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Miltefosine
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<h2 id="medical-uses">Medical uses</h2> <h3>Leishmaniasis</h3> <p>Miltefosine is primarily used for the treatment of <a href="/facts/Visceral_leishmaniasis/bu6ne799">visceral</a> and <a href="/facts/Cutaneous_leishmaniasis/xYoDBt9c">New World cutaneous leishmaniasis</a>, and is undergoing <a href="/facts/Clinical_trial/q8LMr832">clinical trials</a> for this use in several countries.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a><a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> This drug is now listed as a core medication for the treatment of leishmaniasis under the WHO Model List of Essential Medicines.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> Several medical agents have some efficacy against visceral or cutaneous leishmaniasis, however, a 2005 survey concluded that miltefosine is the only effective oral treatment for both forms of leishmaniasis.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p> <h3>Amoeba infections</h3> <p>Miltefosine has been used successfully in some cases of the very rare, but highly lethal, brain infection by the amoeba, <i><a href="/facts/Naegleria_fowleri/Mv4KVfbb">Naegleria fowleri</a></i>, acquired through water entering the nose during a plunge in contaminated water.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> It has orphan drug status in the United States for <a href="/facts/Acanthamoeba_keratitis/9PoVIrFl">acanthamoeba keratitis</a> and <a href="/facts/Primary_amebic_meningoencephalitis/Qdc1sc7T">primary amebic meningoencephalitis</a> (PAM).<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> </p> <h3>Pregnancy and breastfeeding</h3> <p>Miltefosine is listed as pregnancy category D by the FDA. This means there is evidence-based adverse reaction data from investigational or marketing experience or studies in humans of harm to the human fetus.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> Despite this evidence, the potential benefits of miltefosine may warrant use of the drug in pregnant women despite potential risks. A pregnancy test should be done prior to starting treatment. Effective <a href="/facts/Birth_control/qCzhxgH8">birth control</a> should be used while on miltefosine and 5 months after discontinuation of treatment. Its use during breast feeding is most likely unsafe.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> </p> <h2 id="contraindications">Contraindications</h2> <p>Miltefosine is contraindicated in individuals who have a <a href="/facts/Hypersensitivity/j2AWmqCD">hypersensitivity</a> to this medication, pregnant women, and people who have the <a href="/facts/Sj%C3%B6gren-Larsson_syndrome/zRjK5e5k">Sjögren-Larsson syndrome</a>.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> It is embryotoxic and fetotoxic in rats and rabbits, and <a href="/facts/Teratogenic/j4BN6lsB">teratogenic</a> in rats but not in rabbits. It is therefore contraindicated for use during pregnancy, and <a href="/facts/Contraception/qCzhxgH8">contraception</a> is required beyond the end of treatment in women of child-bearing age.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p> <h2 id="side-effects">Side effects</h2> <p>Common <a href="/facts/Adverse_drug_reaction/Ea0ktF6J">side effects</a> from miltefosine treatment are <a href="/facts/Nausea/dyhkcbeD">nausea</a> and <a href="/facts/Vomiting/R2vQkHqV">vomiting</a>, which occur in 60% of people. Other common side effects are dizziness, headache, and daytime sleepiness.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> </p><p>Serious side effects include rash, diarrhea, and arthritis.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> The side effects are more severe in women and young children. The overall effects are quite mild and easily reversed.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> </p> <h2 id="mechanism-of-action">Mechanism of action</h2> <p>Miltefosine primarily acts on <i>Leishmania</i> by affecting the species's promastigote and amastigote stages.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> Miltefosine exerts its activity by interacting with lipids, inhibiting <a href="/facts/Cytochrome_c_oxidase/U67QVCv8">cytochrome c oxidase</a> and causing apoptosis-like cell death.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> This may affect membrane integrity and mitochondrial function of the parasite. </p> <h2 id="history">History</h2> <h3>Cancer</h3> <p>While initially studied as a cancer medication, due to side effects it was never used for this purpose.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> </p><p><a href="/facts/Phospholipid/u6GhNCF5">Phospholipid</a> group <a href="/facts/Alkylphosphocholine/aNnsP1Wl">alkylphosphocholine</a> were known since the early 1980s, particularly in terms of their binding affinity with <a href="/facts/Cobra/s1NUltmX">cobra</a> venom.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> In 1987 the phospholipids were found to be potent toxins on <a href="/facts/Leukemic/WpEfW0Qh">leukemic cell culture</a>.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> Initial <i><a href="/facts/In_vivo/kWcWyl6f">in vivo</a></i> investigation on the <a href="/facts/Antineoplastic/fWTLbaUT">antineoplastic</a> activity showed positive result, but then only at high dosage and at high toxicity.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> At the same time in Germany, Hansjörg Eibl, at the <a href="/facts/Max_Planck_Institute_for_Biophysical_Chemistry/KB3qBk47">Max Planck Institute for Biophysical Chemistry</a>, and Clemens Unger, at the <a href="/facts/University_of_G%C3%B6ttingen/UTUodvX1">University of Göttingen</a>, demonstrated that the <a href="/facts/Antineoplastic/fWTLbaUT">antineoplastic activity</a> of the phospholipid analogue miltefosine (at the time known as hexadecylphosphocholine) was indeed tumour-specific. It was highly effective against <a href="/facts/Methylnitrosourea/9cLK2lf2">methylnitrosourea</a>-induced <a href="/facts/Mammary_carcinoma/6hME580v">mammary carcinoma</a>, but less so on <a href="/facts/Transplantable_organs_and_tissues/B4VP7rMM">transplantable</a> <a href="/facts/Mammary_carcinoma/6hME580v">mammary carcinomas</a> and <a href="/facts/Autochthon_(nature)/03kpM3rf">autochthonous</a> <a href="/facts/Benzo(a)pyrene/44vgzew5">benzo(a)pyrene</a>-induced <a href="/facts/Sarcoma/F5kKDAGx">sarcomas</a>, and relatively inactive on Walker 256 <a href="/facts/Carcinosarcoma/s0Mqa6L3">carcinosarcoma</a> and autochthonous acetoxymethylmethylnitrosamine-induced <a href="/facts/Colon_cancer/nV592sW7">colonic tumors</a> of rats.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> It was subsequently found that miltefosine was structurally unique among lipids having anticancer property in that it lacks the <a href="/facts/Glycerol/sRQ6NBQQ">glycerol</a> group, is highly selective on cell types and acts through different mechanism.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a><a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> </p> <h3>Leishmaniasis</h3> <p>In the same year as the discovery of the anticancer property, miltefosine was reported by S. L. Croft and his team at the <a href="/facts/London_School_of_Hygiene_and_Tropical_Medicine/RgroENaV">London School of Hygiene and Tropical Medicine</a> as having antileishmanial effect as well. The compound was effective against <i><a href="/facts/Leishmania_donovani/8kXHfcP8">Leishmania donovani</a></i> <a href="/facts/Amastigote/nQ7Ig4gh">amastigotes</a> in cultured mouse peritoneal <a href="/facts/Macrophage/z7hkQu3o">macrophages</a> at a dose of 12.8 mg/kg/day in a five-day course.<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> However, priority was given to the development of the compound for cutaneous <a href="/facts/Metastases/4dadbm6z">metastases</a> of <a href="/facts/Breast_cancer/6hME580v">breast cancer</a>. In 1992 a new research was reported in which the compound was highly effective in mouse against different <a href="/facts/Life_cycle_(biology)/1y28aNGG">life cycle stages</a> of different <i>Leishmania</i> species, and in fact, more potent than the conventional <a href="/facts/Sodium_stibogluconate/xU5BNKYU">sodium stibogluconate</a> therapy by a factor of more than 600.<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> Results of the first clinical trial in humans were reported from Indian patients with chronic leishmaniasis with high degree of success and safety.<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> This promising development promulgated a unique public–private partnership collaboration between <a href="/facts/Asta_Medica/5mQzURvL">ASTA Medica</a> (later Zentaris GmbH), the <a href="/facts/World_Health_Organization/YNN3bgug">World Health Organization</a> (WHO) Special Programme for Research and Training in Tropical Diseases, and the <a href="/facts/Government_of_India/BIpETqjv">Government of India</a>. Eventually, several successful Phase II and III trials led to the approval of miltefosine in 2002 as the first and only oral drug for leishmaniasis.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> </p> <h3><i>Naegleria fowleri</i> and <i>Acanthamoeba</i></h3> <p>In 2013, the US <a href="/facts/Centers_for_Disease_Control_and_Prevention/NmoJNDV5">Centers for Disease Control and Prevention</a> recommended miltefosine for the treatment of free-living amoeba infections such as <a href="/facts/Granulomatous_amoebic_encephalitis/GyL7ux1b">granulomatous amoebic encephalitis</a> and <a href="/facts/Primary_amoebic_meningoencephalitis/Qdc1sc7T">primary amoebic meningoencephalitis</a>, two fatal protozoal diseases.<a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a> Historically, only four survivors have been recorded out of 138 confirmed infections in North America. One American survived the infection in 1978 and one individual from Mexico in 2003. In 2013, two children survived and recovered from primary amoebic meningoencephalitis after treatment with miltefosine.<a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a><a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a> In 2016 after treatment that included miltefosine, another child became the fourth person in the United States to survive <i><a href="/facts/Naegleria_fowleri/Mv4KVfbb">Naegleria fowleri</a></i> infection.<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a> </p> <h2 id="society-and-culture">Society and culture</h2> <h3>Availability</h3> <p>Since 2017 Miltefosine is commercially available in the United States through Profounda.<a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a> Previously one could only get it from the <a href="/facts/Centers_for_Disease_Control_and_Prevention/NmoJNDV5">CDC</a> for emergency use under an expanded access <a href="/facts/Investigational_New_Drug/GTHo92ee">IND</a> protocol for treatment of free-living amoeba (FLA) infections: <a href="/facts/Primary_amoebic_meningoencephalitis/Qdc1sc7T">primary amoebic meningoencephalitis</a> caused by <i><a href="/facts/Naegleria_fowleri/Mv4KVfbb">Naegleria fowleri</a></i> and granulomatous amoebic encephalitis caused by <i><a href="/facts/Balamuthia_mandrillaris/9U83RU8f">Balamuthia mandrillaris</a></i> and <i><a href="/facts/Acanthamoeba/vgedK72K">Acanthamoeba</a></i> species.<a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> Miltefosine is almost exclusively produced by Profounda, a private pharmaceutical company.<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> </p> <h3>Economics</h3> <p>In the <a href="/facts/Developing_world/eTfS4kxl">developing world</a> a course of treatment costs US$65 to $150.<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a> In the <a href="/facts/Developed_world/sqwTSDHm">developed world</a> treatment may be 10 to 50 times greater.<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> </p> <h2 id="further-research">Further research</h2> <p>It is active against some <a href="/facts/Bacteria/wC8xSCsU">bacteria</a> and <a href="/facts/Fungi/BHo5DP59">fungi</a>,<a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a><a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a> as well as human <a href="/facts/Trematode/d3J87oDn">trematode</a> <i><a href="/facts/Schistosoma_mansoni/c49TWF1V">Schistosoma mansoni</a></i> and the snail that spreads it <i><a href="/facts/Biomphalaria_alexandrina/vwLEV0P1">Biomphalaria alexandrina</a></i>.<a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a> </p> <h3>Antiprotozoal and antifungal activities</h3> <p>Miltefosine is being investigated by researchers interested in finding treatments for infections which have become resistant to existing drugs. Animal and <i><a href="/facts/In_vitro/evp3hAX6">in vitro</a></i> studies suggest it may have broad anti-protozoal and anti-fungal properties: </p> <ul><li>Animal studies suggest miltefosine may also be effective against <i><a href="/facts/Trypanosoma_cruzi/T9N2Bojt">Trypanosoma cruzi</a></i>, the <a href="/facts/Parasite/HWPcgky7">parasite</a> responsible for <a href="/facts/Chagas%27_disease/C7rKMw5A">Chagas' disease</a>.<a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a></li> <li>Several studies have found the drug to be effective against types of fungus: <i><a href="/facts/Cryptococcus_neoformans/QdwgHGn1">Cryptococcus neoformans</a></i>, <i><a href="/facts/Candida_(genus)/IIYvWvx5">Candida</a></i>, <i><a href="/facts/Aspergillus/pKhecLTW">Aspergillus</a></i> and <i><a href="/facts/Fusarium/mMNDJycW">Fusarium</a></i>.<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a></li> <li>A 2006 <i>in vitro</i> study found that miltefosine is effective against metronidazole-resistant variants of <i><a href="/facts/Trichomonas_vaginalis/BeNyMqnj">Trichomonas vaginalis</a></i>, a sexually transmitted protozoal disease.<a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a></li> <li><a href="/facts/Cetrimonium_bromide/dwKNX6Ky">Cetrimonium bromide</a>, a compound related to miltefosine, was demonstrated in 2007 to exhibit potent <i>in vitro</i> activity against <i><a href="/facts/Plasmodium_falciparum/V8xzgHh0">Plasmodium falciparum</a></i>.<a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a></li> <li>An <i>in vitro</i> test in 2006 showed that miltefosine is effective against the deadly protozoan pathogens, <i>Naegleria fowleri</i>, <i>Balamuthia mandrillaris</i>, and <i>Acanthamoeba</i>.<a class="footnote-ref" id="fnref:57" href="#fn:57"><sup>57</sup></a> However, later <i>in vitro</i> and animal model experiments showed that it is not as potent as other drugs, such as <a href="/facts/Chlorpromazine/oFja1FYA">chlorpromazine</a><a class="footnote-ref" id="fnref:58" href="#fn:58"><sup>58</sup></a> and <a href="/facts/Diminazene_aceturate/HBJnqqhB">diminazene aceturate</a> (Berenil).<a class="footnote-ref" id="fnref:59" href="#fn:59"><sup>59</sup></a></li> <li>In 2013, there were reports of failure of miltefosine in the treatment of leishmaniasis.<a class="footnote-ref" id="fnref:60" href="#fn:60"><sup>60</sup></a><a class="footnote-ref" id="fnref:61" href="#fn:61"><sup>61</sup></a> Although <a href="/facts/Drug_resistance/cgLruXm6">drug resistance</a> was suspected, studies in 2014 reported that miltefosine is not so effective in children, most probably related to a lack of drug exposure in children.<a class="footnote-ref" id="fnref:62" href="#fn:62"><sup>62</sup></a> Moverover, males appeared to have a higher probability of relapse as well.<a class="footnote-ref" id="fnref:63" href="#fn:63"><sup>63</sup></a></li> <li>A 2012 <i>in vitro</i> study found that miltefosine had promising activity against <i><a href="/facts/Candida_albicans/7o27aEFS">Candida albicans</a></i> <a href="/facts/Biofilm/zg93x2w4">biofilms</a>.<a class="footnote-ref" id="fnref:64" href="#fn:64"><sup>64</sup></a></li></ul> <h3>Anti-HIV activity</h3> <p>Miltefosine targets HIV infected <a href="/facts/Macrophages/z7hkQu3o">macrophages</a>, which play a role <a href="/facts/In_vivo/kWcWyl6f">in vivo</a> as long-lived HIV-1 reservoirs. The HIV protein <a href="/facts/Structure_and_genome_of_HIV/YV9J3pku">Tat</a> activates pro-survival <a href="/facts/PI3K/e5rtq0VG">PI3K</a>/<a href="/facts/Akt/odL6duk1">Akt</a> pathway in primary human macrophages. Miltefosine acts by inhibiting the <a href="/facts/PI3K/AKT/mTOR_pathway/bgWlgxQJ">PI3K/Akt pathway</a>, thus removing the infected macrophages from circulation, without affecting healthy cells.<a class="footnote-ref" id="fnref:65" href="#fn:65"><sup>65</sup></a><a class="footnote-ref" id="fnref:66" href="#fn:66"><sup>66</sup></a> It significantly reduces replication of HIV-1 in cocultures of human <a href="/facts/Dendritic_cell/19KBuKFK">dendritic cells</a> (DCs) and <a href="/facts/CD4(%2B)_T_cell/nhwAYkDj">CD4+ T cells</a>, which is due to a rapid secretion of soluble factors and is associated with induction of type-I <a href="/facts/Interferon/63XfwpEh">interferon</a> (IFN) in the human cells.<a class="footnote-ref" id="fnref:67" href="#fn:67"><sup>67</sup></a> </p> <h2 id="external-links">External links</h2> <ul><li><a href="https://druginfo.nlm.nih.gov/drugportal/name/miltefosine">"Miltefosine"</a>. <i>Drug Information Portal</i>. U.S. National Library of Medicine.</li> <li><a href="https://www.drugs.com/international/miltefosine.html">"Miltefosine"</a>. <i>Drugs.com</i>.</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>American Society of Health-System Pharmacists (26 February 2016). "Miltefosine Monograph for Professionals". www.drugs.com. Archived from the original on 17 November 2016. Retrieved 16 November 2016. <a href="https://www.drugs.com/monograph/miltefosine.html" target="_blank">https://www.drugs.com/monograph/miltefosine.html</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>"FDA approves Impavido to treat tropical disease leishmaniasis". U.S. Food and Drug Administration (FDA) (Press release). 19 March 2014. Archived from the original on 3 September 2014. Retrieved 30 August 2014. <a href="https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm389671.htm" target="_blank">https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm389671.htm</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>World Health Organization (March 2010). Control of the leishmaniasis: report of a meeting of the WHO Expert Committee on the Control of Leishmaniases. World Health Organization. pp. 59, 88, 186. hdl:10665/44412. ISBN 978-92-4-120949-6. <a href="978-92-4-120949-6" target="_blank">978-92-4-120949-6</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>"FDA approves Impavido to treat tropical disease leishmaniasis". U.S. Food and Drug Administration (FDA) (Press release). 19 March 2014. Archived from the original on 3 September 2014. Retrieved 30 August 2014. <a href="https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm389671.htm" target="_blank">https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm389671.htm</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>American Society of Health-System Pharmacists (26 February 2016). "Miltefosine Monograph for Professionals". www.drugs.com. Archived from the original on 17 November 2016. Retrieved 16 November 2016. <a href="https://www.drugs.com/monograph/miltefosine.html" target="_blank">https://www.drugs.com/monograph/miltefosine.html</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>American Society of Health-System Pharmacists (26 February 2016). "Miltefosine Monograph for Professionals". www.drugs.com. Archived from the original on 17 November 2016. Retrieved 16 November 2016. <a href="https://www.drugs.com/monograph/miltefosine.html" target="_blank">https://www.drugs.com/monograph/miltefosine.html</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>American Society of Health-System Pharmacists (26 February 2016). "Miltefosine Monograph for Professionals". www.drugs.com. Archived from the original on 17 November 2016. Retrieved 16 November 2016. <a href="https://www.drugs.com/monograph/miltefosine.html" target="_blank">https://www.drugs.com/monograph/miltefosine.html</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>American Society of Health-System Pharmacists (26 February 2016). "Miltefosine Monograph for Professionals". www.drugs.com. Archived from the original on 17 November 2016. 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