Side Effects of Treatment

1) Pentavalent Antimonials – Serious cardiotoxicity is seen in 9-10% of patients. Other side effects are reversible renal insufficiency, pancreatitis, anemia, leukopenia, rash, headache, abdominal pain, nausea, vomiting, arthralgia, myalgia, thrombocytopenia, and transaminase elevation. Effectiveness of treatment increases with longer courses of treatment, however incidence of side effects does as well.

2) Amphotericin B – Infusion-related adverse events can occur with amphotericin B deoxycholate. Toxicities which can be seen are hypokalemia, nephrotoxicity and myocarditis. Liposomal amphotericin B is much safer, with fewer side effects.

3) Miltefosine – Gastrointestinal side effects are the most common and include vomiting. Transient elevation of hepatic enzymes has been observed. The drug is highly teratogenic and as such is contraindicated in pregnant patients and mandatory contraception is recommended for women of child-bearing age through treatment and 2-3 months after.

4) Paromycin – Injection-site pain was the most frequently reported side effect in one study done in India. Ototoxicity and nephrotoxicity are side effects that are common in aminoglycoside antibiotics, however frequency at therapeutic doses is low. Monitoring of hepatic enzymes has been recommended.

5) Pentamidine – The major side effect of pentamidine use is induction of insulin-dependent diabetes mellitus. It a major concern and one of the reasons it is a second line treatment. Other side effects include nausea, vomiting, abdominal pain, and headache.

For more information:

www.cdc.gov

www.rxlist.com

Seifert, K., (2011). Structures, targets and recent approaches in anti-leishmanial drug discovery and development. The Open Medical Chemistry Journal, (5), 31-39.

Distribution Maps from WHO

Geographical distribution of visceral leishmaniasis in the Old and New world

Geographical distribution of cutaneous and mucocutaneous leishmaniasis in the New World

maps from: http://www.who.int/leishmaniasis/leishmaniasis_maps/en/index1.html

Treatment

Since many of those infected with visceral leishmaniasis live in poor, rural areas, availability and cost can significantly limit treatment options. There are several categories of drugs used to treat VL.

1) Pentavalent Antimonials – Includes meglumine antimonite and sodium stibogluconate. These drugs have been used for many years and are still highly effective for previously untreated VL patients. Since they have been a first line treatment for over 60 years resistance has developed in endemic regions. Dosing recommended by the CDC is 20 mg/kg/day of antimony IV or IM for 28-30 days.

2) Amphotericin B – Amphotericin B deoxycholate is an antibiotic that is highly effective and is used as first line treatment where resistance has developed to antimonials and as a second line choice in other areas. The CDC recommends a regimen of 0.75 – 1.0 mg/kg daily for 15-20 days or 0.75-1.0 mg/kg every other day for 30-40 days. A liposomal form of amphotericin B (AmBisome) has been developed and approved for treatment of VL by the FDA and appears to be an effective and simpler alternative. The recommended dose of AmBisome is 3 mg/kg QD on days 1-5, 14 and 21 (total dose of 21 mg/kg). A single dose of 10 mg/kg has been tested and shown to be comparable and less expensive as a treatment option. Cost can be a limiting factor as patients need to be hospitalized and monitored during treatment using Amphotericin B deoxycholate and liposomal amphotericin B (AmBisome) costs around $20 per 50mg vial.

3) Miltefosine – This drug is an alkylphosphocholine and was the first oral anti-leishmanial drug available. Miltefosine (Impavido) is registered to treat VL in India and Germany and in some clinical trials has a cure rate of up to 95%. It is not approved for treatment of leishmaniasis in the United States and as such the CDC has no recommendations for proper doses and treatment regimens.

4) Paromycin – This aminoglycoside antibiotic is another newer anti-leishmanial drug which is registered in India for treatment of VL but not in the United States. A course of 11 mg/kg/day for 21 days was shown to have a cure rate of 92%.

5) Pentamidine – This drug is an aromatic diamidine. It is not often used due to toxicity and side effect issues. It is a second line treatment but is rarely used.

6) Drugs currently being developed – 2-Substituted Quinolines have been shown to be effective in treating new world cutaneious leishmaniasis. 8-Aminoquinolines, such as Sitamaquine, is being developed for oral treatment of VL. Buparvaquone is currently marketed as Butalex for treatment of theileriosis in cattle but has been shown to be highly effective against L. donovani in vitro.  

For more information:

www.CDC.gov

Seifert, K., (2011). Structures, targets and recent approaches in anti-leishmanial drug discovery and development. The Open Medical Chemistry Journal, (5), 31-39.