Human African trypanosomiasis: pharmacological re-engagement with a neglected disease

Abstract

This review discusses the challenges of chemotherapy for human African trypanosomiasis (HAT). The few drugs registered for use against the disease are unsatisfactory for a number of reasons. HAT has two stages. In stage 1 the parasites proliferate in the haemolymphatic system. In stage 2 they invade the central nervous system and brain provoking progressive neurological dysfunction leading to symptoms that include the disrupted sleep wake patterns that give HAT its more common name of sleeping sickness. Targeting drugs to the central nervous system offers many challenges. However, it is the cost of drug development for diseases like HAT, that afflict exclusively people of the world's poorest populations, that has been the principal barrier to new drug development and has led to them becoming neglected. Here we review drugs currently registered for HAT, and also discuss the few compounds progressing through clinical trials. Finally we report on new initiatives that might allow progress to be made in developing new and satisfactory drugs for this terrible disease.

Figure 1

A map of countries infected with HAT. The countries shown in colour have historically reported HAT. Those countries coloured in red are currently reporting in excess of 1000 cases per year. Those in brown currently report between 50 and 1000 cases per year. Those in blue report fewer than 50 cases per year, while those in green currently report no cases of HAT. Nearly 97% of all reported cases are caused by T. b. gambiense. T. b. rhodesiense is found in East and Southern Africa. (Figure courtesy of Dr Pere Simarro at the World Health Organization.) HAT, human African trypanosomiasis.

Figure 2

The life cycle of Trypanosoma brucei. Parasites are transmitted to man by the bite of an infected tsetse fly. Within man, the parasites proliferate first within the haemolymphatic system and later invade the CNS. Proliferative bloodstream slender form parasites (a), transform via an intermediate form (b) into non-proliferative stumpy forms (c). These are pre-adapted to survive within a tsetse fly where they transform into procyclic forms (d) that proliferate in the midgut of this environment before passing through various other stages including the epimastigote form (e) until transforming into metacyclic trypomastigotes (f) in the salivary glands. These forms are preadapted for life in the mammalian host when injected during a bloodmeal. Forms that are capable of division are labelled with a D. CNS, central nervous system.

Figure 3

Structures of some important trypanocidal diamidines.

Figure 4

Structures of suramin, trypan blue and some important trypanocidal arsenicals.

Figure 5

Structures of ornithine and eflornithine and some trypanocidal nitroheterocycles.