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Atovaquone

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Atovaquone
Clinical data
Trade namesMepron
AHFS/Drugs.comMonograph
MedlinePlusa693003
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life2.2–3.2 days
Identifiers
  • trans-2-[4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.158.738 Edit this at Wikidata
Chemical and physical data
FormulaC22H19ClO3
Molar mass366.84 g·mol−1
3D model (JSmol)
Melting point216 to 219 °C (421 to 426 °F)
  • OC=2C(=O)c1ccccc1C(=O)C=2[C@@H]3CC[C@H](CC3)c4ccc(Cl)cc4
  • InChI=1S/C22H19ClO3/c23-16-11-9-14(10-12-16)13-5-7-15(8-6-13)19-20(24)17-3-1-2-4-18(17)21(25)22(19)26/h1-4,9-13,15,26H,5-8H2/t13-,15- checkY
  • Key:KUCQYCKVKVOKAY-CTYIDZIISA-N checkY
 ☒NcheckY (what is this?)  (verify)

Atovaquone, sold under the brand name Mepron,[2] is an naphthoquinone antiprotozoal[3] medication used in the prevention and treatment Pneumocystis jirovecii pneumonia (PCP),[2] and malaria (in combination with proguanil), as well as for treatment of babesiosis (in combination with azithromycin).[4]

Atovaquone is an analogue of ubiquinone (coenzyme Q10) and exerts its pharmaceutical effects by binding to the ubiquinone binding site on the parasitic mitochondrial cytochrome bc1 complex, thus inhibiting a step of protozoal pyrimidine synthesis.[5]

Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of both ubiquinone and lawsone.

Medical uses

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Atovaquone is a medication used to treat and/or prevent:

Pneumocystis pneumonia

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Trimethoprim/sulfamethoxazole (TMP-SMX, Bactrim) is generally considered first-line therapy for PCP (not to be confused with sulfadiazine and pyrimethamine, which is first line for toxoplasmosis). However, atovaquone may be used in patients who cannot tolerate, or are allergic to, sulfonamide medications such as 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.[citation needed]

Atovaquone is given prophylactically to kidney transplant patients to prevent PCP in cases where Bactrim is contraindicated for the patient.[medical citation needed]

Malaria

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Atovaquone, as a combination preparation with proguanil, has been commercially available from GlaxoSmithKline since 2000 as Malarone for the treatment and prevention of malaria.

Atovaquone/proguanil is highly effective against parazites in the asexual, blood-stage, as well as the primary liver stages of P. falciparum; it is ineffective against the liver-stage hypnozoites of the P. vivax.[5]

Chemoprophylaxis

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Atovaquone/proguanil is a standard chemoprophylaxis for P. falciparum malaria prevention; it is one of three main antimalarial chemoprophylaxis regimens alongside doxycycline, and mefloquine (the efficacy of the latter being restricted to regions where microbial resistance has not been established). Its efficacy against liver-stage P. falciparum reduces the required duration of post-exposure prophylaxis. Its safety has been established for up to 20 weeks of continuous use, but it is thought to be safe even in case of years of continuous use.[5]

There is limited evidence regarding efficacy of this chemoprophylactic regiment against other Plasmodium species. P. vivax malaria has been noted following cessation of chemoprophylaxis, suggesting this regiment may fail to exhibit complete efficacy against extra-erythrocytic stages of P. vivax.[5]

Treatment

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It is an effective treatment for uncomplicated (mild-to-moderate[5]) malaria caused by P. falciparum.[3] In treatment of P. vivax, the initial atovaquone/proguanil course must be followed up with a course of primaquine.[5]

Resistance

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Malarial resistance to atovaquene monotherapy develops rapidly by a single-point mutation in the cytochrome b gene. Resistance to the atovaquone/proguanil combination is less frequent.[3][5]

Adverse effects

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Atovaquone is associated with gastrointestinal distress, headache, and rash. Adverse effects may necessitate discontinuation of atovaquone therapy. Vomiting and diarrhoea may aditionally decrease absorption of atovaquone, causing therapeutic failure (re-administration of a dose after vomiting can be an effective salvage). Atovaqune may cause transient elevations of serum transanimase, and amylase.[5]

Pharmacology

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Pharmacodynamics

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Atovaquone is a lipophilic analogue of ubiquinone (coenzyme Q10), which serves as electron acceptor of the parasitic inner mitrochondrial membrane cytochrome bc1 complex, which supplies oxidised ubiquinone to the dihydroorotate dehydrogenase, an enzyme that is crucial for parasitic pyrimidine synthesis.[5]

Atovaquone binds to the ubiquinone site of the cytochrome bc1 site, thus inhibiting electron transport and collapsing the mitochondrial membrane potential. This prevents regeneration of ubiquinone and, consequently, pyrimidine synthesis.[5]

The selectivity of atovaquone for the protozoan cytochrome b may be a result of structural differences between the protozoan and the human enzyme.[5]

Synergism

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In use for malaria, atovaquone acts synergistically with the antifolate proguanil and the two medications are often used in combination; the underlying mechanism of the synergism is unclear as other combinations of electron transport inhibitors and antifolates do not exhibit syngerism.[3] Proguanil may independently enhance atovaquone's action of collapsing the protozoal mitrochondrial membrane potential.[3]

The atovaquone/proguanil comination significantly reduces the incidence of the development of malarial resistance to atovaquone which arises readily with monotherapy; nevertheless, if resistance develops, the synergy diminishes.[5]

Interactions

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Atovaquone may compete for plasma protein binding with some pharmaceuticals.[5]

  • Rifampicin - causes a substantial reduction in atovaquone plasma concentration by an unknown mechanism.[5]
  • Tetracycline - causes a 40% reduction in atovaquone plasma concentration.[5]
  • Zidovudine - atovaquone may increase zidovudine plasma concentrations.[5]

Research

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Atovaquone's antiprotozoal effects have been researched in toxoplasmosis, and visceral leishmaniasis.

COVID-19

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Preliminary research found that atovaquone could inhibit the replication of SARS-CoV-2 in vitro.[11] Clinical trials of atovaquone for the treatment of COVID-19 are planned,[12][13] and ongoing in United States in December 2021.[14][needs update]

Atovaquone has also been found to inhibit human coronavirus OC43 and feline coronavirus in vitro.[15]

In newer researches, atovaquone did not demonstrate evidence of enhanced SARS-CoV-2 viral clearance compared with placebo.[16]

Veterinary use

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Atovaquone is used in livestock veterinary cases of babesiosis in cattle, especially if imidocarb resistance is a concern.[17]

References

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  1. ^ "Wellvone 750mg/5ml oral suspension - Summary of Product Characteristics (SmPC)". (emc). 28 November 2019. Retrieved 18 September 2020.
  2. ^ a b "Atovaquone Oral SUSPENSION- atovaquone suspension". DailyMed. 10 December 2019. Retrieved 18 September 2020.
  3. ^ a b c d e Ritter, James M.; Flower, Rod; Henderson, Graeme; Loke, Yoon Kong; MacEwan, David; Rang, H. P. (2020). Rang & Dale's Pharmacology (9th ed.). Edinburgh London New York: Elsevier. pp. 704–705. ISBN 978-0-7020-7448-6.
  4. ^ Baggish, Aaron L.; Hill, David R. (May 2002). "Antiparasitic agent atovaquone". Antimicrobial Agents and Chemotherapy. 46 (5): 1163–1173. doi:10.1128/AAC.46.5.1163-1173.2002. ISSN 0066-4804. PMC 127192. PMID 11959541.
  5. ^ a b c d e f g h i j k l m n o p Brunton, Laurence L.; Knollmann, Björn C.; Gilman, Alfred; Goodman, Louis Sanford, eds. (2023). Goodman & Gilman's The Pharmacological Basis of Therapeutics. Pharmacology (14th ed.). McGraw Hill. pp. 1248, 1290, 1294–1295, 1302. ISBN 978-1-264-25808-6.
  6. ^ Hughes W, Leoung G, Kramer F, Bozzette SA, Safrin S, Frame P, et al. (May 1993). "Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS". The New England Journal of Medicine. 328 (21): 1521–1527. doi:10.1056/NEJM199305273282103. PMID 8479489.
  7. ^ Dohn MN, Weinberg WG, Torres RA, Follansbee SE, Caldwell PT, Scott JD, et al. (August 1994). "Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Atovaquone Study Group". Annals of Internal Medicine. 121 (3): 174–180. doi:10.7326/0003-4819-121-3-199408010-00003. PMID 7880228. S2CID 24263604.
  8. ^ Malarone: New Malaria Medication With Fewer Side-effects Archived May 14, 2006, at the Wayback Machine
  9. ^ Färnert A, Lindberg J, Gil P, Swedberg G, Berqvist Y, Thapar MM, et al. (March 2003). "Evidence of Plasmodium falciparum malaria resistant to atovaquone and proguanil hydrochloride: case reports". BMJ. 326 (7390): 628–629. doi:10.1136/bmj.326.7390.628. PMC 151974. PMID 12649236.
  10. ^ Krause PJ, Lepore T, Sikand VK, Gadbaw J, Burke G, Telford SR, et al. (November 2000). "Atovaquone and azithromycin for the treatment of babesiosis". The New England Journal of Medicine. 343 (20): 1454–1458. doi:10.1056/NEJM200011163432004. PMID 11078770.
  11. ^ Farag A, Wang P, et al. (May 2020). "Identification of Atovaquone, Ouabain and Mebendazole as FDA-Approved Drugs Targeting SARS-CoV-2". chemRxiv (preprint). doi:10.26434/chemrxiv.12003930.v4. S2CID 219428383. Retrieved 20 June 2020.
  12. ^ "Atovaquone and Azithromycin Combination for Confirmed COVID-19 Infection". ClinicalTrials.gov. Retrieved 22 October 2020.
  13. ^ "Atovaquone for Treatment of COVID-19". ClinicalTrials.gov. Retrieved 22 October 2020.
  14. ^ KATHRINE EMILIE KRISTENSEN (10 December 2021). "Ny forskning finder lægemiddel mod corona: 'Kan redde menneskeliv'". B.T. (in Danish). Retrieved 10 December 2021.
  15. ^ Yang CW, Peng TT, Hsu HY, Lee YZ, Wu SH, Lin WH, et al. (August 2020). "Repurposing old drugs as antiviral agents for coronaviruses". Biomedical Journal. 43 (4): 368–374. doi:10.1016/j.bj.2020.05.003. PMC 7245249. PMID 32563698.
  16. ^ Jain MK, De Lemos JA, McGuire DK, Ayers C, Eitson JL, Sanchez CL, et al. (2022). "Atovaquone for treatment of COVID-19: A prospective randomized, double-blind, placebo-controlled clinical trial". Frontiers in Pharmacology. 13: 1020123. doi:10.3389/fphar.2022.1020123. PMC 9561237. PMID 36249792.
  17. ^ Vial HJ, Gorenflot A (May 2006). "Chemotherapy against babesiosis". Veterinary Parasitology. 138 (1–2): 147–160. doi:10.1016/j.vetpar.2006.01.048. PMID 16504402.

Further reading

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Wikimedia Commons has media related to Atovaquone.
  • "Atovaquone". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on August 18, 2016.
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