Leishmaniasis+2+Sp14


 * DISEASE/DRUG OF INTEREST **: Leishmaniasis (Visceral) and Amphotericin B

The female phlebotomine sandfly is a blood-sucking insect commonly found in tropical and desert regions of the world. It is about one-third the size of a mosquito and the most common transmitter of leishmaniasis, a disease whose effects range from uncomfortable, but generally harmless skin lesions (cutaneous leishmaniasis) to organ failure and death (visceral leishmaniasis). For those infected with visceral leishmaniasis, fever, swelling of the spleen and liver, and anemia are common symptoms. If left untreated, visceral leishmaniasis will likely result in death. Because the sandfly bite often goes unnoticed and symptoms of visceral leishmaniasis frequently do not appear for months after introduction of the parasite, this disease is quite dangerous. There are about 200,000 to 400,000 cases of visceral leishmaniasis in the world every year [1]. Leishmaniasis is quickly transmitted from person to person in sandy regions, which are hotspots for sandflies. (The disease may also be transferred through the sharing of needles, but this occurs in only a small minority of cases.) When a sandfly sucks the blood of an infected individual, it takes in the //Leishmania// and becomes a carrier of the disease. Leishmaniasis is transmitted when sandflies carrying the //Leishmania// parasite engage in a subsequent blood meal, injecting the young parasite, or promastigote, into the flesh wound of the human. Macrophages (immune cells) of the host engulf the //Leishmania// promastigote, which matures inside of the host cell and proceeds to infect other macrophages [2]. Eventually, in the case of visceral leishmaniasis, the parasites will spread to vital organs and cause significant damage. One particular aspect of the parasite’s membrane—the lipophosphoglycan coating—has proven especially advantageous to the parasite in preventing the macrophage from recognizing that it has been invaded. The coating interacts allows the parasite to thrive in the host without being detected and destroyed [3].
 * MOTIVATION AND BACKGROUND **:

A primary method of treatment for visceral leishmaniasis is the compound amphotericin B, which targets the cell membrane of the //Leishmania// parasite. More specifically, the drug binds to and inhibits ergosterol, a sterol that is a key component of many fungal and protozoan cell membranes. At 396.65 g/mol, ergosterol is crucial in maintaining the integrity of the //Leishmania// cell membrane, similar to the function of cholesterol in animal cells [4]. Once amphotericin B has binded to ergosterol, holes develop in the membrane, allowing key components of the cell, such as K+, Na+, H+, and Cl+ ions, to spill out [4]. In essence, it creates an ion channel unmediated by the cell itself. Additionally, ergosterol regulates endocytosis and cell signaling pathways, critical processes which are consequently inhibited by amphotericin B. The drug also induces oxidative burst, in which the macrophage produces several oxidative species that destroy the //Leishmania// [4]. Because ergosterol is not a component of animal cell membranes, human cells remain unscathed as the parasite is destroyed. Furthermore, as very little resistance has developed against the drug, amphotericin B has proven to be highly effective in treating leishmaniasis [5]. A an animated clip of amphotericin B's mechanism of action [12]: media type="custom" key="25133700" width="90" height="90"
 * TARGET INFORMATION **:

Amphotericin B was discovered by Charles E. Smith at the Squibb Institute in 1953 when it was extracted from the bacterium //Streptomyces nodosus// [6]. It was ultimately selected over nystatin and other amphotericins due to its relatively low toxicity and high efficacy. Today, it is produced largely by the company Gilead Sciences and is most commonly known as AmBisome, although its competitors include Fungizone, Fungilin, Abelcet, Amphocil, and Amphotec. The drug is currently patented and a total of thirteen clinical trials regarding its effectiveness in treating leishmaniasis have been completed; six more are currently in progress [7]. It is also one of the few FDA-approved leishmaniasis treatments. The primary method of delivery is via intravenous drip, as the drug does not absorb as well into the bloodstream if administered by mouth [4]. While incredibly effective, amphotericin B also carries a litany of potentially harmful side effects, largely due to the required delivery method of intravenous infusion. These include, but are not limited to: drowsiness, irregular heartbeat, muscle cramps, hypotension, nausea, vomiting, and diarrhea. Other, more serious side effects may be hypokalaemia (low potassium levels in the blood), thrombocytopenia (a decrease in platelet count), and decreased kidney or liver function [8]. Aside from brand competitors of AmBisome, alternatives to amphotericin B itself include sodium stibogluconate (also known as Pentostam), pentavalent antimonial compounds, and paromomycin. Pentostam is less effective and more prone to the development of resistance, while pentavalent antimonial compounds are not licensed for commercial use in the United States [8]. Finally, apart from serving as the primary treatment method for visceral leishmaniasis, amphotericin B is also a potent drug for the treatment of fungal infections such as //Cryptococcal// Meningitis and //Aspergillus// species due to the common presence of ergosterol in these species [8]. // Chemical formula: C47H73NO17 // // Molecular weight: 924.08 g/mol // // CAS number: 1397-89-3 //
 * DRUG INFORMATION: **

For more information on both cutaneous and visceral leishmaniasis, see this site.


 * REFERENCES: **

[1] Centers for Disease Control and Prevention. Parasites-Leishmaniasis. http://www.cdc.gov/parasites/leishmaniasis (accessed Jan 27, 2014). [2] C. G. Stark. MedScape. http://emedicine.medscape.com/article/220298-overview#a0199 (accessed Jan 27, 2014). [3] A. Dostalova, P. Volf, Leishmania development in sand flies: parasite-vector interactions overview. //Parasite Vectors// **2012**, 5, (276), 756-71. [4] Y.D. Paila, B. Saha, A. Chattopadhyay, Amphotericin B inhibits entry of Leishmania donovani into primary macrophages. //Biochem Biophys Res Commun// **2010**, 3, (399), 429-33. [5] K.C. Gray, D.S. Palacios, I. Dailey, M.M. Endo, B.E. Uno, B.C. Wilcock, M.D. Burke, Amphotericin primarily kills yeast by simply binding ergosterol. //PNAS// **2011**, 109, (7), 2234-39. [6] J.D. Dutcher, The discovery and development of amphotericin B. //Dis Chest// **1968**, 1, (54), 296-98. [7] ClinicalTrials.gov. http://clinicaltrials.gov/ct2/home (accessed Feb 2, 2014). [8] O.P. Smith, I.N. Hann, H. Cox, V. Novelli, Visceral leishmaniasis: rapid response to AmBisome treatment. //Arch Dis Child// **1995**, 73, (2), 157-59. [9] A.C. Mesa-Arango, L. Scorzoni, O. Zaragoza, It only takes one to do many jobs: Amphotericin B as antifungal and immunomodulatory drug. //Microbiol// **2012**, 3, (28), 103-109. [10] Pubchem. NCBI. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=8802 (accessed Feb 2, 2014). [11] Real Clear Science. http://www.realclearscience.com/lists/gut-wrenching_pictures_of_parasitic_diseases/visceral_leishmaniasis.html?state=stop (accessed Feb 17, 2014). [12] The Role of Amphotericin. Youtube. http://www.youtube.com/watch?v=H11LP48mbTI (accessed Feb 17, 2014).