Atovaquone/proguanil

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Atovaquone/proguanil
Combination of
AtovaquoneAntimalarial medication
ProguanilAntimalarial medication
Clinical data
Trade namesMalarone, Malanil, others
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: B2
Routes of
administration
By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)[1]
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
ChemSpider
KEGG
CompTox Dashboard (EPA)
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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]

Common side effects include abdominal pain, vomiting, diarrhea, cough, and itchiness.

mitochondria in malaria while proguanil blocks dihydrofolate reductase.[3]

Atovaquone/proguanil was approved for medical use in the United States in 2000.

Medical uses

Malarone tablets, as issued in the UK.

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. Also, stomach irritation may occur if one lies down within a half hour after taking this medicine.[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

Side effects are generally mild.[5] 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.[5]

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.[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]

References

  1. ^ "Atovaquopro Lupin (Generic Health Pty Ltd)". Therapeutic Goods Administration (TGA). 28 September 2022. Archived from the original on 12 October 2022. Retrieved 29 April 2023.
  2. PMID 17848375
    .
  3. ^ a b c d e f g h "Atovaquone and Proguanil Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 12 September 2019.
  4. ^ .
  5. ^ a b c "Malarone Side Effects: Common, Severe, Long Term". Drugs.com. Archived from the original on 16 August 2019. Retrieved 12 September 2019.
  6. ^ "Atovaquone / proguanil Use During Pregnancy". Drugs.com. Archived from the original on 16 August 2019. Retrieved 12 September 2019.
  7. ^ "Generic Malarone Availability". Drugs.com. Archived from the original on 16 August 2019. Retrieved 12 September 2019.
  8. PMID 10348748
    .
  9. .
  10. .
  11. .
  12. .
  13. .
  14. .
  15. ^ "Our prescription medicines | GSK US" (PDF). Archived from the original (PDF) on 4 September 2011. Retrieved 28 September 2011.
  16. ^ "Generic Malarone Availability". Archived from the original on 16 August 2019. Retrieved 23 January 2018.
  17. ^ "Drug Details". Archived from the original on 27 August 2021. Retrieved 1 May 2013.
  18. ^ "Atovaquone Proguanil (Malarone) Patent Revoked & Glenmark Launches First UK Generic". Archived from the original on 16 April 2013. Retrieved 1 May 2013.