FK962 and donepezil act synergistically to improve cognition in rats: potential as an add-on therapy for Alzheimer's disease.

FK962 is a member of a novel class of compounds that promote somatostatin production in the brain, and is being developed as a treatment for patients with Alzheimer's disease. As acetylcholinesterase inhibitors such as Aricept© (donepezil) are widely used to treat these patients, it is important to confirm that potential new medicines in this disease area can be co-administered with drugs such as Aricept. To study the effect of FK962 in combination with donepezil, touchscreen methodology was used to measure the effect on cognition in rats.

Dimeric zanamivir conjugates with various linking groups are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 avian influenza.

The synthesis, antiviral and pharmacokinetic properties of zanamivir (ZMV) dimers 8 and 13 are described. The compounds are highly potent neuraminidase (NA) inhibitors which, along with dimer 3, are being investigated as potential second generation inhaled therapies both for the treatment of influenza and for prophylactic use. They show outstanding activity in a 1 week mouse influenza prophylaxis assay, and compared with ZMV, high concentrations of 8 and 13 are found in rat lung tissue after 1 week.

Potent and long-acting dimeric inhibitors of influenza virus neuraminidase are effective at a once-weekly dosing regimen.

Dimeric derivatives (compounds 7 to 9) of the influenza virus neuraminidase inhibitor zanamivir (compound 2), which have linking groups of 14 to 18 atoms in length, are approximately 100-fold more potent inhibitors of influenza virus replication in vitro and in vivo than zanamivir. The observed optimum linker length of 18 to 22 A, together with observations that the dimers cause aggregation of isolated neuraminidase tetramers and whole virus, indicate that the dimers benefit from multivalent binding via intertetramer and intervirion linkages. The outstanding long-lasting protective activities shown by compounds 8 and 9 in mouse influenza infectivity experiments and the extremely long residence times observed in the lungs of rats suggest that a single low dose of a dimer would provide effective treatment and prophylaxis for influenza virus infections.

Characterization of 2 influenza A(H3N2) clinical isolates with reduced susceptibility to neuraminidase inhibitors due to mutations in the hemagglutinin gene.

Previous studies have shown that amino acid changes in the hemagglutinin (HA) gene of influenza viruses may result in decreased susceptibility to neuraminidase inhibitors (NAIs) in vitro. However, the emergence and characteristics of such HA variants in the clinical setting remain poorly studied. Herein, we report 2 influenza A(H3N2) isolates, from untreated patients, harboring an Arg229-->Ile substitution in the HA1 gene.