Proguanil, also known as chlorguanide and chloroguanide, is a

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...

used to treat and prevent

malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...

. It is often used together with

chloroquine Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medi ...

atovaquone Atovaquone, sold under the brand name Mepron, is an antimicrobial medication for the prevention and treatment of ''Pneumocystis jirovecii'' pneumonia (PCP). Atovaquone is a chemical compound that belongs to the class of naphthoquinones. Atovaq ...

. 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 Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...

, the benefit typically outweighs the risk. If used during pregnancy it should be taken with

folate Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...

. It is likely safe for use during

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...

. Proguanil is converted by the liver to its active metabolite,

cycloguanil Cycloguanil is a dihydrofolate reductase inhibitor, and is a metabolite of the antimalarial drug proguanil; its formation in vivo has been thought to be primarily responsible for the antimalarial activity of proguanil. However, more recent work ...

. Proguanil has been studied at least since 1945. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...

. In the United States and Canada it is only available in combination as

atovaquone/proguanil Atovaquone/proguanil, sold under the brand name Malarone among others, is a fixed-dose combination medication used to treat and prevent malaria, including chloroquine-resistant malaria. It contains atovaquone and proguanil. It is not recommended ...

Medical uses

Proguanil is used for the prevention and treatment of malaria in both adults and children, particularly in areas where

-resistant ''P. falciparum'' malaria has been reported. It is usually taken in combination with

, 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 A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

. Its active metabolite,

, is an inhibitor of

dihydrofolate reductase Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In ...

(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 Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative. Metabolism Human synthesis Tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate. It is co ...

(THF). THF is required for DNA synthesis, amino acid synthesis, and methylation; thus, DHFR inhibition shuts down these processes. Proguanil displays

synergism In Christian theology, synergism is the position of those who hold that salvation involves some form of cooperation between divine grace and human freedom. Synergism is upheld by the Roman Catholic Church, Orthodox Churches, Anabaptist Churches ...

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.

References

External links

* {{Authority control Antimalarial agents Biguanides Chlorobenzenes AstraZeneca brands Isopropyl compounds Prodrugs Protozoal dihydrofolate reductase inhibitors World Health Organization essential medicines Wikipedia medicine articles ready to translate