Makoto Kodama

Shionogi & Co., Ltd., Ōsaka, Ōsaka, Japan

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Publications (13)46.84 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of this study was to investigate the relationship between pharmacokinetic (PK) parameters of intravenous (IV) peramivir and in vivo antiviral activity pharmacodynamic (PD) outcomes in a mouse model of influenza virus infection. Peramivir was administrated to mice in three dosing schedules; once, twice and four times after infection of A/WS/33 (H1N1). The survival rate at day 14 after virus infection was employed as the antiviral activity outcome for analysis. The relationship between day 14 survival and PK parameters, including area under the concentration-time curve (AUC), maximum concentration (Cmax) and time that drug concentration exceeds IC95 (T>IC95), was estimated using a logistic regression model, and model fitness was evaluated by calculation of the Akaike information criterion (AIC) index. The AIC indices of AUC, Cmax and T>IC95 were about 114, 151 and 124, respectively. The AIC of AUC and T>IC95 were smaller than that of Cmax. Therefore, both AUC and T>IC95 were the PK parameters that correlated best with the antiviral activity of peramivir IV against influenza virus infection in mice.
    Antiviral Research 07/2014; 109. DOI:10.1016/j.antiviral.2014.06.016 · 3.43 Impact Factor
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    ABSTRACT: The efficacy of intravenous peramivir against influenza A (H1N1) 2009 virus infection was evaluated in mice of which immune system was suppressed by cyclophosphamide (CP) treatment. The mortality rate of the vehicle control group was 100% and the mice lost 20% of their body weight on average by day 13 post infection (p.i.). Repeated administration of peramivir (40 mg/kg once a day, intravenously for 20 days), starting at 1 h p.i., significantly reduced mortality, body weight loss, viral titers, and cytokine production in infected mice compared with the vehicle administration (p < 0.01). In addition, repeated administration of peramivir, starting at 24 h, 48 h, or 72 h p.i. also resulted in increases in survival rates and reduction of viral titers in the lungs (p < 0.01). The mean days-to-death (MDD) of the vehicle group was 14.5 days, while in the groups treated with peramivir starting at 24 h, 48 h, and 72 h p.i., the MDDs were > 23.0, 20.9, and 21.8 days, respectively. In comparison, repeated administration of oseltamivir phosphate (5 mg/kg twice a day, orally for 20 days), starting at 24 h, 48 h, and 72 h p.i., also significantly prevented body weight loss, whereas no significant differences in mortality rates and viral titers in the lungs were observed when compared with the vehicle group. These data indicated that repeated administration of peramivir was effective in promoting the survival and reducing virus replication in immunosuppressed mice infected with influenza A (H1N1) 2009 virus.
    Antimicrobial Agents and Chemotherapy 03/2013; 57(5). DOI:10.1128/AAC.02324-12 · 4.45 Impact Factor
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    ABSTRACT: Attempts to find a cure for HIV infection are hindered by the presence of viral reservoirs that resist highly active antiretroviral therapy. To identify the properties of these reservoirs, four SIV239-infected Rhesus macaques were treated with combined antiretroviral therapy (cART) for 1 year. While plasma viral RNA (vRNA) was effectively suppressed, a systemic analysis revealed that vRNA was distributed in the following order: lymphatic tissues>lungs and intestine>other tissues. Histochemistry yielded no cells with viral signals. To increase the chance of detection, two additional SIV-infected animals were treated and analyzed on Day 10 after the cessation of cART. These animals exhibited similar vRNA distribution patterns to the former animals, and immunohistochemistry revealed Nef-positive T lymphocytes predominantly in the follicles of mesenteric lymph nodes (MLNs). These data suggest that lymphatic tissues, including MLNs, contain major cellular reservoirs that cause rebound of plasma viremia upon cessation of therapy.
    Virology 12/2011; 423(2):107-18. DOI:10.1016/j.virol.2011.11.024 · 3.28 Impact Factor
  • The Journal of Infectious Diseases 11/2011; 204(10):1641-1643. DOI:10.2307/41329816 · 5.78 Impact Factor
  • The Journal of Infectious Diseases 09/2011; 204(10):1641-2; author's reply 1642-3. DOI:10.1093/infdis/jir610 · 5.78 Impact Factor
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    ABSTRACT: We evaluated the efficacy of a single intravenous dose peramivir for treatment of influenza B virus infection in ferrets and cynomolgus macaques in the present study. A single dose of peramivir (60 mg/kg of body weight) given to ferrets on 1 day postinfection with influenza B virus significantly reduced median area under the curve (AUC) virus titers (peramivir, 8.3 log(10) 50% tissue culture infective doses [TCID(50)s] · day/ml; control, 10.7 log(10) TCID(50)s · day/ml; P < 0.0001). Furthermore, nasal virus titers on day 2 postinfection in ferrets receiving a single injection of peramivir (30 mg/kg) and AUCs of the body temperature increase in ferrets receiving a single injection of peramivir (30 and 60 mg/kg) were lower than those in ferrets administered oral oseltamivir phosphate (30 and 60 mg/kg/day twice daily for 3 days). In macaques infected with influenza B virus, viral titers in the nasal swab fluid on days 2 and 3 postinfection and body temperature after a single injection of peramivir (30 mg/kg) were lower than those after oral administration of oseltamivir phosphate (30 mg/kg/day for 5 days). The two animal models used in the present study demonstrated that inhibition of viral replication at the early time point after infection was critical in reduction of AUCs of virus titers and interleukin-6 production, resulting in amelioration of symptoms. Our results shown in animal models suggest that the early treatment with a single intravenous injection of peramivir is clinically recommended to reduce symptoms effectively in influenza B virus infection.
    Antimicrobial Agents and Chemotherapy 08/2011; 55(11):4961-70. DOI:10.1128/AAC.00412-11 · 4.45 Impact Factor
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    ABSTRACT: Pathogenicity of influenza B virus was examined in cynomolgus macaques to establish a macaque model suitable for vaccine and antiviral drug development. We prepared influenza B viruses for inoculation with minimal passages after isolation from patients. Macaques inoculated with influenza B virus showed higher body temperature than that before infection for 6 to 12 days. Virus was detected in nasal, tracheal, and bronchial samples until 6 days after inoculation followed by an increase in neutralizing antibody. High levels of IL-6 and TNF-α in nasal swabs from the infected macaques were correlated with fever. Symptoms and duration of the viral replication would be sufficient to evaluate efficacy of vaccines and antiviral agents. In addition, measurement of immune responses including antibody and cytokine production would provide an immunological rationale in efficacy of vaccines and antiviral agents. The results suggest that cynomolgus macaques are appropriate model animals for research of influenza B virus.
    Virology 11/2010; 407(2):178-84. DOI:10.1016/j.virol.2010.08.006 · 3.28 Impact Factor
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    ABSTRACT: Resistance passage studies were conducted with five INIs (integrase inhibitors) that have been tested in clinical trials to date: a new naphthyridinone-type INI S/GSK-364735, raltegravir, elvitegravir, L-870,810 and S-1360. In establishing the passage system and starting from concentrations several fold above the EC(50) value, resistance mutations against S-1360 and related diketoacid-type compounds could be isolated from infected MT-2 cell cultures from day 14 to 28. Q148R and F121Y were the two main pathways of resistance to S/GSK-364735. Q148R/K and N155H, which were found in patients failing raltegravir treatment in Phase IIb studies, were observed during passage with raltegravir with this method. The fold resistance of 40 mutant molecular clones versus wild type virus was compared with these five INIs. The overall resistance pattern of S/GSK-364735 was similar to that of raltegravir and other INIs. However, different fold resistances of particular mutations were noted among different INIs, reflecting a potential to develop INIs with distinctly different resistant profiles.
    Antiviral research 08/2008; 80(2):213-22. DOI:10.1016/j.antiviral.2008.06.012 · 3.43 Impact Factor
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    ABSTRACT: Monocytes are known as an alternative target for HIV/SIV infection, but the contribution of monocytes to viral spread in a host is unclear. In this study, CD14 monocytes were monitored in 6 macaques until six weeks postinfection (wpi) with SIVmac239 to evaluate their contribution to viral load. The monocyte count in blood significantly increased with peak viremia at 2 wpi and the expression level of CD14 on monocytes significantly decreased at 1-2 wpi, though the number of CD4(+) T cells was stable in these macaques. The number of CD14 monocytes and the expression level of CD14 on monocytes at 2 wpi were also significantly related to the extent of viremia in plasma. An increased number of monocytes at 2 wpi was associated with a lower postacute viral load, suggesting that monocytes have a role in suppressing the virus. The lower expression level of CD14 in monocytes at 2 wpi was associated with a higher viral load and greater degree of infection of monocytes. This correlation suggests that monocytes with a low level of CD14 may be more susceptible to SIV and may enhance viral replication. The analysis of monocytes in persistently infected macaques revealed that the expression level of CD14 was also significantly low during persistent infection compared with naïve macaques, though the monocyte count was within the normal range. Monocytes may suppress viruses, perhaps by their immune function, during acute infection. However, infection of monocytes may increase the viral load and spread viruses in a host.
    AIDS Research and Human Retroviruses 04/2007; 23(3):372-80. DOI:10.1089/aid.2006.0208 · 2.46 Impact Factor
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    ABSTRACT: We previously reported that a nef-deleted SHIV (SHIV-NI) is nonpathogenic and gave macaques protection from challenge infection with pathogenic SHIV-C2/1. To investigate whether IFN-gamma augments the immune response induced by this vaccination, we examined the antiviral and adjuvant effect of recombinant human IFN-gamma (rIFN-gamma) in vaccinated and unvaccinated monkeys. Nine monkeys were vaccinated with nef-deleted nonpathogenic SHIV-NI. Four of them were administered with rIFN-gamma and the other five monkeys were administered with placebo. After the challenge with pathogenic SHIV-C2/1, CD4(+) T-cell counts were maintained similarly in monkeys of both groups, while those of the unvaccinated monkeys decreased dramatically at 2 weeks after challenge. However, the peaks of plasma viral load were reduced to 100-fold in SHIV-NI vaccinated monkeys combined with rIFN-gamma compared with those in SHIV-NI vaccinated monkeys without rIFN-gamma. The peaks of plasma viral load were inversely correlated with the number of SIV Gag-specific IFN-gamma-producing cells. In SHIV-NI-vaccinated monkeys with rIFN-gamma, the number of SIV Gag-specific IFN-gamma-producing cells of PBMCs increased 2-fold compared with those in SHIV-NI-vaccinated monkeys without rIFN-gamma, and the NK activity and MIP-1alpha production of PBMCs were also enhanced. Thus, vaccination of SHIV-NI in combination with rIFN-gamma was more effective in modulating the antiviral immune system into a Th1 type response than SHIV-NI vaccination alone. These results suggest that IFN-gamma augmented the anti-viral effect by enhancing innate immunity and shifting the immune response to Th1.
    Microbiology and Immunology 02/2005; 49(12):1083-94. DOI:10.1111/j.1348-0421.2005.tb03706.x · 1.31 Impact Factor
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    ABSTRACT: S-1153 is a new imidazole compound that inhibits human immunodeficiency virus (HIV) type 1 (HIV-1) replication by acting as a nonnucleoside reverse transcriptase inhibitor (NNRTI). This compound inhibits replication of HIV-1 strains that are resistant to nucleoside and nonnucleoside reverse transcriptase inhibitors. S-1153 has a 50% effective concentration in the range of 0.3 to 7 ng/ml for strains with single amino acid substitutions that cause NNRTI resistance, including the Y181C mutant, and also has potent activity against clinical isolates. The emergence of S-1153-resistant variants is slower than that for nevirapine, and S-1153-resistant variants contained at least two amino acid substitutions, including F227L or L234I. S-1153-resistant variants are still sensitive to the nucleoside reverse transcriptase inhibitors zidovudine (AZT) and lamivudine. In a mouse and MT-4 (human T-cell line) in vivo HIV replication model, S-1153 and AZT administered orally showed a marked synergy for the inhibition of HIV-1 replication. S-1153 shows a significant accumulation in lymph nodes, where most HIV-1 infection is thought to occur. S-1153 may be an appropriate candidate for two-to three-drug combination therapy for HIV infection.
    Antimicrobial Agents and Chemotherapy 07/1998; 42(6):1340-5. · 4.45 Impact Factor
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    ABSTRACT: In vivo efficacy of anti-HIV compounds is affected by various factors such as bioavailability, metabolism, clearance, and toxicity. Here we report a simple and rapid method that might be useful for preliminary evaluation of in vivo efficacy of anti-HIV compounds. MT-4 cells carrying proviral HTLV-1 were infected with HIV-1 in vitro and injected into the peritoneal cavity of SCID mice or BALB/c mice. Inoculated cells survive for 1-2 days, and support one to two cycles of viral replication which can be monitored by RT activity or p24 content in the supernatants of peritoneal wash fluids. Test compounds were administered either orally or subcutaneously. AZT, DDC and DDI, the nucleoside-type RT inhibitors currently in clinical use, all showed potent anti-HIV-1 activities in this mouse/MT-4 assay. HEPT (E-EBUdM), a non-nucleoside RT inhibitor, also showed potent anti-HIV-1 activity in vivo, whereas TIBO (R82913), another non-nucleoside RT inhibitor, was less active. In protease inhibitors KNI-272 and Ro 31-8959 showed good in vivo activities, while KNI-144, a compound closely related to KNI-272, showed poor in vivo activity. This mouse/MT-4 assay, although having a number of shortcomings as an animal model for HIV-1 infection, may be of some practical utility for preliminary evaluation of in vivo efficacy of potential anti-HIV compounds.
    Antiviral Research 06/1995; 27(1-2):151-63. DOI:10.1016/0166-3542(95)00004-6 · 3.43 Impact Factor
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    ABSTRACT: Vpr and Vpx are the auxiliary proteins of human immunodeficiency viruses (HIVs) selectively incorporated into mature viral particles. We showed that the bacterial chloramphenicol acetyltransferase (CAT) fused to the N-terminus of HIV-1 Vpr, HIV-2 Vpr, or HIV-2 Vpx was incorporated into mature virions in a type-selective manner. By using chimeric proteins between HIV-1 Vpr and HIV-2 Vpx, we found that the N-terminal side of these proteins was mainly important for type-selective virion incorporation. The C-terminal arginine-rich region of HIV-1 Vpr was also found to transport CAT fusion proteins into virions but without any type selectivity. Furthermore, the corresponding regions of HIV-2 Vpr and HIV-2 Vpx had no such activity. This region of HIV-1 Vpr may interact nonspecifically with viral genomic RNA. Collectively, Vpr and Vpx may provide a means to introduce foreign proteins and other molecules into HIV virions for therapeutic purposes.
    Microbiology and Immunology 02/1995; 39(12):1015-9. DOI:10.1111/j.1348-0421.1995.tb03293.x · 1.31 Impact Factor