Lifespan Of Drugs Research Articles

Rapid response to selection, competitive release and increased transmission potential of artesunate-selected Plasmodium chabaudi malaria parasites.

The evolution of drug resistance, a key challenge for our ability to treat and control infections, depends on two processes: de-novo resistance mutations, and the selection for and spread of resistant mutants within a population. Understanding the factors influencing the rates of these two processes is essential for maximizing the useful lifespan of drugs and, therefore, effective disease control. For malaria parasites, artemisinin-based drugs are the frontline weapons in the fight against disease, but reports from the field of slower parasite clearance rates during drug treatment are generating concern that the useful lifespan of these drugs may be limited. Whether slower clearance rates represent true resistance, and how this provides a selective advantage for parasites is uncertain. Here, we show that Plasmodium chabaudi malaria parasites selected for resistance to artesunate (an artemisinin derivative) through a step-wise increase in drug dose evolved slower clearance rates extremely rapidly. In single infections, these slower clearance rates, similar to those seen in the field, provided fitness advantages to the parasite through increased overall density, recrudescence after treatment and increased transmission potential. In mixed infections, removal of susceptible parasites by drug treatment led to substantial increases in the densities and transmission potential of resistant parasites (competitive release). Our results demonstrate the double-edged sword for resistance management: in our initial selection experiments, no parasites survived aggressive chemotherapy, but after selection, the fitness advantage for resistant parasites was greatest at high drug doses. Aggressive treatment of mixed infections resulted in resistant parasites dominating the pool of gametocytes, without providing additional health benefits to hosts. Slower clearance rates can evolve rapidly and can provide a strong fitness advantage during drug treatment in both single and mixed strain infections.

Strategies for the prevention of antimalarial drug resistance: Rationale for combination chemotherapy for malaria

Among the several ‘tropical’ diseases that affect humans, malarin poses special control problems due to the increasing population at risk from the disease, the difficulties in eradicating the mosquito vector in the tropics and the emergence and spread of parasite resistance to commonly used antimalarial drugs. There is both clinical experience and experimental evidence that, however effective when first introduced, the lifespan of drugs is inevitably curtailed by the emergence of resistant parasites. Resistance is the most important factor in determining the useful lifespan of antimalarial drugs. In this review, Nick White and Piero Olliaro discuss the rationale for combination chemotherapy.

Research on avian coccidia: An update

Despite the availability of many anticoccidial drugs, infections caused by species of Eimeria continue to be a source of significant economic loss to the poultry industry. After two decades in which the use world wide of ionophorous antibiotics gave unparalleled control of coccidiosis, drug resistance is once again tipping the balance in favour of the parasites. The realization that even the most spectacularly successful drugs might, after all, have a finite life if not used conservatively, has focused attention on ways in which the life span of drugs can be prolonged. Many drugs with different (if unknown) modes of action are available, and a variety of shuttle and rotation programmes can be considered. In view of the limitations of chemotherapy, particularly for the rearing of replacement flocks, there is considerable interest in the development of vaccines. Prospects for the introduction of live vaccines based on attenuated parasites are now very good, but the availability in the future of genetically engineered vaccines is more uncertain as little is known about the parasite molecules that stimulate protective immunity and, even if isolated, how they can be administered to the host so that it responds in the immunologically correct manner. Current research on Eimeria spp. in the chicken is broadly representative of that being done on other coccidia. Many lines of investigation are not connected with the development of new drugs or vaccination per se (and therefore have no obvious practical applications), but they are providing new insights into the biological complexity of the organisms and the ways in which they interact with their hosts. It remains possible, however, that a more detailed understanding and analysis of the molecules that are essential in the maintenance of the parasitic life style can be exploited in the future to provide alternative targets for chemical or immunological attack. The research topics considered in this review are arbitrarily grouped as studies on: (1) the basic biology of parasites, including aspects of the life cycle, and structure and function of the apical organelles; (2) the molecular biology of the parasites, including analyses of the number and structure of chromosomes, characterization of DNA sequences, and an account of the viral RNA that has been found in some species of Eimeria; and (3) control of coccidiosis, encompassing first immunity and the development of vaccines, and secondly, chemotherapy.