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Treating trypanosomiasis: an ironic history

2 Jul 2010

Paul Chinnock

Source: Parasites & Vectors (see original article or PDF)

 

Citation: Steverding D (2010). The development of drugs for treatment of sleeping sickness: a historical review. Parasit Vectors; 3(1):15

2010 Steverding; licensee BioMed Central Ltd.


Sleeping sickness (human African trypanosomiasis is caused by trypanosomes. The species shown here is Trypanosoma brucei gambiense. [Credit: WHO/TDR/Molyneux.]

Readers of this well presented historical review of the development of treatments for human African trypanosomiasis (sleeping sickness) will be struck by the ironies in the story that author Dietmar Steverding has to tell.

In the history of drug discovery, trypanosomiasis occupies a key position, as it was for the development of anti-sleeping sickness drugs that medicinal chemistry was first applied. Nevertheless, since that exciting period of early research, the process of drug discovery – which has delivered effective treatments with acceptable levels of side effects for so many diseases – has given us very few drugs for this dreadful disease, of which there are still around 10,000 cases every year. Many of the treatments in use today were developed in the first part of the last century; they are of limited effectiveness and carry serious risks. The most widely used drugs are melarsoprol (which is arsenic-based and kills up to one in twenty of the patients who receive it) and eflornithine, which requires a slow infusion every six hours for fourteen days making it expensive and unsuitable for use in the very countries where the disease is most common.

Intriguingly, the explorer David Livingstone suggested, in 1858, the use of solution of potassium arsenite for treating “the tsetse bite” (although his own attempt to do so in the treatment of a horse appears not to have been successful). Not until the early years of the 20th century was sodium arsenite shown to be effective in killing trypanosomes in infected laboratory animals. By this time, medicinal chemistry’s classical period had begun; German and French chemists tested many compounds, in most cases developed in the dyes industry, for their chemotherapeutic properties. Why was trypanosomiasis one of their priorities? Firstly, huge areas of Africa were at that time afflicted by a major epidemic of the disease, in which it is estimated that up to half a million people died. Secondly, European nations were intent on developing their recently acquired African colonies and it was felt that this would be greatly facilitated by a cure for sleeping sickness.

An arsenic-based compound developed by Paul Ehrlich turned out not to be effective against trypanosomes but was more successful against syphilis. The introduction of the drug in question – salvarsan – has become a recognized landmark in medical history.

As far as trypanosomiasis is concerned, the breakthrough came in 1917 with the discovery of a compound known as “Bayer 205”. Steverding tells us: “The Bayer Company understood the political importance of Bayer 205 for the commercial exploitation of African colonies and offered the formula of the drug to the British Government in exchange for the return of Germany’s lost African territories. When the British declined the offer, the Bayer Company refused to disclose the chemical structure of the drug”. The structure was subsequently determined by a French scientist and the drug, known now as suramin, is still in use in the therapy of early-stage T. b. rhodesiense sleeping sickness.

American research led, in 1919, to the synthesis of tryparsamide. As this drug is able to enter the central nervous system, it was possible, for the first time, to treat the second stage of sleeping sickness. Although tryparsamide caused damage to the optical nerve, it remained the drug of choice for chemotherapy of sleeping sickness until the early 1960s.

Melarsoprol, a product of Swiss research, first came into use in 1949. It is still the only effective drug for chemotherapy of second stage of T. b. rhodesiense sleeping sickness.

In the UK, diamidine compounds were also investigated for their trypanocidal properties, leading to the development of the drugs stilbamidine and pentamidine in the 1940s. The latter is still in use.

But once the colonial era was over, the search for more effective and less toxic treatments for sleeping sickness tailed off. No one thought the disease had gone away but for pharmaceutical companies the value of the market was deemed insufficient to justify expenditure on R&D.

Nifurtimox was found, in the 1960s, to have trypanocidal action but was developed as a treatment for another trypanosomal condition – Chagas disease, in Latin America. An unexpected breakthrough, however, occurred in the 1980s when a potential anti-cancer drug, eflornithine, was shown to be an effective trypanocide. In 1990, it was approved for the treatment of human trypanosomiasis caused by T. b. gambiense, but treatment requires hospital admission for at least two weeks, with infusions given every six hours.

In a trial reported last year (and highlighted on TropIKA.net) eflornithine was used in combination with nifurtimox in the treatment of second-stage T. b. gambiense sleeping sickness and found to be of similar effectiveness to eflornithine monotherapy, However, the combination therapy is easier to administer and safer, as fewer eflnornithine infusions of shorter duration are required. The results of the trial are therefore regarded as a major step forward.

However, the neglect of sleeping sickness – as with so many other infectious of diseases of poverty – has led to countless unnecessary deaths. Nifurtimox–flornithine combination therapy (NECT) must not be the end of the story. Research to develop further treatments will still be crucial.

Note: Publication of this article in Parasites & Vectors comes at the time when the journal has been awarded its first impact factor (IF) – a very creditable 2.05. Whilst the IF has many limitations as a metric, it is encouraging that articles published in this young journal have attracted so many citations, and the team behind P&V are to be congratulated on what they have achieved.

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