The pharmacological basis of anti-malarial therapeutics

As we move into module 2 , "Chemotherapy and Resistance", we shift our focus from prophylaxis (prevention) to therapeutics (treatment). Chemotherapy, which is the use of chemical substances for therapy, against malaria is primarily available in the form of antiprotozoal drugs and anti-vector drugs (insecticides). This post will primarily focus on the drugs available and on resistance mechanisms.

There are three major classes of drugs that are clinically useful. Class I agents are used to treat or prevent clinically symptomatic malaria, but are not reliable against primary or latent liver stages or P.falciparum gametocytes.

Class II agents can target the asexual erythrocytic and the primary liver stages.

Class III agent can kill primary and latent liver stages as well as gametocytes.

The drugs are summarized below :

The timeline of drugs used against malaria, their introduction and establishment of resistance have been summarized (click to enlarge):

Current status :

Congeners of Chloroquine have been developed , which seem to be effective against chloroquine-resistant Plasmodium species. The antifolate drug combination (sulfadoxine and pyrimethamine) are still used in preventative therapy. Atovaquone and proguanil have recently also been used for prevention. Artemisinin and its derivatives form the core therapy primarily because of their speed of action, their efficacy against chloroquine-resistant Plasmodium and the additional effect of reducing transmission.
Drugs efficacious against P.falciparum is assumed to be effective against all the other Plasmodium species. However, the hypnozoite form of P.vivax can only be killed by treatment with primaquine.
Many other drugs and combinations are in clinical development. Example : NITD609, which is a spiroindolone that attacks the Na-ATPase PfATP4 is in Phase II trial.


Resistance mechanisms of  Plamodium sps :

These have been summarized :

Abbreviations: PfCRT: P. falciparum chloroquine resistance transporter; PfMDR1: P. falciparum multidrug resistance transporter 1; PfMRP: P. falciparum multidrug resistance protein; CQ: chloroquine; AQ: amodiaquine; MQ: mefloquine; LM: lumefantrine; ART: artemisinin (and derivatives); KO: knock-out; RBC: red blood cell; P: parasite; DV: digestive vacuole.



References :

Ines Petersen, Richard Eastman, Michael Lanzer, Drug-resistant malaria: Molecular mechanisms and implications for public health, FEBS Letters, Volume 585, Issue 11, 6 June 2011, Pages 1551-1562