Development of Safer Drugs for Malaria in U.S. Troops, Civilian Personnel, and Travelers: Clinical Evaluation of Primaquine Enantiomers
Abstract
This project addresses the topic area of malaria, aiming to develop safer drugs that can be used for treatment, prevention, causal prophylaxis, and radical cure of relapsing vivax malaria. None of the existing approved antimalarial drugs, except primaquine (PQ), are effective for preventing relapses, which are caused by dormant stages of the parasite that hide in the liver. Because PQ is the only drug useful for relapsing malaria and is also effective for prophylaxis (prevention) of malaria, it is a very important drug. However, our ability to use the drug is limited because it causes blood toxicity (hemolytic anemia) in certain people with deficiency of an enzyme called glucose-6-phosphate dehydrogenase (G6PD). These deficient subjects comprise a large fraction of the population in some ethnic groups and in some geographic locations. For example, a significant fraction of African Americans in the US military are affected. Our studies in recent years have highlighted a possibility to make PQ safer in G6PD-deficient subjects. PQ s antimalarial effects are well known and doses well defined. The way PQ is manufactured results in a racemic mixture; it has equal amounts of "right-handed" and "left-handed" PQs. For 60 years it has been used this way. But evidence suggests that while both of these appear to work equally well to kill the malaria parasite in the liver of infected monkeys, one of them is more toxic than the other. So the idea for this proposal is to separate the two forms of PQ and to test the metabolism and toxicity of each of them in human volunteers. We have developed methods to easily separate the two forms. If initial studies suggest that one may be safer, they would then be carefully tested in G6PD-deficient subjects (mild forms of disease) at low doses to confirm whether they are safer in this population. Finally, if one form is confirmed to be safer in G6PD deficiency, it would be tested in malaria-infected patients to be sure that the safer form can still kill the parasites in humans. If this approach is successful, it will make immediately available a form of PQ that might be used in G6PD-deficient patients. In addition, the drug could be more readily used in public health programs without having to pretest patients to check for G6PD deficiency. This would be a great advantage for malaria eradication efforts and to the military for prophylaxis programs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510704
Entities
People
- Larry Walker
Organizations
- United States Army
- University of Mississippi