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Skip to 0 minutes and 11 seconds SIMON CROFT: We’ll describe each of the drugs used and their properties in the next slides. It’s important to note that all the drugs have limitations. Some require long courses. Some have well-defined toxicities and safety issues. And some are only used to treat visceral leishmaniasis in certain regions. All but one have to be given by injection. The following slides will give some background to each of the drugs listed here. You will see in here the terms effectiveness and efficacy used. They mean slightly different things. The efficacy of a drug, or its ability to produce a desired or intended result, is often achieved under ideal conditions– for example, in a clinical trial, where everything is optimised and controlled for.

Skip to 1 minute and 6 seconds The effectiveness of a drug is the measure of the amount of benefit that the drug has in a real world clinical setting. There are two commonly used antimonial drugs, sodium stiboglucomate, also known as Pentostam or SSG, and meglumine antimoniate, Glucantine. The former drug contains 33% to 34% antimony, and the latter, about 28% antimony. They’re used for treatment of both visceral and cutaneous leishmaniasis. Some points about their anti-leishmanial activity– these drugs are very active against amastigotes but only have low activity against promastigotes. There is a variation in the activity of antimonial drugs against different species of Leishmania. In vivo, they’re rapidly metabolised and excreted in the urine and are 90% out of the body within eight hours.

Skip to 2 minutes and 13 seconds In the Indian subcontinent, in particular in Bihar state, India, there’s been a 60% decrease in the effectiveness of antimonial treatments since the 1990s. This is caused by drug resistance. Because of this drug resistance, pentavalent antimonials are no longer used in the Indian subcontinent. But they are still effective and used for treatment of visceral leishmaniasis in East Africa. Sodium stiboglucomate and meglumine antimoniate have to be administered by injection. There is very poor oral absorption. The need for long courses of treatment, 28 to 30 days, relates to their poor pharmacokinetics. They are also known to have safety issues with cardiac and renal toxicities.

Skip to 3 minutes and 6 seconds The pentavalent antimonials need to be given parenterally. This means they need to be injected either intravenously or intramuscularly. Even then, the drug must be given daily for up to 30 days, as it is rapidly excreted, and time is needed for the drug to reach therapeutic levels in the liver, spleen, and bone marrow. During treatment, the heart and renal systems of the patient must be monitored, as these heavy metal drugs can cause acute and significant toxicity. Antimonials are still used in Latin America and East Africa to treat visceral leishmaniasis. However, it can be no longer used in South Asia due to drug resistance. Amphotericin B is a natural product, an antibiotic.

Skip to 3 minutes and 59 seconds It was originally developed for the treatment of fungal infections but has been used for the treatment of leishmaniasis since the 1960s. Some points about its anti-leishmanial activity. Amphotericin B is a very potent anti-leishmanial drug, killing both promastigotes and amastigotes at low nanomolar concentrations. Amphotericin B kills fungi and Leishmania by binding to ergosteral, a type of sterol found in the cell membrane of these cells but not in mammalian cells. It has a very small therapeutic window. That is the gap between the concentration that kills microbes and that which is toxic to mammalian cells.

Skip to 4 minutes and 52 seconds The traditional form of Amphotericin B, used for the treatment of VL, visceral leishmaniasis, is in a micellar suspension, Fungizone, as the drug has very poor water solubility. In treatment of VL patients, which we will talk about in the next step of the course, it will be administered by intravenous injection very slowly to avoid renal and other toxicities. As well as its low water solubility, Amphotericin B is poorly absorbed orally so has to be given intravenously. The first formulation, Fungizone, was a colloidal suspension with sodium deoxycholate. It binds strongly to plasma proteins and is slowly metabolised in the liver before being excreted via the urine. It has a half-life of 15 days.

Skip to 5 minutes and 51 seconds It must be given by very slow intravenous infusion in order to avoid adverse side effects. When resistance to antimonials was first reported in India, Fungizone was used to treat many visceral leishmaniasis cases. But more recently, since the 1990s, lipid formulations of Amphotericin B have been developed, which have now been used extensively to treat VL.

Skip to 6 minutes and 22 seconds The most widely used is AmBisome, a small, unilamellar lyposome, which has the drug incorporated into the lipid bilayer of the lipsosome. Not only do liposomes reduce toxicity, but they can also target the drug to the infected macrophages of the liver and spleen due to the way the body handles the drug after it has been injected. Over the past 10 years, AmBisome has been used extensively in India, Nepal, and Bangladesh to treat VL, with a more than 95% success rate. And it is the drug of choice for VL control and elimination programmes in the Indian subcontinent. However, AmBisome is less effective at successfully treating VL in East Africa, and we don’t yet understand the reasons why. Three– Miltefosine.

Skip to 7 minutes and 24 seconds Miltefosine is a synthetic phospholipid drug. It was shown to have anti-leishmanial efficacy at the same time as it was being developed as an anti-cancer drug in the 1980s. As an anti-leishmanial drug, Miltefosine is active in vitro against both promastigotes and intracellular amastigotes. It shows variation in activity against different Leishmania species. It has no one clear mechanism of action, though inhibition of phosphocholine synthesis is considered important. In animal models and humans, it can be administered orally, making it the only oral drug for leishmaniasis. However, it has well-defined toxicities and safety issues. In preclinical studies, it was shown to be teratogenic in some rodent models.

Skip to 8 minutes and 23 seconds Clinically, Miltefosine was shown to be effective in treating VL in adults and children in the late 1990s in India. It was adopted as the drug of choice for the Indian subcontinent VL Elimination Programme, from 2005 to 2014. Limitations of Miltefosine have been associated with A, long courses of treatment– as 28 days oral being required– and more relapses have been reported, possibly due to poor patient compliance. B– ensuring women of childbearing age take contraception during treatment and beyond. In addition, this oral drug has proved to be significantly less effective in treating VL in East Africa than in the Indian subcontinent. Paromomycin is a natural product, a fermentation product of Streptomyces rimosus.

Skip to 9 minutes and 27 seconds It’s an aminoglycoside antibiotic, like neomycin and gentamicin, and it suffers similar issues of renal and oto-toxicity. Paromomycin has very poor oral absorption and has to be injected.

Skip to 9 minutes and 45 seconds Interestingly, it’s also active against gut protozoa, for example Entamoeba and Giardia, for which oral formulations were developed. It was first shown to have anti-leishmanial activity in the 1960s, but it’s also known as Monomycin and Aminosidine. And although it is less potent than anti-leishmanial drugs in vitro, it’s been shown to be effective against visceral leishmaniasis in a series of clinical studies. There was over 95% cure rate in the VL study in India in the 2000s following 21 days of intramuscular administration. But this treatment has not been adopted in the Indian subcontinent. At the dose used in India, Paromomycin was significantly less effective in treating VL cases in East Africa.

Skip to 10 minutes and 43 seconds A clinical study in Sudan showed that a 17-day combination of Paromomycin plus sodium stibogluconate, a pentavalent antimonial, was effective for the treatment of VL, offering a slighter, shorter course of treatment. This is now the first line regimen in the region.

Treatment of VL: antileishmanial drugs

Which are the main therapeutic drugs used for the treatment of visceral leishmaniasis and PKDL?

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Control and Elimination of Visceral Leishmaniasis

London School of Hygiene & Tropical Medicine