Treatment and Disease Management

History and Metabolic Context

Molecular Basis of Disease State

Treatment and Disease Management

Conclusions and Proposals for Future Work

Annotated Bibliography

Currently used drug therapies for HAT. Figure created by Gabrielle Whitney via ChemSketch.
Currently used drug therapies for HAT. Figure created by Gabrielle Whitney via ChemSketch.

Pentamidine

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).

Melarsoprol

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).

Vials of melarsoprol (note the need to keep the in glass vials, lest the drug dissolve plastic), ready to be administered for treatment. Image from Google Images.
Vials of melarsoprol (note the need to keep the in glass vials, lest the drug dissolve plastic), ready to be administered for treatment. Image from Google Images.

Eflornithine

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.

The mechanism by which eflornithine inhibits ornithine decarboxylase. Image from Wikipedia, adapted from Poulin et al, 1992.
The mechanism by which eflornithine inhibits ornithine decarboxylase. Image from Wikipedia, adapted from Poulin et al, 1992.

 

6 Replies to “Treatment and Disease Management”

  1. Hey Gabby,

    Clearly the last drug described sounds epically interesting and promising. I was wondering if there are specific aspects of molecules that result in short half lives in the body? In other words, is there anything structurally significant about the molecule that would point to a short half life in the body, and are there any modifications that could be made to drug to increase its half life without impacting its inhibitory effects? Does the fact that the molecule resembles common metabolites (despite the fluorine) impact its half life?

    My second thought has to do with the fact that the parasite infects hemoglobin and heptaglobin. This might not work because it might be super toxic to the individual, but in early stages of the disease, do you think inducing the affected individual with oxidative stress might destroy the parasite? if there were somehow a safe way to do this so that the stress was somehow localized to the place where the infection was, do you think this might serve as a one time treatment?

    1. Hi Tommy! Thank you for your feedback and questions. I believe that a molecule’s half-life simply depends on the ability of the body’s enzymes to metabolize it. In the case of eflornithine, the kidneys clear it very quickly. Your point about eflornithine resembling common metabolites is interesting- I did not find anything in my reading that listed this as a reason for its short half-life, but, to me, that logically makes sense. Also, structurally, eflornithine works as a “suicide inhibitor-” meaning it covalently binds to ornithine decarboxylase and inhibits it, therefore it is trapped and cannot go on to covalently inhibit any more ornithine decarboxylase. I suppose that it would make sense, then, that “suicide inhibitors” like have a shorter period efficacy.

      You have an interesting point about using oxidative damage as a “treatment’ for HAT. I believe that the problem with this (as you correctly ascertained) is that there is no way to localize the oxidative damage. During the hemolymphatic stage, the trypanosomes have infiltrated the entire circulatory system: blood, blood vessels, lymph, etc- there would be no way to focus on a specific area without doing great damage to the patient. But interesting concept!

  2. Gabbie – Really cool project! It’s always nice to see you basque in the glory of infectious disease (you know what I mean…) Like Tommy, I’m fascinated by Eflornithine. I’m a little bit confused by your writing that it irreversibly inhibits ornithine but it has a short half life so there need to be ongoing injections. Can’t you just “wait it out” and let the drug degrade to restore enzyme function? Whatever the case, could you elaborate on that mechanism of action more? Do you know what the timescale of the half-life is like? And finally, is there any evidence that the parasites become resistant to Eflornithine, or is it really just the almost-perfect fix except for the awful half life?

    1. Hi Zach! Good question about eflornithine. There are a couple things going on here. First, eflornithine can be cleared incredibly quickly by the kidneys, which limits its bioavailability. In addition, eflornithine is a “suicide inhibitor,” and actually binds to ornithine decarboxylase in such a way that it chemically alters the enzyme to get it “stuck” 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 dose of the drug inhibits all the enzyme it can, another dose is needed (Burri & Brun, 2003). The trypanosome can then make more ornithine decarboxylase. The half life is incredibly short, about 3.3 hours (Burri & Brun, 2003).

      So far, there haven’t been many recorded instances of resistance developing to eflornithine, but that is always a worry. Eflornithine is a great drug for HAT, but its half-life is not the only concern- it is also highly complex to synthesize, making it expensive.

  3. Hey Gabbie, cool stuff and great analysis and summaries. I hope I didn’t miss this somewhere on the blog, but is the parasite known to have a latent/dormant period when associated with the host? If so, is there some form of treatment available to remove/kill the parasite? Are there known factors that illicit the parasite into an active phase? Lastly, do you know the context of discovery of pentamidine? I was just curious, given that it was first used in 1940 and does not have a known target; why did they decide to try it? Thanks!

    1. Hi Besher- thanks for your questions! From what I’ve read, I don’t believe that there is a dormant period during infection- once you are infected with trypanosomes, they are actively multiplying and wreaking havoc, therefore there is no way to get rid of them before they do damage (although pentamidine can be used in the hemolymphatic stage before the disease progresses to stage two).

      To answer your question about pentamidine, pentamidine’s trypanocidal effects were actually discovered by accident. In the 1930s, researchers noticed that pathogenic trypanosomes consume a lot of sugar, so they tried 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).

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