atovaquone/proguanil

File:Malarone tablets.jpg

Atovaquone/proguanil is not normally used to treat severe malaria, when an injectable drug such as quinine is used instead.{{cn|date=December 2022}}

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. {{cn|date=December 2022}}

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.{{cite journal | vauthors = Srivastava IK, Vaidya AB | title = A mechanism for the synergistic antimalarial action of atovaquone and proguanil | journal = Antimicrobial Agents and Chemotherapy | volume = 43 | issue = 6 | pages = 1334–1339 | date = June 1999 | pmid = 10348748 | pmc = 89274 | doi = 10.1128/AAC.43.6.1334 }} Specific mutations (Y268S, Y268C) have been shown to confer resistance in vivo,{{cite journal | vauthors = Färnert A, Lindberg J, Gil P, Swedberg G, Berqvist Y, Thapar MM, Lindegårdh N, Berezcky S, Björkman A | display-authors = 6 | title = Evidence of Plasmodium falciparum malaria resistant to atovaquone and proguanil hydrochloride: case reports | journal = BMJ | volume = 326 | issue = 7390 | pages = 628–629 | date = March 2003 | pmid = 12649236 | pmc = 151974 | doi = 10.1136/bmj.326.7390.628 }}{{cite journal | vauthors = Fivelman QL, Butcher GA, Adagu IS, Warhurst DC, Pasvol G | title = Malarone treatment failure and in vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos, Nigeria | journal = Malaria Journal | volume = 1 | pages = 1 | date = February 2002 | pmid = 12057021 | pmc = 111499 | doi = 10.1186/1475-2875-1-1 | doi-access = free }}{{cite journal | vauthors = Schwartz E, Bujanover S, Kain KC | title = Genetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa | journal = Clinical Infectious Diseases | volume = 37 | issue = 3 | pages = 450–451 | date = August 2003 | pmid = 12884171 | doi = 10.1086/375599 | doi-access = free }} but the other mechanisms of resistance remain unknown.{{cite journal | vauthors = Wichmann O, Muehlen M, Gruss H, Mockenhaupt FP, Suttorp N, Jelinek T | title = Malarone treatment failure not associated with previously described mutations in the cytochrome b gene | journal = Malaria Journal | volume = 3 | pages = 14 | date = June 2004 | pmid = 15186499 | pmc = 425592 | doi = 10.1186/1475-2875-3-14 | doi-access = free }}

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.{{cite web |title=Malarone Side Effects: Common, Severe, Long Term |url=https://www.drugs.com/sfx/malarone-side-effects.html |website=Drugs.com |access-date=12 September 2019 |language=en |archive-date=16 August 2019 |archive-url=https://web.archive.org/web/20190816072534/https://www.drugs.com/sfx/malarone-side-effects.html |url-status=live }}

Atovaquone selectively inhibits the malarial cytochrome bc₁ complex in the parasitic electron transport chain, collapsing the mitochondrial membrane potential.{{cite journal | vauthors = Fry M, Pudney M | title = Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4'-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80) | journal = Biochemical Pharmacology | volume = 43 | issue = 7 | pages = 1545–1553 | date = April 1992 | pmid = 1314606 | doi = 10.1016/0006-2952(92)90213-3 }} 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.{{cite journal | vauthors = Srivastava IK, Rottenberg H, Vaidya AB | title = Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite | journal = The Journal of Biological Chemistry | volume = 272 | issue = 7 | pages = 3961–3966 | date = February 1997 | pmid = 9020100 | doi = 10.1074/jbc.272.7.3961 | doi-access = free }}

Proguanil, via its metabolite cycloguanil, functions as a dihydrofolate reductase inhibitor, halting parasitic deoxythymidylate synthesis.{{Cite web|url=http://us.gsk.com/products/assets/us_malarone.pdf|title=Our prescription medicines | GSK US|access-date=28 September 2011|archive-date=4 September 2011|archive-url=https://web.archive.org/web/20110904232305/http://us.gsk.com/products/assets/us_malarone.pdf|url-status=dead}}

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.{{cn|date=December 2022}}

Glaxo Wellcome patented the combination of atovaquone and proguanil to treat malaria in 1999. Patent protection expired in 2013.{{Cite web |url=https://www.drugs.com/availability/generic-malarone.html |title=Generic Malarone Availability |access-date=23 January 2018 |archive-date=16 August 2019 |archive-url=https://web.archive.org/web/20190816072535/https://www.drugs.com/availability/generic-malarone.html |url-status=live }} The U.S. Food and Drug Administration (FDA) approved a generic formulation from Glenmark Generics in 2011.{{Cite web |url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=091211&DrugName=ATOVAQUONE%20AND%20PROGUANIL%20HYDROCHLORIDE&ActiveIngred=ATOVAQUONE%3B%20PROGUANIL%20HYDROCHLORIDE&SponsorApplicant=GLENMARK%20GENERICS&ProductMktStatus=1&goto=Search.DrugDetails |title=Drug Details |access-date=1 May 2013 |archive-date=27 August 2021 |archive-url=https://web.archive.org/web/20210827232613/https://www.accessdata.fda.gov/scripts/cder/daf/ |url-status=dead }} 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.{{Cite web |url=http://www.prnewswire.co.uk/news-releases/atovaquone-proguanil-malarone-patent-revoked--glenmark-launches-first-uk-generic-190203571.html |title=Atovaquone Proguanil (Malarone) Patent Revoked & Glenmark Launches First UK Generic |access-date=1 May 2013 |archive-date=16 April 2013 |archive-url=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 |url-status=live }}

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