Atovaquone/proguanil

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Atovaquone/proguanil
Combination of
Atovaquone Antimalarial medication
Proguanil Antimalarial medication
Clinical data
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
Oral
Legal status
Legal status
  • UK: POM (Prescription only)
  • ℞ (Prescription only)
Identifiers
ATC code P01BB51 (WHO)
PubChem CID 11954242
ChemSpider 21230364 YesY
KEGG D02472 N
 NYesY (what is this?)  (verify)
Malarone anti-malaria tablets, as issued in the UK.

The drug combination atovaquone/proguanil (INNs, trade names Malarone, Malanil) is an antimalarial medication used in both the treatment and prevention of malaria. Atovaquone alone is not indicated for treatment or prevention of malaria as monotherapy (i.e., without proguanil). Atovaquone/proguanil has been commercially available from GlaxoSmithKline since 2000, and its patent expired in 2013.[2] Malarone has applications for treating chloroquine-resistant malaria.[3]

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.

Medical use[edit]

Treatment[edit]

The adult treatment dose is four standard tablets once a day for three days. In children, the drug is prescribed by body weight:

  • 11 to 20 kg: 1 standard tablet once daily for 3 days;
  • 21 to 30 kg: 2 standard tablets once daily for 3 days;
  • 31 to 40 kg: 3 standard tablets once daily for 3 days;
  • 41 kg and above: use adult dose.

Malarone is not licensed for use in children weighing 10 kg or less. The pediatric tablets are not used in malaria treatment, but are used for prophylaxis.

Malarone is not normally used to treat severe malaria, when an injectable drug such as quinine is used instead.

Prevention[edit]

Medical advice should always be taken before choosing a drug for malaria prevention. Because some strains of malaria are resistant, Malarone is not effective for malaria prevention in all parts of the world. It must be taken with a fatty meal or at least some milk to be absorbed adequately, and to avoid painful stomach irritation which proguanil frequently causes when taken without food. Also, stomach irritation may occur if one lies down within a half hour after taking this medicine.

The adult dose is one standard tablet daily starting one or two days before traveling into a malaria-endemic area, and continuing throughout the stay and then for another seven days after returning from the area.

The child dose is prescribed according to body weight:

  • 11–20 kg: 1 pediatric tablet once daily;
  • 21–30 kg: 2 pediatric tablets once daily;
  • 31–40 kg: 3 pediatric tablets once daily;
  • 41 kg and above use adult dose.

The duration of treatment is the same as for adults.

Resistance[edit]

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.[4] Specific mutations (Y268S, Y268C) have been shown to confer resistance in vivo,[5][6][7] but the other mechanisms of resistance remain unknown.[8]

Adverse effects[edit]

Malarone is notable for having far fewer side effects than other, older malaria drugs. 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.[9]

Mechanism of action[edit]

Atovaquone selectively inhibits the malarial cytochrome bc1 complex in the parasitic electron transport chain, collapsing the mitochondrial membrane potential.[10] 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.[11]

Proguanil, via its metabolite cycloguanil, functions as a dihydrofolate reductase inhibitor, halting parasitic deoxythymidilate synthesis.[12]

History[edit]

The combination of atovaquone and proguanil to treat malaria was patented by Glaxo Wellcome in 1999, and its patent protection expired in 2013.[2] Glenmark Generics had a generic formulation approved by the U.S. Food and Drug Administration (FDA) in 2011.[13] In February 2013, the United Kingdom High Court revoked Glaxo's patent on account of obviousness, clearing the way for generic versions to be sold there.[14]

References[edit]

  1. ^ Glaxo Smith Kline monograph on MALARONE
  2. ^ a b Generic Malarone Availability
  3. ^ Nakato, Halima; Vivancos, Roberto; Hunter, Paul R. (2007-11-01). "A systematic review and meta-analysis of the effectiveness and safety of atovaquone–proguanil (Malarone) for chemoprophylaxis against malaria". Journal of Antimicrobial Chemotherapy. 60 (5): 929–936. doi:10.1093/jac/dkm337. ISSN 0305-7453. PMID 17848375. 
  4. ^ Srivastava, Indresh K.; Vaidya, Akhil B. (1999-06-01). "A Mechanism for the Synergistic Antimalarial Action of Atovaquone and Proguanil". Antimicrobial Agents and Chemotherapy. 43 (6): 1334–1339. ISSN 0066-4804. PMC 89274free to read. PMID 10348748. 
  5. ^ Färnet A, Lindberg J, Gil P, et al. (2003). "Evidence of Plasmodium falciparum malaria resistant to atovaquone and proguoanil hydrochloride: case reports". Brit Med J. 326 (7390): 628–29. doi:10.1136/bmj.326.7390.628. PMC 151974free to read. PMID 12649236. 
  6. ^ Fivelman QL, Butcher GA, Adagu IS, et al. (2002). "Malarone treatment failure and in-vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos, Nigeria". Malaria J. 1: 1. doi:10.1186/1475-2875-1-1. 
  7. ^ Schwartz E, Bujanover S, Kain KC (2003). "Genetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveller to east Africa". Clin Infect Dis. 37 (3): 450–51. doi:10.1086/375599. PMID 12884171. 
  8. ^ Wichmann O, Muehlen M, Gruss H, et al. (2004). "Malarone treatment failure not associated with previously described mutations in the cytochrome b gene". Malaria J. 3: 14. doi:10.1186/1475-2875-3-14. PMC 425592free to read. PMID 15186499. 
  9. ^ http://www.drugs.com/sfx/malarone-side-effects.html
  10. ^ Fry, Mitchell; Pudney, Mary (1992-04-01). "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. doi:10.1016/0006-2952(92)90213-3. 
  11. ^ Srivastava, Indresh K.; Rottenberg, Hagai; Vaidya, Akhil B. (1997-02-14). "Atovaquone, a Broad Spectrum Antiparasitic Drug, Collapses Mitochondrial Membrane Potential in a Malarial Parasite". Journal of Biological Chemistry. 272 (7): 3961–3966. doi:10.1074/jbc.272.7.3961. ISSN 0021-9258. 
  12. ^ http://us.gsk.com/products/assets/us_malarone.pdf
  13. ^ Drug Details
  14. ^ Atovaquone Proguanil (Malarone) Patent Revoked & Glenmark Launches First UK Generic