Proguanil
Proguanil, also known as chlorguanide and chloroguanide, is a medication used to treat and prevent malaria. It is often used together with chloroquine or atovaquone. When used with chloroquine the combination will treat mild chloroquine resistant malaria. It is taken by mouth. Side effects include diarrhea, constipation, skin rashes, hair loss, and itchiness. Because malaria tends to be more severe in pregnancy, the benefit typically outweighs the risk. If used during pregnancy it should be taken with folate. It is likely safe for use during breastfeeding. Proguanil is converted by the liver to its active metabolite, cycloguanil. Proguanil has  been studied at least since 1945. It is on the World Health Organization's List of Essential Medicines. In the United States and Canada it is only available in combination as atovaquone/proguanil. Medical uses. Proguanil is used for the prevention and treatment of malaria in both adults and children, particularly in areas where chloroquine-resistant "P. falciparum" malaria has been reported. It is usually taken in combination with atovaquone, another antimalarial drug. It is also effective in the treatment of most other multi-drug resistant forms of "P. falciparum"; the success rate exceeds 93%. Side effects. Proguanil is generally  well tolerated, and most people do not experience side effects. However, common side effects include abdominal pain, nausea, headache, and fever. Taking proguanil with food may lessen these side effects. Proguanil should not be taken by people with severe renal impairment, pregnant women, or women who are breastfeeding children less than 5 kg. There have also been reports of increased levels of liver enzymes, which may remain high for up to 4 weeks after completion of treatment. Mechanism. When used alone, proguanil functions as a prodrug. Its active metabolite, cycloguanil, is an inhibitor of dihydrofolate reductase (DHFR). Although both mammals  and parasites produce DHFR, cycloguanil's inhibitory activity is specific for parasitic DHFR. This enzyme is a critical component of the folic acid cycle. Inhibition of DHFR prevents the parasite from recycling dihydrofolate back to tetrahydrofolate (THF). THF is required for DNA synthesis, amino acid synthesis, and methylation; thus, DHFR inhibition shuts down these processes. Proguanil displays synergism when used in combination with the antimalarial atovaquone. This mechanism of action differs from when proguanil was used as a singular agent. In this case, it is not thought to function as a DHFR inhibitor. The addition of proguanil has shown to  reduce resistance to atovaquone and increase the ability of atovaquone to trigger a mitochondrial apoptotic cascade. This is commonly referred to as "collapse of the mitochondrial membrane potential." Proguanil lowers the effective concentration of atovaquone needed to increase permeability of the mitochondrial membrane.