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| ==Medical Therapy== | | ==Medical Therapy== |
| ===Acute Pharmacotherapy===
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| There are two common therapies containing [[antimony]] (known as [[pentavalent antimonials]]), [[meglumine antimoniate]] (''Glucantim''®) and [[sodium stibogluconate]] (''Pentostam''®). It is not completely understood how these drugs act against the parasite; they may disrupt its energy production or [[trypanothione]] metabolism. Unfortunately, in many parts of the world, the parasite has become resistant to antimony and for visceral or mucocutaneous leishmaniasis,<ref name="Soto2007">{{cite journal | author=Soto J, Toledo JT. | title=Oral miltefosine to treat new world cutaneous leishmaniasis | journal=Lancet Infect Dis | volume=7 | issue=1 | pages=7 }}</ref> but the level of resistance varies according to species.<ref>{{cite journal|author=Arevalo J, Ramirez L, Adaui V,''et al.''|title=Influence of Leishmania (Viannia) species on the response to antimonial treatment in patients with American tegumentary leishmaniasis|journal=J Infect Dis|year=2007|volume=195|pages=1846–51|doi=10.1086/518041}}</ref> [[Amphotericin]] is now the treatment of choice<ref>{{cite journal|journal=Clin Infect Dis|year=2007|volume=45|pages=556–561|title=Amphotericin B Treatment for Indian Visceral Leishmaniasis: Response to 15 Daily versus Alternate-Day Infusions|author=Sundar S, Chakravarty J, Rai VK, ''et al.''|url=http://www.journals.uchicago.edu/CID/journal/issues/v45n5/50485/brief/50485.abstract.html}}</ref>; failure of [[amphotericin|AmBisome]]® to treat visceral leishmaniasis (''Leishmania donovani'') has been reported in Sudan,<ref>{{cite journal | author=Mueller M, Ritmeijer K, Balasegaram M, Koummuki Y, Santana MR, Davidson R. | title=Unresponsiveness to AmBisome® in some Sudanese patients with kala-azar | journal=Trans R Soc Trop Med Hyg | year=2007 | volume=101 | issue=1 | pages=19–24 | doi=10.1016/j.trstmh.2006.02.005 }}</ref> but this failure may be related to host factors such as co-infection with [[human immunodeficiency virus|HIV]] or [[tuberculosis]] rather than parasite resistance. Hypoxanthine-guanine phosphoribosyl transferase (HGPRT; EC 2.4.2.8) is a central enzyme in the purine recycling pathway. Parasitic protozoa (Leishmania donovani) cannot synthesize purines de novo and utilize the salvage pathway to produce purine bases. Thus, this enzyme is targeted in drug discovery and development. The model of the monomeric L. donovani HGPRT showed that this enzyme is an α/β type protein with a PRTase type I folding pattern. Among all of the computationally screened compounds, pentamidine, 1,3-dinitroadamantane, acyclovir and analogs of acyclovir had higher binding affinities than the real substrate (guanosine monophosphate). Amino acids of HGPRT that are frequently involved in the binding of these compounds are Lys 66, Asp 74, Arg 77, Asp 81, Val 88, Tyr 182, Arg 192 and Arg 194. It is predicted that patients suffering from both HIV and visceral leishmaniasis (VL) may benefit if they are treated with acyclovir or pentamidine in conjunction with first-line antileishmanial therapies such as [[miltefosine]] and AmBisome.
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| [[Miltefosine]] (Impavido®), is a new drug for [[visceral]] and [[cutaneous]] leishmaniasis. The cure rate of miltefosine in phase III [[clinical trials]] is 95%; Studies in Ethiopia show that is also effective in Africa. In HIV immunosuppressed people who are coinfected with leishmaniasis it has shown that even in resistant cases 2/3 of the people responded to this new treatment. Clinical trials in Colombia showed a high efficacy for cutaneous leishmaniasis. In mucocutaneous cases caused by L.brasiliensis it has shown to be more effective than other drugs.
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| Miltefosine received approval by the Indian regulatory authorities in 2002 and in Germany in 2004. In 2005 it received the first approval for cutaneous leishmaniasis in Colombia. Miltefosine is also currently being investigated as treatment for mucocutaneous leishmaniasis caused by ''Leishmania braziliensis'' in Colombia,<ref name="Soto2007"/> and preliminary results are very promising. It is now registered in many countries and is the first orally administered breakthrough therapy for visceral and cutaneous leishmaniasis.<ref name="Jha1999">{{cite journal | author=Jha TK, Sundar S, Thakur CP ''et al.'' | title=Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis | year=1999 | journal=New Engl J Med | volume=341 | pages=1795–800 }}</ref>(More, ''et al'', 2003). In October 2006 it received [[orphan drug]] status from the US Food and Drug administration.
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| The drug is generally better tolerated than other drugs. Main side effects are gastrointetinal disturbance in the 1-2 days of treatment which does not affect the efficacy. Because it is available as an oral formulation, the expense and inconvenience of hospitalisation is avoided, which makes it an attractive alternative.
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| The antifungal drug, [[fluconazole]] 200 mg daily, has been shown to be significantly more effective in the treatment of cutaneous leishmaniasis compared to the placebo in a trial done in Saudi Arabia. In another randomized clinical trial from Iran, fluconazole 400 mg daily was shown to be significantly more effective than fluconazole 200 mg daily in the treatment of cutaneous leishmaniasis.<ref name="pmid21315963">{{cite journal| author=Emad M, Hayati F, Fallahzadeh MK, Namazi MR| title=Superior efficacy of oral fluconazole 400 mg daily versus oral fluconazole 200 mg daily in the treatment of cutaneous leishmania major infection: a randomized clinical trial. | journal=J Am Acad Dermatol | year= 2011 | volume= 64 | issue= 3 | pages= 606-8 | pmid=21315963 | doi=10.1016/j.jaad.2010.04.014 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21315963 }} </ref>
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| The Institute for OneWorld Health has developed [[paromomycin]], results with which led to its approval as an [[orphan drug]]. The [[Drugs for Neglected Diseases Initiative]] is also actively facilitating the search for novel therapeutics. A treatment with paromomycin will cost about $10. The drug had originally been identified in 1960s, but had been abandoned because it would not be profitable, as the disease mostly affects poor people.<ref>[http://www.nytimes.com/2006/07/31/health/31charity.html A Small Charity Takes the Reins in Fighting a Neglected Disease], ''[[New York Times]]'', July 31, 2006.</ref> The Indian government approved paromomycin for sale in August 2006.<ref>{{cite web| url = http://www.oneworldhealth.org/drug_program | title = Drug Program – Clinical Trial of Paramomycin | publisher = [[Institute for OneWorld Health]] | accessdate = 10 February 2011}}</ref> A 21-day course of paromomycin produces a definitive cure in >90% of patients with visceral leishmaniasis.<ref>{{Cite journal|author=Sundar S, Agrawal N, Arora R, ''et al.''|title=Short‐course paromomycin treatment of visceral leishmaniasis in India: 14‐day vs 21‐day treatment|journal=Clin Infect Dis|year=2009|volume=49|issue=6|pmid=19673613|pages=850–851|url=http://www.journals.uchicago.edu/doi/abs/10.1086/605438|doi=10.1086/605432}}</ref>
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| Drug-resistant leishmaniasis may respond to [[immunotherapy]] (inoculation with parasite antigens plus an [[adjuvant]]) which aims to stimulate the body's own immune system to kill the parasite.<ref>{{cite journal | author=Immunotherapy for Drug-Refractory Mucosal Leishmaniasis | author=Badaro R, Lobo I, Munõs A, ''et al.'' | journal=J Infect Dis | year=2006 | volume=194 | pages=1151–59 | title=Immunotherapy for drug-refractory mucosal leishmaniasis | url=http://www.journals.uchicago.edu/JID/journal/issues/v194n8/36472/brief/36472.abstract.html }}</ref>
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| ==References== | | ==References== |