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Atovaquone
Systematic (IUPAC) name
trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione
Identifiers
CAS number 95233-18-4
ATC code P01AX06
PubChem 74989
DrugBank APRD00805
ChemSpider 10482034
Chemical data
Formula C 22H19ClO3  
Mol. mass 366.837 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life 2.2 to 3.2 days
Excretion  ?
Therapeutic considerations
Pregnancy cat.  ?
Legal status PoM (UK), Rx [US]
Routes oral only
 Yes check.svgY(what is this?)  (verify)
Malarone anti-malaria tablets, as issued in the UK.

Atovaquone (alternative spelling: atavaquone) is a chemical compound that belongs to the class of naphthalenes. Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystic activity. Its average wholesale price is about US$2.13 per standard 250 mg. tablet.[1] It is also manufactured in the US in the liquid form, or oral suspension, under the brand name Mepron[2], a 30 day supply of which (300ml),is about $1,600.00 without insurance coverage.

Contents

Uses

Atovaquone is a medication used to treat or prevent:

  1. Pneumocystis pneumonia (PCP),[3][4] although it is not approved for treatment of severe PCP.
  2. Toxoplasmosis.[5] The medication has antiparasitic and therapeutic effects.
  3. Malaria. It is one of the two components (along with proguanil) in the drug Malarone. Malarone has fewer side effects and is more expensive than mefloquine.[6] Resistance has been observed.[7]

Trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim) is generally considered first line therapy for PCP or toxoplasmosis. However, atovaquone may be used in patients who cannot tolerate, or are allergic to, TMP-SMX. In addition, atovaquone has the advantage of not causing myelosuppression, which is an important issue in patients who have undergone bone marrow transplantation.

Malaria

Atovaquone is only available as a fixed preparation with proguanil that has been commercially available from GlaxoSmithKline since 2000 as Malarone (sometimes abbreviated A+P). It can be used both to treat and to prevent malaria.

A "standard" tablet of Malarone contains 100 mg of proguanil hydrochloride and 250 mg of atovaquone. A "pediatric" tablet of Malarone contains 25 mg of proguanil hydrochloride and 62.5 mg of atovaquone.

Treatment

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.

The advice of a specialist should always be sought when starting malaria treatment. Malarone should not be used to treat severe malaria, when an injectable drug (quinine or artesunate in the UK; quinidine in the US) should be used instead.

Prevention

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.

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 7 days after returning from the malarious 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

Proguanil acts as a mitochondrial sensitiser and synergizes with atovaquone; also, there is a high natural frequency of cytochrome B mutants which leads to a high failure rate if atovaquone is used on its own to treat malaria. Specific mutations (Y268S, Y268C) have been shown to confer resistance in vivo,[8][9][10] but there are other mechanisms of resistance that remain unknown.[11]

Side Effects

Some people have difficulty sleeping (nightmares, incoherent dreams) while taking Malarone.

References

  1. ^ (ATN) Atovaquone (Mepron; 566C80) Approved for Pneumocystis; Drug Development, Activism Success
  2. ^ Mepron
  3. ^ Hughes W, Leoung G, Kramer F, et al. (May 1993). "Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS". N. Engl. J. Med. 328 (21): 1521–7. PMID 8479489. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=8479489&promo=ONFLNS19.  
  4. ^ Dohn MN, Weinberg WG, Torres RA, et al. (August 1994). "Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Atovaquone Study Group". Ann. Intern. Med. 121 (3): 174–80. PMID 7880228. http://www.annals.org/cgi/pmidlookup?view=long&pmid=7880228.  
  5. ^ Djurković-Djaković O, Milenković V, Nikolić A, Bobić B, Grujić J (December 2002). "Efficacy of atovaquone combined with clindamycin against murine infection with a cystogenic (Me49) strain of Toxoplasma gondii". J. Antimicrob. Chemother. 50 (6): 981–7. doi:10.1093/jac/dkf251. PMID 12461021. http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12461021.  
  6. ^ Malarone: New Malaria Medication With Fewer Side-effects
  7. ^ Färnert A, Lindberg J, Gil P, et al. (March 2003). "Evidence of Plasmodium falciparum malaria resistant to atovaquone and proguanil hydrochloride: case reports". BMJ 326 (7390): 628–9. doi:10.1136/bmj.326.7390.628. PMID 12649236. PMC 151974. http://bmj.com/cgi/pmidlookup?view=long&pmid=12649236.  
  8. ^ 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: 628–29. doi:10.1136/bmj.326.7390.628. PMID 12649236.  
  9. ^ 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.  
  10. ^ 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: 450–51. doi:10.1086/375599.  
  11. ^ 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.  

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