Trypanosomes

It is of interest to mention briefly a rational explanation for the mechanism of action of the arsenicals used in the treatment of trypanosome infections. Chemically three types of arsenicals are employed the trivalent, pentavalent, and arsenobenzene. In general the trivalent arsenicals are effective both in vitro and in vivo, whereas the pentavalent and arsenobenzene types are effective only imder in vivo conditions. It is known that the host reduces the pentavalent arsenicals to the trivalent state and that the arsenobenzenes are oxidized by the trypanosomes to the trivalent state before they become effective. Furthermore, there is substantial evidence to indicate that the trypanosomes have a remarkable affinity for these arsenicals, the fixation taking place in the matter of only a few minutes. In its initial stages the parasiticidal reaction is a reversible process, but in the later stages it passes into an irreversible phase, probably owing to secondary biochemical reactions. 

In view of the recent concepts of heavy metal reactions with SH 

---

Noble M E M, R K Wierenga, A-M Lambeir, F R Opperdoes, W H Thunnissen, K H Kalk, H Groendijk and W G J Hoi 1991. The Adaptability of the Active Site of Trypanosomal Triosephosphate Isomerase as Observed in the Crystal Structures of Three Different Complexes. Proteins Structure, Function and Genetics 10 50-69. 

Eflornithine (difluoromethylornithine, DFMO) inhibits the ornithine decarboxylase of the polyamine pathway, in both the trypanosome and the mammalian cell, by acting as an irreversible competitor of the natural substrate ornithine. Inhibition of ornithine decarboxylase results in depletion of the polyamines, putrescine, spermidine and spermine, which are essential for cell proliferation. Eflornithine selectively harms the parasite and not the mammalian cells, despite acting as an ornithine decarboxylase inhibitor in both cell types. This selectivity is explained by the lower rate of ornithine decarboxylase production in the parasite, as compared to mammalian cells. Due to the high turnover rate, mammalian cells are capable of quickly replenishing inhibited ornithine decarboxylase by newly... 

Melarsoprol, a trivalent organic melaminophenyl arsenic compound, kills intracerebral parasites of both T. brucei gambiense and T. brucei rhodesiense. Melarsoprol accumulates via an adenosine/adenine transporter in trypanosomes and is believed to inhibit glycolytic enzymes. Melarsoprol leads to a rapid lysis of trypanosomes. Melarsoprol is highly toxic to humans. 

Suramin, a symmetrical, polysulfonated naphthyl-amine, inhibits a number of trypanosomal enzymes however, the importance of these effects on parasite killing is not clear. 

Muhich, M.L. Boothroyd, J.C. (1989). Synthesis of trypanosome hsp70 mRNA is resistant to disruption of trans-splicing by heat shock Mol. Cell. Biol. 8, 3837-3846. 

Vickerman, K. (1974). Antigenic variation in African trypanosomes. Ciba Found. Symp. 25, 53-80. 

Hoet S, Stevigny C, Block S, et al. Alkaloids from Cassytha filiformis and related apor-phines anti-trypanosomal activity, cytotoxicity, and interaction with DNA and topoisomerases. Planta Med 2004 70 407-413. 

Welburn, S.C., Arnold, K., Maudlin, I. and Gooday, G.W. (1993) Rickettsia-like organisms and chitinase production in relation to transmission of trypanosomes by tsetse flies. Parasitology 107,141-145. 

Quinoxaline bis-A-oxides have been investigated as potential anti-cancer agents 93 <06BMC6917> and anti-trypanosomal agents 94 <06BMC5503>. In the latter case, a vanadyl complex was prepared in order to increase bioavailability. 

Bangs, J.D., Andrews, N.W., Hart, G.W., and Englund, P.T. (1986) Post-translational modification and intracellular transport of a trypanosome variant surface glycoprotein./. Cell Biol. 103, 255-263. 

The second parasitic disease we want to consider is sleeping sickness, or African trypanosomiasis, as it is also known. Sleeping sickness results from an infection by protozoa called trypanosomes that are closely related to Leishmania, and, like leishmaniasis, sleeping sickness is spread by flies. On a more general level, however, the two diseases seem quite distinct. Leishmaniasis takes several forms, only one of which is fatal, but untreated sleeping sickness invariably leads to death. Leishmaniasis is a menace in much of the... 

Both male and female tsetse live solely on vertebrate blood, and the various species that carry sleeping sickness typically feed not only on humans but also on both domestic and wild animals. Infected flies pass on trypanosomes whenever they take a blood meal, so that the parasites not only move between flies and humans, but also infect a number of other hosts. Infected domestic animals develop nagana, but wild animals may show no sign of illness. They serve instead as healthy animal reservoirs of trypanosomes, permitting tsetse flies to pick up the parasites at any time without necessarily feeding on infected humans or domestic animals. For this reason and also because available drug therapies have proved no more practical here than for leishmaniasis, control of trypanosomiasis has long emphasized eradication of tsetse flies. 

---