Resist Development Issues

Until recently, the resistance of mosquitoes to pyrethroids has not been taken as a serious issue. In Japan, C. p. pallens and Aedes albopictus (Skuse) are the main species living around houses. Although mosquito coils have utilized natural pyrethrins as insecticidal ingredients for about 50 years and then allethrin for about 50 years, there has been no report on resistance development. The reason for this is considered to be the short active time of 4-5 months per year for C. p. pallens. Yasutomi et al. [50] reported in 1989 the presence of pyrethroid-resistant Culex tritaeniorhynchus in Okinawa, but Japanese encephalitis transmitted by C. tritaeniorhynchus decreased markedly after 1992 and disappeared. 

The development of resistance is a major issue for many classes of fungicide, including those that inhibit respiration. However, uncouplers appear to be less susceptible to the onset of resistance than many other fungicides. For example, a study of resistance development in Sphaerotheca Jidiginea in cucumber greenhouses observed no resistance to dinocap, despite it having been used for over 30 years [60]. This was in contrast to other classes of fungicide, such as benzimidazoles, where resistance had developed over a much shorter period. Even under artificial selection pressure, no resistance to dinocap was seen [61]. 

Whilst not well documented, macrolide resistance can also develop during therapy. Lindow and colleagues recently described the first documented evidence of in vivo acquired macrolide resistance in a person infected with C. jejuni, however, it must be emphasised that this was in a controlled human infection as opposed to a natural infection." There are many reasons why this type of data must be viewed with caution, indeed surveillance data shows us that macrolide resistance in C. jejuni in man is not an issue, suggesting that there are many barriers to resistance development in natural infections. 

If a device has defects, the device will not operate properly. A severe case will produce an electrical shorting problem, or the defects may cause shunt loss so that the PV cell cannot attain a good fill factor, due to the small shunt resistance. These issues will be eritieal and will impact the manufacturing cost. If a tool can be developed to define ioeaiized defects and further curing methods are available, this could be a praetieal solution in the OPV field to allow future large scale manufaeturing. 

T-1249 demonstrated substantial activity against enfuvirtide-resistant viruses in clinical studies (Melby et al. 2007a) however, development was discontinued due to formulation issues. Additional peptides with more potent activity were subsequently designed, which also showed much improved pharmacokinetic properties (Dwyer et al. 2007) however, the availability of oral agents in other new classes makes the likelihood of the development of these agents uncertain. 

A crucial issue for antiviral therapy is the fact that all antiviral substances rapidly select for resistance thus, monitoring and overcoming resistance has become a most important clinical paradigm of antiviral therapy. This calls for cautious use of antiviral drugs and implementation of combination therapies. In parallel, efforts in drug discovery have to be continued to develop compounds with novel mode-of-action and activity against resistant strains. This book reviews the current status of antiviral therapy, from the roads to development of new compounds to their clinical use and cost effectiveness. Individual chapters address in more detail all available drug classes and outline new approaches currently under development. 

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