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Jin Jung Kwon, Won-Suk Choi, Ju Hwan Jeong, Eun-Ha Kim, Ok-Jun Lee, Sun-Woo Yoon, Jungwon Hwang, Richard J Webby, Elena A Govorkova, Young Ki Choi, Yun Hee Baek, Min-Suk Song
The resistance of influenza viruses to neuraminidase (NA) inhibitors (NAIs; i.e. oseltamivir, zanamivir, peramivir and laninamivir) can be associated with several NA substitutions, with differing effects on viral fitness. To identify novel molecular markers conferring multi-NAI resistance, the NA gene of oseltamivir-resistant (H275Y, N1 numbering) 2009 pandemic influenza [A(H1N1)pdm09] virus was enriched with random mutations. This randomly mutated viral library was propagated in Madin-Darby canine kidney (MDCK) cells under zanamivir pressure and gave rise to additional changes within NA, including an I436N substitution located outside the NA enzyme active site...
March 2018: Journal of General Virology
Nobuhisa Ishiguro, Naoko Koseki, Miki Kaiho, Tadashi Ariga, Hideaki Kikuta, Koji Oba, Takehiro Togashi, Keisuke Morita, Akira Inagawa, Akiko Okamura, Shigeru Yamazaki, Satoru Shida, Mutsuko Konno, Nobuaki Kawamura, Akihito Ishizaka, Kimihiko Takada, Keiji Tsubakihara, Naoko Nagano, Mutsuo Shibata, Hideto Furuyama, Yoshihiro Matsuzono, Akemi Koike, Mari Murashita, Yoshio Hatae, Hideki Arioka, Tatsuru Yamanaka, Toru Watanabe, Yuuichi Tabata, Yoshihiro Kumita, Kyosuke Hazama, Yasushi Akutsu, Hayato Aoyagi, Chie Tobise, Katsuki Azuma, Kohichi Yasoshima, Yoko Sawada, Kazuyuki Uetsuji, Akira Tsuchida, Akira Tsuchiyama, Kazue Yasuda, Yasuhisa Odagawa, Mikio Yoshioka
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...
February 24, 2018: Journal of Infection and Chemotherapy: Official Journal of the Japan Society of Chemotherapy
Masatoki Sato, Koichi Hashimoto, Yukihiko Kawasaki, Mitsuaki Hosoya
BACKGROUND: Immune response after intravenous peramivir administration, which is approved for children with influenza infection in Japan, is unclear. METHODS: Kinetics of viral load and serum cytokine levels before and after peramivir therapy were analysed in 17 and 8 hospitalized children infected with influenza A and B, respectively. Additionally, haemadsorption inhibition (HI) titre was measured. The first day of hospital admission was defined as day 0. RESULTS: Serum interleukin (IL)-6 levels in influenza A-infected children significantly decreased after peramivir administration, unlike in those with influenza B where a decrease on day 1 was followed by an increase on day 2...
January 26, 2018: Antiviral Therapy
Peng-Cheng Wang, Din-Chi Chiu, Jia-Tsrong Jan, Wen-I Huang, Yin-Chen Tseng, Ting-Ting Li, Ting-Jen Cheng, Keng-Chang Tsai, Jim-Min Fang
Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range...
December 24, 2017: European Journal of Medicinal Chemistry
Nozomu Yoshino, Ai Kawamura, Akira Ishii, Katsuyuki Yoshida, Tamami Watanabe, Takeshi Yamashita, Takahiko Fukuchi, Fumihiko Toyoda, Akihiko Kakehashi, Hitoshi Sugawara
We herein report a case of a 31-year-old Japanese man who simultaneously had a positive influenza A virus antigen test result and Vogt-Koyanagi-Harada disease (VKHD), demonstrated by both diffuse multiple early hyperfluorescent points on fluorescein fundus photography and serous retinal detachments on optical coherence tomography. He had meningitis. It was difficult to determine whether the main cause of meningitis was influenza A or VKHD. After initial treatment with peramivir for influenza A and then methylprednisolone pulse with subsequent corticosteroid therapy for VKHD, his symptoms improved gradually...
January 11, 2018: Internal Medicine
Nobuo Hirotsu, Yutaka Saisho, Takahiro Hasegawa, Takao Shishido
BACKGROUND: 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). METHODS: Patients (n = 123) aged 4-12 years with influenza A virus infection were randomized to intravenous peramivir, oral oseltamivir, inhaled zanamivir, or inhaled laninamivir...
December 29, 2017: Expert Review of Anti-infective Therapy
Yuuki Nakamura, Tamie Sugawara, Yasushi Ohkusa, Kiyosu Taniguchi, Chiaki Miyazaki, Mariko Momoi, Nobuhiko Okabe
An earlier study using the number of abnormal behaviors reported to the study group as the numerator and the number of influenza patient prescribed each neuraminidase inhibitor (NI) estimated by respective pharmaceutical companies found no significant difference among incidence rates of the most severe abnormal behaviors by type of NI throughout Japan. However, the dataset for the denominator used in that earlier study was the estimated number of prescriptions. In the present study, to compare the incidence rates of abnormal behavior more precisely among influenza patients administered several sorts of NI or administered no NI, we used data obtained from the National Database of Electronic Medical Claims (NDBEMC) as the denominator to reach a definitive conclusion...
December 19, 2017: Journal of Infection and Chemotherapy: Official Journal of the Japan Society of Chemotherapy
Din-Chi Chiu, Tzu-Chen Lin, Wen-I Huang, Ting-Jen Cheng, Keng-Chang Tsai, Jim-Min Fang
Peramivir is an effective anti-influenza drug in the clinical treatment of influenza, but its efficacy toward the H275Y mutant is reduced. The previously reported cocrystal structures of inhibitors in the mutant neuraminidase (NA) suggest that the hydrophobic side chain should be at the origin of reduced binding affinity. In contrast, zanamivir having a hydrophilic glycerol side chain still possesses high affinity toward the H275Y NA. We thus designed five peramivir analogues (5-9) carrying hydrophilic glycol or glycerol side chains, and evaluated their roles in anti-influenza activity, especially for the H275Y mutant...
November 29, 2017: Organic & Biomolecular Chemistry
Clément Fage, Véronique Tu, Julie Carbonneau, Yacine Abed, Guy Boivin
BACKGROUND: Peramivir is a parenteral neuraminidase inhibitor (NAI) approved for treating influenza infections in a few countries. We determined peramivir susceptibilities of several uncharacterized influenza A and B neuraminidase (NA) and haemagglutinin (HA) mutants selected with different NAIs. METHODS: Recombinant wild-type (WT) and mutant NA proteins were expressed in 293T cells and susceptibility to peramivir, oseltamivir and zanamivir was determined by NA inhibition assay using the MUNANA substrate...
March 22, 2017: Antiviral Therapy
Rohini K, Shanthi V
Neuraminidase (NA), a surface protein, facilitates the release of nascent virus and thus spreads infection. It has been renowned as a potential drug target for influenza A virus infection. The drugs such as oseltamivir, zanamivir, peramivir, and laninamivir are approved for the treatment of influenza infection. Additionally, investigational drugs namely MK2206, tamiphosphor, crenatoside, and dehydroepiandrosterone (DHEA) are also available for the treatment. However, recent outbreaks of highly pathogenic and drug-resistant influenza A strains highlighted the need to discover novel NA inhibitor...
October 23, 2017: Applied Biochemistry and Biotechnology
Won-Suk Choi, Ju Hwan Jeong, Jin Jung Kwon, Su Jeong Ahn, Khristine Kaith S Lloren, Hyeok-Il Kwon, Hee Bok Chae, Jungwon Hwang, Myung Hee Kim, Chul-Joong Kim, Richard J Webby, Elena A Govorkova, Young Ki Choi, Yun Hee Baek, Min-Suk Song
Several subtypes of avian influenza viruses (AIVs) are emerging as novel human pathogens, and the frequency of related infections has increased in recent years. Although neuraminidase (NA) inhibitors (NAIs) are the only class of antiviral drugs available for therapeutic intervention for AIV-infected patients, studies on NAI resistance among AIVs have been limited and markers of resistance are poorly understood. Previously, we identified unique NAI-resistance substitutions in AIVs of N3, N7, and N9 NA subtypes...
October 18, 2017: Journal of Virology
Mingdao Lei, Wei Gan, Yongbing Sun
A simple HPLC-MS/MS method has been developed for the determination of peramivir in rat plasma in the present study. The analytes were separated on a C18 column (50×2.1mm, 1.7 μm) and a triple-quadrupole mass spectrometry equipped with an electrospray ionization (ESI) source was applied for the detection. A phospholipid-free cartridge SPE was used to pretreat the plasma and eliminate the endogenous phospholipid. The in-source collisionally induced dissociation (CID) approach showed that this pretreatment could result in the negligible ion suppression from the extracted sample, and could bring cleaner samples when compared with the protein precipitation...
October 4, 2017: Biomedical Chromatography: BMC
Larisa V Gubareva, Katrina Sleeman, Zhu Guo, Hua Yang, Erin Hodges, Charles T Davis, Tatiana Baranovich, James Stevens
Background: 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. Methods: 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...
September 15, 2017: Journal of Infectious Diseases
Masayoshi Higashiguchi, Tomoshige Matsumoto, Takashi Fujii
BACKGROUND: 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. METHODS: 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. RESULTS: Nine studies in treatment settings and three studies in prophylaxis settings were eligible for this meta-analysis...
September 4, 2017: Antiviral Therapy
Larisa V Gubareva, Terry G Besselaar, Rod S Daniels, Alicia Fry, Vicki Gregory, Weijuan Huang, Aeron C Hurt, Patricia A Jorquera, Angie Lackenby, Sook-Kwan Leang, Janice Lo, Dmitriy Pereyaslov, Helena Rebelo-de-Andrade, Marilda M Siqueira, Emi Takashita, Takato Odagiri, Dayan Wang, Wenqing Zhang, Adam Meijer
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) assessed antiviral susceptibility of 14,330 influenza A and B viruses collected by WHO-recognized National Influenza Centres (NICs) between May 2015 and May 2016. Neuraminidase (NA) inhibition assay was used to determine 50% inhibitory concentration (IC50) data for NA inhibitors (NAIs) oseltamivir, zanamivir, peramivir and laninamivir...
August 10, 2017: Antiviral Research
Shigeki Nakamura, Taiga Miyazaki, Koichi Izumikawa, Hiroshi Kakeya, Yutaka Saisho, Katsunori Yanagihara, Yoshitsugu Miyazaki, Hiroshi Mukae, Shigeru Kohno
BACKGROUND: Clinical studies comparing the different neuraminidase inhibitors for treatment of at-risk patients with influenza have not been performed. To optimize such treatments, we assessed the efficacy and safety of intravenous peramivir compared with oral oseltamivir in treating seasonal influenza A or B virus infection. METHODS: A multicenter, randomized, controlled clinical trial was conducted from December 2012 to May 2014 in high-risk patients infected with seasonal influenza...
2017: Open Forum Infectious Diseases
Kazufumi Takamatsu, Satoshi Marumo, Motonari Fukui, Atsuko Hata
We retrospectively analyzed data of 38 elderly patients, each with an underlying disease, to evaluate peramivir safety and efficacy. Six patients (15.8%) experienced adverse events, all tolerated. Median time from administration until the return to normal temperatures was 31.5 h (95% CI: 22.4-40.6). Results confirm intravenous peramivir's usefulness.
August 2017: Journal of Microbiology, Immunology, and Infection, Wei Mian Yu Gan Ran za Zhi
Masaki Shimamoto, Satoshi Okada, Takeshi Terashima
A 19-year-old man presented with a fever, convulsions, and loss of consciousness at our hospital. The patient had a Glasgow Coma Scale score of 12. Influenza B virus infection was diagnosed using the rapid test kit, and an eight-fold increase in the serum levels of anti-influenza B virus antibody was confirmed using the complement fixation test. Brain magnetic resonance imaging showed multifocal high-signal lesions, and an electroencephalogram showed diffuse slowing of the background activity, indicating acute encephalopathy...
2017: Internal Medicine
Ching-Yuan Yeh, Fu-Der Wang, Yu-Chung Chuang, Chia-Jui Yang, Shiang-Fen Huang, Wen-Sung Weng, Chun-Hsin Liaw, Wang-Huei Sheng
BACKGROUND: Few studies have investigated patients with severe influenza who receive intravenous peramivir for salvage therapy. METHODS: We retrospectively analyzed data from 71 patients with severe influenza who received intravenous peramivir therapy in the intensive care units of three medical centers between 2012 and 2016. All patients received oseltamivir or zanamivir before the administration of peramivir. RESULTS: A total of 44 men and 27 women with a median age of 55 years were enrolled...
June 26, 2017: Journal of Microbiology, Immunology, and Infection, Wei Mian Yu Gan Ran za Zhi
Matthew Carl Kirchoff, Jerome F Pierson
The paradigm for the use of investigational drugs in public health emergencies has been recently tested to prevent and treat highly infectious and lethal diseases. Examples include the successful implementation of vaccine and therapeutic clinical trials during the recent Ebola outbreak in West Africa. On the other end of the spectrum was the Emergency Use Authorization (EUA) of peramivir in the treatment of H1N1 influenza virus that did not provide an opportunity to collect data or understand the effectiveness of the EUA program...
March 2017: Therapeutic Innovation & Regulatory Science
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