Atovaquone/proguanil explained

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.[1] [2] It contains atovaquone and proguanil.[2] It is not recommended for severe or complicated malaria.[2] It is taken by mouth.[2]

Common side effects include abdominal pain, vomiting, diarrhea, cough, and itchiness.[2] Serious side effects may include anaphylaxis, Stevens–Johnson syndrome, hallucinations, and liver problems.[2] [3] Side effects are generally mild. It is unclear if use during pregnancy or breastfeeding is safe for the baby.[4] It is not recommended to prevent malaria in those with poor kidney function.[3] Atovaquone works by interfering with the function of mitochondria in malaria while proguanil blocks dihydrofolate reductase.[2]

Atovaquone/proguanil was approved for medical use in the United States in 2000.[2] It has been available as a generic medication since 2011.[5]

Medical uses

Malaria treatment

Atovaquone/proguanil is not normally used to treat severe malaria, when an injectable drug such as quinine 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 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.[6] Specific mutations (Y268S, Y268C) have been shown to confer resistance in vivo,[7] [8] [9] but the other mechanisms of resistance remain unknown.[10]

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.[11]

Mechanism of action

Atovaquone selectively inhibits the malarial cytochrome bc1 complex in the parasitic electron transport chain, collapsing the mitochondrial membrane potential.[12] 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.[13]

Proguanil, via its metabolite cycloguanil, functions as a dihydrofolate reductase inhibitor, halting parasitic deoxythymidylate synthesis.[14]

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 patented the combination of atovaquone and proguanil to treat malaria in 1999. Patent protection expired in 2013.[15] The U.S. Food and Drug Administration (FDA) approved a generic formulation from Glenmark Generics in 2011.[16] 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.[17]

Notes and References

  1. Nakato H, Vivancos R, Hunter PR . A systematic review and meta-analysis of the effectiveness and safety of atovaquone proguanil (Malarone) for chemoprophylaxis against malaria . The Journal of Antimicrobial Chemotherapy . 60 . 5 . 929–936 . November 2007 . 17848375 . 10.1093/jac/dkm337 . free .
  2. Web site: Atovaquone and Proguanil Hydrochloride Monograph for Professionals . Drugs.com . American Society of Health-System Pharmacists . 12 September 2019 . en . 20 December 2016 . https://web.archive.org/web/20161220223925/https://www.drugs.com/monograph/atovaquone-and-proguanil-hydrochloride.html . live .
  3. Book: British national formulary : BNF 76. 2018. Pharmaceutical Press. 9780857113382. 604. 76.
  4. Web site: Atovaquone / proguanil Use During Pregnancy . Drugs.com . 12 September 2019 . en . 16 August 2019 . https://web.archive.org/web/20190816072546/https://www.drugs.com/pregnancy/atovaquone-proguanil.html . live .
  5. Web site: Generic Malarone Availability . Drugs.com . 12 September 2019 . en . 16 August 2019 . https://web.archive.org/web/20190816072535/https://www.drugs.com/availability/generic-malarone.html . live .
  6. Srivastava IK, Vaidya AB . A mechanism for the synergistic antimalarial action of atovaquone and proguanil . Antimicrobial Agents and Chemotherapy . 43 . 6 . 1334–1339 . June 1999 . 10348748 . 89274 . 10.1128/AAC.43.6.1334 .
  7. Färnert A, Lindberg J, Gil P, Swedberg G, Berqvist Y, Thapar MM, Lindegårdh N, Berezcky S, Björkman A . 6 . Evidence of Plasmodium falciparum malaria resistant to atovaquone and proguanil hydrochloride: case reports . BMJ . 326 . 7390 . 628–629 . March 2003 . 12649236 . 151974 . 10.1136/bmj.326.7390.628 .
  8. Fivelman QL, Butcher GA, Adagu IS, Warhurst DC, Pasvol G . Malarone treatment failure and in vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos, Nigeria . Malaria Journal . 1 . 1 . February 2002 . 12057021 . 111499 . 10.1186/1475-2875-1-1 . free .
  9. Schwartz E, Bujanover S, Kain KC . Genetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa . Clinical Infectious Diseases . 37 . 3 . 450–451 . August 2003 . 12884171 . 10.1086/375599 . free .
  10. Wichmann O, Muehlen M, Gruss H, Mockenhaupt FP, Suttorp N, Jelinek T . Malarone treatment failure not associated with previously described mutations in the cytochrome b gene . Malaria Journal . 3 . 14 . June 2004 . 15186499 . 425592 . 10.1186/1475-2875-3-14 . free .
  11. Web site: Malarone Side Effects: Common, Severe, Long Term . Drugs.com . 12 September 2019 . en . 16 August 2019 . https://web.archive.org/web/20190816072534/https://www.drugs.com/sfx/malarone-side-effects.html . live .
  12. Fry M, Pudney M . Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4'-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80) . Biochemical Pharmacology . 43 . 7 . 1545–1553 . April 1992 . 1314606 . 10.1016/0006-2952(92)90213-3 .
  13. Srivastava IK, Rottenberg H, Vaidya AB . Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite . The Journal of Biological Chemistry . 272 . 7 . 3961–3966 . February 1997 . 9020100 . 10.1074/jbc.272.7.3961 . free .
  14. Web site: Our prescription medicines | GSK US. 28 September 2011. 4 September 2011. https://web.archive.org/web/20110904232305/http://us.gsk.com/products/assets/us_malarone.pdf. dead.
  15. Web site: Generic Malarone Availability . 23 January 2018 . 16 August 2019 . https://web.archive.org/web/20190816072535/https://www.drugs.com/availability/generic-malarone.html . live .
  16. Web site: Drug Details . 1 May 2013 . 27 August 2021 . https://web.archive.org/web/20210827232613/https://www.accessdata.fda.gov/scripts/cder/daf/ . live .
  17. Web site: Atovaquone Proguanil (Malarone) Patent Revoked & Glenmark Launches First UK Generic . 1 May 2013 . 16 April 2013 . https://web.archive.org/web/20130416001054/http://www.prnewswire.co.uk/news-releases/atovaquone-proguanil-malarone-patent-revoked--glenmark-launches-first-uk-generic-190203571.html . live .

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