Biomedical subjects
Publications and source records attributed to I J Owens.
Cerenkov free-electron lasers have primarily operated on the fundamental guided mode of the dielectric waveguide. Higher-order generation would allow short wavelength emission in a relatively large scale resonator. In comparison to the fundamental mode, we find that gain on higher-order modes can be significant in a planar geometry. This analysis is presented with a discussion of practical limits.
Zanamivir is a highly selective neuraminidase (NA) inhibitor with demonstrated clinical efficacy against influenza A and B virus infections. In phase II clinical efficacy trials (NAIB2005 and NAIB2008), virological substudies showed mean reductions in virus shedding after 24 h of treatment of 1.5 to 2.0 log(10) 50% tissue culture infective doses compared to a placebo, with no reemergence of virus after the completion of therapy. Paired isolates (n = 41) obtained before and during therapy with zanamivir demonstrated no shifts in susceptibility to zanamivir when measured by NA assays, although for a few isolates NA activity was too low to evaluate. In plaque reduction assays in MDCK cells, the susceptibility of isolates to zanamivir was extremely variable even at baseline and did not correlate with the speed of resolution of virus shedding. Isolates with apparent limited susceptibility to zanamivir by plaque reduction proved highly susceptible in vivo in the ferret model. Further sequence analysis of paired isolates revealed no changes in the hemagglutinin and NA genes in the majority of isolates. The few changes observed were all natural variants. No amino acid changes that had previously been identified in vitro as being involved with reduced susceptibility to zanamivir were observed. These studies highlighted problems associated with monitoring susceptibility to NA inhibitors in the clinic, in that no reliable cell-based assay is available. At present the NA assay is the best available predictor of susceptibility to NA inhibitors in vivo, as measured in the validated ferret model of infection.
Zanamivir (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid; Relenza; GG167) is a potent and highly specific neuraminidase (sialidase) inhibitor with inhibitory activity in vivo against both influenza A and B viruses. This compound has been extensively tested in both mouse and ferret models of influenza and has recently been approved for the treatment of influenza in Europe and Australasia. The compound markedly reduces the clinical course of disease in humans when given therapeutically by inhalation directly into the respiratory tract. In addition, experimental influenza infections in phase I clinical trials have shown the benefit of giving a single prophylactic dose of zanamivir in addition to a therapeutic regime. The studies reported here were designed to determine the persistence of zanamivir, as assessed by its antiviral activity in vivo, in the respiratory tracts of infected animals. We have shown that the prophylactic administration of zanamivir, when the drug is given in a single dose by the intranasal route, can significantly reduce lung virus titers in the mouse and can reduce both viral titers and symptoms in the ferret. Whole-body autoradiographical analyses of mice have indicated a long retention time for this compound in respiratory tract tissues when it is given in a single dose by the intranasal route. These results indicate that zanamivir may have clinical value as a prophylactic agent in protecting at-risk groups from influenza virus infection. In addition, these data may be useful in the design of prophylactic protocols for humans, in that the dosing schedule may only need to be intermittent to provide protection.
We have previously described a 4-guanidino-Neu5Ac2en (zanamivir)-resistant neuraminidase (NA) variant G70C4-G, with an active site mutation Glu 119 to Gly. This variant has been found to also harbor a hemagglutinin (HA) mutation in the receptor binding site, Ser 186 to Phe. Examination of early passages of the G70C4-G virus revealed that this HA mutation had arisen by the first passage. From a subsequent passage two transient variants were isolated which had each acquired a different second HA mutation, Ser 165 to Asn and Lys 222 to Thr. Both were highly drug resistant and drug dependent and their ability to adsorb to and penetrate cells was decreased. Comparison of drug sensitivities between the variant, with the additional HA mutation at Ser 165, and viruses with either mutation alone revealed that these two HA mutations acted synergistically to increase resistance. To determine the contribution to resistance of each of the NA and HA mutations in G70C4-G, the NA mutation was separated from the HA mutation by reassorting. The NA mutation and the HA mutation each conferred low-level resistance to zanamivir, while the two mutations interacted synergistically in the double mutant to give higher resistance in vitro. Infectivity was not adversely affected in the double mutant and while there was a small decrease in sensitivity to zanamivir in the mouse model, there was no detectable resistance to zanamivir in the ferret model.