Combination of | |
---|---|
Atovaquone | Antimalarial medication |
Proguanil | Antimalarial medication |
Clinical data | |
Trade names | Malarone, Malanil, others |
AHFS/Drugs.com | Monograph |
License data | |
Pregnancy category |
|
Routes of administration | By mouth |
ATC code | |
Legal status | |
Legal status | |
Identifiers | |
CAS Number | |
PubChem CID | |
ChemSpider | |
KEGG | |
CompTox Dashboard (EPA) | |
(what is this?) (verify) |
Atovaquone/proguanil, sold under the brand name Malarone among others, is a fixed-dose combination medication used to treat and prevent malaria, including chloroquine-resistant malaria. [2] [3] It contains atovaquone and proguanil. [3] It is not recommended for severe or complicated malaria. [3] It is taken by mouth. [3]
Common side effects include abdominal pain, vomiting, diarrhea, cough, and itchiness. [3] Serious side effects may include anaphylaxis, Stevens–Johnson syndrome, hallucinations, and liver problems. [3] [4] Side effects are generally mild. [5] It is unclear if use during pregnancy or breastfeeding is safe for the baby. [6] It is not recommended to prevent malaria in those with poor kidney function. [4] Atovaquone works by interfering with the function of mitochondria in malaria while proguanil blocks dihydrofolate reductase. [3]
Atovaquone/proguanil was approved for medical use in the United States in 2000. [3] It has been available as a generic medication since 2011. [7]
Atovaquone/proguanil is not normally used to treat severe malaria, when an injectable drug such as quinine is used instead.[ citation needed ]
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. Also, stomach irritation may occur if one lies down within a half hour after taking this medicine.[ citation needed ]
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. [8] Specific mutations (Y268S, Y268C) have been shown to confer resistance in vivo, [9] [10] [11] but the other mechanisms of resistance remain unknown. [12]
Side effects are generally mild. [5] 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. [5]
Atovaquone selectively inhibits the malarial cytochrome bc1 complex in the parasitic electron transport chain, collapsing the mitochondrial membrane potential. [13] 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. [14]
Proguanil, via its metabolite cycloguanil, functions as a dihydrofolate reductase inhibitor, halting parasitic deoxythymidylate synthesis. [15]
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.[ citation needed ]
Glaxo Wellcome patented the combination of atovaquone and proguanil to treat malaria in 1999. Patent protection expired in 2013. [16] The U.S. Food and Drug Administration (FDA) approved a generic formulation from Glenmark Generics in 2011. [17] 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. [18]
Malaria is a mosquito-borne infectious disease that affects humans and other vertebrates. Human malaria causes symptoms that typically include fever, fatigue, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. Symptoms usually begin 10 to 15 days after being bitten by an infected Anopheles mosquito. If not properly treated, people may have recurrences of the disease months later. In those who have recently survived an infection, reinfection usually causes milder symptoms. This partial resistance disappears over months to years if the person has no continuing exposure to malaria.
Mefloquine, sold under the brand name Lariam among others, is a medication used to prevent or treat malaria. When used for prevention it is typically started before potential exposure and continued for several weeks after potential exposure. It can be used to treat mild or moderate malaria but is not recommended for severe malaria. It is taken by mouth.
Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young children and pregnant women. As of 2018, modern treatments, including for severe malaria, continued to depend on therapies deriving historically from quinine and artesunate, both parenteral (injectable) drugs, expanding from there into the many classes of available modern drugs. Incidence and distribution of the disease is expected to remain high, globally, for many years to come; moreover, known antimalarial drugs have repeatedly been observed to elicit resistance in the malaria parasite—including for combination therapies featuring artemisinin, a drug of last resort, where resistance has now been observed in Southeast Asia. As such, the needs for new antimalarial agents and new strategies of treatment remain important priorities in tropical medicine. As well, despite very positive outcomes from many modern treatments, serious side effects can impact some individuals taking standard doses.
Plasmodium is a genus of unicellular eukaryotes that are obligate parasites of vertebrates and insects. The life cycles of Plasmodium species involve development in a blood-feeding insect host which then injects parasites into a vertebrate host during a blood meal. Parasites grow within a vertebrate body tissue before entering the bloodstream to infect red blood cells. The ensuing destruction of host red blood cells can result in malaria. During this infection, some parasites are picked up by a blood-feeding insect, continuing the life cycle.
Plasmodium falciparum is a unicellular protozoan parasite of humans, and the deadliest species of Plasmodium that causes malaria in humans. The parasite is transmitted through the bite of a female Anopheles mosquito and causes the disease's most dangerous form, falciparum malaria. It is responsible for around 50% of all malaria cases. P. falciparum is therefore regarded as the deadliest parasite in humans. It is also associated with the development of blood cancer and is classified as a Group 2A (probable) carcinogen.
Artemisinin and its semisynthetic derivatives are a group of drugs used in the treatment of malaria due to Plasmodium falciparum. It was discovered in 1972 by Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine for her discovery. Artemisinin-based combination therapies (ACTs) are now standard treatment worldwide for P. falciparum malaria as well as malaria due to other species of Plasmodium. Artemisinin is extracted from the plant Artemisia annua a herb employed in Chinese traditional medicine. A precursor compound can be produced using a genetically engineered yeast, which is much more efficient than using the plant.
Primaquine is a medication used to treat and prevent malaria and to treat Pneumocystis pneumonia. Specifically it is used for malaria due to Plasmodium vivax and Plasmodium ovale along with other medications and for prevention if other options cannot be used. It is an alternative treatment for Pneumocystis pneumonia together with clindamycin. It is taken by mouth.
Proguanil, also known as chlorguanide and chloroguanide, is a medication used to treat and prevent malaria. It is often used together with chloroquine or atovaquone. When used with chloroquine the combination will treat mild chloroquine resistant malaria. It is taken by mouth.
Plasmodium vivax is a protozoal parasite and a human pathogen. This parasite is the most frequent and widely distributed cause of recurring malaria. Although it is less virulent than Plasmodium falciparum, the deadliest of the five human malaria parasites, P. vivax malaria infections can lead to severe disease and death, often due to splenomegaly. P. vivax is carried by the female Anopheles mosquito; the males do not bite.
Plasmodium ovale is a species of parasitic protozoon that causes tertian malaria in humans. It is one of several species of Plasmodium parasites that infect humans, including Plasmodium falciparum and Plasmodium vivax which are responsible for most cases of malaria in the world. P. ovale is rare compared to these two parasites, and substantially less dangerous than P. falciparum.
Atovaquone, sold under the brand name Mepron, is an antimicrobial medication for the prevention and treatment of Pneumocystis jirovecii pneumonia (PCP).
Halofantrine is a drug used to treat malaria. Halofantrine's structure contains a substituted phenanthrene, and is related to the antimalarial drugs quinine and lumefantrine. Marketed as Halfan, halofantrine is never used to prevent malaria and its mode of action is unknown, although a crystallographic study showed that it binds to hematin in vitro, suggesting a possible mechanism of action. Halofantrine has also been shown to bind to plasmepsin, a haemoglobin degrading enzyme unique to the malarial parasites.
Dihydroartemisinin is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds and is also available as a drug in itself. It is a semi-synthetic derivative of artemisinin and is widely used as an intermediate in the preparation of other artemisinin-derived antimalarial drugs. It is sold commercially in combination with piperaquine and has been shown to be equivalent to artemether/lumefantrine.
Malaria prophylaxis is the preventive treatment of malaria. Several malaria vaccines are under development.
Tafenoquine, sold under the brand name Krintafel among others, is a medication used to prevent and to treat malaria. With respect to acute malaria, it is used together with other medications to prevent relapse by Plasmodium vivax. It may be used to prevent all types of malaria. It is taken by mouth.
Cycloguanil is a dihydrofolate reductase inhibitor, and is a metabolite of the antimalarial drug proguanil; its formation in vivo has been thought to be primarily responsible for the antimalarial activity of proguanil. However, more recent work has indicated that, while proguanil is synergistic with the drug atovaquone, cycloguanil is in fact antagonistic to the effects of atovaquone, suggesting that, unlike cycloguanil, proguanil may have an alternative mechanism of antimalarial action besides dihydrofolate reductase inhibition.
The administration of drugs to whole populations irrespective of disease status is referred to as mass drug administration (MDA) or mass dispensing.
Pregnancy-associated malaria (PAM) or placental malaria is a presentation of the common illness that is particularly life-threatening to both mother and developing fetus. PAM is caused primarily by infection with Plasmodium falciparum, the most dangerous of the four species of malaria-causing parasites that infect humans. During pregnancy, a woman faces a much higher risk of contracting malaria and of associated complications. Prevention and treatment of malaria are essential components of prenatal care in areas where the parasite is endemic – tropical and subtropical geographic areas. Placental malaria has also been demonstrated to occur in animal models, including in rodent and non-human primate models.
Ganaplacide is a drug in development by Novartis for the purpose of treating malaria. It belongs to the class of the imidazolopiperazines. It has shown activity against the Plasmodium falciparum and Plasmodium vivax forms of the malaria parasite.
Yagya Dutta Sharma is an Indian molecular biologist, professor and head of the department of biotechnology at the All India Institute of Medical Sciences, Delhi. An elected fellow of all three major Indian science academies — Indian National Science Academy, Indian Academy of Sciences, and National Academy of Sciences, India — Sharma is known for his research on the molecular biology of malaria. The Council of Scientific and Industrial Research, the apex agency of the Government of India for scientific research, awarded him the Shanti Swarup Bhatnagar Prize for Science and Technology for his contributions to medical sciences in 1994.