Experimental amoebiasis and the development of anti-amoebic compounds

Abstract

In the ideal situation, the development of new amoebicides, or more accurately anti-amoebic compounds which are compounds with activity against Entamoeba histolytica, should initially proceed with the study of parasite-specific metabolic pathways and their inhibition, followed by whole parasite in vitro studies, experimental in vivo models and finally clinical trial. However, there are considerable gaps in our knowledge which will be discussed below, and consequently many investigators consider that empirically selected compounds should be tested experimentally in addition to specifically designed compounds. Before clinical trials can begin, extensive examination of the candidate amoebicide in experimental animals is required in order to investigate possible toxicological hazards.In addition to inhibiting the amoebic parasite, the drug has to reach the parasite in several different sites in the body, thus there is also a problem of pharmacokinetics and distribution. Prior to the discovery of the nitroimidazole class of amoebicides, the multi-site attack was solved by the use of several drugs, sometimes in sequence during the treatment of an individual case (Powell, 1972). The discovery of the nitroimidazole class of compound changed the situation dramatically and these have shown a clinical and parasitological effect against extra-intestinal and intestinal wall infections. The effect on intralumenal infection (that is mildly symptomatic or asymptomatic infections) of the large intestine is, however, less certain (Finegold, 1977; Spillman, Ayala & Sanchez, 1976).Although the treatment of amoebiasis appears to be satisfactory at the present time, it is difficult to predict problems which might arise in the future, and therefore it is valuable to continue the pre-clinical development, especially the investigation of parasite metabolism, in order to define parasite-specific points of chemotherapeutic attack.The chemotherapy of amoebiasis was reviewed comprehensively by Woolf (1963, 1965). The present account of the development of amoebicides therefore starts from the Woolfe reviews.