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Peter G Kremsner - One of the best experts on this subject based on the ideXlab platform.

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

    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.

  • Atovaquone and Proguanil for plasmodium falciparum malaria
    The Lancet, 1996
    Co-Authors: P D Radloff, Peter G Kremsner, J Philips, M Nkeyi, D Hutchinson
    Abstract:

    Abstract Summary Background The increasing spread of multidrug-resistant Plasmodium falciparum malaria emphasises the urgent need for alternative treatment regimens. The objective of the study was to establish the efficacy of a novel drug combination. We compared a combination of Atovaquone and Proguanil with amodiaquine in the treatment of acute uncomplicated P falciparum malaria in Lambarene, Gabon. Methods 142 adults were randomly allocated either a combination treatment of Atovaquone 1000 mg daily and Proguanil 400 mg daily for 3 days or treatment with amodiaquine 600 mg on admission, 600 mg 24 h later, and 300 mg after a further 24 h. Symptoms and clinical signs were recorded and giemsa-stained thick blood smears were done every 12 h until patients had been symptom-free and aparasitaemic for 24 h. 126 patients were followed up for 28 days or until recrudescence. Findings In the Atovaquone Plus Proguanil group 62 (87%) of 71 patients were cured and only one had recrudescent infection. By contrast, the cure rate was significantly lower (p=0·022) with amodiaquine (51 [72%] of 71; there were 12 recrudescences in the amodiaquine group). Eight patients in each group were lost to follow-up. Patients treated with Atovaquone Plus Proguanil complained of nausea (33%) and vomiting (29%), and the most commonly reported adverse effects of amodiaquine were pruritus (43%) and insomnia (27%). Interpretation Atovaquone and Proguanil was a highly effective and safe drug combination in patients with acute uncomplicated P falciparum malaria in Gabon.

Barbara Bannister - One of the best experts on this subject based on the ideXlab platform.

  • uk malaria treatment guidelines
    Journal of Infection, 2007
    Co-Authors: David G Lalloo, Christopher J. M. Whitty, Delane Shingadia, Geoffrey Pasvol, Nicholas J. Beeching, Peter L. Chiodini, David R. Hill, David A Warrell, Barbara Bannister
    Abstract:

    Summary Malaria is the tropical disease most commonly imported into the UK, with 1500–2000 cases reported each year, and 10–20 deaths. Approximately three-quarters of reported malaria cases in the UK are caused by Plasmodium falciparum , which is capable of invading a high proportion of red blood cells and rapidly leading to severe or life-threatening multi-organ disease. Most non-falciparum malaria cases are caused by Plasmodium vivax ; a few cases are caused by the other two species of Plasmodium : Plasmodium ovale or Plasmodium malariae . Mixed infections with more than 1 species of parasite can occur; they commonly involve P. falciparum with the attendant risks of severe malaria. Management of malaria depends on awareness of the diagnosis and on performing the correct diagnostic tests: the diagnosis cannot be excluded until 3 blood specimens have been examined by an experienced microscopist. There are no typical clinical features of malaria, even fever is not invariably present. The optimum diagnostic procedure is examination of thick and thin blood films by an expert to detect and speciate the malarial parasites; P. falciparum malaria can be diagnosed almost as accurately using rapid diagnostic tests (RDTs) which detect plasmodial antigens or enzymes, although RDTs for other Plasmodium species are not as reliable. The treatment of choice for non-falciparum malaria is a 3-day course of oral chloroquine, to which only a limited proportion of P. vivax strains have gained resistance. Dormant parasites (hypnozoites) persist in the liver after treatment of P. vivax or P. ovale infection: the only currently effective drug for eradication of hypnozoites is primaquine. This must be avoided or given with caution under expert supervision in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD), in whom it may cause severe haemolysis. Uncomplicated P. falciparum malaria can be treated orally with quinine, Atovaquone Plus Proguanil (Malarone ® ) or co-artemether (Riamet ® ); quinine is highly effective but poorly tolerated in prolonged dosage and is always supplemented by additional treatment, usually with oral doxycycline. ALL patients treated for P. falciparum malaria should be admitted to hospital for at least 24h, since patients can deteriorate suddenly, especially early in the course of treatment. Severe falciparum malaria, or infections complicated by a relatively high parasite count (more than 2% of red blood cells parasitized), should be treated with intravenous therapy until the patient is well enough to continue with oral treatment. In the UK, the treatment of choice for severe or complicated malaria is currently an infusion of intravenous quinine. This may exacerbate hypoglycaemia that can occur in malaria; patients treated with intravenous quinine therefore require careful monitoring. Intravenous artesunate reduces high parasite loads more rapidly than quinine and is more effective in treating severe malaria in selected situations. It can also be used in patients with contra-indications to quinine. Intravenous artesunate is unlicensed in the EU. Assistance in obtaining artesunate may be sought from specialist tropical medicine centres, on consultation, for named patients. Patients with severe or complicated malaria should be managed in a high dependency or intensive care environment. They may require haemodynamic support and management of acute respiratory distress syndrome, disseminated intravascular coagulation, renal impairment/failure, seizures, and severe intercurrent infections including gram-negative bacteraemia/septicaemia. Falciparum malaria in pregnancy is more likely to be severe and complicated: the placenta contains high levels of parasites. Stillbirth or early delivery may occur and diagnosis can be difficult if parasites are concentrated in the placenta and scanty in the blood. The treatment of choice for falciparum malaria in pregnancy is quinine; doxycycline is contraindicated in pregnancy but clindamycin can be substituted for it, and is equally effective. Primaquine (for eradication of P. vivax or P. ovale hypnozoites) is contraindicated in pregnancy; after treatment for these infections a pregnant woman should take weekly chloroquine prophylaxis until after delivery when hypnozoite eradication can be considered. Children are over-represented in the incidence of malaria in the UK, probably because completely susceptible UK-born children accompany their overseas-born parents on visits to family and friends in endemic areas. Malaria in children (and sometimes in adults) may present with misleading symptoms such as gastrointestinal features, sore throat or lower respiratory complaints; the diagnosis must always be sought in a feverish or very sick child who has visited malaria-endemic areas. Children can be treated with most of the antimalarial regimens which are effective in adults, with appropriate dosage adjustment. Doxycycline Plus quinine should not be given to children under 12 years as doxycycline is contraindicated in this age group, but clindamycin can be substituted for doxycycline, and pyrimethamine–sulfadoxine (Fansidar ® ) may also be an effective substitute. An acute attack of malaria does not confer protection from future attacks: individuals who have had malaria should take effective anti-mosquito precautions and chemoprophylaxis during future visits to endemic areas.

David G Lalloo - One of the best experts on this subject based on the ideXlab platform.

  • uk malaria treatment guidelines
    Journal of Infection, 2007
    Co-Authors: David G Lalloo, Christopher J. M. Whitty, Delane Shingadia, Geoffrey Pasvol, Nicholas J. Beeching, Peter L. Chiodini, David R. Hill, David A Warrell, Barbara Bannister
    Abstract:

    Summary Malaria is the tropical disease most commonly imported into the UK, with 1500–2000 cases reported each year, and 10–20 deaths. Approximately three-quarters of reported malaria cases in the UK are caused by Plasmodium falciparum , which is capable of invading a high proportion of red blood cells and rapidly leading to severe or life-threatening multi-organ disease. Most non-falciparum malaria cases are caused by Plasmodium vivax ; a few cases are caused by the other two species of Plasmodium : Plasmodium ovale or Plasmodium malariae . Mixed infections with more than 1 species of parasite can occur; they commonly involve P. falciparum with the attendant risks of severe malaria. Management of malaria depends on awareness of the diagnosis and on performing the correct diagnostic tests: the diagnosis cannot be excluded until 3 blood specimens have been examined by an experienced microscopist. There are no typical clinical features of malaria, even fever is not invariably present. The optimum diagnostic procedure is examination of thick and thin blood films by an expert to detect and speciate the malarial parasites; P. falciparum malaria can be diagnosed almost as accurately using rapid diagnostic tests (RDTs) which detect plasmodial antigens or enzymes, although RDTs for other Plasmodium species are not as reliable. The treatment of choice for non-falciparum malaria is a 3-day course of oral chloroquine, to which only a limited proportion of P. vivax strains have gained resistance. Dormant parasites (hypnozoites) persist in the liver after treatment of P. vivax or P. ovale infection: the only currently effective drug for eradication of hypnozoites is primaquine. This must be avoided or given with caution under expert supervision in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD), in whom it may cause severe haemolysis. Uncomplicated P. falciparum malaria can be treated orally with quinine, Atovaquone Plus Proguanil (Malarone ® ) or co-artemether (Riamet ® ); quinine is highly effective but poorly tolerated in prolonged dosage and is always supplemented by additional treatment, usually with oral doxycycline. ALL patients treated for P. falciparum malaria should be admitted to hospital for at least 24h, since patients can deteriorate suddenly, especially early in the course of treatment. Severe falciparum malaria, or infections complicated by a relatively high parasite count (more than 2% of red blood cells parasitized), should be treated with intravenous therapy until the patient is well enough to continue with oral treatment. In the UK, the treatment of choice for severe or complicated malaria is currently an infusion of intravenous quinine. This may exacerbate hypoglycaemia that can occur in malaria; patients treated with intravenous quinine therefore require careful monitoring. Intravenous artesunate reduces high parasite loads more rapidly than quinine and is more effective in treating severe malaria in selected situations. It can also be used in patients with contra-indications to quinine. Intravenous artesunate is unlicensed in the EU. Assistance in obtaining artesunate may be sought from specialist tropical medicine centres, on consultation, for named patients. Patients with severe or complicated malaria should be managed in a high dependency or intensive care environment. They may require haemodynamic support and management of acute respiratory distress syndrome, disseminated intravascular coagulation, renal impairment/failure, seizures, and severe intercurrent infections including gram-negative bacteraemia/septicaemia. Falciparum malaria in pregnancy is more likely to be severe and complicated: the placenta contains high levels of parasites. Stillbirth or early delivery may occur and diagnosis can be difficult if parasites are concentrated in the placenta and scanty in the blood. The treatment of choice for falciparum malaria in pregnancy is quinine; doxycycline is contraindicated in pregnancy but clindamycin can be substituted for it, and is equally effective. Primaquine (for eradication of P. vivax or P. ovale hypnozoites) is contraindicated in pregnancy; after treatment for these infections a pregnant woman should take weekly chloroquine prophylaxis until after delivery when hypnozoite eradication can be considered. Children are over-represented in the incidence of malaria in the UK, probably because completely susceptible UK-born children accompany their overseas-born parents on visits to family and friends in endemic areas. Malaria in children (and sometimes in adults) may present with misleading symptoms such as gastrointestinal features, sore throat or lower respiratory complaints; the diagnosis must always be sought in a feverish or very sick child who has visited malaria-endemic areas. Children can be treated with most of the antimalarial regimens which are effective in adults, with appropriate dosage adjustment. Doxycycline Plus quinine should not be given to children under 12 years as doxycycline is contraindicated in this age group, but clindamycin can be substituted for doxycycline, and pyrimethamine–sulfadoxine (Fansidar ® ) may also be an effective substitute. An acute attack of malaria does not confer protection from future attacks: individuals who have had malaria should take effective anti-mosquito precautions and chemoprophylaxis during future visits to endemic areas.

Anders Björkman - One of the best experts on this subject based on the ideXlab platform.

  • Time-dependent pharmacokinetics and drug metabolism of Atovaquone Plus Proguanil (Malarone) when taken as chemoprophylaxis
    European Journal of Clinical Pharmacology, 2002
    Co-Authors: Mita M. Thapar, Sabina Nivelius, Niklas Lindegardh, Yngve Bergqvist, Michael Ashton, Inger Johansson, Anders Björkman
    Abstract:

    Objective : To determine the pharmacokinetic profiles of Atovaquone (ATO), Proguanil (PROG) and its active metabolite cycloguanil (CYCLO) with respect to possible accumulation and kinetic interaction upon repeated dosing with Malarone. Methods : Thirteen healthy volunteers first received a single dose and then after 1 week, repetitive daily doses of Malarone (one tablet) for 13 days. For analysis of plasma drug concentrations, blood samples were collected at regular intervals over 8 days after a single dose and over 12 days after the last day of multiple dosing. Single-dose and steady-state pharmacokinetic parameters were determined for each individual. Genotyping of the gene coding for CYP2C19, a major enzyme catalyzing PROG metabolism, was performed using polymerase chain reaction, and in vitro enzyme kinetic experiments were carried out to study the possible effect of ATO on the catalytic activities of CYP2C19 and 3A4 using fluorometric assays. Results : For ATO, the ratio of the area under the concentration–time curve (AUC) during the last dose interval to the AUC after the single dose (AUC_0– _τ/AUC_0– _∞) was found to be 0.90 [95% confidence interval (CI) 0.56, 1.24] indicating absence of undue accumulation. AUC_0– _τ, and peak plasma concentration at steady state (C_max,ss) values were, however, threefold lower than those reported in human immunodeficiency virus-infected subjects after 12 multiple daily doses of 250 mg ATO alone. Four volunteers, with mean CYCLO/PROG AUC_0– _τ of 0.03 (–0.23, 0.09) were classified as poor metaboliser (PM) phenotypes. There was a significant increase in the AUC of PROG at steady state with a PROG AUC_0– _τ/AUC_0– _∞ ratio of 1.38 (1.07, 1.69) in extensive metaboliser (EM) phenotypes. CYCLO/PROG AUC ratios were significantly lower 0.67 (0.54, 0.81) at steady state than that after the first single dose in EM phenotypes. The in vitro kinetic experiments on recombinant enzymes (CYP2C19 and CYP3A4) suggested a possible inhibition of catalytic activity of CYP3A4 by ATO. Conclusions : There was no unexpected accumulation of ATO following repeated administrations of the combination. In EM phenotypes, PROG elimination was reduced at steady state. Also, at steady state, either the elimination of CYCLO was increased or its formation clearance decreased the latter possibly by inhibition of CYP3A4 by ATO.

Le M Bras - One of the best experts on this subject based on the ideXlab platform.

  • Atovaquone Plus Proguanil versus halofantrine for the treatment of imported acute uncomplicated plasmodium falciparum malaria in non immune adults a randomized comparative trial
    American Journal of Tropical Medicine and Hygiene, 2000
    Co-Authors: Olivier Bouchaud, E Monlun, K Muanza, Arnaud Fontanet, T Scott, A Goetschel, J D Chulay, Le J Bras, M Danis, Le M Bras
    Abstract:

    In endemic zones, the Atovaquone-Proguanil (AP) combination is well tolerated and effective in treating acute, uncomplicated malaria. Trials involving non-immune patients are lacking, however. We conducted a randomized, multicenter open-label trial to determine the efficacy and tolerability of the AP combination (1,000 mg + 400 mg once daily for 3 days) in comparison with halofantrine (HF) (1,500 mg in 3 doses) in non-immune adults with imported uncomplicated Plasmodium falciparum malaria. Follow-up visits were programmed on Days 7, 14, 21, 28, and 35 after hospital discharge. Out of 48 patients enrolled in the study, 41 were assessable for the cure rate (21 in the AP group and 20 in the HF group). All the patients were cured. The mean parasite clearance time was longer (63+/-23 hours) in the AP group than in the HF group (48+/-15 hours) (P = 0.02). The frequency of gastrointestinal adverse events was higher in the AP group. No noteworthy electrocardiographic changes were observed, particularly in the QTc interval. The AP combination appears to be a valuable alternative treatment in non-immune adults.