Atovaquone malaria

Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystic activity. Since 2000 atovaquone is available as a fixed dose preparation (Malarone) with proguanil for the oral treatment of falciperum malaria. Its activity probably is based on a selective inhibiton of mitochondrial electron transport with consequent inhibition of pyrimidin synthesis. Malarone should not be used to treat severe malaria, when an injectable drug is needed. 

For uncomplicated falciparum malaria there are several options (with the major drawback in brackets) halofantrine (arrhytmia), mefloquine (neurotoxicity), quinine (vomiting, tinnitus), artemether (recrudescence), atovaquone-proguanil (possible fast development of resistance). 

Atovaquone is a naphthoquinone whose mechanism of action involves inhibition of the mitochondrial electron transport system in the protozoa. Malaria parasites depend on de novo pyrimidine biosynthesis through dihy-droorotate dehydrogenase coupled to electron transport. Plasmodia are unable to salvage and recycle pyrimidines as do mammalian cells. 

A. Liposomal amphotericin B was approved by the US. Food and Drug Administration to treat visceral leishmaniasis. Pentavalent antimony compounds, pentamidine, amphotericin B, and aminosi-dine (paromomycin) have all been demonstrated efficacious here. The liposomal amphotericin appears to be better taken up by the reticuloendothelial system, where the parasite resides, and partitions less in the kidney, where amphotericin B traditionally manifests its toxicity. In addition to being better tolerated by patients, it has proved to be very effective in India, where resistance to antimony drugs is widespread. This patient appears to have acquired his infection there, where many infected patients develop darkening of the skin, hence the name kala-azar, or black sickness. Albendazole, an anthelmintic, has no role here. Atovaquone, a naphthoquinone, is used to treat malaria, babesiosis, and pneumocystosis. Pyrimethamine-sulfadoxine is used to treat malaria and toxoplasmosis. Proguanil inhibits the dihydrofolate reductase of malaria parasites and is used in combination with atovaquone. 

Atovaquone/proguanil (Malarone) for malaria. Med Lett Drugs Ther 2000 42 109-111. 

Looareesuwan S et al. Malarone (atovaquone and proguanil hydrochloride) A review of its clinical development for treatment of malaria. Am J Trop Med Hyg 1999 60 533-541. 

Atovaquone, a hydroxynaphthoquinone (Figure 52-2), was initially developed as an antimalarial agent, and as a component of Malarone is recommended for treatment and prevention of malaria. Atovaquone has also been approved by the FDA for the treatment of mild to moderate P jiroveci pneumonia. 

Boggild AK et al Atovaquone-proguanil Report from the CDC expert meeting on malaria chemoprophylaxis (II). Am J Trop Med Hyg 2007 76 208. [PMID 17297027]... 

Ling J et al Randomized, placebo-controlled trial of atovaquone/proguanil for the prevention of Plasmodium falciparum or Plasmodium vivax malaria among migrants to Papua, Indonesia. Clin Infect Dis 2002 35 825. [PMID 12228819]... 

Clinical Use. Atovaquone (Mepron) is used primarily to treat the protozoon that causes toxoplasmosis and the fungus that causes pneumocystis pneumonia in immunocompromised patients.6 This drug is not typically the primary treatment for pneumocystis, but is often reserved for patients who cannot tolerate more traditional treatments using sulfamethoxazole and trimethoprim (see Chapter 34) or pentamidine (see later). Atovaquone can also be used to prevent and treat resistant cases of malaria, and the antimalarial effects of this drug seem especially useful when combined with proguanil.48... 

Patel SN, Kain KC. Atovaquone/proguanil for the prophylaxis and treatment of malaria. Expert Rev Anti Infect Ther. 2005 3 849-861. 

McGready R, Stepniewska K, Edstein MD, Cho T, Gilveray CT, Looareesuwan S et al. The pharmacokinetics of atovaquone and proguanil in pregnant women with acute falciparum malaria. Eur J Clin Pharmacol 2003 59 545-52. 

Lundgren, J.D., Gragsted, U.B. Atovaquone / proguanil. Prophylaxis and treatment of malaria. Ugesker. Laeger. 2000 162 4177-4181... 

Atovaquone acts synergistically with proguanil, and the combination of these two drugs (Malarone ) is highly efficacious in the treatment of uncomplicated malaria (8), including that against multidrug resistant forms, and in prophylaxis (9). It has not yet been widely marketed, so data on rare adverse effects are currently sparse. 

An inpatient study of 79 patients given proguanil + atovaquone compared with 79 patients given mefloquine showed no malaria-independent adverse effects (10). Although there was a significant transient increase in liver enzymes, this was probably of limited clinical importance. 

Shanks GD, Gordon DM, Klotz FW, Aleman GM, Qloo AJ, Sadie D, Scott TR. Efficacy and safety of atovaquone/pro-guanil as suppressive prophylaxis for Plasmodium falciparum malaria. Clin Infect Dis 1998 27(3) 494-9. 

Lell B, Luckner D, Ndjave M, Scott T, Kremsner PG. Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. Lancet 1998 351(9104) 709-13. 

Anonymous. Atovaquone -f proguanil for malaria prophylaxis. Drug Ther Bull 2001 39(10) 73-5. 

Anabwani G, Canfield CJ, Hutchinson DB. Combination atovaquone and proguanil hydrochloride vs. halofantrine for treatment of acute Plasmodium falciparum malaria in children. Pediatr Infect Dis J 1999 18(5) 456-61. 

Overbosch D, Schilthuis H, Bienzle U, Behrens RH, Kain KC, Clarke PD, Toovey S, Knobloch J, Nothdurft HD, Shaw D, Roskell NS, Chulay JD Malarone International Study Team. Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers results from a randomized, double-blind study. Clin Infect Dis 200I 33(7) 1015-21. 

Proguanil is one of the antimalarial drugs most widely used for prophylactic purposes, usually in combination with chloroquine or atovaquone in malaria prophylaxis, and with atovaquone in malaria treatment (SEDA-21, 297). A biguanide, it is rapidly absorbed in standard doses and mainly excreted by the kidneys. Its antimalarial effect is due to its metabolite cycloguanU. However, its metabolism varies individually, and this is reflected in a variable degree of efficacy (SEDA-17, 328). 

Bustos DG, Canfield CJ, Canete-Miguel E, Hutchinson DB. Atovaquone-proguanil compared with chloroquine and chloroquine-sulfadoxine-pyrimethamine for treatment of acute Plasmodium falciparum malaria in the Philippines. J Infect Dis 1999 179(6) 1587-90. 

Another alternative regimen for chemoprophylaxis is the combination of atovaquone and proguanil (Malarone) 1 tablet daily beginning 1 to 2 days prior to travel and continuing for the duration of stay and 1 week after leaving the area. Daily primaquine 15 mg (base) also has been recommended for prophylaxis for both P. vivax and P falciparum malaria. ... 

Looareesuwan S, Wilairatana P, Hutchinson DBA, et al. Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 1999 60 526-532. 

Atovaquone 250 mg plus Proguanil 100 mg Prevention and treatment of P. falciparum malaria Abdominal pain, nausea, vomiting and headache 13, 23, 24, 25, 39-40... 

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