Atovaquone/proguanil, sold under the brand name Malarone among others, is a

fixed-dose combination A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form. Terms like "combination drug" or "combination drug product" can be common shorthand for a FDC pr ...

medication 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 ...

, including

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 ...

-resistant malaria. It contains atovaquone and proguanil. It is not recommended for severe or complicated malaria. It is taken by mouth. Common side effects include abdominal pain, vomiting, diarrhea, cough, and itchiness. Serious side effects may include

anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the foll ...

Stevens–Johnson syndrome Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis (TEN) and Stevens–Johnson/toxic epidermal necrolysis (SJS/TEN), it forms a spectrum of disease, with SJS being less severe. Erythema ...

, hallucinations, and liver problems. Side effects are generally mild. It is unclear if use during pregnancy or breastfeeding is safe for the baby. It is not recommended to prevent malaria in those with poor kidney function. Atovaquone works by interfering with the function of mitochondria in malaria while proguanil blocks dihydrofolate reductase. Atovaquone/proguanil was approved for medical use in the United States in 2000. It has been available as a generic medication since 2011.

Medical uses

Malaria treatment

Atovaquone/proguanil is not normally used to treat severe malaria, when an injectable drug such as

quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to '' Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal le ...

is used instead.

Malaria prevention

Since some malaria strains are resistant to atovaquone/proguanil, it is not effective in all parts of the world. It must be taken with a fatty meal, or at least some milk, for the body to absorb it adequately—and to avoid painful stomach irritation, which proguanil frequently causes if taken without food. Also, stomach irritation may occur if one lies down within a half hour after taking this medicine.

Resistance

Proguanil acts as a mitochondrial sensitiser and synergizes with atovaquone. When atovaquone is used as a sole agent, a high natural frequency of

cytochrome b Cytochrome b within both molecular and cell biology, is a protein found in the mitochondria of eukaryotic cells. It functions as part of the electron transport chain and is the main subunit of transmembrane cytochrome bc1 and b6f complexes. F ...

mutants leads to a high failure rate. This is potentially due to the high lipophilicity and slow uptake of atovaquone, which results in a relatively prolonged period of parasite exposure at ineffective concentrations. Specific mutations (''Y268S'', ''Y268C'') have been shown to confer resistance ''in vivo'', but the other mechanisms of resistance remain unknown.

Adverse effects

Side effects are generally mild. While some people experience side effects, such as coughing, diarrhea, dizziness, headache, loss of appetite, mouth sores, nausea, stomach pain, vomiting, or weakness, the majority have none or few of these.

Mechanism of action

Atovaquone selectively inhibits the malarial cytochrome ''bc''₁ complex in the parasitic electron transport chain, collapsing the mitochondrial membrane potential. The malarial electron transport chain does not contribute significantly to ATP synthesis; thus, it is believed that parasite death is due to the indirect inhibition of dihydroorotate dehydrogenase, which requires transport chain function and is essential to pyrimidine biosynthesis. Proguanil, via its metabolite cycloguanil, functions as a

dihydrofolate reductase inhibitor A dihydrofolate reductase inhibitor (DHFR inhibitor) is a molecule that inhibits the function of dihydrofolate reductase, and is a type of antifolate. Since folate is needed by rapidly dividing cells to make thymine, this effect may be used to th ...

, halting parasitic deoxythymidylate synthesis.

Chemistry

A standard tablet of Malarone contains 100 mg of proguanil hydrochloride and 250 mg of atovaquone. A pediatric tablet contains 25 mg of proguanil hydrochloride and 62.5 mg of atovaquone.

History

Glaxo Wellcome GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the ten ...

patented the combination of atovaquone and proguanil to treat malaria in 1999. Patent protection expired in 2013.Generic Malarone Availability
/ref> The U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) approved a generic formulation from Glenmark Generics in 2011.Drug Details
/ref> In February 2013, the

United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the European mainland, continental mainland. It comprises England, Scotlan ...

High Court revoked Glaxo's patent on grounds of obviousness, which clears the way for firms to sell generic versions there.Atovaquone Proguanil (Malarone) Patent Revoked & Glenmark Launches First UK Generic
/ref>

References

External links

* {{DEFAULTSORT:Atovaquone Proguanil Combination drugs Antimalarial agents Antiprotozoal agents GSK plc brands Wikipedia medicine articles ready to translate