Trypanosomiasis: Medications, seldom used

• Diminazene (Berenil®). Discovered in 1955. Officially registered only for veterinary use. Can be administered intramuscularly (less painful than IM Pentacarinat®). Daily dose 5-7 mg/kg, to be repeated after 2 and 4 days. Can be useful in cases of resistance, but in view of the official restriction it is used very rarely. It was initially considered to be quite neurotoxic, but in practice this does not appear to be such a big problem. Other commercial names for diminazene are Veriben®, Ganasegur®, Ganaseg®, Azidine®. Cross-resistance between diminazene, used in the treatment of animal trypanosomiasis, and melarsoprol used in the treatment of African trypanosomiasis in man can be selected with relative ease. Both drugs, or their active metabolites, can enter trypanosomes via the P2 aminopurine transporter, and loss of this transporter can impair uptake of the drugs into parasites. It is therefore possible that melarsoprol resistance is linked to selection of diminazene resistance through treatment of animals. At present, this is still a hypothesis. Since selection of resistance to diminazene in animals might lead to melarsoprol resistance in humans, caution must be exercised in the choice of trypanocide used to clear cattle of trypanosomes. Therefore, although resistance to isometamidium and homidium can arise more quickly in cattle than can resistance to diminazene, these drugs could be better choices in terms of implications for human health.

• Nifurtimox (Lampit®): Cf. Chagas' disease. Very difficult to obtain outside South America. Its place in therapy is not very clear. Sometimes used in cases of melarsoprol resistance (several schemes, including 15 mg/kg/day PO for 60 days). Toxic to the central nervous system (more toxic at higher doses such as 30 mg/kg/day).

• Cymelarsene. Structurally very closely related to melarsoprol.

• IMOL 881 (experimental). Is yet to be evaluated.

• Trybizine. This is a diamidine that can cure acute trypanosomiasis in cattle and rodents. It was developed in China. Attempts are being made to synthesise analogues that are less toxic and that pass through the blood-brain barrier

• Megazol. A fairly active, but still experimental 5-nitro-imidazole derivative. However, the substance is mutagenic in the Ames test. Megazol does not contain arsenic. [The Ames test screens possible carcinogens. The test uses a specific histidine synthesis deficient Salmonella strain. If the tested substance causes mutations that restore the ability to produce histidine, the substance is regarded as potentially carcinogenic].

• Experimental. The surface glycoproteins (VSG) are anchored in the cell membrane with a glycosyl phosphatidyl inositol (GPI) anchor (see above). When GPI synthesis is blocked by elimination of any single gene along the biochemical pathway, the parasite dies. A search is now being made for suitable inhibitors of an enzyme from this reaction chain that is specific to the trypanosome. Trans-sialidase is another enzyme that is being closely investigated. Trypanosomes are themselves unable to produce sialic acid. In trypanosomes, many enzymes of the pentose phosphate pathway and several other pathways are related to cyanobacterial isoforms rather than to those of eukaryotes. This association has led to a suggestion that the ancestors of trypanosomatids harboured a now lost endosymbiont at some time in their evolutionary past. The pathway's third enzyme (6-phosphogluconate dehydrogenase) is essential to trypanosomes. The search is on to determine if structural differences to its mammalian counterpart could be exploited in design of selective inhibitors. DB289 is an experimental, orally available prodrug, which is converted after absorption into a trypanocidal dicationic form. Acidocalcisomes are membrane-bound acidic cell compartments rich in calcium and pyrophosphate. Inhibitors of such acidocalsisomes (e.g. pamidronate, a bisphosphonate) could be useful, but have still to be tested in formal trials.

• V

  Megazol.

  eterary: Homidium, isometamidium and diminazene are drugs used in cattle, sheep and goats. Suramin, quinapyramine and melarsomine are used in horses, camels and buffalos.

Category: Medicine Notes