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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glaxo Wellcome announced in November 1996 its intent to donate up to 1 million treatment courses per year of its new antimalarial drug, Malarone, to countries in Africa, Southeast Asia, and South America, where malaria is endemic. Because the effectiveness of the small number of available antimalarial drugs is threatened by the emergence of drug resistance, the advantages of introduction of this new drug to a given area should be given careful consideration. Chloroquine, for example, is nearing the end of its effectiveness as a first-line drug for the treatment of uncomplicated falciparum malaria in many areas of East and Central Africa. The lifespan of its replacement, sulfadoxine-pyrimethamine, is likely to be even shorter given its long half-life and the ease with which resistance-conferring mutations occur. In Southeast Asia and the Amazon basin of South America, where multidrug-resistant Plasmodium falciparum malaria is a serious problem, the advantages of Malarone introduction clearly outweigh any disadvantages. In sub-Saharan Africa, the premature distribution and increasing use of artemisinins may jeopardize their long-term effectiveness, however. Another factor complicating decisions to introduce Malarone is its required 3-day course of treatment, necessitating hospitalization if compliance is to be ensured. The donation project gives patients in developing countries access to an expensive drug that would otherwise be unavailable. Time must be taken, however, to fully debate the project's pros and cons, resolve inherent logistic problems, and establish guidelines for Malarone use in sub-Saharan Africa.
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PMID:Malarone-donation programme in Africa. 950 Mar 54

Malaria poses a major health risk to people who are exposed to infection in malaria-endemic areas. A randomized, double-blind, placebo-controlled study was conducted to determine the efficacy and safety of Malarone (250 mg of atovaquone/100 mg of proguanil hydrochloride per tablet) for the chemoprophylaxis of Plasmodium falciparum malaria in Zambia. Adult volunteers received a three-day treatment course of Malarone to eliminate pre-existing parasitemia and were then immediately randomized to treatment with either one Malarone tablet daily (n = 136), or one placebo tablet daily (n = 138) for at least 10 weeks. Malaria blood smears were prepared on a weekly basis and a failure of chemoprophylaxis was defined as any subject who had a positive blood smear, or who withdrew from the study due to a treatment-related adverse event. The prophylaxis success rates in the Malarone and placebo groups were 98% and 63%, respectively (P < 0.001). The most commonly reported adverse events with at least a possible causal relationship to study medication were headache and abdominal pain, which occurred with a higher incidence in the placebo group. No subjects were withdrawn from the study due to a treatment-related adverse event. Thus, Malarone appears to have an excellent safety and efficacy profile for the chemoprophylaxis of P. falciparum infection.
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PMID:A randomized, double-blind, placebo-controlled field trial to determine the efficacy and safety of Malarone (atovaquone/proguanil) for the prophylaxis of malaria in Zambia. 1034 23

The continuing spread of drug-resistant malaria emphasizes the need for new antimalarial drugs. Atovaquone is a broad-spectrum antiprotozoal drug with a novel mechanism of action, via inhibition of parasite mitochondrial electron transport, and a favorable safety profile. Early studies with atovaquone alone for treatment of malaria demonstrated good initial control of parasitemia but an unacceptable rate of recrudescent parasitemia. Parasites isolated during recrudescence after treatment with atovaquone alone were resistant to atovaquone in vitro. The combination of atovaquone and proguanil is synergistic in vitro, and clinical studies demonstrated enhanced efficacy of the combination compared to either drug alone for treatment of malaria. Malarone, a fixed-dose combination of 250 mg of atovaquone and 100 mg of proguanil hydrochloride, is available in many countries for treatment of acute, uncomplicated malaria caused by Plasmodium falciparum. At the recommended dose (in adults, four tablets once a day for three days), the overall cure rate was > 98% in more than 500 patients with falciparum malaria. In four randomized, controlled clinical trials, treatment with atovaquone and proguanil hydrochloride was significantly more effective than mefloquine (Thailand), amodiaquine (Gabon), chloroquine (Peru and the Philippines) or chloroquine plus pyrimethamine/sulfadoxine (Philippines). In clinical trials where the comparator drug was highly effective, treatment with atovaquone and proguanil hydrochloride was equally effective. Parasites isolated during recrudescence after treatment with the combination of atovaquone and proguanil were not resistant to atovaquone in vitro. The most commonly reported adverse events in clinical trials (abdominal pain, anorexia, nausea, vomiting, diarrhea and coughing) occurred with similar frequency in patients treated with a comparator drug. Malarone is a safe and effective new agent for treatment of malaria.
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PMID:Malarone (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Malarone Clinical Trials Study Group. 1034 25

Several important developments have occurred in recent years in the chemotherapy for and prophylaxis of parasitic infections. Although mefloquine is clearly the most effective agent for prevention of chloroquine-resistant falciparum malaria, its use has been compromised by side effects, both real and imagined. Well-designed studies have shown that side effects occur no more frequently with low-dose mefloquine than with chloroquine. Use of mefloquine in pregnant women has not been associated with birth defects, but the incidence of stillbirths may be increased. Malarone is a new agent that combines atovaquone and proguanil, and it may be as effective as mefloquine; however, it is not yet available in the United States. Several newer agents have appeared in response to the development of multidrug resistant Plasmodium falciparum, especially in Southeast Asia. Halofantrine is available for the treatment of mild to moderate malaria due to P. falciparum and for P. vivax infections. Because of severe toxic effects, use of halofantrine should be restricted to only those unusual and rare situations in which other agents cannot be used. Artemisinin (an extract of the Chinese herbal remedy qinghaosu) and two derivatives, artesunate and artemether, are active against multidrug resistant P. falciparum and are widely used in Asia in oral, parenteral, and rectal forms. The antibacterial azithromycin in combination with atovaquone or quinine has now been reported to treat babesiosis effectively in experimental animals and in a few patients. Azithromycin in combination with paromomycin has also shown promise in the treatment of cryptosporidiosis (and toxoplasmosis when combined with pyrimethamine) in patients with the acquired immunodeficiency syndrome (AIDS). Albendazole is currently the only systemic agent available for treatment of microsporidiosis, an infection primarily of patients with AIDS. In addition, albendazole and ivermectin have emerged as effective broad-spectrum antihelminthics, with albendazole becoming the drug of choice for hydatid disease (echinococcosis), neurocysticercosis, and most intestinal nematode infections (except strongyloidiasis and trichuriasis). Liposomal amphotericin B is the first drug approved by the Food and Drug Administration for the treatment of visceral leishmaniasis.
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PMID:Antiparasitic agents. 1056 Jun 6

Despite its recognized importance, the prevention of patients with malaria from continuing to infect mosquitoes after treatment is not always achieved in practice. An inevitable consequence of the prolonged life-span and relative metabolic stasis of the mature gametocytes of Plasmodium falciparum is that they are not cleared by most antimalarials, and few antimalarials block infection in the mosquito vector. Previous research on the constituents of Malarone, a new 'combined antimalarial', suggested that the active components, atovaquone and proguanil, might inhibit infectivity of gametocytes to mosquitoes. We contrast here the impact of atovaquone-proguanil and chloroquine on the transmission of P. falciparum and P. berghei. While chloroquine enhanced infectivity of P. falciparum, atovaquone-proguanil caused a significant reduction. Surprisingly, sporontocidal activity against the rodent parasite persisted long after the levels of the constituent drugs would have been expected to have fallen below effective plasma concentrations on the basis of the established pharmacokinetics of atovaquone and proguanil. The P. berghei model may thus have provided a sensitive bioassay, detecting drug(s) at levels below that normally found with the usual chemical assays.
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PMID:The mosquito transmission of malaria: the effects of atovaquone-proguanil (Malarone) and chloroquine. 1074 6

Atovaquone is the major active component of the new antimalarial drug Malarone. Considerable evidence suggests that malaria parasites become resistant to atovaquone quickly if atovaquone is used as a sole agent. The mechanism by which the parasite develops resistance to atovaquone is not yet fully understood. Atovaquone has been shown to inhibit the cytochrome bc(1) (CYT bc(1)) complex of the electron transport chain of malaria parasites. Here we report point mutations in Plasmodium falciparum CYT b that are associated with atovaquone resistance. Single or double amino acid mutations were detected from parasites that originated from a cloned line and survived various concentrations of atovaquone in vitro. A single amino acid mutation was detected in parasites isolated from a recrudescent patient following atovaquone treatment. These mutations are associated with a 25- to 9,354-fold range reduction in parasite susceptibility to atovaquone. Molecular modeling showed that amino acid mutations associated with atovaquone resistance are clustered around a putative atovaquone-binding site. Mutations in these positions are consistent with a reduced binding affinity of atovaquone for malaria parasite CYT b.
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PMID:Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. 1089 82

Malarone is a combination of the two drugs atovaquone and proguanil. Malarone is useful as prophylaxis and for the treatment of falciparum malaria. Monotherapy using atovaquone or proguanil results in treatment failure in 30% and 90% respectively, whereas treatment failure is rare when a combination of the drugs is used (< 2%). This reflects the synergistic effect of this drug combination. Used as a chemoprophylaticum against falciparum malaria Malarone has an effect of > 95%. The protective mechanism is likely to act via the mitochondrial cytochrome bc complex, thus a different mechanism from other malaria drugs. For this reason, cross-resistance with other malaria drugs is not expected. The documentation of effect and safety profile of Malarone in malaria prophylaxis makes it a suitable alternative to mefloquine and doxycycline in case of contraindications. Malarone is effective for the treatment of acute uncomplicated malaria, and may be used as an alternative to mefloquine.
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PMID:[Atovaquone/proguanil. Prophylaxis and treatment of malaria]. 1096 33

The efficacy and safety of a fixed-dose combination of atovaquone and proguanil hydrochloride (Malarone) were compared with chloroquine or pyrimethamine/sulfadoxine in patients with acute falciparum malaria in northern Peru. Patients were initially randomized to receive 1,000 mg atovaquone and 400 mg proguanil hydrochloride daily for 3 days (n=15) or 1,500 mg chloroquine (base) over a 3 day period (n=14) (phase 1). The cure rate with chloroquine was lower than expected and patients were subsequently randomized to receive a single dose of 75 mg pyrimethamine and 1,500 mg sulfadoxine (n=9) or atovaquone/proguanil as before (n=5) (phase 2). In phase 1, atovaquone/proguanil was significantly more effective than chloroquine (cure rate 100% [14/14] vs. 8% [1/13], P<0.0001). In phase 2, atovaquone/proguanil and pyrimethamine/sulfadoxine were both highly effective (cure rates 100% [5/5] and 100% [7/7]). There were no significant differences between treatment groups in parasite or fever clearance times. Adverse events were typical of malarial symptoms and did not differ significantly between groups. Overall efficacy of atovaquone/proguanil was 100% for treatment of acute falciparum malaria in a region with a high prevalence of chloroquine resistance.
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PMID:Atovaquone and proguani hydrochloride compared with chloroquine or pyrimethamine/sulfodaxine for treatment of acute Plasmodium falciparum malaria in Peru. 1149 11

Concerns about the tolerability of mefloquine highlight the need for new drugs to prevent malaria. Atovaquone-proguanil (Malarone; GlaxoSmithKline) was safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but experience in nonimmune people is limited. In a randomized, double-blind study, nonimmune travelers received malaria prophylaxis with atovaquone-proguanil (493 subjects) or mefloquine (483 subjects). Information about adverse events (AEs) and potential episodes of malaria was obtained 7, 28, and 60 days after travel. AEs were reported by an equivalent proportion of subjects who had received atovaquone-proguanil or mefloquine (71.4% versus 67.3%; difference, 4.1%; 95% confidence interval, -1.71 to 9.9). Subjects who received atovaquone-proguanil had fewer treatment-related neuropsychiatric AEs (14% versus 29%; P=.001), fewer AEs of moderate or severe intensity (10% versus 19%; P=.001), and fewer AEs that caused prophylaxis to be discontinued (1.2% versus 5.0%; P=.001), compared with subjects who received melfoquine. No confirmed diagnoses of malaria occurred in either group. Atovaquone-proguanil was better tolerated than was mefloquine, and it was similarly effective for malaria prophylaxis in nonimmune travelers.
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PMID:Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study. 1194 58

When U.S. troops first encountered drug resistant malaria during the Vietnam war, the United States Army responded by establishing a malaria drug research program. In 1988, the Walter Reed Army Institute of Research developed mefloquine (WR 149240) and halofantrine (WR 171669). Actually, in association with SmithKline Beecham, the WRAIR is developing tafenoquine (WR 238605), an analog of primaquine, which is expected to be effective in both preventing and treating malaria in deployed military personnel. Final phase III studies leading to U.S. Food and Drug Administration approval are planned for 2000. Applied research is also carried out with the association atovaquone-proguanil (Malarone) or with azithromycin, but also with primaquine, the associations paludrine-dapsone or lapudrine-dapsone, analogs of floxacrine (WR 243251), and a guanylhydrazone (WR 182393). The future scientific directions must focus on basic and applied research for a better understanding of the modes of action and mechanisms of resistance to standard and developmental drugs. Using new techniques, the design and synthesis of new drugs would hopefully result in the development of drugs that circumvent the malaria parasites elusive mechanisms of drug resistance.
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PMID:Development of new drugs for chemoprophylaxis of malaria. 1158 54


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