Atovaquone/proguanil
Chemical compound
From Wikipedia, the free encyclopedia
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.[2][3] It contains atovaquone and proguanil.[3] It is not recommended for severe or complicated malaria.[3] It is taken by mouth.[3]
| Combination of | |
|---|---|
| Atovaquone | Antimalarial medication |
| Proguanil | Antimalarial medication |
| Clinical data | |
| Trade names | Malarone, Malanil, others |
| AHFS/Drugs.com | Monograph |
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| Routes of administration | By mouth |
| ATC code | |
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Common side effects include abdominal pain, vomiting, diarrhea, cough, and itchiness.[3] Serious side effects may include anaphylaxis, Stevens–Johnson syndrome, hallucinations, and liver problems.[3][4] Side effects are generally mild.[5] It is unclear if use during pregnancy or breastfeeding is safe for the baby.[6] It is not recommended to prevent malaria in those with poor kidney function.[4] Atovaquone works by interfering with the function of mitochondria in malaria while proguanil blocks dihydrofolate reductase.[3]
Atovaquone/proguanil was approved for medical use in the United States in 2000.[3] It has been available as a generic medication since 2011.[7]
Medical uses
Malaria treatment
Atovaquone/proguanil is not normally used to treat severe malaria, when an injectable drug such as quinine is used instead.[citation needed]
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. [citation needed]
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 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.[8] Specific mutations (Y268S, Y268C) have been shown to confer resistance in vivo,[9][10][11] but the other mechanisms of resistance remain unknown.[12]
Adverse effects
Mechanism of action
Atovaquone selectively inhibits the malarial cytochrome bc1 complex in the parasitic electron transport chain, collapsing the mitochondrial membrane potential.[13] 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 – a process required for DNA replication. [14]
Proguanil, via its metabolite cycloguanil, functions as a dihydrofolate reductase inhibitor, halting parasitic deoxythymidylate synthesis.[15]
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.[citation needed]
History
Glaxo Wellcome patented the combination of atovaquone and proguanil to treat malaria in 1999. Patent protection expired in 2013.[16] The U.S. Food and Drug Administration (FDA) approved a generic formulation from Glenmark Generics in 2011.[17] In February 2013, the United Kingdom High Court revoked Glaxo's patent on grounds of obviousness, which clears the way for firms to sell generic versions there.[18]
