Histoplasmosis+Sp14


 * DISEASE/DRUG OF INTEREST: **


 * Histoplasmosis/Amphotericin B **


 * MOTIVATION AND BACKGROUND: **

Histoplasmosis is an infectious disease caused by the spores of the fungus //Histoplasma capsulatum//. It was first noted a little over a century ago by an American physician named Samuel Darling who was working in the Panama Canal Zone [1]. //H. capsulatum// can be found throughout the entire world, but is most commonly found in North and Central America. More specifically, //H. capsulatum// is most prevalent in the Ohio River and Mississippi Valley regions of the United States [1]. The fungus //H. capsulatum// grows optimally in soil rich in organic material such as decaying bat guano and bird droppings [1]. Commercial construction, cleanup projects, and excavations have the potential to release these spores from the soil, causing them to become airborne. Once airborne, the infectious agent can then be inhaled, making its way into the lungs where it settles into the alveoli, tiny membranous sacs where gas diffusion occurs. While the disease primarily affects the lungs, the spores can be taken up by macrophages which can then potentially spread the disease around the body to other organ systems [5]. Farmers, landscapers, gardeners, construction workers, and those who are immunocompromised, such as HIV or AIDS patients, are far more likely to contract the disease. Generally speaking, though, histoplasmosis remains a relatively rare disease.

Primarily affecting the lungs, one of the major complications caused by histoplasmosis is acute respiratory distress syndrome [1]. This condition prevents enough oxygen from getting to the lungs and the bloodstream. Once in the lungs, transported by macrophages, the disease has the potential to affect other organs including the kidneys, liver, brain, and heart. Most individuals affected with this disease, however, will never develop symptoms and will remain completely unaware that they are even infected [1]. Individuals with a healthy immune system generally have the ability to fight off the infection without the need for hospitalization and antifungal medication. If the disease does become severe, symptoms will generally present themselves within 3 to 17 days after exposure [5]. Acute histoplasmosis is often characterized by nonspecific respiratory symptoms which are often similar to a cough or the flu. If the disease becomes severe enough a person may experience symptoms such as fever, chills, headaches, muscle aches, a dry cough, and chest discomfort. If the disease becomes disseminated, meaning it spreads to the entire body, histoplasmosis can cause heart complications, adrenal insufficiency, and even meningitis. Untreated disseminated histoplasmosis is generally fatal [5].




 * TARGET INFORMATION: **

In severe cases, a drug called Amphotericin B is administered to treat histoplasmosis. This drug works by targeting a protein in the  fungus H. capsulatum called ergosterol [2]. Ergosterol is a component of the fungal cell membrane. It has a molecular formula of C28H44O and a molecular weight of 396.65 g/mol. It is closely related to and serves a similar function as cholesterol in the animal cell membrane. It is also a precursor to vitamin D2 when broken down by ultraviolet light. Because it is found only in fungal cell membranes and not animal cell membranes, it makes an ideal target for drugs such as Amphotericin  B [2].




 * DRUG INFORMATION: **[[image:vdsstream/TylerAmphotericinB.gif width="361" height="271" align="right" caption="Figure 3: Amphotericin B molecule"]]

 The drug Amphotericin B was originally extracted from the bacterium Streptomyces nodosus in 1955 at the Squibb Institute for Medical Research [1]. Amphotericin B has a molecular formula of C47H73NO17 and a molecular weight of 924.08 g/mol. Amphotericin B effectively treats histoplasmosis by physically binding with the plasma membrane protein ergosterol [2]. This interaction between drug and target creates a polar pore through which ions, such as K+, Na+, H+, and Cl-, can leak out of the cell. Without these essential ions, the fungal cells can no longer function and will eventually die [2]. Amphotericin B can only be administered as an intramuscular injection or intravenously [2]. Unfortunately, Amphotericin B is often used as a last resort in treating severe cases of histoplasmosis [2]. The drug has potentially lethal side effects which can include hepatotoxicity, nephrotoxicity, serious cardiac arrhythmias, and ardiac failure [2]. Amphotericin B is patented and is marketed under the brand names Amphocin and Fungizone and manufactured by Astellas pharma US inc. [5]. In my research, I was only able to find one specific clinical trial in which Amphotericin B was used to treat histoplasmosis [4]. Because of its potentially lethal side effects, other drugs such as Itraconazole are often used as a substitute for or in conjunction with Amphotericin B. It is often believed that the use of traconazole before the use of Amphotericin B helps to provide a safer and more effective treatment of histoplasmosis [4]. Amphotericin B is also used as a drug of last resort in treating other various systemic fungal infections as well as parasitic protozoan infections which do not respond to other, safer alternatives [4].

**A view of histoplasmosis in the lungs**

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 * REFERENCES: **

[1] Kauffman, Carol A., Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev 2007, 20, (1), 115-132.

[2] Laniado-Laborin, R.; Cabrales-Vargas, MM., Amphotericin B: side effects and toxicity. Rev Iberoam Micol 2009, 26, (4), 223-227.

[3] Histoplasmosis Statistics. . (accessed 02/02/2014).

[4] Janssen, LP. Randomized, Open, Comparative Multicenter Study if Initial Treatment with Intravenous Itraconazole Versus Amphotericin B Followed by Consolidation Treatment With Itraconazole Capsules in Patients with Blastomycosis or Histoplasmosis. <http://www.clinicaltrials.gov/ct2/show/NCT00002159?term=amphotericin B histoplasmosis&rank=1>. (accessed 02/02/2014).

[5] Histoplasmosis. <http://www.mayoclinic.org/diseases-conditions/histoplasmosis/basics/definition/con-20026585>. (accessed 02/02/2014).

<span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif; font-size: 150%;">Think you have histoplasmosis? Check out these websites for more information. <span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif; font-size: 150%;">Mayo Clinic - http://www.mayoclinic.org/diseases-conditions/histoplasmosis/basics/definition/con-20026585 <span style="font-family: 'Palatino Linotype','Book Antiqua',Palatino,serif; font-size: 150%;">Centers for Disease Control and Prevention - http://www.cdc.gov/fungal/histoplasmosis/