivir showed a similar binding pattern to all four NAs, but strong hydrogen bonding interactions were only found in the WT strain, with a slightly lowered contribution at some drug contact residues being observed in the H274Y mutation. This is in good agreement with the experimental data that the H274Y mutant has a small increase (1.3–7.5-fold, which was not statistically significant) in the IC50 value of laninamivir. [Copyright &y& Elsevier]