Disease/Drug of interest:

Human African Trypanosomiasis (HAT)/ Pentamidine


Motivation and Background:

Human African Trypanosomiasis (HAT), commonly known as African sleeping sickness, has been a serious public health problem in rural Africa. It is considered a neglected disease that affects the world’s poorest population—it is rarely a problem in U.S. where tsetse fly is not found, but the population of sub-Saharan region is susceptible for this disease. Fewer than 10,000 cases are reported each year but many go unreported [1]. African Trypanosomiasis is caused by tsetse flies carrying microscopic parasites of species Trypanosoma brucei while feeding on animals and can be classified into two types: T. b. rhodesiense and T. b. gambiense. T. b. rhodesiense happens in Eastern African regions and progresses faster due to higher concentration of parasite in the infected body. The signs of illness show up in one to two weeks and if left untreated, it becomes fatal in three weeks. T. b. gambiense happens in Western African regions and the symptoms show up in one to two years [1]. In the first stage of both types of typanosomiasis, the parasite is found in bloodstream and lymphatic system. General symptoms includes fever, headache, and adenopathy. During the second stage the parasite invades the central nervous system and causes various neuropsychiatric symptoms, tremors, and eventually coma that leads to death. Sleep disturbance is the leading symptom during this stage, hence the name “sleeping sickness” [2, 6].


african tryp. region.png
Fig. 1 Number of HAT cases reported in endemic and nonendemic regions, by natives and travelers [2].


Target Information:

Size: molecular weight of the protein

  • Parasitic protozoa Trypanosome
    • length: 16-42um; width: 1-3um
    • about 1000 genes in its genome can randomly switch on and off at each generation
    • hard to develop a vaccine
  • Exact target and mechanism of pentamidine is unknown
    • binds to kinetoplast DNA (mitochondria region of the parasite)binds to AT-rich DNA duplexes and fits in the 4-5 bp groove site while amidinium group and N3 atoms of adenine are hydrogen bonded to each other [5].
      • lead to dyskinetoplastic cells
      • but no effect on nuclear DNA
    • binds to Ca.LSU RNA and inhibits self-splicing introns from the transcripts of the geneserves as an inhibitor enzyme in the polyamine biosynthetic pathway called S-adenosylmethionine decarboxylase [4].
      • incorrect folding and inability to return to its catalytically active form


tryp. and red blood.jpgtrypanosoma.jpg
Fig 2.Trypanosomes and red blood cells Fig 3. Trypanosome internal structure

Location:

bloodstream
1st stage: lymphatic stage
2nd stage: central nervous system

Function in a normal cell:

Foreign to human body



Drug Information:



pentamidinne pic.png
Fig 4. Schematic figure of pentamidine http://www.scbt.com/datasheet-208158-pentamidine.html


Formula

C19H24N4O2

Molecular weight

340.42g/mol

CAS Number:

100-33-4

Delivery method

Chemotherapy (IV) or Nebulizer (inhaled)

Side effects:

nausea, headache, abdominal pain, aseptic abscess, diabetes, hypoglycemia, proteninuria, and rhabdomyolysis
toxic symptoms: decreased blood glucose level, nephrotoxicity, leucopenia, and liver enzyme abnormalities

Other names

NebuPent

Maker or company

Sanofi-Aventis and Bayer

Is it patented?

2832 patents

Clinical Trials Info:

According to National Institutes of Health, there has been 52 clinical trials involving pentamidine. Most of these research are studying the best route of administration, adjustment of dosage, alternate use, toxicity, and resistance of the drug.

Origin:

Pentamidine isethionate is a synthetic antiprotozoal medicine that has been used since 1940s

Alternatives to this drug:

If T. b. gambiense progresses to the second stage or if it is T. b. rhodesiense, pentamidine is no longer effective and other drug must be used for treatment. For the second stage of T. b. gambiense, eflornithine or combination of both eflornithine and nifurtimox is used. For T. b. rhodesiense, suramin is used for the first stage and melarsoprol for the second stage [2]. All the drugs used to treat African trypanosomiasis are toxic to human body and come with various side effects, particularly the ones that are used for the second stage and treat the central nervous system. Melarsoprol, for example, is very toxic and may lead to encephalopathic syndrome, skin reaction, and arrhythmia. Long term treatment of melarsoprol increases the chance of treatment failure to 30% [2].

Miscellaneous:

toxicity of pentamidine makes it hard to carry out clinical trials on volunteers

Other uses

Pentamidine is an antiprotozoan drug but also has an alternate use as a prophylaxis against Pneumocystis carnii pneumonia (PCP), a serious lung infection that is the most common complication of HIV [5].


References:

[1] Centers for Disease Control and Prevention. Parasites—African Trypanosomiasis. http://www.cdc.gov/parasites/sleepingsickness/ (accessed Feb 04, 2016).

[2] Brun, R.; Blum, J., Human African Trypanosomiasis, Infectious Disease Clinics of North America, 2012, 26, (2), 261-273.


[3] National Center for Biotechnology Information, Aerosolized pentamidine as alternative primary prophylaxis against Pneumocystis carinii pneumonia in adult hepatic and renal transplant recipients. http://www.ncbi.nlm.nih.gov/pubmed/8625676 (accessed Feb 04, 2016).


[4] Barret, M.; Boykin, D.; Brun, R.; Tidwell, R., Human African trypanosomiasis: pharmacological re-engagement with a neglected disease, US National Library of Medicine [Online] 2007, 152, (8), 1155-1171 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441931/ (accessed Feb 04, 2016).

[5] Zhang, Y.; Li, Z.; Pilch, D.; Leibowitz, M., Pentamidine inhibits catalytic activity of group I intron Ca.LSU by altering RNA folding, Nucleic Acids Research, 2002, 30, (13), 2961-2971.
[6] Bacchi, C. Chemotherapy of Human African Trypanosomiasis. Hindawi Publishing Corporation. [Online] 2009, 2009, 195040-5 http://www.hindawi.com/journals/ipid/2009/195040/ (accessed Feb 04, 2016).

External link


http://www.scbt.com/datasheet-208158-pentamidine.html