Summary



The Drug Search for Leishmaniasis team has begun lab testing potential treatments for this serious—yet neglected—tropical disease. In this update, Dr. Carlos Muskus discusses the results of topical (on the skin) testing of four compounds.



Sandflies, such as the P. papatasi shown above, are responsible for the spread of leishmaniasis.

Background

Leishmaniasis is one of the most neglected tropical diseases in the world, infecting more than two million people in 98 countries. One form of the disease, caused by Leishmania infantum in America, mainly affects children, who can die if adequate treatment is not provided promptly. The classical treatments for all forms of Leishmaniasis can cause severe side effects, including death. Furthermore, drug resistant parasites are causing major problems in many endemic countries. For these reasons, there is an urgent need for new, safe, and inexpensive drug compounds.

Identifying Potential Compounds

After analyzing many compounds with the best docking score based on the data from the project on World Community Grid and our further testing, 10 compounds were finally selected to test in vitro. The in vitro evaluation involved cytotoxicity analysis against human-derived cell lines. (As part of the process of drug discovery, we do testing to ensure that the promising compounds do not affect human cells, thus decreasing the chance of side effects.) In addition, we evaluate the effectiveness of each compound against Leishmania, the parasites that cause leishmaniasis. The best compounds are those that kill the parasites at a low dose and do not affect the human cells even at higher doses.

Lab Testing of Potential Compounds

After in vitro testing, four compounds were selected to evaluate in vivo in hamsters. Hamsters and humans have similar reactions to leishmaniasis, so we can use hamsters to evaluate potential compounds.

Each compound was prepared as a topical formulation and applied daily for 10 days on the hamster's lesions. The hamsters were followed for two months. Groups of five hamsters per compound were used, and a summary of the compound, dose, and an outcome is presented in the table below. The different dosages used for each compound were selected based on the previous in vitro assays.

Compound Dose mg /day Results (%) 1107818 0,14 / 10 Improvement of the lesion between 11,1 - 15,7% 20287460 1,3 / 10 Cure in 2 out 5 hamsters and improvement between 18,9-44,2% 20312719 2,8 / 10 Improvement in 35,7% 20325767 0,6 / 10 Improvement between 18,9-66%

Improvement: Percentage of reduction of the lesion size.

Cure: Complete re-epithelization of the lesion.

For the four compounds, different degrees of improvement were observed. The compound Amb 20287460 induced an almost complete curing of the lesions in two out of five hamsters. The compound 20312719 decreased the size of the lesions to various degrees. The remaining two compounds only induced small decreases in lesion size.

Next Steps

We still have a small remaining quantity of one of the compounds that produced some of the best result in the in vitro assay, but unfortunately the company that provided it did not synthesize it in sufficient quantity. We plan to contact another company to order more of this compound.

In addition, we are planning to re-test the compound that induced a complete cure in two of five hamsters. In future tests, we will probably change the method of administration to injection or oral, and closely monitor the outcomes.

Thank you to everyone who supported this project. We will keep you updated on our progress.