Introduction to Miltefosine
For decades, leishmaniasis treatment primarily involved injectable therapies. The introduction of miltefosine, initially an anticancer agent, provided the first oral option, enhancing patient access and convenience. Approved in India in 2002 and the U.S. in 2014, oral miltefosine (Impavido) is effective against specific types of visceral (VL), cutaneous (CL), and mucocutaneous (ML) leishmaniasis.
How Miltefosine Works Against Leishmania
Miltefosine, an alkyl phospholipid and synthetic phosphatidylcholine analog, works by disrupting the Leishmania parasite's cellular functions through multiple mechanisms. It interferes with lipid metabolism by integrating into the parasite's cell membranes, which disrupts lipid synthesis and membrane function. The drug also induces an apoptosis-like cell death and can disrupt calcium homeostasis by affecting calcium channels and acidocalcisomes, leading to a damaging increase in intracellular calcium.
Therapeutic Uses and Efficacy
Miltefosine is used for various forms of leishmaniasis, but its efficacy is influenced by the Leishmania species and geographical area.
Visceral Leishmaniasis (VL)
In the Indian subcontinent, initial high cure rates for VL caused by L. donovani have declined, with increased treatment failures and emerging resistance. Efficacy varies in other regions, showing moderate success in East Africa and less clear results in the Mediterranean and Latin America.
Cutaneous Leishmaniasis (CL)
Miltefosine shows variable efficacy against New World CL species, with high cure rates reported for L. panamensis in Colombia, but lower rates for L. braziliensis. Promising results have also been seen for Old World CL caused by L. major in Iran.
Mucocutaneous Leishmaniasis (ML)
Miltefosine has been used for New World ML, with longer treatment courses potentially improving cure rates in studies from Bolivia.
Administration and Side Effects
Miltefosine is administered orally. Taking it with food helps reduce common gastrointestinal side effects like nausea, vomiting, diarrhea, and abdominal pain, which are typically mild and transient. Rare, transient elevations in liver enzymes and creatinine can occur. Miltefosine is teratogenic and strictly contraindicated in pregnancy. Women of child-bearing potential must use effective contraception during treatment and for several months afterward.
Oral Miltefosine vs. Other Systemic Leishmaniasis Treatments
| Feature | Oral Miltefosine | Parenteral Antimonials (e.g., SSG) | Liposomal Amphotericin B (L-AmB) |
|---|---|---|---|
| Administration | Oral capsules | Intramuscular or intravenous injection | Intravenous infusion |
| Convenience | High (outpatient possible) | Low (requires daily injections and medical supervision) | Low (requires infusion and medical supervision) |
| Duration | Shorter course (e.g., ) or single high dose | ||
| Common Side Effects | Gastrointestinal upset (nausea, vomiting, diarrhea), mild liver/kidney changes | Cardiotoxicity, arthralgia, myalgia, pancreatitis | Infusion-related fever and chills, nephrotoxicity |
| Toxicity | Teratogenic (contraindicated in pregnancy) | Significant, especially cardiotoxicity | Lower than conventional Amphotericin B, but still a concern |
| Cost | Generally more accessible than L-AmB, but can still be high | Relatively inexpensive, but resistance is an issue | Very high, limiting availability in many endemic areas |
Alternatives, Combination Therapies, and Future Directions
Due to limitations like decreasing efficacy, particularly in certain regions, alternatives and combination therapies are important. Effective parenteral drugs like liposomal amphotericin B remain crucial. Combination treatments, such as miltefosine with paromomycin, are being investigated to shorten treatment and address resistance. Research continues to find new, safer, and more effective oral leishmaniasis treatments.
Conclusion
Miltefosine is the primary oral drug for leishmaniasis. As the first effective oral treatment, it has improved patient care by allowing outpatient management and increasing access to therapy for visceral, cutaneous, and mucocutaneous forms. However, considerations include its regional efficacy, potential side effects, and the critical contraindication in pregnancy. Effective management requires accurate diagnosis, parasite species identification, and close monitoring to ensure successful treatment and reduce resistance risk. Learn more about leishmaniasis treatment from the CDC.
