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Michael D. Edstein - One of the best experts on this subject based on the ideXlab platform.
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The pharmacokinetics of atovaquone and Proguanil in pregnant women with acute falciparum malaria
European Journal of Clinical Pharmacology, 2003Co-Authors: Rose Mcgready, G. Gilveray, Kasia Stepniewska, Michael D. Edstein, Sornchai Looareesuwan, Francois NostenAbstract:Objective To determine the pharmacokinetic properties of atovaquone, Proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-Proguanil. Methods Serial plasma concentrations of atovaquone, Proguanil and cycloguanil were measured in 24 women at baseline and after the final dose of the 3-day treatment with atovaquone (20 mg/kg/day) plus Proguanil (8 mg/kg/day) plus artesunate (4 mg/kg/day) daily. Results The triple combination was well tolerated and highly effective. The outcomes of pregnancy were all normal. Population mean (± SEM) oral clearance (Cl/F) estimates were 313±33 ml/h/kg and 1109±43 ml/h/kg, total apparent volume of distribution (Vd/F) 13.0±1.3 l/kg and 22.9±1.4 l/kg, and terminal elimination half-life; 29.1 h and 14.3 h, for atovaquone and Proguanil, respectively. Using conventional and population pharmacokinetic analyses, Cl/F and Vd/F estimates for both drugs were approximately twice, and plasma concentrations less than half those reported previously in healthy subjects and patients with acute malaria. Conclusion Artesunate-atovaquone-Proguanil is a promising treatment for multi-drug resistant falciparum malaria during pregnancy, but the dose of atovaquone-Proguanil may need to be increased.
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the pharmacokinetics of atovaquone and Proguanil in pregnant women with acute falciparum malaria
European Journal of Clinical Pharmacology, 2003Co-Authors: G. Gilveray, Rose Mcgready, Kasia Stepniewska, Michael D. Edstein, Sornchai Looareesuwan, Francois NostenAbstract:Objective To determine the pharmacokinetic properties of atovaquone, Proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-Proguanil.
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Absence of an interaction between artesunate and atovaquone--Proguanil.
European Journal of Clinical Pharmacology, 1999Co-Authors: Michele Van Vugt, Stephane Proux, Michael D. Edstein, Sornchai Looareesuwan, Francois NostenAbstract:Objective: Atovaquone plus Proguanil is a new, well-tolerated and highly effective antimalarial drug. In order to protect it from the development of resistance, it may be deployed in combination with an artemisinin derivative. To investigate whether artesunate affects the pharmacokinetics of atovaquone plus Proguanil, and to provide preliminary information regarding the tolerability of the triple drug combination (artesunate plus atovaquone plus Proguanil), a cross over study was conducted in adult volunteers.
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Antimalarial activity of the triple combination of Proguanil, atovaquone and dapsone
Acta Tropica, 1997Co-Authors: Michael D. Edstein, Karl H. RieckmannAbstract:Abstract The combination of Proguanil and atovaquone has been shown to be more effective in curing drug-resistant infections of falciparum malaria than atovaquone or Proguanil alone. Our current study sought to determine whether the antimalarial activity could be increased by adding dapsone. Plasma samples, obtained from individuals 4–72 h after Proguanil-atovaquone administration, were 2–3 times more active against Plasmodium falciparum in vitro when dapsone was added to them. The enhanced activity of the combination of Proguanil, atovaquone and dapsone is probably due to the combined activity of two synergistic combinations: Proguanil-atovaquone and cycloguanil (metabolite of Proguanil)-dapsone. These findings suggest that further studies are needed to evaluate the clinical value of the triple drug combination of Proguanil, atovaquone and dapsone in the treatment of multi-drug resistant malaria.
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ex vivo antimalarial activity of Proguanil combined with dapsone against cycloguanil resistant plasmodium falciparum isolates
Acta Tropica, 1997Co-Authors: Michael D. Edstein, G. Dennis Shanks, Karl H. RieckmannAbstract:The ex vivo antimalarial activity of plasma samples obtained from 20 healthy Caucasian volunteers following daily Proguanil (200 mg) plus dapsone (8 mg) for malaria chemoprophylaxis inhibited five cycloguanil-resistant Thai isolates of Plasmodium falciparum. All volunteers were phenotyped as extensive metabolisers (EMs) of Proguanil. Three of the five isolates were obtained from Thai soldiers who had failed malaria prophylaxis on daily Proguanil (200 mg) plus dapsone (4.0 or 12.5 mg). The Thai soldiers were also classified as EMs, but had relatively lower plasma cycloguanil concentrations compared to values reported in the literature for Caucasians and black Kenyans. Although the high level of parasite resistance to cycloguanil was the most likely explanation for the Thai soldiers failing prophylaxis on Proguanil plus dapsone, their low cycloguanil concentrations may have also contributed to their lack of protection. However, in areas where parasites are more susceptible to cycloguanil, such as in certain regions of Africa, Proguanil plus dapsone may still be an effective chemoprophylactic drug combination. (C) 1997 Elsevier Science B.V.
Karl H. Rieckmann - One of the best experts on this subject based on the ideXlab platform.
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Antimalarial activity of the triple combination of Proguanil, atovaquone and dapsone
Acta Tropica, 1997Co-Authors: Michael D. Edstein, Karl H. RieckmannAbstract:Abstract The combination of Proguanil and atovaquone has been shown to be more effective in curing drug-resistant infections of falciparum malaria than atovaquone or Proguanil alone. Our current study sought to determine whether the antimalarial activity could be increased by adding dapsone. Plasma samples, obtained from individuals 4–72 h after Proguanil-atovaquone administration, were 2–3 times more active against Plasmodium falciparum in vitro when dapsone was added to them. The enhanced activity of the combination of Proguanil, atovaquone and dapsone is probably due to the combined activity of two synergistic combinations: Proguanil-atovaquone and cycloguanil (metabolite of Proguanil)-dapsone. These findings suggest that further studies are needed to evaluate the clinical value of the triple drug combination of Proguanil, atovaquone and dapsone in the treatment of multi-drug resistant malaria.
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ex vivo antimalarial activity of Proguanil combined with dapsone against cycloguanil resistant plasmodium falciparum isolates
Acta Tropica, 1997Co-Authors: Michael D. Edstein, G. Dennis Shanks, Karl H. RieckmannAbstract:The ex vivo antimalarial activity of plasma samples obtained from 20 healthy Caucasian volunteers following daily Proguanil (200 mg) plus dapsone (8 mg) for malaria chemoprophylaxis inhibited five cycloguanil-resistant Thai isolates of Plasmodium falciparum. All volunteers were phenotyped as extensive metabolisers (EMs) of Proguanil. Three of the five isolates were obtained from Thai soldiers who had failed malaria prophylaxis on daily Proguanil (200 mg) plus dapsone (4.0 or 12.5 mg). The Thai soldiers were also classified as EMs, but had relatively lower plasma cycloguanil concentrations compared to values reported in the literature for Caucasians and black Kenyans. Although the high level of parasite resistance to cycloguanil was the most likely explanation for the Thai soldiers failing prophylaxis on Proguanil plus dapsone, their low cycloguanil concentrations may have also contributed to their lack of protection. However, in areas where parasites are more susceptible to cycloguanil, such as in certain regions of Africa, Proguanil plus dapsone may still be an effective chemoprophylactic drug combination. (C) 1997 Elsevier Science B.V.
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Disposition of Proguanil in Thai patients with uncomplicated falciparum Malaria
The American journal of tropical medicine and hygiene, 1997Co-Authors: Michael D. Edstein, Polrat Wilairatana, Sornchai Looareesuwan, Vanijanonta S, Dennis E. Kyle, Karl H. RieckmannAbstract:The objective of this study was to examine the disposition of Proguanil in malaria-infected Thai patients with acute uncomplicated falciparum malaria. Eleven patients were administered 500 mg of Proguanil twice a day for three days (total dose = 3,000 mg). Four patients were tentatively classified as extensive metabolizers (EMs) and seven as poor metabolizers (PMs). The mean plasma clearances of Proguanil for EMs and PMs were 1.31 and 1.10 L/hr/kg, respectively. The mean elimination half-life of Proguanil was statistically longer in PMs than EMs (19.6 hr versus 16.1 hr; P = 0.01). Plasma clearance and elimination half-life of Proguanil in the malaria patients were comparable with those reported in the literature for healthy Thai volunteers. In contrast to other ethnic groups, Thai EM patients had relatively low plasma concentrations of cycloguanil, the active metabolite of Proguanil. None of the 11 patients treated with Proguanil were cured of malaria and their phenotypic status did not affect the treatment outcome. Although high levels of parasite resistance to cycloguanil were probably responsible for the poor response to Proguanil treatment, the inability of Thai EM and PM patients to produce cycloguanil may have also contributed to the treatment outcome.
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a statistical analysis of the antimalarial activity of Proguanil and cycloguanil in human volunteers
Annals of Tropical Medicine and Parasitology, 1994Co-Authors: Michael D. Edstein, G. Dennis Shanks, Karl H. RieckmannAbstract:Proguanil, an orally administered antimalarial drug, was given to 36 individuals (200 mg daily for 3 days). The antimalarial activity in plasma samples collected after the drug administration was then determined by bioassay. Concentrations of Proguanil and cycloguanil (the principal active metabolite) in these samples were also measured by high performance liquid chromatography. A regression analysis was then performed on these variables to determine if the antimalarial activity of the samples was due to Proguanil alone or to Proguanil and cycloguanil together. The analysis indicated that cycloguanil is the main determinant of antimalarial activity after Proguanil administration and that the activity of cycloguanil is not influenced by the presence of Proguanil.
David B A Hutchinson - One of the best experts on this subject based on the ideXlab platform.
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atovaquone and Proguanil hydrochloride compared with chloroquine or pyrimethamine sulfadoxine for treatment of acute plasmodium falciparum malaria in peru
Brazilian Journal of Infectious Diseases, 2001Co-Authors: Alejandro Llanoscuentas, P Campos, M Clendenes, C J Canfield, David B A HutchinsonAbstract: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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atovaquone Proguanil compared with chloroquine and chloroquine sulfadoxine pyrimethamine for treatment of acute plasmodium falciparum malaria in the philippines
The Journal of Infectious Diseases, 1999Co-Authors: Dorina G Bustos, Craig J Canfield, Editha Canetemiguel, David B A HutchinsonAbstract: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.
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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, 1999Co-Authors: Sornchai Looareesuwan, Craig J Canfield, K Chalermarut, Y Rattanapong, Polrat Wilairatana, David B A HutchinsonAbstract: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.
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Combination atovaquone and Proguanil hydrochloride vs. halofantrine for treatment of acute Plasmodium falciparum malaria in children.
The Pediatric Infectious Disease Journal, 1999Co-Authors: Gabriel Anabwani, Craig J Canfield, David B A HutchinsonAbstract:BACKGROUND Malaria is a major cause of pediatric mortality in sub-Saharan Africa. Worldwide estimates of mortality among children with Plasmodium falciparum malaria range from 1 to 2 million deaths per year. Management of malaria is increasingly difficult because of the global spread of drug-resistant strains of P. falciparum. There is an urgent need for safe and effective new therapies to treat multidrug-resistant malaria. METHODS This open label, randomized trial compared atovaquone and Proguanil hydrochloride with halofantrine for treatment of acute, uncomplicated P. falciparum malaria in children age 3 to 12 years (84 patients per group). Study drug dosages were adjusted by weight (approximately 20 and 8 mg/kg daily for three doses for atovaquone and Proguanil hydrochloride and 8 mg/kg every 6 h for three doses for halofantrine). Patients were monitored by serial clinical and laboratory assessments for 28 days after starting treatment. RESULTS Both regimens were effective (cure rate, 93.8% for atovaquone and Proguanil hydrochloride and 90.4% for halofantrine) and produced prompt defervescence. Mean parasite clearance times were 50.2 h for halofantrine and 64.9 h for atovaquone and Proguanil hydrochloride. More adverse experiences were reported in children treated with halofantrine (119) than with atovaquone and Proguanil hydrochloride (73). CONCLUSIONS In Kenyan children the combination of atovaquone and Proguanil hydrochloride has efficacy comparable with that of halofantrine for treatment of acute uncomplicated multidrug-resistant falciparum malaria and is associated with a lower rate of adverse events.
Sornchai Looareesuwan - One of the best experts on this subject based on the ideXlab platform.
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Short report: no evidence of cardiotoxicity of atovaquone-Proguanil alone or in combination with artesunate.
American Journal of Tropical Medicine and Hygiene, 2005Co-Authors: Ravindra K. Gupta, Michele Van Vugt, Thra Slight, Lucy Paiphun, Sornchai Looareesuwan, Francois NostenAbstract:Combinations are set to become the mainstay in treatment and prophylaxis of malaria due to Plasmodium falciparum. Various antimalarials have been implicated in cardiotoxicity via prolongation of the QTc interval. Atovaquone-Proguanil is an effective and increasingly popular antimalarial choice when used alone or with artesunate in areas of drug resistance. We report the results of an investigation carried out on the Thai-Burmese border in 42 patients randomized to receive either atovaquone-Proguanil or atovaquone-Proguanil-artesunate for three days. Electrocardiographic recordings were made at baseline and one hour after each dose. There was no statistically significant change in QTc interval between baseline and any subsequent readings in either treatment group or the cohort as a whole. We conclude that atovaquone-Proguanil shows no evidence of cardiotoxicity either alone or when combined with artesunate.
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The pharmacokinetics of atovaquone and Proguanil in pregnant women with acute falciparum malaria
European Journal of Clinical Pharmacology, 2003Co-Authors: Rose Mcgready, G. Gilveray, Kasia Stepniewska, Michael D. Edstein, Sornchai Looareesuwan, Francois NostenAbstract:Objective To determine the pharmacokinetic properties of atovaquone, Proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-Proguanil. Methods Serial plasma concentrations of atovaquone, Proguanil and cycloguanil were measured in 24 women at baseline and after the final dose of the 3-day treatment with atovaquone (20 mg/kg/day) plus Proguanil (8 mg/kg/day) plus artesunate (4 mg/kg/day) daily. Results The triple combination was well tolerated and highly effective. The outcomes of pregnancy were all normal. Population mean (± SEM) oral clearance (Cl/F) estimates were 313±33 ml/h/kg and 1109±43 ml/h/kg, total apparent volume of distribution (Vd/F) 13.0±1.3 l/kg and 22.9±1.4 l/kg, and terminal elimination half-life; 29.1 h and 14.3 h, for atovaquone and Proguanil, respectively. Using conventional and population pharmacokinetic analyses, Cl/F and Vd/F estimates for both drugs were approximately twice, and plasma concentrations less than half those reported previously in healthy subjects and patients with acute malaria. Conclusion Artesunate-atovaquone-Proguanil is a promising treatment for multi-drug resistant falciparum malaria during pregnancy, but the dose of atovaquone-Proguanil may need to be increased.
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the pharmacokinetics of atovaquone and Proguanil in pregnant women with acute falciparum malaria
European Journal of Clinical Pharmacology, 2003Co-Authors: G. Gilveray, Rose Mcgready, Kasia Stepniewska, Michael D. Edstein, Sornchai Looareesuwan, Francois NostenAbstract:Objective To determine the pharmacokinetic properties of atovaquone, Proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-Proguanil.
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Absence of an interaction between artesunate and atovaquone--Proguanil.
European Journal of Clinical Pharmacology, 1999Co-Authors: Michele Van Vugt, Stephane Proux, Michael D. Edstein, Sornchai Looareesuwan, Francois NostenAbstract:Objective: Atovaquone plus Proguanil is a new, well-tolerated and highly effective antimalarial drug. In order to protect it from the development of resistance, it may be deployed in combination with an artemisinin derivative. To investigate whether artesunate affects the pharmacokinetics of atovaquone plus Proguanil, and to provide preliminary information regarding the tolerability of the triple drug combination (artesunate plus atovaquone plus Proguanil), a cross over study was conducted in adult volunteers.
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Atovaquone and Proguanil hydrochloride for treatment of malaria.
Journal of travel medicine, 1999Co-Authors: Peter G Kremsner, Sornchai Looareesuwan, J.d. ChulayAbstract: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.
Francois Nosten - One of the best experts on this subject based on the ideXlab platform.
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Short report: no evidence of cardiotoxicity of atovaquone-Proguanil alone or in combination with artesunate.
American Journal of Tropical Medicine and Hygiene, 2005Co-Authors: Ravindra K. Gupta, Michele Van Vugt, Thra Slight, Lucy Paiphun, Sornchai Looareesuwan, Francois NostenAbstract:Combinations are set to become the mainstay in treatment and prophylaxis of malaria due to Plasmodium falciparum. Various antimalarials have been implicated in cardiotoxicity via prolongation of the QTc interval. Atovaquone-Proguanil is an effective and increasingly popular antimalarial choice when used alone or with artesunate in areas of drug resistance. We report the results of an investigation carried out on the Thai-Burmese border in 42 patients randomized to receive either atovaquone-Proguanil or atovaquone-Proguanil-artesunate for three days. Electrocardiographic recordings were made at baseline and one hour after each dose. There was no statistically significant change in QTc interval between baseline and any subsequent readings in either treatment group or the cohort as a whole. We conclude that atovaquone-Proguanil shows no evidence of cardiotoxicity either alone or when combined with artesunate.
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The pharmacokinetics of atovaquone and Proguanil in pregnant women with acute falciparum malaria
European Journal of Clinical Pharmacology, 2003Co-Authors: Rose Mcgready, G. Gilveray, Kasia Stepniewska, Michael D. Edstein, Sornchai Looareesuwan, Francois NostenAbstract:Objective To determine the pharmacokinetic properties of atovaquone, Proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-Proguanil. Methods Serial plasma concentrations of atovaquone, Proguanil and cycloguanil were measured in 24 women at baseline and after the final dose of the 3-day treatment with atovaquone (20 mg/kg/day) plus Proguanil (8 mg/kg/day) plus artesunate (4 mg/kg/day) daily. Results The triple combination was well tolerated and highly effective. The outcomes of pregnancy were all normal. Population mean (± SEM) oral clearance (Cl/F) estimates were 313±33 ml/h/kg and 1109±43 ml/h/kg, total apparent volume of distribution (Vd/F) 13.0±1.3 l/kg and 22.9±1.4 l/kg, and terminal elimination half-life; 29.1 h and 14.3 h, for atovaquone and Proguanil, respectively. Using conventional and population pharmacokinetic analyses, Cl/F and Vd/F estimates for both drugs were approximately twice, and plasma concentrations less than half those reported previously in healthy subjects and patients with acute malaria. Conclusion Artesunate-atovaquone-Proguanil is a promising treatment for multi-drug resistant falciparum malaria during pregnancy, but the dose of atovaquone-Proguanil may need to be increased.
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the pharmacokinetics of atovaquone and Proguanil in pregnant women with acute falciparum malaria
European Journal of Clinical Pharmacology, 2003Co-Authors: G. Gilveray, Rose Mcgready, Kasia Stepniewska, Michael D. Edstein, Sornchai Looareesuwan, Francois NostenAbstract:Objective To determine the pharmacokinetic properties of atovaquone, Proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-Proguanil.
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Absence of an interaction between artesunate and atovaquone--Proguanil.
European Journal of Clinical Pharmacology, 1999Co-Authors: Michele Van Vugt, Stephane Proux, Michael D. Edstein, Sornchai Looareesuwan, Francois NostenAbstract:Objective: Atovaquone plus Proguanil is a new, well-tolerated and highly effective antimalarial drug. In order to protect it from the development of resistance, it may be deployed in combination with an artemisinin derivative. To investigate whether artesunate affects the pharmacokinetics of atovaquone plus Proguanil, and to provide preliminary information regarding the tolerability of the triple drug combination (artesunate plus atovaquone plus Proguanil), a cross over study was conducted in adult volunteers.
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Single dose pharmacokinetics of Proguanil and its metabolites in pregnancy
European Journal of Clinical Pharmacology, 1993Co-Authors: J. Wangboonskul, F. Kuile, R. R. Moody, Francois Nosten, R B TaylorAbstract:Plasma and whole blood concentrations of Proguanil, its active metabolite cycloguanil, and the inactive metabolite 4-chlorophenyl-biguanide, were measured by HPLC in 10 healthy Karen women in the last trimester of pregnancy, following a 200 mg single oral dose of Proguanil. Four of these women were restudied 2 months after delivery. The pharmacokinetic properties of Proguanil were similar during and after pregnancy. Median peak plasma concentrations of Proguanil during pregnancy and following delivery were 212 and 215 ng·ml^−1, and occurred at 4.5 and 5 h, respectively. Mean plasma AUC values for Proguanil during and following pregnancy were 94 and 98 ng·h·ml^−1·kg^−1, respectively. Corresponding whole blood AUC values were 361 and 396 ng·h·ml^−1·kg^−1. The mean elimination half lives and mean residence times of Proguanil in plasma and whole blood were 12.3 and 19.6 h and 13.8 and 20.7 h respectively during pregnancy. Following pregnancy these values were 17.1 and 19.7 h for plasma and 19.7 h and 20.2 h for whole blood respectively. Mean peak plasma and whole blood concentrations of cycloguanil following pregnancy were 25 and 22 ng·ml^−1 respectively. During pregnancy peak cycloguanil concentrations in both plasma and whole blood were markedly lower, 13 and 12 ng ml^−1, respectively. Two pregnant women (neither of whom were restudied) were probably poor metabolisers of Proguanil. The mean ratio of Proguanil to cycloguanil plasma AUC was 16.7 in the third trimester of pregnancy and 7.8 following pregnancy, compared with less than 5 in previously reported studies. The concentrations of 4-chlorophenylbiguanide in both plasma and whole blood in pregnant subjects were also lower than those after pregnancy. These data show that blood concentrations of the active antimalarial metabolite cycloguanil are reduced in late pregnancy and that the currently recommended dose of Proguanil could be inadequate for antimalarial prophylaxis in pregnant women.
