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David B A Hutchinson – 1st expert on this subject based on the ideXlab platform

  • Atovaquone proguanil compared with chloroquine and chloroquine sulfadoxine pyrimethamine for treatment of acute plasmodium falciparum malaria in the philippines
    The Journal of Infectious Diseases, 1999
    Co-Authors: Dorina G Bustos, Craig J Canfield, Editha Canetemiguel, David B A Hutchinson


    This randomized, open-label clinical trial compared a fixed-dose combination of Atovaquone and proguanil (n = 55) with chloroquine (n = 23) or a combination of chloroquine, sulfadoxine, and pyrimethamine (n = 32) for treatment of acute falciparum malaria in the Philippines. Patients were hospitalized for 28 days to ensure medication compliance and prevent reinfection. Atovaquone-proguanil produced a significantly higher cure rate (100%) compared with that for chloroquine (30.4%; P<.0001) or chloroquine-sulfadoxine-pyrimethamine (87.5%; P<.05). Treatments did not differ significantly with respect to parasite clearance time (mean: 46.7 h for Atovaquone-proguanil, 60.0 h for chloroquine, and 42.8 h for chloroquine-sulfadoxine-pyrimethamine) or fever clearance time (mean, 38.8, 46.8, and 34.5 h, respectively). Adverse events were typical of malaria symptoms; the most frequently reported events were vomiting (18% for Atovaquone-proguanil, 17% for chloroquine, and 9% for chloroquine-sulfadoxine-pyrimethamine), abdominal pain (15%, 17%, and 3%, respectively), anorexia (11%, 13%, and 0%, respectively), and headache (6%, 17%, and 3%, respectively). Atovaquone-proguanil was well tolerated and more effective than chloroquine or chloroquine-sulfadoxine-pyrimethamine for treatment of multidrug-resistant falciparum malaria in the Philippines.

  • malarone Atovaquone and proguanil hydrochloride a review of its clinical development for treatment of malaria malarone clinical trials study group
    American Journal of Tropical Medicine and Hygiene, 1999
    Co-Authors: Sornchai Looareesuwan, J D Chulay, Craig J Canfield, David B A Hutchinson


    The continuing spread of drug-resistant malaria emphasizes the need for new antimalarial drugs. Ato- vaquone is a broad-spectrum antiprotozoal drug with a novel mechanism of action, via inhibition of parasite mito- chondrial 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 com- bination 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 y, 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, treat- ment 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 cough- ing) occurred with similar frequency in patients treated with a comparator drug. Malarone is a safe and effective new agent for treatment of malaria.

  • efficacy and safety of Atovaquone proguanil compared with mefloquine for treatment of acute plasmodium falciparum malaria in thailand
    American Journal of Tropical Medicine and Hygiene, 1999
    Co-Authors: S Looareesuwan, Craig J Canfield, Polrat Wilairatana, K Chalermarut, Y Rattanapong, David B A Hutchinson


    The increasing frequency of therapeutic failures in falciparum malaria underscores the need for novel, rapidly effective antimalarial drugs or drug combinations. Atovaquone and proguanil are blood schizonticides that demonstrate synergistic activity against multi-drug-resistant Plasmodium falciparum in vitro. In an open-label, randomized, controlled clinical trial conducted in Thailand, adult patients with acute P. falciparum malaria were randomly assigned to treatment with Atovaquone and proguanil/hydrochloride (1,000 mg and 400 mg, respectively, administered orally at 24-hr intervals for three doses) or mefloquine (750 mg administered orally, followed 6 hr later by an additional 500-mg dose). Efficacy was assessed by cure rate (the percentage of patients in whom parasitemia was eliminated and did not recur during 28 days of follow-up), parasite clearance time (PCT), and fever clearance time (FCT). Safety was assessed by sequential clinical and laboratory assessments for 28 days. Atovaquone/proguanil was significantly more effective than mefloquine (cure rate 100% [79 of 79] vs. 86% [68 of 79]; P < 0.002). The Atovaquone/proguanil and mefloquine treatments did not differ with respect to PCT (mean = 65 hr versus 74 hr) or FCT (mean = 59 hr versus 51 hr). Adverse events were generally typical of malaria symptoms and each occurred in < 10% of the patients in either group, with the exception of increased vomiting found in the Atovaquone/proguanil group. Transient elevations of liver enzyme levels occurred more frequently in patients treated with Atovaquone/proguanil than with mefloquine, but the differences were not significant and values returned to normal by day 28 in most patients. The combination of Atovaquone and proguanil was well tolerated and more effective than mefloquine in the treatment of acute uncomplicated multidrug-resistant falciparum malaria in Thailand.

Neil S Roskell – 2nd expert on this subject based on the ideXlab platform

  • Atovaquone proguanil versus chloroquine proguanil for malaria prophylaxis in nonimmune pediatric travelers results of an international randomized open label study
    Clinical Infectious Diseases, 2004
    Co-Authors: D Camus, Felix Djossou, Herbert Schilthuis, Birthe Hogh, Emmanuel Dutoit, Denis Malvy, Neil S Roskell, Corinne Hedgley, Erika H De Boever, Gerri B Miller


    7 Collegeville, Pennsylvania, and 8 Research Triangle Park, North Carolina Atovaquone-proguanil has been shown to be effective and well tolerated for malaria prophylaxis in residents of countries of endemicity and in nonimmune adult travelers, but data about traveling children are limited. In a randomized, open-label, multicenter prophylaxis trial, 221 nonimmune pediatric travelers (age, 2-17 years) received either Atovaquone-proguanil or chloroquine-proguanil. Safety and clinical outcome were eval- uated 7, 28, and 60 days after travel. By posttravel day 7, a total of 39 (35%) of 110 Atovaquone-proguanil and 41 (37%) of 111 chloroquine-proguanil recipients reported 1 adverse event. The data indicate that, over the course of treatment, fewer Atovaquone-proguanil recipients had treatment-related adverse events (8% vs. 14%), including gastrointestinal complaints (5% vs. 10%). Two subjects discontinued prophylaxis because of drug-related adverse events; both had received chloroquine-proguanil. Observed compliance with prophylaxis was similar before and during travel, but it was higher for Atovaquone-proguanil in the posttravel period. No study participant developed malaria. Atovaquone-proguanil was well tolerated and is an important addition to the limited arsenal of prophylactic agents available to children.

  • Atovaquone proguanil versus chloroquine proguanil for malaria prophylaxis in non immune travellers a randomised double blind study
    The Lancet, 2000
    Co-Authors: Birthe Hogh, David Overbosch, Kevin C Kain, D Camus, Paul Clarke, Hans Dieter Nothdurft, Matthias Gunther, Izak Joubert, Dea Shaw, Neil S Roskell


    Summary Background Chloroquine plus proguanil is widely used for malaria chemoprophylaxis despite low effectiveness in areas where multidrug-resistant malaria occurs. Studies have shown that Atovaquone and proguanil hydrochloride is safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but little is known about non-immune travellers. Methods In a double-blind equivalence trial, 1083 participants travelling to a malaria-endemic area were randomly assigned to two treatment groups: Atovaquone-proguanil plus placebos for chloroquine and proguanil, or chloroquine, proguanil, and placebo for Atovaquone-proguanil. Follow-up was by telephone 7 and 60 days after travel and at a clinic at 28 days. Serum samples were tested for antibodies to a malaria circumsporozoite protein. Blood and serum samples of participants with a potential malaria diagnosis were tested in a reference laboratory. Findings 7 days after travel, at least one adverse event was reported by 311 (61%) of 511 participants who received Atovaquone-proguanil and 329 (64%) of 511 who received chloroquine-proguanil. People receiving Atovaquone-proguanil had a lower frequency of treatment-related gastrointestinal adverse events (59 [12%] vs 100 [20%], p=0·001), and of treatment-related adverse events of moderate or severe intensity (37 [7%] vs 56 [11%], p=0·05). There were fewer treatment-related adverse events that caused prophylaxis to be discontinued in the Atovaquone-proguanil group than in the chloroquine-proguanil group (one [0·2%] vs ten [2%], p=0·015). Interpretation Overall the two preparations were similarly tolerated. However, significantly fewer adverse gastro-intestinal events were observed in the Atovaquone-proguanil group in than in the chloroquine-proguanil group.

P G Kremsner – 3rd expert on this subject based on the ideXlab platform

  • Atovaquone and proguanil hydrochloride for treatment of malaria.
    Journal of travel medicine, 1999
    Co-Authors: P G Kremsner, S Looareesuwan, J D Chulay


    Safe and effective new drugs are needed for treatment of malaria. Atovaquone and proguanil hydrochloride is a new antimalarial combination that has recently become available in many countries.
    Data from clinical trials evaluating Atovaquone/proguanil for treatment of malaria were reviewed.
    In 10 open-label clinical trials, treatment of uncomplicated falciparum malaria with 1000 mg Atovaquone and 400 mg proguanil hydrochloride (or the equivalent based on body weight in patients < or = 40 kg) once daily for 3 days achieved cure in 514 of 521 (99%) evaluable patients. Treatment-limiting adverse events occurred in < 1% of patients (vomiting in four, anaphylaxis in one). Atovaquone/proguanil has been used to provide radical cure of asymptomatic Plasmodium falciparum infections prior to initiation of placebo-controlled trials of malaria prophylaxis. Recurrent parasitemia occurred within 28 days in 0 of 99 subjects who subsequently received prophylaxis with Atovaquone/proguanil and 1 of 81 subjects who subsequently received placebo. Atovaquone/proguanil is also effective for treatment of malaria caused by the other three Plasmodium species that cause malaria in humans. For treatment of vivax malaria, therapy with primaquine in addition to Atovaquone/proguanil is needed to prevent relapse from latent hepatic hypnozoites.
    Atovaquone and proguanil hydrochloride is a safe and effective combination for treatment of malaria.

  • Atovaquone and proguanil hydrochloride for prophylaxis of malaria
    Journal of Travel Medicine, 1999
    Co-Authors: G D Shanks, P G Kremsner, T Y Sukwa, J D Van Der Berg, T A Shapiro, T R Scott, J D Chulay


    BACKGROUND: The spread of drug-resistant malaria and appreciation of side effects associated with existing antimalarial drugs emphasize the need for new drugs to prevent malaria. The combination of Atovaquone and proguanil hydrochloride was previously shown to be safe and highly effective for treatment of malaria, including multi-drug-resistant Plasmodium falciparum. METHODS: We reviewed results of clinical trials that evaluated either a fixed-dose combination of Atovaquone and proguanil hydrochloride for malaria prophylaxis or Atovaquone alone for causal prophylactic activity against P. falciparum. RESULTS: In three placebo-controlled trials, 331 subjects received 250 mg Atovaquone and 100 mg proguanil hydrochloride (or an equivalent dose based on body weight in children) once daily for 10 to 12 weeks. The overall efficacy for preventing parasitemia was 98%. Among 175 nonimmune volunteers taking the same dose of Atovaquone/proguanil once daily for 10 weeks while temporarily residing in a malaria-endemic area, malaria developed in one patient who was noncompliant with therapy. Results of volunteer challenge studies indicate that both Atovaquone and proguanil have causal prophylactic activity directed against the liver stages of P. falciparum. Adverse events occurred with similar or lower frequencies in subjects treated with Atovaquone/proguanil compared to placebo. Less than 1% of patients discontinued from these studies due to a treatment-related adverse event. CONCLUSION: A fixed-dose combination of Atovaquone and proguanil hydrocloride is a promising new alternative for malaria prophylaxis.

  • randomised placebo controlled study of Atovaquone plus proguanil for malaria prophylaxis in children
    The Lancet, 1998
    Co-Authors: P G Kremsner, Bertrand Lell, Doris Luckner, Maryse Ndjave, Trevor Scott


    Summary Background The combination of Atovaquone and proguanil is highly effective and safe for the treatment of Plasmodium falciparum malaria. We aimed in this randomised, double-blind, placebo-controlled study to assess the efficacy and safety of this combination for malaria prophylaxis. Methods 320 children who lived in a hyperendemic area for P falciparum malaria were stratified by weight and randomly assigned Atovaquone plus proguanil or placebo once daily for 12 weeks. All children received initial curative treatment with Atovaquone and proguanil before the start of chemosuppression. We recorded adverse events daily and collected thick blood smears once a week. The primary endpoint was a positive blood smear. Findings 25 of 140 children in the placebo group and none of the 125 children in the Atovaquone plus proguanil group had positive smears during chemosuppression (p Interpretation The combination of Atovaquone plus proguanil is a highly effective and well-tolerated chemosuppressive antimalarial in children. This drug combination could replace current regimens.