There are not currently many treatments available for HAT. The treatment a patient receives depends on the stage to which the disease has progressed. If the disease is still in stage one, a drug called pentamidine can be used- it is ineffective against the trypanosomes if they have crossed into the central nervous system (Wang, 1995). This drug has been in use since the early 1940s.
Pentamidine’s trypanocidal effects were discovered by accident. In the 1930s, researchers noticed that pathogenic trypanosomes consume a large amount of sugar, so they decided to investigate drugs that lower blood glucose levels. One of these drugs was synthalin, a diamidine (like pentamidine). This was effective at treating trypanocidal infection in mice, but not because it lowered blood sugar: it was trypanocidal by its nature. This began the development of diamidines as trypanocidal agents, which culminated with the creation of pentamidine (Steverding, 2010).
The exact target of pentamidine is unknown, but it is known that trypanosomes take it up via an adenine/adenosine transporter, leading to much higher levels pentamidine levels within the trypanosome than within the bloodstream (Carter, Berger, & Fairlamb, 1995). It is known to interact with the minor groove of mitochondrial DNA, so it is possible that it disrupts mitochondrial DNA synthesis, but it is known to have no deleterious effect against already-formed nuclear DNA (Barret, Brun, & Tidwell, 2007). Others have suggested that pentamidine inhibits a biosynthetic pathway. Its slow rate of effacacy has caused some researchers to suggest that it inhibits nucleic acid metabolism (Wang, 1995).
Until 1990, the only option to treat stage two HAT was a drug called melarsoprol. This drug is derived from arsenic, and is still in use, despite having quite adverse side effects. It is a drug that is insoluble in water, and is dissolved in propylene glycol. It must be administered intravenously, which is very painful and can lead to the destruction of veins (Bacchi, 2009). In about of 10% of patients, treatment results in arsenical-induced encephalopathy and death (Priotti et al, 2006). It is thought to lyse trypanosomes via inhibition of the glycolytic pathway, primarily targeting pyruvate kinase and stopping the production of fructose 2,6 bisphosphate (Wang, 1995). It also thought to interact with a trypanosomal metabolite called trypanothione by forming an adduct that inhibits trypanothione reductase, part of a pathway thought to contribute to redox balance within the trypanosome (Fairlamb, Henderson, & Cerami, 1989). Melarsoprol is also taken up via an adenine/adenosine transporter (Carter, Berger, & Fairlamb, 1995).
Currently, there is one other option to treat stage two HAT: a drug called eflornithine. Eflornithine irreversibly inhibits the polyamine biosynthestic pathway by disabling its first enzyme, ornithine decarboxylase (Bacchi et al, 1980). When practiced correctly, this treatment is highly effective, and lacks the severe side effects of melarsoprol (Checchi et al, 2007). The downside of this therapy is that is needs to be administered constantly due to the drug’s short half-life (Bacchi et al, 1980). This is unrealistic given the conditions in which HAT is usually treated- in rural clinics where doctors do not have constant supervision of their patients.
The reason for this short half-life (3.3 hours) is two-pronged (Burri & Brun, 2003). eflornithine can be cleared incredibly quickly by the kidneys, which limits its bioavailability. In addition, eflornithine is a “suicide inhibitor,” and binds to ornithine decarboxylase in such a way that it chemically alters the enzyme to “stick” it in an inactive state. The drug is then safe from degradation, as it has been incorporated into the enzyme, but it also can’t be used again to inhibit another copy of ornithine decarboxylase. Therefore, once the given dose of the drug inhibits all the enzyme it can, another dose is needed (Burri & Brun, 2003). All the while, the trypanosome can be making more ornithine decarboxylase.
So far, there haven’t been many recorded instances of resistance developing to eflornithine, but drug resistance is always a worry. Eflornithine is an excellent drug for HAT, but its half-life is not the only concern- it is also highly complex to synthesize, making it expensive. For this reason, melarsoprol is still used.