Tamiflu
Immunological effects of the orally administered neuraminidase inhibitor oseltamivir in influenza virus-infected and uninfected mice.

Burger RA, Billingsley JL, Huffman JH, Bailey KW, Kim CU, Sidwell RW.

Center for Persons with Disabilities, Utah State University, Logan, UT 84322-6895, USA. roger cpd2.usu.edu

Oseltamivir (GS4104), the ethyl ester prodrug of the carbocyclic transition state sialic acid analog GS4071, has been reported to be a striking inhibitor of influenza A and B virus infections in mice and ferrets. Multiple studies indicate this material to also be active against the disease in humans, and it has recently been approved for human use. The effect of oral gavage (p.o.) therapy of oseltamivir on various immune factors considered to be of importance in primary influenza virus infection was studied in mice. Both uninfected animals and those infected with influenza A/NWS/33 (H1N1) virus were used. Doses of 100 mg kg(-1) day(-1) were administered twice daily for 5 days beginning 16 h pre-virus exposure. Two hours after end of treatment, the mice were killed and their spleens assayed for cytotoxic T lymphocyte (CTL) and natural killer (NK) cell activity. Subpopulations of splenic T, T-helper, T-cytotoxic and B lymphocytes as well as macrophages were determined using flow cytometry. Similar significant (P<0.01) increases in CTL activity were seen at effector:target cell ratios of 60:1 and 30:1 in the infected mice treated with oseltamivir or with placebo. NK cell activity was greater in the infected mice than in uninfected mice; the levels in all animals were not significantly affected by treatment with oseltamivir. Macrophage, T, T-helper, T-cytotoxic and B lymphocyte populations were similar in both treated and untreated animals. These data indicate treatment with oseltamivir does not adversely affect the primary in vivo cellular immune responses to influenza virus infection assayed in this study. The experiment was repeated to show that treatment with this compound significantly prevented the development of the infection and inhibited virus titers in the lung. Surviving treated mice on day 21 had mean neutralizing antibody titers of 1:208, and withstood rechallenge with the virus at this time, indicating the initial virus-inhibitory effect also did not prevent the animals from developing an adequate humoral immunity to the virus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10708809&dopt=Abstract oseltamivir Tamiflu



Tamiflu
Neuraminidase inhibitor, oseltamivir blocks GM1 ganglioside-regulated excitatory opioid receptor-mediated hyperalgesia, enhances opioid analgesia and attenuates tolerance in mice.

Crain SM, Shen KF.

Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva University, 1300 Morris Park Ave., Bronx, NY 10461, USA. smcrain aecom.yu.edu

The endogenous glycolipid GM1 ganglioside plays a critical role in nociceptive neurons in regulating opioid receptor excitatory signaling demonstrated to mediate "paradoxical" morphine hyperalgesia and to contribute to opioid tolerance/dependence. Neuraminidase (sialidase) increases levels of GM1, a monosialoganglioside, in these neurons by enzymatic removal of sialic acid from abundant polysialylated gangliosides. In this study, acute treatment of mice with the neuraminidase inhibitor, oseltamivir enhanced morphine analgesia. Acute oseltamivir also reversed "paradoxical" hyperalgesia induced by an extremely low dose of morphine, unmasking potent analgesia. In chronic studies, co-administration of oseltamivir with morphine prevented and reversed the hyperalgesia associated with morphine tolerance. These results provide the first evidence indicating that treatment with a neuraminidase inhibitor, oseltamivir, blocks morphine's hyperalgesic effects by decreasing neuronal levels of GM1. The present study further implicates GM1 in modulating morphine analgesia and tolerance, via its effects on the underlying excitatory signaling of Gs-coupled opioid receptors. Finally, this work suggests a remarkable, previously unrecognized effect of oseltamivir-which is widely used clinically as an antiviral agent against influenza-on glycolipid regulation of opioid excitability functions in nociceptive neurons.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14672816&dopt=Abstract oseltamivir Tamiflu



Tamiflu
In vitro and in vivo activities of T-705 and oseltamivir against influenza virus.

Takahashi K, Furuta Y, Fukuda Y, Kuno M, Kamiyama T, Kozaki K, Nomura N, Egawa H, Minami S, Shiraki K.

Research Laboratories, Toyama Chemical Co., Ltd., Toyama, Japan. KAZUMI_TAKAHASHI toyama-chemical.co.jp

T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has a potent and selective inhibitory activity against influenza virus. We studied the effects of an infectious dose on the anti-influenza virus activities of T-705 and oseltamivir, a commercially available neuraminidase inhibitor, both in vitro and in vivo. Plaque formation of influenza A/PR/8/34 virus was completely inhibited by 10 microg/ml of T-705 after 72 h incubation, whereas visible plaque formation was detected in the plate treated with GS 4071, the active form of oseltamivir (10 microg/ml). The antiviral activity of T-705 was not influenced by an increase in multiplicity of infection (MOI) from 0.0001 to 1, but that of GS 4071 was influenced in a yield reduction assay. No increase in viral yield was seen in either culture supernatant or cells after removal of T-705 (10 microg/ml) but, in contrast, productive infection recurred in culture supernatant and in cells after removal of GS 4071. In mice infected with a high challenge dose of influenza A/PR/8/34 virus, orally administered T-705 (200 and 400 mg/kg/day) completely prevented the death of mice and the survival rates of mice were significantly higher than those in mice treated with oseltamivir (P<0.01). When the treatment was delayed at 1, 13 and 25 h post infection, oral administration of 200 mg/kg of T-705 significantly prevented the death of mice (P<0.01), and the survival rates of mice treated with T-705 were comparable to those of mice treated with oseltamivir. These results suggest that T-705 has the potential to be a potent inhibitor of human influenza virus infections.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14694986&dopt=Abstract oseltamivir Tamiflu



Tamiflu
Susceptibility of human influenza viruses from Australasia and South East Asia to the neuraminidase inhibitors zanamivir and oseltamivir.

Hurt AC, Barr IG, Hartel G, Hampson AW.

WHO Collaborating Centre for Reference and Research on Influenza, 45 Poplar Road, Parkville, Vic. 3052, Australia. Aeron_Hurt csl.com.au

Human influenza viruses isolated from Australasia (Australia and New Zealand) and South East Asia were analysed to determine their sensitivity to the NA inhibitor drugs, zanamivir and oseltamivir. A total of 532 strains isolated between 1998 and 2002 were tested using a fluorescence-based assay to measure the relative inhibition of NA activity over a range of drug concentrations. Based on median IC50 values, influenza A viruses (with neuraminidase subtypes N1 and N2) were more sensitive to both the NA inhibitors than were influenza B strains. Influenza A viruses with a N1 subtype and influenza B strains both demonstrated a greater sensitivity to zanamivir than to oseltamivir carboxylate, whereas influenza A strains with a N2 subtype were more susceptible to oseltamivir carboxylate. For each of the neuraminidase types, IC50 values for viruses from Australasia and South East Asia were found to be comparable. Based on the data prior to and following the licensing of the drugs into the respective regions, the use of the NA inhibitors did not appear to have a significant impact on the susceptibility of the viruses tested to zanamivir or oseltamivir carboxylate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15026200&dopt=Abstract oseltamivir Tamiflu



Tamiflu
[Pharmacoeconomic evaluation of oseltamivir as prophylaxis against influenza infection]

[Article in Japanese]

Sakamaki H, Ikeda S, Ikegami N.

Department of Health Policy and Management, Keio University School of Medicine, Tokyo, Japan. hiro 1992.jukuin.keio.ac.jp

A pharmacoeconomic evaluation was made of prophylaxis against influenza using the oral neuraminidase inhibitor oseltamivir. Two patterns consisting of administration for 7 days as postcontact prophylaxis (7 day model) and seasonal administration for 6 weeks (6 week model) were examined. Decision analysis models were created on the basis of reports of clinical studies and epidemiologic studies relating to the drug and vaccination, and cost-effectiveness analyses were conducted based on the number of persons who had influenza and pneumonia as health outcomes. Costs were estimated with respect to health expenditures from the societal perspective as well as productivity costs. In the case of administration for 1-week postcontact prophylaxis, the health outcomes improved and costs were reduced in comparison with nontreatment, thus making this administration schedule the dominant choice. With administration for 6 weeks during the infectious period, vaccination involved lower costs and was superior in terms of health outcomes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15067184&dopt=Abstract oseltamivir Tamiflu