Nuclear techniques in the study of resistance to anti-parasitic agents

The prevalence of resistance to chemotherapy in Plasmodium, Trypanosoma and helminths of man and animals is increasing, while few completely new anti-parasitic agents are being found. Therefore, there is a need to keep the existing drugs active and, if possible, make them more effective, less toxic and more convenient to use, as well as maintaining the search for new alternatives. Recent advances in diagnosis of resistance and modes of action of anti-parasitic agents are discussed. The pharmacokinetic behaviour of drugs in relation to resistance and tolerance, and many important unanswered questions are highlighted with particular emphasis on using radiolabelled drugs and metabolites. Reduction in the uptake of the toxicant by resistant parasites appears to be the most common mechanism of resistance and drug tolerance. Other mechanisms include reduced sensitivity of the target, increased level of the target enzyme, reduced importance of the target for parasite survival, detoxification systems, and altered parasite location resulting in reduced exposure or susceptibility to the toxicant. In many cases of resistance, mechanisms are still not understood. The selective toxicity of an anti-parasitic agent may be due to the drug's specificity for the parasite's metabolism and/or to its pharmacokinetic behaviour. Many factors, such as the dose, route of administration and formulation of the drug, and the disease, nutritional and immunological state of the host, as well as individual and racial differences in drug metabolism, can affect the amount of drug reaching the parasite. Interesting developments in liposome encapsulation, polymer complexing, long-acting devices and alterations in drug structure and route of administration offer hope of increasing the effectiveness, reducing the toxicity and simplifying mass chemotherapy