African+trypanosomiasis

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]. ====

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

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

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

**Location: **
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">bloodstream <span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">1st stage: lymphatic stage <span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">2nd stage: central nervous system

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Function in a normal cell:
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Foreign to human body

=<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Drug Information: =

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif; font-size: 80%;">Fig 4. Schematic figure of pentamidine []

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Formula
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">C19H24N4O2

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">**Molecular weight**
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">340.42g/mol

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">**CAS Number**:
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">100-33-4

**<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Delivery method **
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Chemotherapy (IV) or Nebulizer (inhaled)

**<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Side effects: **
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">nausea, headache, abdominal pain, aseptic abscess, diabetes, hypoglycemia, proteninuria, and rhabdomyolysis <span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">toxic symptoms: decreased blood glucose level, nephrotoxicity, leucopenia, and liver enzyme abnormalities

**<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Other names **
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">NebuPent

**<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Maker or company **
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Sanofi-Aventis and Bayer

**<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Is it patented? **
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">2832 patents

**<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Clinical Trials Info: **
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">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.

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Origin:
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Pentamidine isethionate is a synthetic antiprotozoal medicine that has been used since 1940s

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Alternatives to this drug:
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">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].

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Miscellaneous:
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">toxicity of pentamidine makes it hard to carry out clinical trials on volunteers

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">Other uses
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">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].

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">References:
<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">[1] Centers for Disease Control and Prevention. Parasites—African Trypanosomiasis. [] (accessed Feb 04, 2016).

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">[2] Brun, R.; Blum, J., Human African Trypanosomiasis, Infectious Disease Clinics of North America, 2012, 26, (2), 261-273.

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">[3] National Center for Biotechnology Information, Aerosolized pentamidine as alternative primary prophylaxis against Pneumocystis carinii pneumonia in adult hepatic and renal transplant recipients. [] (accessed Feb 04, 2016).

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">[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 [] (accessed Feb 04, 2016).

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">[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. <span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">[6] Bacchi, C. Chemotherapy of Human African Trypanosomiasis. Hindawi Publishing Corporation. [Online] 2009, 2009, 195040-5 [] (accessed Feb 04, 2016).

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif;">External link
<span style="font-family: Calibri,sans-serif; font-size: 11pt;">[]