Compounds that treat malaria and prevent malaria transmission
Inventors
Su, Xin-Zhuan • Yuan, Jing • Raj, Dipak • Pattaradilokrat, Sittiporn • Johnson, Ron • Huang, Ruili
Assignees
US Department of Health and Human Services
Publication Number
US-9375424-B2
Publication Date
2016-06-28
Expiration Date
2030-08-27
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Abstract
The invention provides methods and compounds for the treatment and prevention of malaria infection and transmission in a mammal by administering compounds of the invention to a mammal having or suspected of having a malaria infection. The invention also provides pharmaceutical compositions that can kill or arrest the growth of Plasmodium organisms, and especially Plasmodium falciparum, thereby preventing or blocking transmission of malaria as well as treating malaria infection.
Core Innovation
The invention provides methods and compounds for the treatment and prevention of malaria infection and transmission in a mammal by administering compounds of the invention to a mammal having or suspected of having a malaria infection. The invention includes pharmaceutical compositions that can kill or arrest the growth of Plasmodium organisms, especially Plasmodium falciparum, thereby preventing or blocking transmission of malaria as well as treating malaria infection.
Malaria, caused by Plasmodium falciparum, has a complex lifecycle involving intracellular and extracellular stages in humans and mosquitoes. There is no vaccine currently available, and there is growing resistance to existing antimalarial drugs. Only primaquine is used to kill non-erythrocytic stages but has serious side effects and potential resistance concerns.
Thus, the problem being solved is the urgent need for new malarial drugs that effectively treat non-erythrocytic stages such as gametocytes and liver stages, to disrupt the infectious cycle, prevent transmission between individuals, and eradicate infection before the erythrocytic stage develops.
The invention identifies compounds effective in the treatment and prevention of malaria transmission by using quantitative high-throughput screening integrated with genetic mapping. These compounds kill or arrest growth of Plasmodium, including in non-erythrocytic stages, and can be used alone or in combination with other antimalarial drugs to treat or prevent malaria infection and block transmission of the parasite.
Claims Coverage
The patent contains one independent claim focused on a method of blocking transmission of Plasmodium parasites using specific drug administration regimens.
Method of blocking Plasmodium transmission by administering artemisinin and ketotifen
A method of preventing or slowing transmission of Plasmodium between mammals by blocking oocyst formation and transmission by administering artemisinin together with one or two doses of ketotifen at doses between 0.1 mg/kg and 0.5 mg/kg to a mammal infected with or suspected of malaria infection.
Use of additional therapeutically effective antimalarial drugs in combination
The method may further comprise administering a therapeutically effective amount of at least one selected from artesunate, artemether, dihydroartemisinin, lumefantrine, amodiaquine, mefloquine, sulfadoxine, and pyrimethamine alongside artemisinin and ketotifen.
Specific ketotifen dosing regimens
Administration of ketotifen as a single dose or as two doses, including specific dose amounts of 0.5 mg/kg, alone or in combination with the other drugs.
Specific artemisinin dosing
Artemisinin is administered at a dose of 5 mg/kg in combination with ketotifen as described.
The claims focus on the inventive combination treatment method to prevent or slow Plasmodium transmission between mammals by using artemisinin combined with low doses of ketotifen, optionally with additional antimalarial drugs, specifying dosing regimens to block oocyst formation and malaria transmission effectively.
Stated Advantages
Compounds of the invention effectively kill or arrest Plasmodium growth in non-erythrocytic stages, thereby blocking malaria transmission.
The compounds can be used in combination with existing antimalarial drugs to treat both erythrocytic and non-erythrocytic stages, improving overall treatment efficacy.
Ketotifen and related compounds achieve substantial reduction or near elimination of oocyst formation at doses significantly lower than primaquine, a known gametocytocidal drug.
Documented Applications
Treatment of malaria infection in mammals by administering compounds that kill Plasmodium organisms, including non-erythrocytic stages.
Prevention of malaria infection by blocking transmission through killing Plasmodium gametocytes and inhibiting oocyst formation in mosquitoes.
Use of pharmaceutical compositions containing the compounds for prophylaxis or therapeutic use in mammals.
Combination therapy involving compounds of the invention with artemisinin compounds and third antimalarial drugs to treat and prevent malaria and its transmission.
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