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.

Efficacy of Antiamebic Drugs in a Mouse Model

“…Chloroquine, for example, was entirely ineffective in vitro , even at concentrations of 5 μg/mL, but it exhibited reasonable efficacy in vivo . The lack of in vitro effect has been shown before, 23 and the mechanism of action in vivo is unclear. 4 Emetine has long been used for severe amebiasis, both hepatic and intestinal, and dehydroemetine remains available in the United States through the Centers for Disease Control and Prevention.…”

Caecal-inoculation of entamoeba histolytica in the immunodepressed swiss albino mice treated with Cyclophosphamide

“…The successful production of intestinal E. histolytica infection in laboratory animals is a vital problem in chemotherapeutic research on amoebiasis (Bhopale et al 1995). Although, small population of laboratory animals are not the natural hosts of E. histolytica, numerous reports indicate that there is a fairly good correlation between antiamoebic drug responses in the natural and experimental hosts (Neal 1983). Although, attempts have also been made to establish caecal amoebiasis in albino mouse (Neal andHarris 1975, Gold andKagan 1978), the variability in infection rate and development of lesions usually make this model unsuitable for drug screening.…”

“…World-wide morbidity and mortality due to amoebiasis is difficult to estimate. An estimate suggests that approximately 500 million people are infected worldwide with this parasite and causing about 110,000 deaths per year (Walsh 1986, Neal 1983, Robinson 1968, Bhopale et al 1995.…”

“…Although a variety of laboratory animals have been used, the mouse whose genetic and immunology is well-known has been seldom used. A very few investigators have attempted to establish caecal amoebiasis in mice (Neal andHarris 1975, Gold andKagan 1978) but the results were inconclusive.…”

Isolation and in vitro antiamoebic activity of iridoids isolated from Kigelia pinnata

“…Numerous plants are used in the indigenous system of medicine of many countries for the treatment of dysentery. [5][6][7][8][9][10][11] They require more thorough investigation in order to validate their activity and that may uncover new leads for amoebicidal drugs.…”