Leishmaniasis

=__**Disease/Drug of interest** : __= Leishmaniasis/Sodium Stibogluconate

**Motivation and Background** :
Leishmaniasis is an infectious skin disease that is caused by infection of the Leishmania parasites, parasites that are spread through the bite of phlebotomine sand flies [1]. Since the disease is contracted through the bite of sand flies, people of all age and race are susceptible to the disease. It is most common in the regions of subtropics, tropics, and southern Europe around the Mediterranean River. It is also less commonly found in Southeast Asia, Africa, and Americas [1]. There are several different types of Leishmaniasis available in human, the most common types being cutaneous Leishmaniasis and visceral Leishmaniasis [1]. Cutaneous Leishmaniasis causes painless skin ulcers, difficulty in breathing, or nose bleeds within fewagrias months or years [2]. Visceral Leishmaniasis has some slightly harsher effects on an individual and will be the main focus of this paper. Within two to six months after infection, visceral Leishmaniasis can cause weight loss, fever that lasts weeks or months, enlarged spleen and/or liver, decreased red blood cells production, scaly skin, thinning hair, and other infections. In fact, visceral Leishmaniasis is one of the main concerns of public health due to its severity [3]. Annually, there are 200000-400000 cases of visceral Leishmaniasis. Furthermore, 40% of patients who were infected with visceral Leishmaniasis are coinfected with HIV, making this disease a significant public health problem [4]. The coinfection of HIV causes less accurate serological tests of visceral Leishmaniasis. It also causes 60% of treated patients to relapse within a year [4]. Therefore, the present method of controlling this disease is only partially effective, and a more effective strategy needs to be developed [3].

It is known from images of skin deformities displayed on potteries from the first century that Leishmaniasis was prevalent even during the first century AD [figure 1]. The first written evidence of Leishmaniasis was from the 15th-16th century and written by the Incans and Spanish conquistadors who called this disease “white leprosy” or “valley sickness” [5]. Leishmaniasis received its name in 1903. A Glaswegian doctor, who was serving with the British Army in India, named William Leishman discovered in the spleen of British soldiers, who were suffering from anemia, fever, atrophy, and swelling of the spleen, ovoid bodies [5]. He believed it was a regional disease, but Charles Donovan saw similar symptoms in other patients infected with kal-azar. They developed stains of Leishmaniasis and examined the parasites to discover the cause of Leishmaniasis [5]. The amastigotes were later named Leishman-Donovan bodies until it officially became a species called Leishmanias Donovani [5].

Although Leishmaniasis had been a known disease since the first century AD, information regarding Leishmaniasis and its treatments such as sodium stibogluconate still lack greatly in the present world [6]. This may be due to visceral Leishmaniasis being mostly prevalent in third world countries that cannot afford the research. Within two years, patients in third world countries who do not receive some sort of treatment for visceral Leishmaniasis has a fatality rate as high as 100% [7]. Therefore, more information on Leishmaniasis needs to be researched as soon as possible.

[3] Camargo L. B.; Langoni H., Impact of Leishmaniasis on public health. //Journal of Venomous Animals and Toxins// **2006,** //12// (4), 527-548. [4] van Griensven J.; Zijlstra E. E.; Hailu A., Visceral Leishmaniasis and HIV coinfection: time for concerted action. //PLoS Negl Trop Dis// **2013,** //8// (8), 3023. [6] Berman, J. D.; Waddell, D.; Hanson, B. D., Biochemical mechanisms of the antileishmanial activity of sodium stibogluconate. //Antimicrobial Agents and Chemotherapy// **1985,** 27 (6), 916-920. [8] Berman, J. D.; Gallalee, J. V.; Best, J. M., Sodium stibogluconate (pentostam) inhibition of glucose catabolism via the glycolytic pathway, and fatty acid β-oxidation in //leishmania mexicana// amastigotes. //Biochemical Pharmacology// **1987,** //36// (2), 197-201. [11, Figure 3] Frézard, F.; Martins, P. S.; Barbosa, M. C. M.; Pimenta A. M. C.; Ferreira W. A.; de Melo, J. E.; Mangrum J. B.; Demicheli C., New insights into the chemical structure and composition of the pentavalent antimonial drugs, meglumine antimonate and sodium stibogluconate. //Journal of Inorganic Biochemistry// **2008,** //102// (4), 656-665. [14] // Toxicological profile for antimony and compounds // ; U.S. Dept. of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry: Atlanta, GA, 1992. [15] Kimutai, R.; Musa, A. M.; Njoroge, S.; Omollo, R.; Alves, F.; Hailu, A.; Khalil, E. A. G.; Diro, E.; Soipei, P.; Musa, B.; Salman, K.; Ritmeijer, K.; Chappuis, F.; Rashid, J.; Mohammed, R.; Jameneh, A.; Makonnen, E.; Olobo, J.; Okell, L.; Sagaki, P.; Strub, N.; Ellis, S.; Alvar, J.; Balasegaram, M.; Alirol, E.; Wasunna, M., Safety and effectiveness of sodium stibogluconate and paromomycin combination for the treatment of visceral leishmaniasis in eastern Africa: results from a pharmacovigilance programme. //Clinical Drug Investigation// **2017,** 1-14.
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**External links:**
[1] Global Health - Division of Parasitic Diseases, Parasites - Leishmaniasis. https://www.cdc.gov/parasites/leishmaniasis/ (accessed Feb 1, 2017). [2] Cafasso, J.; Kim, S., Leishmaniasis. http://www.healthline.com/health/leishmaniasis#Overview1 (accessed Feb 1, 2017). [5] Stanford University, Leishmaniasis history. https://web.stanford.edu/group/parasites/ParaSites2006/Leishmaniasis/history.htm (accessed Feb 1, 2017). [7] World Health Organization, Visceral leishmaniasis. http://www.who.int/leishmaniasis/visceral_leishmaniasis/en/ (accessed Feb 6, 2017). [9] PubChem, Adenosine 5'-diphosphate. https://pubchem.ncbi.nlm.nih.gov/compound/Adenosine_diphosphate#section=Top (accessed Feb 2, 2017). [10] PubChem, Adenosine triphosphate. https://pubchem.ncbi.nlm.nih.gov/compound/Adenosine_triphosphate#section=Top (accessed Feb 2, 2017). [12] USPTO, CPC definition – subclass A61K. https://www.uspto.gov/web/patents/classification/cpc/html/defA61K.html (accessed Feb 5, 2017). [13] Clinicaltrials,gov, Sodium stibogluconate. https://www.clinicaltrials.gov/ct2/results?term=sodium%2Bstibogluconate&Search=Search (accessed Feb 5, 2017). [Figure 1] Iranderma. Leishmaniasis http://www.iranderma.com/leishmaniasis.htm (accessed Feb 3, 2017). [Figure 2] Socratic, How does atp store and release energy?. https://socratic.org/questions/how-does-atp-store-and-release-energy (accessed Feb 3, 2017). =__**Target Information** : __= A study hypothesizes that sodium stibogluconate treat visceral Leishmaniasis by inhibiting adenosine diphosphates (ADPs) from phosphorylating into adenosine triphosphates (ATPs) in the glycolysis pathway [8]. However, exact target is not known.

** Size ** :
ADP = MW: 427.203 g/mol ATP = MW:507.181 g/mol

** Location ** :
Mitochondrial Matrix

** Function in a normal cell ** :
ATP is the biggest source of energy for the cell and is very essential for the body [figure 2].

=__**Drug Information**** : **__= Sodium stibogluconate [figure 3], a pentavalent antimonial drug, is most commonly used to treat visceral Leishmaniasis [6]. Sodium stibogluconate kills the //Leishmania// parasites by inhibiting fatty acid oxidation and glycolytic enzymes. In general, most antimonial drugs, including the sodium stibogluconate, treat visceral Leishmaniasis by inhibiting the glycolysis pathway in some way, indicating that the location of these drugs' target is somewhere in the mitochonrial = = matrix [9]. However, the exact biochemical mechanism and the true target of the drug to treat visceral Leishmaniasis is virtually uninvestigated [9]. A study hypothesizes that sodium stibogluconate treat visceral Leishmaniasis by inhibiting adenosine diphosphates (ADPs) from phosphorylating into adenosine triphosphates (ATPs) in the glycolysis pathway [10]. ADP is an organic compound that can gain a phosphate group in order to phosphorylate into ATP, which contains energy for cells to perform chemical reactions [11,12]. = =

Figure 3 shown above C ₁₂ H ₁₇ O ₁₇ Sb ₂ · 3Na · 9H ₂ O Its molecular mass is commonly hypothesized to be 907.880g/mol, but analysis using molecular sieve chromatography showed that its exact molecular mass is around between 100-4000 Daltons [11]. 16037-91-5 Injection Coughing, chest pains, joint pains, muscle aches, anaphylaxis, dizziness, nausea, reduced appetite, and etc. N/A GlaxoSmithKline, a company in the United Kingdom According to uspto.gov, sodium stibogluconate is patented [12]. There have only been twenty-two clinical trials for the drug sodium stibogluconate [13]. Out of the twenty-two clinical trials, 14 are completed, 4 are currently in progress, 2 are terminated, 1 is withdrawn, and 1 is currently in an unknown state [13]. __** Origin ** : __ The origin of sodium stibogluconate could not be found. Parts of the world that do not use sodium stibogluconate instead use miltefosine or amphotericin. However, these drugs are not as effective as sodium stibogluconate [14]. N/A Sodium stibogluconate treated 56% of people with both HIV and visceral Leishmaniasis, proving its effectiveness but does not treat HIV itself. Therefore, sodium stibogluconate does not treat other diseases/conditions [15].
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