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The History of Drugs Used to Treat Human African Trypanosomiasis (Sleeping Sickness)

Writter: Josue Navarro ‘25

Editor: Naphat Permpredanun '24

Image 1. Trypanosoma brucei (1)


Human African Trypanosomiasis, also known as African Sleeping Sickness, is a disease caused by a parasite called Trypanosoma brucei (2). This parasite was discovered by David Bruce, who worked to identify the infectious agent of a disease known as N’gara in the 1890s (2). T. brucei is transmitted by tsetse flies (2). These flies are found in sub-Saharan Africa, but only some species of this insect can transmit the parasite to human hosts (3). These are Trypanosoma brucei gambienese and Trypanosoma brucei rhodesiense, with T. brucei gambienese accounting for 97% of human infections (3). T. brucei is an obligate extracellular parasite, meaning it resides in the bloodstream and never physically enters its host’s cells (4). The issue with T. brucei is that it moves incredibly fast and is able to spread easily throughout the entire body. The first stage of the disease allows T. brucei to enter the bloodstream to multiply (4). Then, the parasite enters the brain via the cerebrospinal fluid or blood (4). This means that the parasite must cross the blood-brain barrier. When it does so, the immune system has a hard time attacking it. This is because the brain does not contain the same immune system we associate with the rest of the body. This protects the brain from the harsh responses the immune system mounts against pathogens. Therefore, when T. brucei enters, there is little stopping it from causing a lot of harm. Without any treatment, infection is very likely fatal.


The discovery of T. brucei occurred after scientists studied diseases aboard the River Gambia steamship–a ship used during the African slave trade (5). The master of the steamship presented fever and lethargy (5). Since malaria was a common disease affecting people in Africa, the steamship master was prescribed quinine to cure him. This was done to stop Plasmodium (malarial parasite) from growing and dividing. Unfortunately, this did not work. Blood smears were taken from the steamship master in hopes of finding the causative of his disease. These blood smears pointed to trypanosomes as the causative agent of the disease (5). Therefore, new treatments had to be developed to stop this disease from spreading and causing more harm.


In the mid-1800s, the development of the dyestuff industry for colorants of textiles and other products took hold, primarily in Germany (5, 6). Scientists like Paul Erlich took advantage of this by using the properties of dyes to develop chemotherapies (5, 6). In 1901, Erlich began studying potential chemotherapeutic trypanosomiasis treatments. He tested 100 different compounds to see if they exhibited anti-trypanocidal properties. It was found that a dye compound called benzopurpurin was the most effective in combating T. brucei infection by causing the elimination of the parasite (5). For several years, scientists tested different derivatives of this dye, but the results were either unsuccessful or ineffective for humans. In 1906, trypan blue effectively eliminated all trypanosomes from the blood (5). But as the name suggests, this was a blue dye. And unfortunately, it stained animals (used for testing) blue, which made it unfit for use on humans. In 1917, Bayer 205 was synthesized (5). It was a colorless compound that was effective at curing trypanosomiasis in animals and humans. This was an incredible achievement, and today, this drug is still in use to treat patients infected with T. b. rhodesiense.


The use of arsenicals has also been used to treat trypanosomiasis (5). These compounds contain arsenic, making them very potent and dangerous if they are not used properly. Atoxyl was developed in the 1860s to treat HAT (5). A study was conducted in East Africa, which showed that this compound was toxic, however. 2% of the patients were blinded due to a disturbance in their optic nerve (5). Another drug that was tested was melarsoprol (5). This compound did not have the same blinding effects. However, it caused encephalitis in 5-10% of patients using it, killing 1-5% of them (5). This is also a very unpleasant drug since it damages veins when administered, creating an antifreeze sensation (5). Nonetheless, this drug is the only one that works effectively in patients with brain-stage HAT caused by T. b. rhodesiense.


In the 1960s, nifurtimox was developed to combat a similar disease caused by Trypanosoma cruzi (5). This drug was tested on patients with HAT, and it worked to cure patients at high doses. Today, another drug called eflornithine is used in combination with nifurtimox to combat T. b. gambienese (5). These drugs come in NECT kits that can be distributed to areas where HAT is a big problem. They have to be given over a period of 10 days to work effectively. These drugs have lower toxicity and are very effective.


The road to creating drugs that cause minimal side effects and discomfort is still some time away; the development of treatments is complicated for new and more complex diseases, like those caused by protists. However, our technologies are rapidly advancing, and soon, we can expect to develop better drugs to treat harsher diseases that affect humans.



Citations:

  1. Powell, Martha, Trypanosoma brucei [Illustration]. 2017. Future Science Group. Biotechniques

  2. CDC. Parasites - African Trypanosomiasis (also known as Sleeping Sickness) [Internet]. Centers for Disease Control and Prevention. 2022 [cited 2023May1]. Available from: https://www.cdc.gov/parasites/sleepingsickness/index.html

  3. WHO. Trypanosomiasis, Human African (Sleeping Sickness) [Internet]. World Health Organization. 2023 [cited 2023May2]. Available from: https://www.who.int/news-room/fact-sheets/detail/trypanosomiasis-human-african-(sleeping-sickness)

  4. Ooi C-P, Bastin P. More Than Meets the Eye: Understanding Trypanosoma brucei Morphology in the Tsetse. Frontiers in Cellular and Infection Microbiology. 2013;3.

  5. Steverding D. The Development of Drugs for Treatment of Sleeping Sickness: A Historical Review. Parasites Vectors. 2010;3(1):15.

  6. Wollheim Memorial. The Genesis of the German Dye Industry in the Nineteenth Century [Internet]. Wollheim Memorial. 2010 [cited 2023May6]. Available from: http://www.wollheim-memorial.de/en/entstehung_der_deutschen_farbenindustrie_en


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